0	34001163	Inhibition of mutant KRAS-driven overexpression of ARF6 and MYC by an eIF4A inhibitor drug improves the effects of anti-PD-1 immunotherapy for pancreatic cancer Many clinical trials are being conducted to clarify effective combinations of various drugs for immune checkpoint blockade (ICB) therapy.	('KRAS', 'Gene', (21, 25))	('KRAS', 'Gene', '16653', (21, 25))	('PD-1', 'Gene', '18566', (120, 124))	('improves', 'PosReg', (91, 99))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (143, 160))	('ARF6', 'Gene', (51, 55))	('MYC', 'Gene', '17869', (60, 63))	('eIF4', 'cellular_component', 'GO:0008304', ('70', '74'))	('overexpression', 'PosReg', (33, 47))	('PD-1', 'Gene', (120, 124))	('effects', 'MPA', (104, 111))	('eIF4A', 'Gene', '1974', (70, 75))	('pancreatic cancer', 'Disease', 'MESH:D010190', (143, 160))	('ARF6', 'Gene', '11845', (51, 55))	('mutant', 'Var', (14, 20))	('eIF4A', 'Gene', (70, 75))	('MYC', 'Gene', (60, 63))	('pancreatic cancer', 'Disease', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
5	34001163	KRAS mutations are prevalent in PDACs.	('PDACs', 'Chemical', '-', (32, 37))	('prevalent', 'Reg', (19, 28))	('mutations', 'Var', (5, 14))	('PDACs', 'Disease', (32, 37))	('KRAS', 'Gene', (0, 4))
6	34001163	We have shown previously that oncogenic KRAS mutations are the major cause of the aberrant overexpression of ARF6 and AMAP1, in which KRAS signaling enhances eukaryotic initiation factor 4A (eIF4A)-dependent ARF6 mRNA translation and eIF4E-dependent AMAP1 mRNA translation.	('enhances', 'PosReg', (149, 157))	('eIF4E', 'Gene', '13684', (234, 239))	('mutations', 'Var', (45, 54))	('eIF4A', 'Gene', '1974', (191, 196))	('translation', 'biological_process', 'GO:0006412', ('218', '229'))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('eIF4', 'cellular_component', 'GO:0008304', ('191', '195'))	('eIF4A', 'Gene', (191, 196))	('eIF4', 'cellular_component', 'GO:0008304', ('234', '238'))	('eIF4E', 'Gene', (234, 239))	('eukaryotic', 'MPA', (158, 168))	('translation', 'biological_process', 'GO:0006412', ('261', '272'))
9	34001163	Using a KPC mouse model of human PDAC (LSL-Kras(G12D/+); LSL-Trp53(R172H/+)); Pdx-1-Cre), we here demonstrate that inhibition of the ARF6-AMAP1 pathway by shRNAs in cancer cells results in therapeutic synergy with an anti-PD-1 antibody in vivo; and furthermore, that silvestrol improves the efficacy of anti-PD-1 therapy, whereas silvestrol on its own promotes tumor growth in vivo.	('therapeutic synergy', 'MPA', (189, 208))	('human', 'Species', '9606', (27, 32))	('tumor', 'Disease', (361, 366))	('efficacy', 'MPA', (291, 299))	('antibody', 'cellular_component', 'GO:0019815', ('227', '235'))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (361, 366))	('R172H', 'Mutation', 'p.R172H', (67, 72))	('antibody', 'cellular_component', 'GO:0019814', ('227', '235'))	('silvestrol', 'Chemical', 'MESH:C489897', (267, 277))	('G12D', 'Mutation', 'rs121913529', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('silvestrol', 'Chemical', 'MESH:C489897', (330, 340))	('mouse', 'Species', '10090', (12, 17))	('cancer', 'Disease', (165, 171))	('PDAC', 'Chemical', '-', (33, 37))	('antibody', 'molecular_function', 'GO:0003823', ('227', '235'))	('promotes', 'PosReg', (352, 360))	('ARF6-AMAP1 pathway', 'Pathway', (133, 151))	('antibody', 'cellular_component', 'GO:0042571', ('227', '235'))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('inhibition', 'Var', (115, 125))	('improves', 'PosReg', (278, 286))
11	34001163	We demonstrate that silvestrol substantially mitigates the overexpression of ARF6 and MYC in KRAS-mutated cells, whereas the suppression is moderate in KRAS-intact cells.	('overexpression', 'MPA', (59, 73))	('MYC', 'Gene', '17869', (86, 89))	('mitigates', 'NegReg', (45, 54))	('MYC', 'Gene', (86, 89))	('silvestrol', 'Chemical', 'MESH:C489897', (20, 30))	('KRAS-mutated', 'Var', (93, 105))	('ARF6', 'Protein', (77, 81))
12	34001163	We propose that targeting eIF4A, as well as mutant KRAS, provides novel methods to improve the efficacy of anti-PD-1 and associated ICB therapies against PDACs, in which ARF6 and AMAP1 overexpression, as well as KRAS mutations of cancer cells are biomarkers to identify patients with drug-susceptible disease.	('mutant', 'Var', (44, 50))	('patients', 'Species', '9606', (270, 278))	('PDACs', 'Chemical', '-', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('eIF4', 'cellular_component', 'GO:0008304', ('26', '30'))	('eIF4A', 'Gene', '1974', (26, 31))	('overexpression', 'PosReg', (185, 199))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('eIF4A', 'Gene', (26, 31))	('PDACs', 'Disease', (154, 159))
13	34001163	The same may be applicable to other cancers with KRAS mutations.	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('mutations', 'Var', (54, 63))	('cancers', 'Disease', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('KRAS', 'Gene', (49, 53))
16	34001163	A double mutation in KRAS and TP53 is a hallmark of PDAC, although it seldomly occurs in other types of cancers unless they become highly malignant.	('TP53', 'Gene', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('PDAC', 'Chemical', '-', (52, 56))	('double mutation', 'Var', (2, 17))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('KRAS', 'Gene', (21, 25))	('TP53', 'Gene', '22059', (30, 34))	('cancers', 'Disease', (104, 111))	('PDAC', 'Disease', (52, 56))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
17	34001163	Mutations in the cell cycle suppressor CDKN2A and the tumor suppressor SMAD4/DPC4 also frequently occur in PDACs, and these mutations are thought to further facilitate cancer cell proliferation, primarily driven by KRAS/TP53 mutations.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('54', '70'))	('TP53', 'Gene', (220, 224))	('PDACs', 'Disease', (107, 112))	('cell cycle', 'biological_process', 'GO:0007049', ('17', '27'))	('SMAD4', 'Gene', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cancer', 'Disease', (168, 174))	('cell proliferation', 'biological_process', 'GO:0008283', ('175', '193'))	('DPC4', 'Gene', '17128', (77, 81))	('tumor suppressor', 'biological_process', 'GO:0051726', ('54', '70'))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('TP53', 'Gene', '22059', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Mutations', 'Var', (0, 9))	('CDKN2A', 'Gene', '12578', (39, 45))	('CDKN2A', 'Gene', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('SMAD4', 'Gene', '17128', (71, 76))	('PDACs', 'Chemical', '-', (107, 112))	('DPC4', 'Gene', (77, 81))	('mutations', 'Var', (124, 133))	('mutations', 'Var', (225, 234))	('tumor', 'Disease', (54, 59))	('occur', 'Reg', (98, 103))	('facilitate', 'PosReg', (157, 167))
27	34001163	We recently clarified that the KRAS/TP53 double mutation activates the ARF6-AMAP1 pathway, i.e., oncogenic KRAS mutations promote the eukaryotic initiation factor 4A (eIF4A)- and eIF4E-dependent mRNA translation processes, leading to overexpression of the ARF6 protein and AMAP1 protein, respectively.	('AMAP1 protein', 'Protein', (273, 286))	('mutations', 'Var', (112, 121))	('promote', 'PosReg', (122, 129))	('eIF4', 'cellular_component', 'GO:0008304', ('179', '183'))	('eukaryotic', 'Enzyme', (134, 144))	('TP53', 'Gene', (36, 40))	('eIF4', 'cellular_component', 'GO:0008304', ('167', '171'))	('protein', 'cellular_component', 'GO:0003675', ('279', '286'))	('eIF4E', 'Gene', '13684', (179, 184))	('KRAS', 'Gene', (107, 111))	('eIF4A', 'Gene', '1974', (167, 172))	('TP53', 'Gene', '22059', (36, 40))	('eIF4A', 'Gene', (167, 172))	('ARF6-AMAP1 pathway', 'Pathway', (71, 89))	('overexpression', 'PosReg', (234, 248))	('translation', 'biological_process', 'GO:0006412', ('200', '211'))	('ARF6 protein', 'Protein', (256, 268))	('mRNA translation processes', 'MPA', (195, 221))	('activates', 'PosReg', (57, 66))	('protein', 'cellular_component', 'GO:0003675', ('261', '268'))	('eIF4E', 'Gene', (179, 184))
28	34001163	In addition, oncogenic TP53 mutations have been shown to facilitate processes activating ARF6 by external ligands, via their known functions in promoting the expression of platelet-derived growth factor receptor and several enzymes involved in the mevalonate pathway.	('activating', 'MPA', (78, 88))	('TP53', 'Gene', '22059', (23, 27))	('expression', 'MPA', (158, 168))	('growth factor receptor', 'Gene', (189, 211))	('ARF6', 'Gene', (89, 93))	('growth factor receptor', 'Gene', '20187', (189, 211))	('mevalonate', 'Chemical', 'MESH:D008798', (248, 258))	('TP53', 'Gene', (23, 27))	('facilitate', 'PosReg', (57, 67))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('172', '202'))	('mutations', 'Var', (28, 37))	('promoting', 'PosReg', (144, 153))
33	34001163	It was also shown that mutant KRAS promotes MYC expression, although whether this augmentation is mediated by eIF4A has not been confirmed.	('eIF4A', 'Gene', '1974', (110, 115))	('eIF4', 'cellular_component', 'GO:0008304', ('110', '114'))	('MYC', 'Gene', (44, 47))	('promotes', 'PosReg', (35, 43))	('eIF4A', 'Gene', (110, 115))	('MYC', 'Gene', '17869', (44, 47))	('KRAS', 'Gene', (30, 34))	('mutant', 'Var', (23, 29))
38	34001163	In this study, we aimed to clarify whether inhibition of the ARF6-AMAP1 pathway in cancer cells improves the anti-tumor effects of an anti-PD-1 antibody (Ab) in vivo.	('anti-PD-1', 'Var', (134, 143))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('inhibition', 'Var', (43, 53))	('antibody', 'cellular_component', 'GO:0042571', ('144', '152'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('antibody', 'cellular_component', 'GO:0019815', ('144', '152'))	('tumor', 'Disease', (114, 119))	('improves', 'PosReg', (96, 104))	('antibody', 'cellular_component', 'GO:0019814', ('144', '152'))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('antibody', 'molecular_function', 'GO:0003823', ('144', '152'))	('ARF6-AMAP1 pathway', 'Pathway', (61, 79))	('cancer', 'Disease', (83, 89))
44	34001163	However, we next found that silvestrol demonstrates robust synergy with the anti-PD-1 Ab in intact KPC cells, as seen with shAmap1 pretreatment (Fig.	('Amap1', 'Gene', '104601', (125, 130))	('silvestrol', 'Chemical', 'MESH:C489897', (28, 38))	('anti-PD-1', 'Var', (76, 85))	('synergy', 'MPA', (59, 66))	('Amap1', 'Gene', (125, 130))
48	34001163	These results indicated that although suppression of the Arf6-Amap1 pathway on its own mitigates the immune evasive properties of KPC tumor cells to some extent, as we have shown previously, inhibition of this pathway results in therapeutic synergy with the anti-PD-1 Ab.	('inhibition', 'Var', (191, 201))	('Arf6', 'Gene', '11845', (57, 61))	('immune evasive properties', 'CPA', (101, 126))	('KPC tumor', 'Disease', (130, 139))	('therapeutic synergy', 'MPA', (229, 248))	('Amap1', 'Gene', (62, 67))	('KPC tumor', 'Disease', 'MESH:C565455', (130, 139))	('suppression', 'NegReg', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('mitigates', 'NegReg', (87, 96))	('Amap1', 'Gene', '104601', (62, 67))	('Arf6', 'Gene', (57, 61))
50	34001163	Our results moreover suggest that it might be possible to determine dosages of the eIF4A inhibitor(s) that are low enough to mitigate mutant KRAS-driven overexpression of ARF6 and MYC in cancer cells, with minimal effects on normal cells.	('overexpression', 'PosReg', (153, 167))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('mitigate', 'NegReg', (125, 133))	('eIF4', 'cellular_component', 'GO:0008304', ('83', '87'))	('eIF4A', 'Gene', (83, 88))	('MYC', 'Gene', '17869', (180, 183))	('KRAS-driven', 'Gene', (141, 152))	('MYC', 'Gene', (180, 183))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('ARF6', 'Protein', (171, 175))	('eIF4A', 'Gene', '1974', (83, 88))	('mutant', 'Var', (134, 140))
53	34001163	Therefore, targeting mutant KRAS might also be effective against cancer cells with a highly active ARF6-AMAP1 pathway, when combined with specific ICB therapies.	('KRAS', 'Gene', (28, 32))	('mutant', 'Var', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('ARF6-AMAP1 pathway', 'Pathway', (99, 117))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
55	34001163	Inhibition of this pathway in cancer cells not only mitigates their invasion, metastasis, and immune evasion, but also makes cancer cells prone to death by enhancing their mitochondria-based oxidative catastrophe.	('mitigates', 'NegReg', (52, 61))	('immune evasion', 'biological_process', 'GO:0042783', ('94', '108'))	('cancer', 'Disease', (30, 36))	('mitochondria-based oxidative catastrophe', 'MPA', (172, 212))	('invasion', 'CPA', (68, 76))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('immune', 'CPA', (94, 100))	('death', 'Disease', 'MESH:D003643', (147, 152))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('death', 'Disease', (147, 152))	('Inhibition', 'Var', (0, 10))	('immune evasion', 'biological_process', 'GO:0051842', ('94', '108'))	('cancer', 'Disease', (125, 131))	('metastasis', 'CPA', (78, 88))	('enhancing', 'PosReg', (156, 165))	('mitochondria', 'cellular_component', 'GO:0005739', ('172', '184'))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
58	34001163	Furthermore, high expression levels of ARF6 and/or AMAP1, as well as the KRAS mutation, may act as biomarkers to identify patients in whom these treatments are effective.	('KRAS', 'Gene', (73, 77))	('mutation', 'Var', (78, 86))	('high expression levels', 'MPA', (13, 35))	('ARF6', 'Protein', (39, 43))	('AMAP1', 'Gene', (51, 56))	('patients', 'Species', '9606', (122, 130))
133	32191395	Although the surgical safety of concomitant PVR during PD has been shown in many series, a meta-analysis by Giovinazzo and co-workers14 including more than 1500 patients who had PD with PVR for pancreatic cancer demonstrated a higher postoperative morbidity rate (39 per cent) and higher chance of incomplete resection (R1-2, 37 per cent) after PD with PVR, compared with 32 and 31 per cent respectively after PD without PVR (morbidity: P = 0 03; incomplete resection: P < 0 001).	('postoperative morbidity', 'CPA', (234, 257))	('PD', 'Disease', 'MESH:D010300', (410, 412))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (194, 211))	('PD', 'Disease', 'MESH:D010300', (178, 180))	('R1-2', 'Gene', '2840;910;913', (320, 324))	('PD', 'Disease', 'MESH:D010300', (345, 347))	('pancreatic cancer', 'Disease', 'MESH:D010190', (194, 211))	('R1-2', 'Gene', (320, 324))	('patients', 'Species', '9606', (161, 169))	('pancreatic cancer', 'Disease', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('PVR', 'Var', (353, 356))	('PD', 'Disease', 'MESH:D010300', (55, 57))
142	32191395	Instead of SMA resection, the present authors excised en bloc the right side of the periarterial neural plexus around the SMA when perioperative CT showed tumour to SMA contact of less than 180 10, 20 and, because of concern for intractable diarrhoea caused by overly aggressive neural dissection with no proven survival advantage21, 22, 23, they do not recommend routine dissection around the  SMA.	('diarrhoea', 'Disease', (241, 250))	('intractable diarrhoea', 'Phenotype', 'HP:0002041', (229, 250))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('diarrhoea', 'Disease', 'MESH:D003967', (241, 250))	('less', 'Var', (180, 184))	('diarrhoea', 'Phenotype', 'HP:0002014', (241, 250))	('tumour', 'Disease', (155, 161))
292	31979186	However, in a recent population-based study conducted in the UK, PERT was associated with a statistically and clinically significant survival advantage in PC patients when compared with matched, non-PERT-treated controls, and this was even despite the reported low usage of PERT (21.7%).	('PERT', 'Var', (65, 69))	('survival', 'CPA', (133, 141))	('PC', 'Disease', 'MESH:D010190', (155, 157))	('PERT', 'Chemical', '-', (274, 278))	('advantage', 'PosReg', (142, 151))	('patients', 'Species', '9606', (158, 166))	('PERT', 'Chemical', '-', (65, 69))	('PERT', 'Chemical', '-', (199, 203))	('PC', 'Phenotype', 'HP:0002894', (155, 157))
293	31979186	Furthermore, survival was significantly greater among subjects receiving PERT, regardless of the studied subgroup with respect to the use of surgery or CT.	('greater', 'PosReg', (40, 47))	('survival', 'MPA', (13, 21))	('PERT', 'Chemical', '-', (73, 77))	('PERT', 'Var', (73, 77))
353	31979186	wrote the section on maldigestion and treatment in unresectable and metastatic pancreatic cancer patients, M.M.	('M.M', 'Var', (107, 110))	('pancreatic cancer', 'Disease', 'MESH:D010190', (79, 96))	('pancreatic cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (79, 96))	('patients', 'Species', '9606', (97, 105))
380	31861620	Over 90% of early PanIN-1 have KRAS mutations, and mutations in KRAS, BRAF, p16/CDKN2A or GNAS are present in over 99% of early lesions.	('CDKN2A', 'Gene', '1029', (80, 86))	('KRAS mutations', 'Var', (31, 45))	('p16', 'Gene', '1029', (76, 79))	('GNAS', 'Gene', '2778', (90, 94))	('mutations', 'Var', (36, 45))	('KRAS', 'Gene', (64, 68))	('GNAS', 'Gene', (90, 94))	('BRAF', 'Gene', '673', (70, 74))	('p16', 'Gene', (76, 79))	('CDKN2A', 'Gene', (80, 86))	('BRAF', 'Gene', (70, 74))
381	31861620	Despite extensive genomic characterization, individual DNA mutations are yet to provide theranostic information for PDA.	('PDA', 'Disease', 'MESH:D021441', (116, 119))	('DNA', 'Gene', (55, 58))	('PDA', 'Disease', (116, 119))	('mutations', 'Var', (59, 68))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))
469	31861620	Here, the engineered mutation lies downstream of a "Lox-STOP-Lox" (LSL) cassette and the interbreeding of mice carrying the mutant allele with a Cre driver mouse allows the expression of the target gene mutation in a tissue-specific manner.	('mice', 'Species', '10090', (106, 110))	('mutant', 'Var', (124, 130))	('mutation', 'Var', (203, 211))	('mouse', 'Species', '10090', (156, 161))	('expression', 'MPA', (173, 183))
470	31861620	Mice expressing Pdx1-Cre and LSL-KrasG12D spontaneously develop metastatic adenocarcinomas at a low frequency.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('LSL-KrasG12D', 'Var', (29, 41))	('develop', 'PosReg', (56, 63))	('Mice', 'Species', '10090', (0, 4))	('Pdx1-Cre', 'Var', (16, 24))	('adenocarcinomas', 'Disease', 'MESH:D000230', (75, 90))	('adenocarcinomas', 'Disease', (75, 90))
472	31861620	The combination of activated KrasG12D expression with full body deletion of p16Ink4a/p19Arf has been reported to induce rapid progression of PanIN to invasive and metastatic PDA.	('PDA', 'Disease', 'MESH:D021441', (174, 177))	('invasive', 'Disease', (150, 158))	('p19', 'cellular_component', 'GO:0070743', ('85', '88'))	('deletion', 'Var', (64, 72))	('PDA', 'Disease', (174, 177))	('PanIN', 'Disease', (141, 146))	('p16Ink4a/p19Arf', 'Gene', (76, 91))
474	31861620	Conditional Tgfbr2 deletion in the context of Kras activation (Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox) leads to PDA with prominent desmoplasia.	('leads to', 'Reg', (106, 114))	('PDA', 'Disease', (115, 118))	('deletion', 'Var', (19, 27))	('Tgfbr2', 'Gene', (12, 18))	('Ptf1', 'Species', '32651', (63, 67))	('PDA', 'Disease', 'MESH:D021441', (115, 118))	('prominent desmoplasia', 'Disease', 'MESH:C538270', (124, 145))	('prominent desmoplasia', 'Disease', (124, 145))
476	31861620	Although genetic loss of the p53 tumor suppressor has been associated with metastasis in PDA, a direct comparison of mice bearing mutant p53R172H (Pdx1-Cre;LSL-KrasG12D;p53R172H/+) to conditional deletion of p53 (Pdx1-Cre;LSL-KrasG12D;p53flox/flox) revealed that metastasis was observed only in p53R172H mutant-expressing PDA, suggesting that the R172H mutation is a p53-gain of function mutation that promotes PDA metastasis.	('PDA', 'Disease', 'MESH:D021441', (322, 325))	('p53', 'Gene', (169, 172))	('PDA', 'Disease', (322, 325))	('mice', 'Species', '10090', (117, 121))	('R172H', 'Mutation', 'p.R172H', (140, 145))	('p53', 'Gene', (367, 370))	('p53', 'Gene', (137, 140))	('R172H', 'Mutation', 'p.R172H', (172, 177))	('PDA', 'Disease', 'MESH:D021441', (89, 92))	('R172H', 'Mutation', 'p.R172H', (298, 303))	('PDA', 'Disease', (89, 92))	('p53', 'Gene', (208, 211))	('promotes', 'PosReg', (402, 410))	('tumor', 'Disease', (33, 38))	('p53', 'Gene', '22059', (235, 238))	('p53', 'Gene', '22059', (29, 32))	('p53', 'Gene', (295, 298))	('R172H', 'Mutation', 'p.R172H', (347, 352))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('R172H', 'Var', (347, 352))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('p53', 'Gene', '22059', (169, 172))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('p53', 'Gene', '22059', (367, 370))	('metastasis', 'CPA', (415, 425))	('p53', 'Gene', '22059', (137, 140))	('PDA', 'Disease', 'MESH:D021441', (411, 414))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('p53', 'Gene', (29, 32))	('p53', 'Gene', '22059', (208, 211))	('PDA', 'Disease', (411, 414))	('p53', 'Gene', (235, 238))	('p53', 'Gene', '22059', (295, 298))	('mutant', 'Var', (130, 136))
477	31861620	Mice expressing KrasG12D in the context of double heterozygosity for p53 and p16Ink4a or heterozygosity for p19Arf and p16Ink4a in the pancreas exhibited longer latency and higher propensity for metastasis relative to mice that express KrasG12D in the context of the homozygous deletion of p53 or p16Ink4a/p19Arf separately, highlighting the cooperative role for double heterozygous p16Ink4a and p19Arf-p53 in PDA progression.	('PDA', 'Disease', (410, 413))	('p53', 'Gene', '22059', (403, 406))	('p19', 'cellular_component', 'GO:0070743', ('306', '309'))	('Mice', 'Species', '10090', (0, 4))	('higher', 'PosReg', (173, 179))	('p53', 'Gene', '22059', (69, 72))	('longer', 'PosReg', (154, 160))	('p53', 'Gene', '22059', (290, 293))	('KrasG12D', 'Var', (16, 24))	('metastasis', 'CPA', (195, 205))	('mice', 'Species', '10090', (218, 222))	('p53', 'Gene', (403, 406))	('p19Arf', 'Var', (108, 114))	('latency', 'MPA', (161, 168))	('p53', 'Gene', (69, 72))	('p19', 'cellular_component', 'GO:0070743', ('396', '399'))	('p16Ink4a', 'Var', (77, 85))	('p19', 'cellular_component', 'GO:0070743', ('108', '111'))	('p53', 'Gene', (290, 293))	('PDA', 'Disease', 'MESH:D021441', (410, 413))
514	31861620	This study showed that KRAS activation leads to the formation of invasive pancreatic cancer with a similar aggressive behavior as human pancreatic cancer, including the propensity to metastasize.	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('formation', 'biological_process', 'GO:0009058', ('52', '61'))	('aggressive behavior', 'Phenotype', 'HP:0000718', (107, 126))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('activation', 'Var', (28, 38))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('aggressive behavior', 'biological_process', 'GO:0002118', ('107', '126'))	('KRAS', 'Gene', (23, 27))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('invasive pancreatic cancer', 'Disease', 'MESH:D010190', (65, 91))	('invasive pancreatic cancer', 'Disease', (65, 91))	('pancreatic cancer', 'Disease', (136, 153))	('human', 'Species', '9606', (130, 135))
519	31861620	Using this model, Fujimura and colleagues reported that the translation initiation factor 5A (eIF5A) is necessary for PDA metastasis, as knocking down its expression reduces the number of metastasis in the liver.	('eIF5A', 'Gene', (94, 99))	('translation initiation', 'biological_process', 'GO:0006413', ('60', '82'))	('expression', 'MPA', (155, 165))	('eIF5A', 'Gene', '1984', (94, 99))	('reduces', 'NegReg', (166, 173))	('PDA', 'Disease', 'MESH:D021441', (118, 121))	('number', 'CPA', (178, 184))	('knocking down', 'Var', (137, 150))	('PDA', 'Disease', (118, 121))
549	31861620	In fact, the authors demonstrated that biallelic p120ctn loss is necessary for lung metastasis and prevents liver metastasis, whereas monoallelic p120ctn loss accelerates the formation of metastasis in the liver.	('liver metastasis', 'CPA', (108, 124))	('biallelic', 'Var', (39, 48))	('formation', 'biological_process', 'GO:0009058', ('175', '184'))	('prevents', 'NegReg', (99, 107))	('p120ctn', 'Gene', (49, 56))	('formation of', 'CPA', (175, 187))	('p120ctn', 'Gene', '1500', (49, 56))	('p120ctn', 'Gene', (146, 153))	('accelerates', 'PosReg', (159, 170))	('lung metastasis', 'CPA', (79, 94))	('p120ctn', 'Gene', '1500', (146, 153))
553	31861620	This is pertinent given that patients with lymph node metastasis have worse survival rates than those without it.	('patients', 'Species', '9606', (29, 37))	('lymph node metastasis', 'Var', (43, 64))	('worse', 'NegReg', (70, 75))	('survival', 'MPA', (76, 84))
570	31310125	Dysregulation of DDR1 is frequently detected in a variety of human cancers and involved in several key cellular processes, such as cell differentiation, proliferation, adhesion, migration, and invasion.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('involved in', 'Reg', (79, 90))	('adhesion', 'CPA', (168, 176))	('cancers', 'Disease', (67, 74))	('cell differentiation', 'biological_process', 'GO:0030154', ('131', '151'))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('detected', 'Reg', (36, 44))	('cell differentiation', 'CPA', (131, 151))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('proliferation', 'CPA', (153, 166))	('migration', 'CPA', (178, 187))	('DDR1', 'Gene', (17, 21))	('human', 'Species', '9606', (61, 66))	('invasion', 'CPA', (193, 201))
572	31310125	Pharmacological inhibition of DDR1 by a selective DDR1 inhibitor 7rh (compound 1, Figure 1) successfully slowed tumor progression and enhanced chemosensitivity to standard-of-care pancreatic cancer regimens.	('tumor', 'Disease', (112, 117))	('slowed', 'NegReg', (105, 111))	('enhanced', 'PosReg', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('chemosensitivity', 'CPA', (143, 159))	('pancreatic cancer', 'Disease', 'MESH:D010190', (180, 197))	('pancreatic cancer', 'Disease', (180, 197))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('DDR1', 'Gene', (30, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (180, 197))	('inhibition', 'Var', (16, 26))
593	31310125	The only small difference between binding modes of 6 with DDR1 and TrkC is that the methyl group on tetrahydroisoquinoline occupied a small hydrophobic pocket formed by Val552, Ala570, Lys572, and Phe617 to achieve some hydrophobic interactions in TrkC.	('binding', 'molecular_function', 'GO:0005488', ('34', '41'))	('Ala', 'Chemical', 'MESH:C026593', (177, 180))	('Lys572', 'Var', (185, 191))	('hydrophobic interactions', 'MPA', (220, 244))	('TrkC', 'Gene', (248, 252))	('Val552', 'Chemical', 'MESH:C513153', (169, 175))	('tetrahydroisoquinoline', 'Chemical', 'MESH:D044005', (100, 122))	('Phe617', 'Var', (197, 203))	('methyl', 'Chemical', 'MESH:C031105', (84, 90))	('TrkC', 'Gene', '18213', (67, 71))	('TrkC', 'Gene', (67, 71))	('Ala570', 'Var', (177, 183))	('Val552', 'Var', (169, 175))	('Phe617', 'Chemical', 'MESH:C482241', (197, 203))	('TrkC', 'Gene', '18213', (248, 252))
595	31310125	Further computational investigation demonstrated that 7a failed to fit nicely into the DDR1 ATP binding pocket (PDB ID: 5FDP, data not shown), whereas compound 7b could form weak hydrogen bonds (HBs) with the hinge residue Met704, but there was no other interaction between the isoindoline scaffold and DDR1 (Figure S1).	('ATP', 'Chemical', 'MESH:D000255', (92, 95))	('hydrogen', 'Chemical', 'MESH:D006859', (179, 187))	('hydrogen bonds', 'MPA', (179, 193))	('Met704', 'Var', (223, 229))	('ATP binding', 'molecular_function', 'GO:0005524', ('92', '103'))	('isoindoline', 'Chemical', 'MESH:C531933', (278, 289))	('5FDP', 'Chemical', 'MESH:C020332', (120, 124))
602	31310125	The nitrogen atom of pyrimidine was observed to form a hydrogen bond with hinge residue Met704, whereas the amino group at 2-position of the indene formed a hydrogen bond with gatekeeper residue Thr701.	('Met704', 'Var', (88, 94))	('hydrogen bond', 'MPA', (55, 68))	('hydrogen', 'Chemical', 'MESH:D006859', (157, 165))	('pyrimidine', 'Chemical', 'MESH:C030986', (21, 31))	('nitrogen', 'Chemical', 'MESH:D009584', (4, 12))	('hydrogen', 'Chemical', 'MESH:D006859', (55, 63))	('gatekeeper', 'Species', '111938', (176, 186))	('Thr701', 'Chemical', 'MESH:C033167', (195, 201))	('amino', 'Chemical', 'MESH:D000596', (108, 113))
605	31310125	It was shown that the pyrimidinyl moiety of 7c would still be able to form a hydrogen bond (~3.1 A) with the key residue Met620 in TrkC (Figure 3D), but the gatekeeper Phe617 of TrkC altered the three-dimensional (3D) structure of the ATP pocket relative to DDR1, which would both preclude a key hydrogen bond and additionally introduce a steric clash with 7c.	('ATP', 'Chemical', 'MESH:D000255', (235, 238))	('preclude', 'NegReg', (281, 289))	('Phe617', 'Chemical', 'MESH:C482241', (168, 174))	('hydrogen bond', 'MPA', (296, 309))	('TrkC', 'Gene', (178, 182))	('pyrimidinyl', 'Chemical', 'MESH:C037921', (22, 33))	('altered', 'Reg', (183, 190))	('TrkC', 'Gene', '18213', (131, 135))	('TrkC', 'Gene', (131, 135))	('hydrogen', 'Chemical', 'MESH:D006859', (77, 85))	('steric', 'MPA', (339, 345))	('gatekeeper', 'Species', '111938', (157, 167))	('hydrogen', 'Chemical', 'MESH:D006859', (296, 304))	('Phe617', 'Var', (168, 174))	('TrkC', 'Gene', '18213', (178, 182))	('introduce', 'Reg', (327, 336))
606	31310125	Superposition of DDR1 (PDB: 6HP9, gray) and a homology model of DDR2 (orange) indicated that DDR1 possessed a small hydrophobic groove formed by Ile685, Thr701, and Asp703, whereas no such pocket existed in DDR2 because of its outward shifting of Glu93 and Ile76 (Figure 4A).	('DDR2', 'Gene', (207, 211))	('Ile76', 'Chemical', 'MESH:C018419', (257, 262))	('DDR2', 'Gene', '18214', (64, 68))	('Asp703', 'Chemical', 'MESH:C409586', (165, 171))	('DDR2', 'Gene', (64, 68))	('Thr701', 'Chemical', 'MESH:C033167', (153, 159))	('groove', 'cellular_component', 'GO:0097610', ('128', '134'))	('Thr701', 'Var', (153, 159))	('Ile685', 'Var', (145, 151))	('DDR1', 'Var', (93, 97))	('DDR2', 'Gene', '18214', (207, 211))	('Asp703', 'Var', (165, 171))
610	31310125	Computational investigation supported the idea that a methyl group (7f) could fit into a small hydrophobic pocket formed by Ile685, Thr701, and Asp702, whereas loss of a hydrogen bond with Thr701 would contribute to the DDR1 potency decrease (Figure 4B).	('DDR1', 'Enzyme', (220, 224))	('loss', 'NegReg', (160, 164))	('Thr701', 'Chemical', 'MESH:C033167', (189, 195))	('hydrogen bond', 'MPA', (170, 183))	('decrease', 'NegReg', (233, 241))	('Thr701', 'Chemical', 'MESH:C033167', (132, 138))	('Thr701', 'Var', (132, 138))	('Asp702', 'Var', (144, 150))	('Asp702', 'Chemical', 'MESH:C482243', (144, 150))	('methyl', 'Chemical', 'MESH:C031105', (54, 60))	('hydrogen', 'Chemical', 'MESH:D006859', (170, 178))	('Ile685', 'Var', (124, 130))
613	31310125	A replacement of the trifluoromethyl with a methyl group (7i) caused an approximately 43-fold decrease in DDR1 potency.	('DDR1 potency', 'MPA', (106, 118))	('trifluoromethyl', 'Chemical', 'MESH:C056508', (21, 36))	('methyl', 'Chemical', 'MESH:C031105', (30, 36))	('methyl', 'Chemical', 'MESH:C031105', (44, 50))	('replacement', 'Var', (2, 13))	('decrease', 'NegReg', (94, 102))
785	31310125	For immunofluorescent staining, cells were treated with 50 mug/mL collagen and indicated concentration of 7f for 24 h. Cells were fixed with methanol and stained with E-cadherin (24E10, Cell Signaling #3195), N-cadherin (13A9, Cell Signaling #3195), and DAPI.	('N-cadherin', 'Gene', '12558', (209, 219))	('N-cadherin', 'Gene', (209, 219))	('Signaling', 'biological_process', 'GO:0023052', ('232', '241'))	('methanol', 'Chemical', 'MESH:D000432', (141, 149))	('E-cadherin', 'Gene', '12550', (167, 177))	('cadherin', 'molecular_function', 'GO:0008014', ('211', '219'))	('24E10', 'Var', (179, 184))	('E-cadherin', 'Gene', (167, 177))	('cadherin', 'molecular_function', 'GO:0008014', ('169', '177'))	('collagen', 'molecular_function', 'GO:0005202', ('66', '74'))	('mug', 'molecular_function', 'GO:0043739', ('59', '62'))	('13A9', 'Var', (221, 225))	('Signaling', 'biological_process', 'GO:0023052', ('191', '200'))
844	31514732	In addition, we detected the GSTM3TV2 expression was significantly upregulated in pancreatic cancer tissues, and high expression of GSTM3TV2 had a worse prognosis.	('GSTM3', 'Gene', (29, 34))	('high expression', 'Var', (113, 128))	('GSTM3', 'Gene', (132, 137))	('expression', 'MPA', (38, 48))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (82, 99))	('GSTM3', 'Gene', '2947', (132, 137))	('GSTM3', 'Gene', '2947', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('pancreatic cancer', 'Disease', (82, 99))	('upregulated', 'PosReg', (67, 78))	('pancreatic cancer', 'Disease', 'MESH:D010190', (82, 99))
864	31514732	The pcDNA3.1-GSTM3TV2 construct containing point mutations at the putative let-7 binding sites was synthesized by Imagen Therapeutics (Beijing, China) and named pcDNA3.1-GSTM3TV2-Mut.	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('GSTM3', 'Gene', (170, 175))	('point mutations', 'Var', (43, 58))	('let-7', 'Gene', (75, 80))	('GSTM3', 'Gene', '2947', (170, 175))	('let-7', 'Chemical', '-', (75, 80))	('GSTM3', 'Gene', (13, 18))	('GSTM3', 'Gene', '2947', (13, 18))	('Imagen', 'Chemical', '-', (114, 120))
886	31514732	Then, we revealed that the lncRNAs n407039 (Homo sapiens glutathione S-transferase mu 3, transcript variant 2, noncoding RNA, GSTM3TV2; NCBI Reference Sequence: NR_024537.1) (Probe ID: n407039) and n407040 (NCBI Reference Sequence: NR_024538.1) might be the predicted key nodes for regulating chemoresistance in the ceRNA network.	('n407040', 'Var', (198, 205))	('n407039', 'Var', (35, 42))	('glutathione S-transferase mu 3', 'Gene', (57, 87))	('glutathione S-transferase mu 3', 'Gene', '2947', (57, 87))	('Homo sapiens', 'Species', '9606', (44, 56))	('GSTM3', 'Gene', (126, 131))	('RNA', 'cellular_component', 'GO:0005562', ('121', '124'))	('GSTM3', 'Gene', '2947', (126, 131))	('chemoresistance in the', 'CPA', (293, 315))
894	31514732	To ascertain the role of GSTM3TV2 in chemoresistance in vitro, we employed a gain- or loss-of-function strategy to overexpress or knock down GSTM3TV2 in pancreatic cancer cells (Additional file 6: Figure S2A).	('GSTM3', 'Gene', '2947', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (153, 170))	('loss-of-function', 'NegReg', (86, 102))	('gain-', 'PosReg', (77, 82))	('pancreatic cancer', 'Disease', (153, 170))	('pancreatic cancer', 'Disease', 'MESH:D010190', (153, 170))	('GSTM3', 'Gene', '2947', (141, 146))	('knock down', 'Var', (130, 140))	('GSTM3', 'Gene', (25, 30))	('overexpress', 'PosReg', (115, 126))	('GSTM3', 'Gene', (141, 146))
899	31514732	The in vivo results revealed that in mice treated with gemcitabine, the tumours generated from Rv-AsPC-1-GSTM3TV2 cells grew significantly faster than the control cells (Fig.	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('Rv-AsPC-1-GSTM3TV2', 'Var', (95, 113))	('gemcitabine', 'Chemical', 'MESH:C056507', (55, 66))	('faster', 'PosReg', (139, 145))	('Rv-AsPC-1-GSTM3TV2', 'CellLine', 'CVCL:R816', (95, 113))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumours', 'Disease', (72, 79))	('mice', 'Species', '10090', (37, 41))
903	31514732	4a), we first examined let-7 expression that was upregulated in MIAPaCa-2/GR cells with GSTM3TV2 knockdown and downregulated in GSTM3TV2-overexpressing AsPC-1 cells (Fig.	('GSTM3', 'Gene', (128, 133))	('knockdown', 'Var', (97, 106))	('let-7', 'Gene', (23, 28))	('GSTM3', 'Gene', (88, 93))	('let-7', 'Chemical', '-', (23, 28))	('GSTM3', 'Gene', '2947', (128, 133))	('GSTM3', 'Gene', '2947', (88, 93))	('AsPC-1', 'CellLine', 'CVCL:0152', (152, 158))	('downregulated', 'NegReg', (111, 124))	('upregulated', 'PosReg', (49, 60))	('MIAPaCa-2', 'CellLine', 'CVCL:0428', (64, 73))	('expression', 'MPA', (29, 39))
905	31514732	Next, we constructed luciferase reporter plasmids containing the GSTM3TV2 coding sequences containing either wild-type (WT) or mutated let-7 binding sites to identify target effectors.	('let-7', 'Chemical', '-', (135, 140))	('GSTM3', 'Gene', (65, 70))	('binding', 'Interaction', (141, 148))	('binding', 'molecular_function', 'GO:0005488', ('141', '148'))	('GSTM3', 'Gene', '2947', (65, 70))	('mutated', 'Var', (127, 134))	('let-7', 'Gene', (135, 140))
906	31514732	We found that the let-7d-5p, let-7f-5p and let-7 g-5p mimics reduced the luciferase activities of the WT reporter vector, indicating that the let-7 family of miRNAs target GSTM3TV2 in 293A cells (Fig.	('luciferase', 'Enzyme', (73, 83))	('let-7', 'Chemical', '-', (29, 34))	('let-7f-5p', 'Var', (29, 38))	('let-7', 'Chemical', '-', (43, 48))	('let-7', 'Var', (43, 48))	('activities', 'MPA', (84, 94))	('293A', 'CellLine', 'CVCL:6910', (184, 188))	('GSTM3', 'Gene', '2947', (172, 177))	('let-7', 'Chemical', '-', (18, 23))	('let-7', 'Chemical', '-', (142, 147))	('GSTM3', 'Gene', (172, 177))	('reduced', 'NegReg', (61, 68))	('let-7d-5p', 'Var', (18, 27))
907	31514732	We also performed an RNA immunoprecipitation (RIP) assay to pull down endogenous miRNAs associated with GSTM3TV2 and used qRT-PCR to show that the RIP of GSTM3TV2 in AsPC-1 cells was significantly enriched with let-7d-5p, let-7f-5p and let-7 g-5p compared to the RIP of IgG, empty vector (MS2) and GSTM3TV2 with mutations at the let-7-targeting sites (Fig.	('RNA', 'cellular_component', 'GO:0005562', ('21', '24'))	('GSTM3', 'Gene', '2947', (104, 109))	('let-7', 'Chemical', '-', (211, 216))	('let-7', 'Chemical', '-', (236, 241))	('let-7', 'Chemical', '-', (329, 334))	('let-7f-5p', 'Var', (222, 231))	('GSTM3', 'Gene', (298, 303))	('let-7d-5p', 'Var', (211, 220))	('GSTM3', 'Gene', (154, 159))	('GSTM3', 'Gene', '2947', (154, 159))	('AsPC-1', 'CellLine', 'CVCL:0152', (166, 172))	('let-7', 'Chemical', '-', (222, 227))	('GSTM3', 'Gene', '2947', (298, 303))	('mutations', 'Var', (312, 321))	('GSTM3', 'Gene', (104, 109))	('let-7 g-5p', 'Var', (236, 246))
923	31514732	Data showed that MIAPaCa-2/GR and Rv-AsPC-1-GSTM3TV2 cells transfected with the let-7 mimics were more sensitive to gemcitabine than cells transfected with mimic controls (Fig.	('gemcitabine', 'Chemical', 'MESH:C056507', (116, 127))	('let-7', 'Gene', (80, 85))	('more', 'PosReg', (98, 102))	('sensitive to gemcitabine', 'MPA', (103, 127))	('mimics', 'Var', (86, 92))	('Rv-AsPC-1-GSTM3TV2', 'CellLine', 'CVCL:R816', (34, 52))	('MIAPaCa-2', 'CellLine', 'CVCL:0428', (17, 26))	('let-7', 'Chemical', '-', (80, 85))
968	31514732	We observed that LAT2 and OLR1 were upregulated in gemcitabine-resistant pancreatic cell lines and that inhibiting their expression enhanced the chemosensitivity of pancreatic cancer cells to gemcitabine.	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('LAT2', 'Gene', '23428', (17, 21))	('gemcitabine', 'Chemical', 'MESH:C056507', (51, 62))	('expression', 'MPA', (121, 131))	('inhibiting', 'Var', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('pancreatic', 'Disease', (165, 175))	('pancreatic cancer', 'Disease', (165, 182))	('upregulated', 'PosReg', (36, 47))	('gemcitabine', 'Chemical', 'MESH:C056507', (192, 203))	('OLR1', 'Gene', '4973', (26, 30))	('pancreatic', 'Disease', 'MESH:D010195', (73, 83))	('OLR1', 'Gene', (26, 30))	('enhanced', 'PosReg', (132, 140))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('LAT2', 'Gene', (17, 21))	('pancreatic', 'Disease', (73, 83))	('chemosensitivity', 'CPA', (145, 161))	('pancreatic', 'Disease', 'MESH:D010195', (165, 175))
970	31514732	Meanwhile, GSTM3TV2-mediated chemoresistance could be depressed by knocking down LAT2 and OLR1.	('LAT2', 'Gene', '23428', (81, 85))	('OLR1', 'Gene', '4973', (90, 94))	('LAT2', 'Gene', (81, 85))	('chemoresistance', 'CPA', (29, 44))	('depressed', 'NegReg', (54, 63))	('GSTM3', 'Gene', (11, 16))	('OLR1', 'Gene', (90, 94))	('knocking', 'Var', (67, 75))	('GSTM3', 'Gene', '2947', (11, 16))
1000	31279157	This interesting observation has to be counterbalanced by other studies demonstrating high expression of TMEM16A in liver metastasis of CRC or an amplification of the TMEM16A gene in metastasis from HNSCC.	('amplification', 'Var', (146, 159))	('expression', 'MPA', (91, 101))	('TMEM16A', 'Gene', '55107', (167, 174))	('liver metastasis of CRC', 'Disease', (116, 139))	('TMEM16A', 'Gene', (105, 112))	('TMEM16A', 'Gene', (167, 174))	('liver metastasis of CRC', 'Disease', 'MESH:D015179', (116, 139))	('TMEM16A', 'Gene', '55107', (105, 112))
1006	31279157	TMEM16A could also represent a valuable therapeutic target as its pharmacological inhibition of TMEM16A reduces tumor growth in vivo and promotes the sensitivity of other chemotherapy and its expression could be correlated to the improvement of clinical outcomes by chemotherapy.	('TMEM16A', 'Gene', '55107', (0, 7))	('promotes', 'PosReg', (137, 145))	('TMEM16A', 'Gene', '55107', (96, 103))	('inhibition', 'Var', (82, 92))	('reduces', 'NegReg', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('sensitivity of other chemotherapy', 'MPA', (150, 183))	('tumor', 'Disease', (112, 117))	('TMEM16A', 'Gene', (0, 7))	('TMEM16A', 'Gene', (96, 103))
1013	31279157	Thus, molecular or pharmacological silencing of TMEM16A in cancer cells could impair proliferation, cell cycle, tumor growth in vivo, or the ability to form colony (Figure 2).	('TMEM16A', 'Gene', (48, 55))	('silencing', 'Var', (35, 44))	('cell cycle', 'biological_process', 'GO:0007049', ('100', '110'))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cell cycle', 'CPA', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('TMEM16A', 'Gene', '55107', (48, 55))	('tumor', 'Disease', (112, 117))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('proliferation', 'CPA', (85, 98))	('impair', 'NegReg', (78, 84))
1015	31279157	Most of investigations across multiple cancer types have demonstrated that TMEM16A expression sustains cancer cell viability and impair apoptosis (Figure 2).	('impair', 'NegReg', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('apoptosis', 'CPA', (136, 145))	('cancer', 'Disease', (103, 109))	('TMEM16A', 'Gene', (75, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))	('TMEM16A', 'Gene', '55107', (75, 82))	('expression', 'Var', (83, 93))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('sustains', 'PosReg', (94, 102))
1019	31279157	In this investigation, Shiwarski and colleagues show that in HNSCC cancer cells, TMEM16A expression inhibits cancer cell migration and invasion while also preventing the epithelial-to-mesenchymal transition (EMT), a critical process for cancer cells to develop metastasis and secondary tumors.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('cell migration', 'biological_process', 'GO:0016477', ('116', '130'))	('secondary tumors', 'Disease', (276, 292))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('preventing', 'NegReg', (155, 165))	('inhibits', 'NegReg', (100, 108))	('TMEM16A', 'Gene', (81, 88))	('epithelial-to-mesenchymal transition', 'CPA', (170, 206))	('cancer', 'Disease', (237, 243))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('170', '206'))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('HNSCC cancer', 'Disease', 'MESH:D000077195', (61, 73))	('expression', 'Var', (89, 99))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('HNSCC cancer', 'Disease', (61, 73))	('EMT', 'biological_process', 'GO:0001837', ('208', '211'))	('TMEM16A', 'Gene', '55107', (81, 88))	('secondary tumors', 'Disease', 'MESH:D060085', (276, 292))	('invasion', 'CPA', (135, 143))	('cancer', 'Disease', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (237, 243))
1026	31279157	At the genomic level, amplification of the locus 11q13 is the most frequently mechanism associated to TMEM16A over-expression in cancers (Figure 3).	('TMEM16A', 'Gene', '55107', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('over-expression', 'PosReg', (110, 125))	('cancers', 'Disease', (129, 136))	('amplification', 'Var', (22, 35))	('TMEM16A', 'Gene', (102, 109))	('associated', 'Reg', (88, 98))
1028	31279157	Hypermethylation of the promoter region of the TMEM16A gene has been observed in HPV-positive HNSCC and in distant metastasis of HNSCC and it correlates with a low expression of TMEM16A suggesting that hypermethylation of TMEM16A promoter could repress TMEM16A transcription.	('hypermethylation', 'Var', (202, 218))	('TMEM16A', 'Gene', '55107', (222, 229))	('TMEM16A', 'Gene', '55107', (178, 185))	('TMEM16A', 'Gene', '55107', (47, 54))	('expression', 'MPA', (164, 174))	('transcription', 'MPA', (261, 274))	('TMEM16A', 'Gene', (253, 260))	('TMEM16A', 'Gene', (178, 185))	('TMEM16A', 'Gene', (47, 54))	('transcription', 'biological_process', 'GO:0006351', ('261', '274'))	('TMEM16A', 'Gene', (222, 229))	('repress', 'NegReg', (245, 252))	('TMEM16A', 'Gene', '55107', (253, 260))
1029	31279157	Thus, even if direct evidence of the hypomethylation of this particular genomic region in cancer has not been reported, it is conceivable that hypomethylation of TMEM16A promoter could be a putative mechanism contributing to its over-expression in cancer.	('cancer', 'Disease', (248, 254))	('hypomethylation', 'Var', (143, 158))	('TMEM16A', 'Gene', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('TMEM16A', 'Gene', '55107', (162, 169))	('over-expression', 'PosReg', (229, 244))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
1043	31279157	Over the years, the modulation of TMEM16A expression or activity in cancer cells has been associated with the up- or down-regulation of different proteins, making it possible to create a network of protein targets of TMEM16A in cancer cells (Figure 3).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('TMEM16A', 'Gene', '55107', (217, 224))	('regulation', 'biological_process', 'GO:0065007', ('122', '132'))	('cancer', 'Disease', (228, 234))	('activity', 'MPA', (56, 64))	('TMEM16A', 'Gene', '55107', (34, 41))	('down-regulation', 'NegReg', (117, 132))	('proteins', 'Protein', (146, 154))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('up-', 'PosReg', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('cancer', 'Disease', (68, 74))	('TMEM16A', 'Gene', (217, 224))	('TMEM16A', 'Gene', (34, 41))	('modulation', 'Var', (20, 30))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
1045	31279157	Alteration of TMEM16A expression affects proteins dedicated to transcription or cell division (Figure 3).	('TMEM16A', 'Gene', (14, 21))	('cell division', 'biological_process', 'GO:0051301', ('80', '93'))	('Alteration', 'Var', (0, 10))	('affects', 'Reg', (33, 40))	('TMEM16A', 'Gene', '55107', (14, 21))	('proteins dedicated to transcription', 'MPA', (41, 76))	('transcription', 'biological_process', 'GO:0006351', ('63', '76'))	('cell', 'CPA', (80, 84))
1061	31279157	Interestingly, the pharmacological inhibition of TMEM16A enhanced the sensitivity to EGFR-based therapeutic strategies in HNSCC cancer cells strengthening the relationship between EGFR and TMEM16A.	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (85, 89))	('relationship', 'Interaction', (159, 171))	('TMEM16A', 'Gene', '55107', (49, 56))	('TMEM16A', 'Gene', '55107', (189, 196))	('pharmacological inhibition', 'Var', (19, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('HNSCC cancer', 'Disease', 'MESH:D000077195', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('EGFR', 'molecular_function', 'GO:0005006', ('180', '184'))	('HNSCC cancer', 'Disease', (122, 134))	('enhanced', 'PosReg', (57, 65))	('TMEM16A', 'Gene', (49, 56))	('TMEM16A', 'Gene', (189, 196))
1065	31279157	Moreover, TMEM16A expression has a profound effect on the phosphoproteome of pancreatic cancer cells and impairs the EGFR-related signaling pathways.	('TMEM16A', 'Gene', (10, 17))	('impairs', 'NegReg', (105, 112))	('EGFR', 'molecular_function', 'GO:0005006', ('117', '121'))	('TMEM16A', 'Gene', '55107', (10, 17))	('EGFR', 'Gene', '1956', (117, 121))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('EGFR', 'Gene', (117, 121))	('phosphoproteome', 'MPA', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('effect', 'Reg', (44, 50))	('pancreatic cancer', 'Disease', (77, 94))	('expression', 'Var', (18, 28))	('signaling', 'biological_process', 'GO:0023052', ('130', '139'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
1072	31279157	Similarly, the use of T16Ainh-A01 does not reproduce the effect observed with the silencing of TMEM16A expression on the viability of the colorectal cancer cell line HCT-116.	('HCT-116', 'CellLine', 'CVCL:0291', (166, 173))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('TMEM16A', 'Gene', (95, 102))	('colorectal cancer', 'Disease', (138, 155))	('silencing', 'Var', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('T16Ainh-A01', 'Chemical', 'MESH:C578466', (22, 33))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))	('TMEM16A', 'Gene', '55107', (95, 102))
1074	31279157	However, other investigations observed that TMEM16A blockers inhibit cancer cell proliferation and/or migration to the same extent as the molecular silencing of TMEM16A.	('molecular silencing', 'Var', (138, 157))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('TMEM16A', 'Gene', '55107', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('TMEM16A', 'Gene', (44, 51))	('blockers', 'Var', (52, 60))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('inhibit', 'NegReg', (61, 68))	('migration', 'CPA', (102, 111))	('TMEM16A', 'Gene', (161, 168))	('TMEM16A', 'Gene', '55107', (44, 51))	('cancer', 'Disease', (69, 75))
1075	31279157	Moreover, over-expression of non-conductive TMEM16A mutants (R621E, K668E and K610A) failed to reproduce the increase of proliferation observed with wild-type TMEM16A.	('TMEM16A', 'Gene', (159, 166))	('K610A', 'Mutation', 'p.K610A', (78, 83))	('K668E', 'Mutation', 'p.K668E', (68, 73))	('K610A', 'Var', (78, 83))	('TMEM16A', 'Gene', (44, 51))	('R621E', 'Var', (61, 66))	('R621E', 'Mutation', 'p.R621E', (61, 66))	('TMEM16A', 'Gene', '55107', (159, 166))	('K668E', 'Var', (68, 73))	('TMEM16A', 'Gene', '55107', (44, 51))
1082	31279157	TMEM16A interaction with radixin was observed by co-immunoprecipitation in HNSCC cell lines and has been found to be mediated by the phosphorylation of S970 in the TMEM16A C-terminal domain.	('mediated by', 'Reg', (117, 128))	('TMEM16A', 'Gene', '55107', (164, 171))	('TMEM16A', 'Gene', '55107', (0, 7))	('S970', 'CellLine', 'CVCL:7312', (152, 156))	('phosphorylation', 'MPA', (133, 148))	('TMEM16A', 'Gene', (164, 171))	('radixin', 'Gene', (25, 32))	('interaction', 'Interaction', (8, 19))	('radixin', 'Gene', '5962', (25, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('133', '148'))	('TMEM16A', 'Gene', (0, 7))	('S970', 'Var', (152, 156))
1083	31279157	Interestingly, while the over-expression of TMEM16A inhibits EMT and promotes proliferation in T24 cell line, over-expressing TMEM16A S970A (a mutant not interacting with radixin) fails to inhibit EMT but still promotes T24 proliferation.	('TMEM16A', 'Gene', '55107', (126, 133))	('S970A', 'Var', (134, 139))	('radixin', 'Gene', '5962', (171, 178))	('T24', 'CellLine', 'CVCL:0554', (95, 98))	('TMEM16A', 'Gene', (44, 51))	('promotes', 'PosReg', (69, 77))	('radixin', 'Gene', (171, 178))	('TMEM16A', 'Gene', (126, 133))	('inhibits', 'NegReg', (52, 60))	('T24 proliferation', 'CPA', (220, 237))	('proliferation', 'CPA', (78, 91))	('S970A', 'Mutation', 'p.S970A', (134, 139))	('T24', 'CellLine', 'CVCL:0554', (220, 223))	('EMT', 'biological_process', 'GO:0001837', ('61', '64'))	('EMT', 'biological_process', 'GO:0001837', ('197', '200'))	('EMT', 'CPA', (61, 64))	('promotes', 'PosReg', (211, 219))	('TMEM16A', 'Gene', '55107', (44, 51))
1115	31279157	PIP2 is the precursor of inositol triphosphate (IP3) obtained by the cleavage of PIP2 by phospholipase C (PLC) (which can be activated by EGFR).	('EGFR', 'Gene', '1956', (138, 142))	('IP3', 'Chemical', 'MESH:D015544', (48, 51))	('PLC', 'cellular_component', 'GO:0042824', ('106', '109'))	('cleavage', 'Var', (69, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('138', '142'))	('EGFR', 'Gene', (138, 142))	('inositol triphosphate', 'Chemical', '-', (25, 46))	('PIP2', 'Gene', (81, 85))	('PIP2', 'Chemical', 'MESH:D019269', (0, 4))	('PIP2', 'Chemical', 'MESH:D019269', (81, 85))
1195	31453247	Luciferase and GFP expressing MIA PaCa-2 cells were added to whole blood in known concentrations (20000 cells/ml, 10000 cells/ml, 5000 cells/ml, 1000 cells/ml, 500 cells/ml, 25 cells/ml and 0 cells/ml).	('10000 cells/ml', 'Var', (114, 128))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (30, 40))	('20000 cells/ml', 'Var', (98, 112))
1261	31114368	Survival analysis showed that the median overall survival (OS) and recurrence-free survival (RFS) were significantly better in patients with low SIRI.	('overall survival', 'CPA', (41, 57))	('better', 'PosReg', (117, 123))	('patients', 'Species', '9606', (127, 135))	('low SIRI', 'Var', (141, 149))	('recurrence-free survival', 'CPA', (67, 91))
1317	31114368	In addition, we also found that patients with high level of SIRI were more likely to have pancreatic head tumor (P=0.004) and advanced TNM stage (P=0.033) in the training cohort.	('TNM', 'Gene', (135, 138))	('patients', 'Species', '9606', (32, 40))	('TNM', 'Gene', '10178', (135, 138))	('SIRI', 'Var', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('pancreatic head tumor', 'Disease', (90, 111))	('pancreatic head tumor', 'Disease', 'MESH:D010190', (90, 111))
1327	31114368	Multivariate analysis revealed that high level of SIRI remained an independent predictor of OS (HR =2.114, P=0.002), together with advanced TNM stage (HR =1.472, P=0.003) and postoperative chemotherapy (HR =0.457, P<0.001).	('SIRI', 'Var', (50, 54))	('high level', 'Var', (36, 46))	('TNM', 'Gene', (140, 143))	('TNM', 'Gene', '10178', (140, 143))
1332	31114368	In the training cohort, patients with SIRI >0.69 had a median OS and RFS of 19.3 months and 8.4 months, significantly shorter than 28.2 months (HR =1.922, P<0.001) and 14.5 months (HR =1.753, P<0.001) in the low SIRI group.	('SIRI >0.69', 'Var', (38, 48))	('shorter', 'NegReg', (118, 125))	('patients', 'Species', '9606', (24, 32))
1333	31114368	Similarly, the median OS and RFS of patients with high SIRI in the validation cohort were 23.2 months and 10.0 months, also significantly shorter than 33.5 months (HR =2.133, P<0.001) and 19.5 months (HR =1.640, P=0.001) in the low SIRI group.	('shorter', 'NegReg', (138, 145))	('high SIRI', 'Var', (50, 59))	('RFS', 'CPA', (29, 32))	('patients', 'Species', '9606', (36, 44))
1352	31114368	CA19-9 is currently the most widely used tumor biomarker in the diagnosis and treatment of pancreatic cancer.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', (41, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('CA19-9', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('pancreatic cancer', 'Disease', (91, 108))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))
1354	31114368	We further investigated the prognostic value of SIRI in patients who had normal level of CA19-9 and found that those with higher SIRI had significantly poorer OS and RFS, both in the training cohort and in the validation cohort.	('patients', 'Species', '9606', (56, 64))	('higher', 'PosReg', (122, 128))	('RFS', 'CPA', (166, 169))	('SIRI', 'Var', (129, 133))	('poorer', 'NegReg', (152, 158))
1358	31114368	On subgroup analysis, the median OS and RFS were both longer in patients with low SIRI compared with patients with high SIRI who had received postoperative chemotherapy.	('patients', 'Species', '9606', (101, 109))	('low SIRI', 'Var', (78, 86))	('patients', 'Species', '9606', (64, 72))	('longer', 'PosReg', (54, 60))	('RFS', 'MPA', (40, 43))
1379	29702208	Despite the complexity of PDA initiation, it has been established that the KRAS mutation is a key driver of tumor progression and multiple studies report that tumors are highly dependent on this oncogene for tumor maintenance.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (108, 113))	('tumors', 'Disease', (159, 165))	('tumor', 'Disease', (159, 164))	('PDA', 'Chemical', '-', (26, 29))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('KRAS', 'Gene', (75, 79))	('tumor', 'Disease', (208, 213))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('mutation', 'Var', (80, 88))	('PDA', 'Phenotype', 'HP:0006725', (26, 29))
1382	29702208	In PDA, KRAS is most commonly mutated at the G12 residue preventing the interaction with GAPs which results in KRAS bound to GTP and is therefore constitutively active.	('interaction', 'Interaction', (72, 83))	('PDA', 'Phenotype', 'HP:0006725', (3, 6))	('mutated', 'Var', (30, 37))	('preventing', 'NegReg', (57, 67))	('GTP', 'Chemical', 'MESH:D006160', (125, 128))	('PDA', 'Chemical', '-', (3, 6))	('GAPs', 'Protein', (89, 93))	('bound', 'Interaction', (116, 121))
1385	29702208	Recently, however, the development of inhibitors targeting specific KRAS mutations (G12C) have provided evidence that some mutations lead to vulnerabilities that can be exploited for therapeutic gain.	('mutations (G12C', 'Var', (73, 88))	('lead to', 'Reg', (133, 140))	('vulnerabilities', 'MPA', (141, 156))	('KRAS', 'Gene', (68, 72))	('G12C', 'Mutation', 'rs121913530', (84, 88))
1405	29702208	This includes oncogenes such as KRAS and MYC as well as the TP53 tumor suppressor.	('tumor', 'Disease', (65, 70))	('tumor suppressor', 'biological_process', 'GO:0051726', ('65', '81'))	('KRAS', 'Var', (32, 36))	('MYC', 'Gene', '4609', (41, 44))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('65', '81'))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('TP53', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('MYC', 'Gene', (41, 44))
1410	29702208	Indeed, dysregulation of autophagy has been implicated in a number of different pathological conditions, including neurodegenerative diseases, inflammation and cancer.	('dysregulation', 'Var', (8, 21))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('neurodegenerative diseases', 'Disease', (115, 141))	('autophagy', 'CPA', (25, 34))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (115, 141))	('cancer', 'Disease', (160, 166))	('autophagy', 'biological_process', 'GO:0016236', ('25', '34'))	('implicated', 'Reg', (44, 54))	('inflammation', 'Disease', 'MESH:D007249', (143, 155))	('inflammation', 'Disease', (143, 155))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (115, 141))	('inflammation', 'biological_process', 'GO:0006954', ('143', '155'))	('autophagy', 'biological_process', 'GO:0006914', ('25', '34'))
1411	29702208	The major function of autophagy is understood to be pro-survival, as has been shown in the initial mouse studies where autophagy genes were deleted embryonically and resulted in death soon after weaning.	('mouse', 'Species', '10090', (99, 104))	('resulted in', 'Reg', (166, 177))	('autophagy genes', 'Gene', (119, 134))	('deleted', 'Var', (140, 147))	('autophagy', 'biological_process', 'GO:0006914', ('119', '128'))	('autophagy', 'biological_process', 'GO:0016236', ('22', '31'))	('autophagy', 'biological_process', 'GO:0006914', ('22', '31'))	('pro-survival', 'biological_process', 'GO:0043066', ('52', '64'))	('autophagy', 'biological_process', 'GO:0016236', ('119', '128'))
1419	29702208	These transcription factors are constitutively activated in PDA in a nutrient-independent manner and conversely, knockdown of MiT/TFE factors impairs PDA lysosomal function and autophagic flux.	('PDA', 'Phenotype', 'HP:0006725', (60, 63))	('autophagic flux', 'CPA', (177, 192))	('transcription', 'biological_process', 'GO:0006351', ('6', '19'))	('PDA', 'Chemical', '-', (150, 153))	('lysosomal function', 'CPA', (154, 172))	('MiT/TFE factors', 'Gene', (126, 141))	('PDA', 'Chemical', '-', (60, 63))	('knockdown', 'Var', (113, 122))	('impairs', 'NegReg', (142, 149))	('PDA', 'Phenotype', 'HP:0006725', (150, 153))
1421	29702208	Utilizing genetically engineered mouse models of cancer harboring mutations or deletions in essential autophagy genes, the function of autophagy in cancer progression and initiation have been studied.	('cancer', 'Disease', (148, 154))	('mutations', 'Var', (66, 75))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('autophagy', 'biological_process', 'GO:0016236', ('135', '144'))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('deletions', 'Var', (79, 88))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('autophagy', 'Gene', (102, 111))	('autophagy', 'biological_process', 'GO:0006914', ('135', '144'))	('autophagy', 'biological_process', 'GO:0016236', ('102', '111'))	('mouse', 'Species', '10090', (33, 38))	('autophagy', 'biological_process', 'GO:0006914', ('102', '111'))	('cancer', 'Disease', (49, 55))
1428	29702208	Expectedly, genetic ablation of autophagy using ATG5 or ATG7 conditional null mouse models results in attenuated growth and progression of KRAS-driven PDA tumors.	('PDA tumors', 'Disease', (151, 161))	('progression', 'CPA', (124, 135))	('attenuated', 'NegReg', (102, 112))	('PDA tumors', 'Disease', 'MESH:D004374', (151, 161))	('PDA', 'Phenotype', 'HP:0006725', (151, 154))	('ATG7', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('ATG5', 'Gene', '11793', (48, 52))	('ATG7', 'Gene', '74244', (56, 60))	('ATG5', 'Gene', (48, 52))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('autophagy', 'biological_process', 'GO:0016236', ('32', '41'))	('autophagy', 'CPA', (32, 41))	('genetic ablation', 'Var', (12, 28))	('mouse', 'Species', '10090', (78, 83))	('autophagy', 'biological_process', 'GO:0006914', ('32', '41'))	('growth', 'CPA', (113, 119))
1473	29702208	Expectedly, silencing of oncogenic Kras expression in tumors markedly diminishes glucose uptake and flux through the glycolytic pathway and associated anabolic branches (described in detail below).	('flux', 'MPA', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('glycolytic pathway', 'Pathway', (117, 135))	('diminishes', 'NegReg', (70, 80))	('glucose uptake', 'MPA', (81, 95))	('anabolic branches', 'MPA', (151, 168))	('silencing', 'Var', (12, 21))	('glucose uptake', 'biological_process', 'GO:0046323', ('81', '95'))	('glucose', 'Chemical', 'MESH:D005947', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('Kras', 'Gene', (35, 39))	('tumors', 'Disease', (54, 60))
1475	29702208	It has been shown that TP53 regulates glycolysis through a variety of mechanisms including transcriptional repression of glucose transporters (e.g.	('glucose', 'Chemical', 'MESH:D005947', (121, 128))	('regulates', 'Reg', (28, 37))	('transcriptional repression', 'Var', (91, 117))	('glycolysis', 'MPA', (38, 48))	('glucose', 'MPA', (121, 128))	('TP53', 'Gene', (23, 27))	('glycolysis', 'biological_process', 'GO:0006096', ('38', '48'))
1496	29702208	Interestingly, it has been shown that oncogenic KRAS in PDA tumors increases glucose carbon flux exclusively through the non-oxidative arm of the PPP.	('PDA tumors', 'Disease', 'MESH:D004374', (56, 66))	('tumors increases glucose', 'Disease', (60, 84))	('KRAS', 'Var', (48, 52))	('PDA tumors', 'Disease', (56, 66))	('tumors increases glucose', 'Disease', 'MESH:D009369', (60, 84))	('PDA', 'Phenotype', 'HP:0006725', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('oncogenic KRAS', 'Var', (38, 52))	('carbon', 'Chemical', 'MESH:D002244', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
1515	29702208	Indeed, it has been shown that ERK reactivation is a major cause of treatment resistance to upstream inhibitors (RAF, MEK) in RAS mutant cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ERK', 'Gene', (31, 34))	('reactivation', 'Var', (35, 47))	('RAS', 'Gene', (126, 129))	('RAF', 'Gene', '22882', (113, 116))	('ERK', 'molecular_function', 'GO:0004707', ('31', '34'))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('MEK', 'Gene', (118, 121))	('cancers', 'Disease', (137, 144))	('treatment', 'MPA', (68, 77))	('ERK', 'Gene', '5594', (31, 34))	('mutant', 'Var', (130, 136))	('RAF', 'Gene', (113, 116))	('MEK', 'Gene', '5609', (118, 121))
1524	29702208	KRAS mutant PDA cells suppress levels of GLUD1 and increase levels of cytosolic aspartate aminotransferase (GOT1), resulting in reprogrammed glutamine metabolism.	('increase', 'PosReg', (51, 59))	('aspartate', 'Chemical', 'MESH:D001224', (80, 89))	('GOT1', 'Gene', (108, 112))	('glutamine', 'Chemical', 'MESH:D005973', (141, 150))	('PDA', 'Chemical', '-', (12, 15))	('PDA', 'Gene', (12, 15))	('reprogrammed', 'Reg', (128, 140))	('GOT1', 'Gene', '2805', (108, 112))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('141', '161'))	('suppress', 'NegReg', (22, 30))	('mutant', 'Var', (5, 11))	('GLUD1', 'Gene', '2746', (41, 46))	('PDA', 'Phenotype', 'HP:0006725', (12, 15))	('GLUD1', 'Gene', (41, 46))
1530	29702208	Indeed perturbation at multiple steps of this pathway (GLS, GOT1, ME1) results in redox imbalance and decreased cellular proliferation.	('redox imbalance', 'MPA', (82, 97))	('ME1', 'Gene', '4199', (66, 69))	('cellular proliferation', 'CPA', (112, 134))	('GOT1', 'Gene', '2805', (60, 64))	('redox imbalance', 'Phenotype', 'HP:0025463', (82, 97))	('GOT1', 'Gene', (60, 64))	('imbalance', 'Phenotype', 'HP:0002172', (88, 97))	('ME1', 'Gene', (66, 69))	('perturbation', 'Var', (7, 19))	('decreased', 'NegReg', (102, 111))
1548	29702208	To this end, human pancreatic ductal epithelial cells (HPNE) transformed with the KRAS oncogene increase lipid uptake from the environment.	('lipid uptake', 'biological_process', 'GO:0140354', ('105', '117'))	('human', 'Species', '9606', (13, 18))	('transformed', 'Var', (61, 72))	('lipid uptake from the environment', 'MPA', (105, 138))	('pancreatic ductal', 'Disease', (19, 36))	('increase lipid', 'Phenotype', 'HP:0003077', (96, 110))	('KRAS', 'Gene', (82, 86))	('pancreatic ductal', 'Disease', 'MESH:D021441', (19, 36))	('increase', 'PosReg', (96, 104))	('lipid', 'Chemical', 'MESH:D008055', (105, 110))
1549	29702208	Additionally, Fatty acid synthase (FASN), a key enzyme in fatty acid synthesis (FAS), is upregulated by EGFR/ERK signaling and inhibition of this enzyme is detrimental to PDA cells.	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('FASN', 'Gene', '2194', (35, 39))	('fatty acid', 'Chemical', 'MESH:D005227', (58, 68))	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('58', '78'))	('FAS', 'Chemical', '-', (80, 83))	('EGFR', 'Gene', (104, 108))	('PDA', 'Chemical', '-', (171, 174))	('Fatty acid synthase', 'Gene', '2194', (14, 33))	('PDA', 'Phenotype', 'HP:0006725', (171, 174))	('upregulated', 'PosReg', (89, 100))	('ERK', 'Gene', '5594', (109, 112))	('inhibition', 'Var', (127, 137))	('FASN', 'Gene', (35, 39))	('FAS', 'Chemical', '-', (35, 38))	('ERK', 'molecular_function', 'GO:0004707', ('109', '112'))	('EGFR', 'Gene', '1956', (104, 108))	('ERK', 'Gene', (109, 112))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))	('Fatty acid synthase', 'Gene', (14, 33))
1569	29702208	The palmitate generated through de novo synthesis has a number of intracellular functions, including regulation of signaling networks in PDA and perturbations at multiple steps (ACC, FASN) attenuates PDA growth.	('perturbations', 'Var', (145, 158))	('PDA', 'Phenotype', 'HP:0006725', (137, 140))	('palmitate', 'Chemical', 'MESH:D010168', (4, 13))	('PDA', 'Disease', (200, 203))	('attenuates', 'NegReg', (189, 199))	('PDA', 'Chemical', '-', (200, 203))	('FASN', 'Gene', (183, 187))	('signaling', 'MPA', (115, 124))	('regulation', 'Reg', (101, 111))	('FASN', 'Gene', '2194', (183, 187))	('PDA', 'Chemical', '-', (137, 140))	('intracellular', 'cellular_component', 'GO:0005622', ('66', '79'))	('synthesis', 'biological_process', 'GO:0009058', ('40', '49'))	('PDA', 'Phenotype', 'HP:0006725', (200, 203))	('regulation of signaling', 'biological_process', 'GO:0023051', ('101', '124'))
1570	29702208	It has been recently reported that high FASN expression correlates with gemcitabine resistance in PDA and combination treatment of Orlistat (FASN inhibitor) and gemcitabine results in a synergistic response.	('PDA', 'Phenotype', 'HP:0006725', (98, 101))	('gemcitabine', 'Chemical', 'MESH:C056507', (161, 172))	('gemcitabine resistance', 'MPA', (72, 94))	('gemcitabine', 'Chemical', 'MESH:C056507', (72, 83))	('PDA', 'Disease', (98, 101))	('PDA', 'Chemical', '-', (98, 101))	('FASN', 'Gene', (141, 145))	('FASN', 'Gene', '2194', (141, 145))	('FASN', 'Gene', (40, 44))	('Orlistat', 'Chemical', 'MESH:D000077403', (131, 139))	('FASN', 'Gene', '2194', (40, 44))	('high', 'Var', (35, 39))
1590	29702208	Through increased pyrimidine biosynthesis imparted by MUC-1/HIF1 crosstalk, PDA tumors develop resistance to gemcitabine.	('pyrimidine biosynthesis', 'MPA', (18, 41))	('PDA tumors', 'Disease', (76, 86))	('PDA tumors', 'Disease', 'MESH:D004374', (76, 86))	('HIF1', 'Gene', (60, 64))	('resistance to gemcitabine', 'MPA', (95, 120))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('develop', 'PosReg', (87, 94))	('gemcitabine', 'Chemical', 'MESH:C056507', (109, 120))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('MUC-1', 'Gene', (54, 59))	('MUC-1', 'Gene', '4582', (54, 59))	('PDA', 'Phenotype', 'HP:0006725', (76, 79))	('increased', 'PosReg', (8, 17))	('pyrimidine', 'Chemical', 'MESH:C030986', (18, 28))	('HIF1', 'Gene', '3091', (60, 64))	('crosstalk', 'Var', (65, 74))	('biosynthesis', 'biological_process', 'GO:0009058', ('29', '41'))
1591	29702208	These results demonstrate another instance where the plasticity of PDA metabolism leads to treatment resistance, yet highlights potential therapeutic targets that may improve clinical outcome.	('PDA', 'Chemical', '-', (67, 70))	('treatment resistance', 'MPA', (91, 111))	('plasticity', 'Var', (53, 63))	('PDA', 'Phenotype', 'HP:0006725', (67, 70))	('metabolism', 'biological_process', 'GO:0008152', ('71', '81'))	('leads to', 'Reg', (82, 90))
1598	29702208	Inactivation of PTEN causes aberrant downstream signaling through PI3K/AKT and activation of pro-survival genes contributing to oncogenesis.	('AKT', 'Gene', '207', (71, 74))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('pro-survival', 'Gene', (93, 105))	('PI3K', 'molecular_function', 'GO:0016303', ('66', '70'))	('PTEN', 'Gene', (16, 20))	('oncogenesis', 'biological_process', 'GO:0007048', ('128', '139'))	('pro-survival', 'biological_process', 'GO:0043066', ('93', '105'))	('PTEN', 'Gene', '5728', (16, 20))	('activation', 'PosReg', (79, 89))	('AKT', 'Gene', (71, 74))	('downstream signaling', 'MPA', (37, 57))	('Inactivation', 'Var', (0, 12))
1607	29702208	Another mechanism in PDA to counteract excessive ROS accumulation is through upregulation of the transcription factor NRF2 by oncogenic KRAS.	('excessive ROS accumulation', 'Phenotype', 'HP:0025464', (39, 65))	('PDA', 'Phenotype', 'HP:0006725', (21, 24))	('ROS', 'Chemical', 'MESH:D017382', (49, 52))	('transcription factor', 'molecular_function', 'GO:0000981', ('97', '117'))	('oncogenic KRAS', 'Var', (126, 140))	('NRF2', 'Gene', (118, 122))	('PDA', 'Disease', (21, 24))	('upregulation', 'PosReg', (77, 89))	('PDA', 'Chemical', '-', (21, 24))	('transcription', 'biological_process', 'GO:0006351', ('97', '110'))
1609	29702208	Indeed, it has been shown that NRF2 plays a role in oncogenesis of KRAS mutant PDA tumors and deletion results in significantly decreased tumors in KPC mice.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('deletion', 'Var', (94, 102))	('decreased tumors', 'Disease', 'MESH:D009369', (128, 144))	('mutant', 'Var', (72, 78))	('NRF2', 'Gene', (31, 35))	('PDA', 'Phenotype', 'HP:0006725', (79, 82))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('KRAS', 'Gene', (67, 71))	('decreased tumors', 'Disease', (128, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('mice', 'Species', '10090', (152, 156))	('oncogenesis', 'biological_process', 'GO:0007048', ('52', '63'))	('PDA tumors', 'Disease', 'MESH:D004374', (79, 89))	('PDA tumors', 'Disease', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
1611	29702208	The loss of NRF2 in PDA in vitro and in vivo leads to the oxidation of proteins involved in mRNA translation resulting in decreased tumor growth.	('decreased tumor', 'Disease', (122, 137))	('mRNA translation', 'MPA', (92, 108))	('PDA', 'Chemical', '-', (20, 23))	('PDA', 'Phenotype', 'HP:0006725', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('translation', 'biological_process', 'GO:0006412', ('97', '108'))	('NRF2', 'Gene', (12, 16))	('proteins', 'Protein', (71, 79))	('oxidation of', 'MPA', (58, 70))	('decreased tumor', 'Disease', 'MESH:D009369', (122, 137))	('loss', 'Var', (4, 8))
1629	29993037	Silencing of MUC20 suppresses the malignant character of pancreatic ductal adenocarcinoma cells through inhibition of the HGF/MET pathway Mucins are heavily glycosylated proteins that play critical roles in the pathogenesis of tumour malignancies.	('inhibition', 'NegReg', (104, 114))	('MUC20', 'Gene', '200958', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('HGF', 'Gene', (122, 125))	('tumour', 'Phenotype', 'HP:0002664', (227, 233))	('suppresses', 'NegReg', (19, 29))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (57, 89))	('HGF', 'Gene', '3082', (122, 125))	('pancreatic ductal adenocarcinoma', 'Disease', (57, 89))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (57, 89))	('tumour malignancies', 'Disease', 'MESH:D009369', (227, 246))	('tumour malignancies', 'Disease', (227, 246))	('pathogenesis', 'biological_process', 'GO:0009405', ('211', '223'))	('MUC20', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))
1634	29993037	In this study, immunohistochemical staining demonstrated that high MUC20 expression correlated with poor progression-free survival and high local recurrence rate of PDAC patients (n = 61).	('patients', 'Species', '9606', (170, 178))	('PDAC', 'Chemical', '-', (165, 169))	('local recurrence', 'CPA', (140, 156))	('MUC20', 'Gene', (67, 72))	('expression', 'MPA', (73, 83))	('PDAC', 'Disease', (165, 169))	('PDAC', 'Phenotype', 'HP:0006725', (165, 169))	('progression-free survival', 'CPA', (105, 130))	('poor', 'NegReg', (100, 104))	('high', 'Var', (62, 66))
1637	29993037	In intraperitoneal, subcutaneous, and orthotopic injection models, MUC20 knockdown decreased tumour growth in immunodeficient mice.	('mice', 'Species', '10090', (126, 130))	('decreased', 'NegReg', (83, 92))	('tumour growth in immunodeficient', 'Disease', (93, 125))	('MUC20', 'Gene', (67, 72))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour growth in immunodeficient', 'Disease', 'MESH:D006130', (93, 125))	('knockdown', 'Var', (73, 82))
1638	29993037	Phospho-RTK array and western blot analysis indicated that MUC20 knockdown decreased HGF-mediated phosphorylation of MET in PDAC cells.	('phosphorylation', 'biological_process', 'GO:0016310', ('98', '113'))	('HGF', 'Gene', (85, 88))	('PDAC', 'Chemical', '-', (124, 128))	('HGF', 'Gene', '3082', (85, 88))	('knockdown', 'Var', (65, 74))	('MUC20', 'Gene', (59, 64))	('PDAC', 'Phenotype', 'HP:0006725', (124, 128))	('decreased', 'NegReg', (75, 84))
1639	29993037	Moreover, HGF-induced malignant phenotypes could be suppressed by MUC20 knockdown.	('HGF', 'Gene', (10, 13))	('HGF', 'Gene', '3082', (10, 13))	('suppressed', 'NegReg', (52, 62))	('knockdown', 'Var', (72, 81))	('MUC20', 'Gene', (66, 71))
1640	29993037	These findings suggest that MUC20 knockdown suppresses the malignant phenotypes of PDAC cells at least partially through the inhibition of the HGF/MET pathway and that MUC20 could act as a potential therapeutic target.	('malignant phenotypes of', 'CPA', (59, 82))	('PDAC', 'Chemical', '-', (83, 87))	('suppresses', 'NegReg', (44, 54))	('HGF', 'Gene', (143, 146))	('HGF', 'Gene', '3082', (143, 146))	('PDAC', 'Phenotype', 'HP:0006725', (83, 87))	('knockdown', 'Var', (34, 43))	('MUC20', 'Gene', (28, 33))	('inhibition', 'NegReg', (125, 135))
1673	29993037	MUC20 knockdown significantly suppressed viability in both HPAC and HPAF-II cells (Fig.	('suppressed', 'NegReg', (30, 40))	('viability', 'CPA', (41, 50))	('MUC20', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('HPAF-II', 'CellLine', 'CVCL:0313', (68, 75))
1674	29993037	These results suggest that MUC20 knockdown inhibits 10% FBS-induced viability, but not migration and invasion, in PDAC cells.	('FBS-induced', 'Protein', (56, 67))	('PDAC', 'Phenotype', 'HP:0006725', (114, 118))	('knockdown', 'Var', (33, 42))	('PDAC', 'Chemical', '-', (114, 118))	('inhibits', 'NegReg', (43, 51))	('MUC20', 'Gene', (27, 32))
1678	29993037	MUC20 knockdown tumours were smaller and weighed less than control tumours for both HPAC (P = 0.0244) and HPAF-II cells (P = 0.0233) (Fig.	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('tumours', 'Disease', (16, 23))	('weighed', 'CPA', (41, 48))	('tumours', 'Disease', (67, 74))	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('MUC20', 'Gene', (0, 5))	('HPAF-II', 'CellLine', 'CVCL:0313', (106, 113))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('knockdown', 'Var', (6, 15))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('less', 'NegReg', (49, 53))
1679	29993037	In the subcutaneous injection model, MUC20 knockdown decreased the sizes and weights of HPAF-II tumour cells compared with the control group in NOD/SCID mice (P = 0.0082, Fig.	('knockdown', 'Var', (43, 52))	('SCID', 'Disease', (148, 152))	('MUC20', 'Gene', (37, 42))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('HPAF-II tumour', 'Disease', (88, 102))	('SCID', 'Disease', 'MESH:D053632', (148, 152))	('mice', 'Species', '10090', (153, 157))	('decreased', 'NegReg', (53, 62))	('HPAF-II tumour', 'Disease', 'MESH:D009369', (88, 102))
1680	29993037	Moreover, MUC20 knockdown decreased tumour formation after four weeks of orthotopic injection with HPAF-II cells in NOD/SCID mice.	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('SCID', 'Disease', 'MESH:D053632', (120, 124))	('SCID', 'Disease', (120, 124))	('knockdown', 'Var', (16, 25))	('mice', 'Species', '10090', (125, 129))	('formation', 'biological_process', 'GO:0009058', ('43', '52'))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('HPAF-II', 'CellLine', 'CVCL:0313', (99, 106))	('decreased', 'NegReg', (26, 35))	('MUC20', 'Gene', (10, 15))
1682	29993037	These findings suggest that MUC20 knockdown inhibits PDAC tumour growth in immunodeficient mice.	('mice', 'Species', '10090', (91, 95))	('tumour growth in immunodeficient', 'Disease', (58, 90))	('inhibits', 'NegReg', (44, 52))	('PDAC', 'Phenotype', 'HP:0006725', (53, 57))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('PDAC', 'Disease', (53, 57))	('tumour growth in immunodeficient', 'Disease', 'MESH:D006130', (58, 90))	('knockdown', 'Var', (34, 43))	('MUC20', 'Gene', (28, 33))	('PDAC', 'Chemical', '-', (53, 57))
1689	29993037	Inhibition of p-JNK activity using SP600125 could suppress MUC20 expression induced by serum deprivation (Supplementary Fig.	('SP600125', 'Var', (35, 43))	('MUC20', 'Protein', (59, 64))	('JNK', 'Gene', (16, 19))	('suppress', 'NegReg', (50, 58))	('JNK', 'Gene', '5599', (16, 19))	('JNK', 'molecular_function', 'GO:0004705', ('16', '19'))	('SP600125', 'Chemical', 'MESH:C432165', (35, 43))
1696	29993037	MUC20 knockdown significantly decreased migration and invasion induced by PSC co-culture in both HPAC and HPAF-II cells (Fig.	('knockdown', 'Var', (6, 15))	('MUC20', 'Gene', (0, 5))	('HPAF-II', 'CellLine', 'CVCL:0313', (106, 113))	('decreased', 'NegReg', (30, 39))
1698	29993037	MUC20 knockdown significantly suppressed migration and invasion induced by the PSC-conditioned medium in both HPAC and HPAF-II cells (Fig.	('suppressed', 'NegReg', (30, 40))	('MUC20', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('HPAF-II', 'CellLine', 'CVCL:0313', (119, 126))
1699	29993037	These results suggest that MUC20 knockdown inhibits migration and invasion of PDAC cells during PSC co-culture or in PSC-conditioned medium.	('migration', 'CPA', (52, 61))	('PDAC', 'Phenotype', 'HP:0006725', (78, 82))	('knockdown', 'Var', (33, 42))	('PDAC', 'Chemical', '-', (78, 82))	('inhibits', 'NegReg', (43, 51))	('MUC20', 'Gene', (27, 32))
1701	29993037	Results from a human phospho-RTK array showed that MUC20 knockdown decreased phospho-MET levels in HPAF-II cells induced by the PSC-conditioned medium (Fig.	('MUC20', 'Gene', (51, 56))	('knockdown', 'Var', (57, 66))	('phospho-MET levels', 'MPA', (77, 95))	('human', 'Species', '9606', (15, 20))	('decreased', 'NegReg', (67, 76))	('HPAF-II', 'CellLine', 'CVCL:0313', (99, 106))
1704	29993037	Western blotting results showed that MUC20 knockdown inhibited HGF-triggered phosphorylation of MET and AKT in HPAC and HPAF-II cells (Fig.	('phosphorylation', 'MPA', (77, 92))	('inhibited', 'NegReg', (53, 62))	('AKT', 'Gene', (104, 107))	('HGF', 'Gene', (63, 66))	('knockdown', 'Var', (43, 52))	('MUC20', 'Gene', (37, 42))	('AKT', 'Gene', '207', (104, 107))	('HGF', 'Gene', '3082', (63, 66))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('MET', 'MPA', (96, 99))	('HPAF-II', 'CellLine', 'CVCL:0313', (120, 127))
1705	29993037	However, ERK and NF-kB activities were not affected by MUC20 knockdown (Supplementary Fig.	('ERK', 'molecular_function', 'GO:0004707', ('9', '12'))	('ERK', 'Gene', '5594', (9, 12))	('NF-kB', 'CPA', (17, 22))	('MUC20', 'Gene', (55, 60))	('ERK', 'Gene', (9, 12))	('knockdown', 'Var', (61, 70))
1708	29993037	The Transwell migration assay and Matrigel invasion assay revealed that MUC20 knockdown decreased HGF-induced cell migration and invasion (Fig.	('HGF', 'Gene', (98, 101))	('knockdown', 'Var', (78, 87))	('invasion', 'CPA', (129, 137))	('HGF', 'Gene', '3082', (98, 101))	('cell migration', 'biological_process', 'GO:0016477', ('110', '124'))	('decreased', 'NegReg', (88, 97))	('MUC20', 'Gene', (72, 77))
1711	29993037	MTT assays showed that MUC20-mediated cell viability was significantly inhibited by PHA665757, but was enhanced by HGF (Fig.	('inhibited', 'NegReg', (71, 80))	('PHA665757', 'Var', (84, 93))	('enhanced', 'PosReg', (103, 111))	('HGF', 'Gene', (115, 118))	('MTT', 'Chemical', '-', (0, 3))	('HGF', 'Gene', '3082', (115, 118))	('MUC20-mediated cell viability', 'CPA', (23, 52))
1714	29993037	Taken together, these results suggest that MUC20 enhances the HGF/MET signalling pathway in PDAC cells.	('signalling pathway', 'biological_process', 'GO:0007165', ('70', '88'))	('MUC20', 'Var', (43, 48))	('PDAC', 'Phenotype', 'HP:0006725', (92, 96))	('HGF', 'Gene', (62, 65))	('HGF', 'Gene', '3082', (62, 65))	('PDAC', 'Chemical', '-', (92, 96))	('enhances', 'PosReg', (49, 57))
1715	29993037	MUC20 physically interacted with MET, and MUC20 knockdown decreased the association of MET with MUC20 in HPAC and HPAF-II cells (Fig.	('MUC20', 'Gene', (96, 101))	('association', 'Interaction', (72, 83))	('decreased', 'NegReg', (58, 67))	('HPAF-II', 'CellLine', 'CVCL:0313', (114, 121))	('MUC20', 'Gene', (42, 47))	('knockdown', 'Var', (48, 57))
1718	29993037	Interestingly, the results of the co-immunoprecipitation assay indicated that both wild-type and truncated MUC20 interacted with MET in HPAC and HPAF-II cells (Fig.	('interacted', 'Interaction', (113, 123))	('HPAF-II', 'CellLine', 'CVCL:0313', (145, 152))	('MUC20', 'Gene', (107, 112))	('truncated', 'Var', (97, 106))
1728	29993037	Furthermore, MUC20 knockdown inhibits tumour cell growth both in vitro and in vivo.	('knockdown', 'Var', (19, 28))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('inhibits', 'NegReg', (29, 37))	('MUC20', 'Gene', (13, 18))	('tumour', 'Disease', (38, 44))	('cell growth', 'biological_process', 'GO:0016049', ('45', '56'))
1732	29993037	In this study, MUC20 knockdown decreased migration and invasion of PDAC cells induced by PSCs and PSC-conditioned medium.	('PDAC', 'Phenotype', 'HP:0006725', (67, 71))	('MUC20', 'Gene', (15, 20))	('decreased', 'NegReg', (31, 40))	('PDAC', 'Chemical', '-', (67, 71))	('knockdown', 'Var', (21, 30))
1733	29993037	These findings suggest that MUC20 enhances PDAC malignant behaviours by modulating factors secreted by PSCs.	('PDAC', 'Disease', (43, 47))	('PDAC', 'Phenotype', 'HP:0006725', (43, 47))	('modulating', 'Reg', (72, 82))	('enhances', 'PosReg', (34, 42))	('MUC20', 'Var', (28, 33))	('PDAC', 'Chemical', '-', (43, 47))
1736	29993037	In this study, MUC20 knockdown inhibited the phospho-MET activity triggered by PSC-conditioned medium and recombinant HGF in PDAC cells.	('MUC20', 'Gene', (15, 20))	('phospho-MET activity', 'MPA', (45, 65))	('PDAC', 'Chemical', '-', (125, 129))	('HGF', 'Gene', (118, 121))	('inhibited', 'NegReg', (31, 40))	('knockdown', 'Var', (21, 30))	('PDAC', 'Phenotype', 'HP:0006725', (125, 129))	('HGF', 'Gene', '3082', (118, 121))
1737	29993037	Additionally, MUC20-increased cell viability was inhibited by a MET inhibitor, but was increased by HGF.	('HGF', 'Gene', (100, 103))	('MUC20-increased', 'Var', (14, 29))	('HGF', 'Gene', '3082', (100, 103))	('MET inhibitor', 'MPA', (64, 77))	('inhibited', 'NegReg', (49, 58))	('cell viability', 'CPA', (30, 44))
1738	29993037	These data support the view that MUC20 can enhance the malignant behaviours at least partly through the HGF/MET signalling pathway in PDAC cells.	('PDAC', 'Chemical', '-', (134, 138))	('malignant behaviours', 'CPA', (55, 75))	('HGF', 'Gene', (104, 107))	('PDAC', 'Phenotype', 'HP:0006725', (134, 138))	('signalling pathway', 'biological_process', 'GO:0007165', ('112', '130'))	('HGF', 'Gene', '3082', (104, 107))	('enhance', 'PosReg', (43, 50))	('MUC20', 'Var', (33, 38))
1742	29993037	This study indicates that MUC20 enhances the HGF-induced phosphorylation of MET and AKT in PDAC cells.	('enhances', 'PosReg', (32, 40))	('PDAC', 'Chemical', '-', (91, 95))	('AKT', 'Gene', '207', (84, 87))	('MUC20', 'Var', (26, 31))	('HGF', 'Gene', (45, 48))	('PDAC', 'Phenotype', 'HP:0006725', (91, 95))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('AKT', 'Gene', (84, 87))	('HGF', 'Gene', '3082', (45, 48))	('phosphorylation', 'MPA', (57, 72))	('MET', 'Pathway', (76, 79))
1743	29993037	found that MUC20 suppresses HGF-induced Grb2/p-ERK, but not p-MET/p-AKT activity, in primary normal renal cells.	('p-ERK', 'Gene', '9451', (45, 50))	('p-ERK', 'Gene', (45, 50))	('HGF', 'Gene', (28, 31))	('suppresses', 'NegReg', (17, 27))	('AKT', 'Gene', '207', (68, 71))	('MUC20', 'Var', (11, 16))	('Grb2', 'Gene', (40, 44))	('HGF', 'Gene', '3082', (28, 31))	('ERK', 'molecular_function', 'GO:0004707', ('47', '50'))	('AKT', 'Gene', (68, 71))	('Grb2', 'Gene', '2885', (40, 44))
1744	29993037	Unexpectedly, we found that the truncated MUC20 still interacted with MET in PDAC cells without a loss of binding activity.	('binding', 'molecular_function', 'GO:0005488', ('106', '113'))	('PDAC', 'Chemical', '-', (77, 81))	('PDAC', 'Phenotype', 'HP:0006725', (77, 81))	('interacted', 'Interaction', (54, 64))	('truncated', 'Var', (32, 41))	('MUC20', 'Gene', (42, 47))
1747	29993037	MUC20 knockdown decreases PDAC tumour growth in immunodeficient mouse models.	('tumour growth in immunodeficient', 'Disease', (31, 63))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('PDAC', 'Disease', (26, 30))	('PDAC', 'Phenotype', 'HP:0006725', (26, 30))	('tumour growth in immunodeficient', 'Disease', 'MESH:D006130', (31, 63))	('MUC20', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('decreases', 'NegReg', (16, 25))	('mouse', 'Species', '10090', (64, 69))	('PDAC', 'Chemical', '-', (26, 30))
1748	29993037	Furthermore, PSC-mediated malignant phenotypes are inhibited by MUC20 knockdown in PDAC cells through the HGF/MET signalling pathway.	('knockdown', 'Var', (70, 79))	('PDAC', 'Chemical', '-', (83, 87))	('HGF', 'Gene', (106, 109))	('PSC-mediated', 'Disease', (13, 25))	('HGF', 'Gene', '3082', (106, 109))	('PDAC', 'Phenotype', 'HP:0006725', (83, 87))	('inhibited', 'NegReg', (51, 60))	('MUC20', 'Gene', (64, 69))	('signalling pathway', 'biological_process', 'GO:0007165', ('114', '132'))
1749	29993037	Our results suggest that MUC20 physically interacts with MET and enhances HGF-mediated phosphorylation of MET and AKT, thereby promoting malignant phenotypes of PDAC cells (Fig.	('MET', 'Protein', (106, 109))	('AKT', 'Gene', '207', (114, 117))	('PDAC', 'Chemical', '-', (161, 165))	('promoting', 'PosReg', (127, 136))	('HGF', 'Gene', '3082', (74, 77))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))	('AKT', 'Gene', (114, 117))	('interacts', 'Interaction', (42, 51))	('PDAC', 'Disease', (161, 165))	('PDAC', 'Phenotype', 'HP:0006725', (161, 165))	('malignant phenotypes', 'CPA', (137, 157))	('enhances', 'PosReg', (65, 73))	('MUC20', 'Var', (25, 30))	('HGF', 'Gene', (74, 77))
1761	29993037	For stable MUC20 knockdown and its control cells, sh-MUC20/pLKO.1 plasmid and pLKO.1 vector (RNAi Core, Academia Sinica, Taiwan) were used in lentivirus-based infection system, respectively, and selected with 2 mug/ml puromycin (Sigma.	('MUC20', 'Gene', (11, 16))	('mug', 'molecular_function', 'GO:0043739', ('211', '214'))	('RNAi', 'biological_process', 'GO:0016246', ('93', '97'))	('infection system', 'Disease', (159, 175))	('puromycin', 'Chemical', 'MESH:D011691', (218, 227))	('Academia Sinica', 'Disease', 'None', (104, 119))	('knockdown', 'Var', (17, 26))	('infection system', 'Disease', 'MESH:D034721', (159, 175))	('Academia Sinica', 'Disease', (104, 119))
1766	29993037	Antibodies against MET (GTX100637), AKT (GTX121937), NFkappaB (GTX102090), and p-NFkappaB (GTX50098) were purchased from GeneTex Inc. (Irvine, CA, USA).	('GTX121937', 'Var', (41, 50))	('NFkappaB', 'Gene', '4790', (53, 61))	('NFkappaB', 'Gene', (53, 61))	('NFkappaB', 'Gene', (81, 89))	('AKT', 'Gene', '207', (36, 39))	('NFkappaB', 'Gene', '4790', (81, 89))	('GTX100637', 'Var', (24, 33))	('AKT', 'Gene', (36, 39))	('GTX102090', 'Var', (63, 72))
1767	29993037	Antibodies for immunoprecipitation of MET (#8198) and for MET pY1234/5 (#3077), p-AKT (#4060), ERK (#9102), and p-ERK (#9101) were purchased from Cell Signaling Technology, Inc. (Danvers, MA, USA).	('Signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('ERK', 'Gene', '5594', (95, 98))	('ERK', 'Gene', (114, 117))	('ERK', 'Gene', (95, 98))	('#3077', 'Var', (72, 77))	('#4060', 'Var', (87, 92))	('ERK', 'molecular_function', 'GO:0004707', ('114', '117'))	('AKT', 'Gene', '207', (82, 85))	('ERK', 'molecular_function', 'GO:0004707', ('95', '98'))	('pY1234/5', 'Var', (62, 70))	('p-ERK', 'Gene', '9451', (112, 117))	('p-ERK', 'Gene', (112, 117))	('ERK', 'Gene', '5594', (114, 117))	('#9102', 'Var', (100, 105))	('AKT', 'Gene', (82, 85))	('#8198', 'Var', (43, 48))
1769	29993037	PHA665752, MET inhibitor, was purchased from Tocris Bioscience (Bristol, UK).	('PHA665752', 'Var', (0, 9))	('Tocris Bioscience', 'Disease', 'None', (45, 62))	('Tocris Bioscience', 'Disease', (45, 62))
1770	29993037	SP600125, JNK inhibitor, was purchased from Selleckchem (Houston, TX, USA).	('JNK', 'Gene', '5599', (10, 13))	('JNK', 'Gene', (10, 13))	('SP600125', 'Var', (0, 8))	('SP600125', 'Chemical', 'MESH:C432165', (0, 8))	('JNK', 'molecular_function', 'GO:0004705', ('10', '13'))
1792	30271576	Here, we discuss recent studies on how changes in cell adhesion, EMT, and the acquisition of stem cell properties can promote invasive cancer development.	('EMT', 'CPA', (65, 68))	('stem cell properties', 'CPA', (93, 113))	('cell adhesion', 'biological_process', 'GO:0007155', ('50', '63'))	('changes', 'Var', (39, 46))	('invasive cancer', 'Disease', (126, 141))	('cell adhesion', 'CPA', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('EMT', 'biological_process', 'GO:0001837', ('65', '68'))	('invasive cancer', 'Disease', 'MESH:D009362', (126, 141))	('promote', 'PosReg', (118, 125))
1812	30271576	In a study with human breast cancer cells, CTC clusters were shown to be more metastatic than single CTCs .	('CTC clusters', 'Var', (43, 55))	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('more', 'PosReg', (73, 77))	('human', 'Species', '9606', (16, 21))	('metastatic', 'CPA', (78, 88))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
1815	30271576	Interestingly, breast cancer cells expressing plakoglobin that are shed into the circulation as multicellular clusters were more metastatic than plakoglobin-deficient single cells .	('plakoglobin', 'Var', (46, 57))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('more', 'PosReg', (124, 128))	('metastatic', 'CPA', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (15, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
1820	30271576	Moreover, in a set of mammary tumor cell lines, the loss of E-cadherin was shown to induce stem cell-like behavior (enrichment in CD44 high/CD24 low stem-like cells and ability to form mammospheres) .	('loss', 'Var', (52, 56))	('stem cell-like behavior', 'CPA', (91, 114))	('CD44', 'Gene', '960', (130, 134))	('cadherin', 'molecular_function', 'GO:0008014', ('62', '70'))	('CD44', 'Gene', (130, 134))	('CD24', 'Gene', '100133941', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('E-cadherin', 'Protein', (60, 70))	('CD24', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('induce', 'PosReg', (84, 90))	('tumor', 'Disease', (30, 35))
1827	30271576	For example, loss of the EMT-TF Prrx1 in breast cancer cells induces MET and leads to the establishment of a CSC niche and was required for metastasis .	('induces', 'PosReg', (61, 68))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('Prrx1', 'Gene', (32, 37))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('loss', 'Var', (13, 17))	('MET', 'MPA', (69, 72))	('Prrx1', 'Gene', '5396', (32, 37))	('EMT', 'biological_process', 'GO:0001837', ('25', '28'))	('leads to', 'Reg', (77, 85))
1828	30271576	In squamous cell carcinoma (SCC), a Twist-1-mediated EMT was necessary in primary tumor cells for local invasion and the intravasation of tumor cells into the circulation, but the silencing of Twist-1 and the re-acquisition of E-cadherin were necessary for extravasation and colonization in the distant tissue .	('EMT', 'biological_process', 'GO:0001837', ('53', '56'))	('Twist-1', 'Gene', (36, 43))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('Twist-1', 'Gene', (193, 200))	('cadherin', 'molecular_function', 'GO:0008014', ('229', '237'))	('tumor', 'Disease', (138, 143))	('silencing', 'Var', (180, 189))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('SCC', 'Phenotype', 'HP:0002860', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Twist-1', 'Gene', '7291', (193, 200))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (82, 87))	('Twist-1', 'Gene', '7291', (36, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('squamous cell carcinoma', 'Disease', (3, 26))
1834	30271576	Twist-1 levels in skin cancer cells determine the extent of their invasiveness, but both low Twist-1 (low E-cadherin, benign papilloma) and high Twist-1 (no E-cadherin, malignant tumor) cells showed stem cell-like behavior, indicating that stemness traits in cancer cells do not require a complete loss of the epithelial phenotype .	('benign papilloma', 'Disease', (118, 134))	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('low', 'NegReg', (89, 92))	('stem cell-like behavior', 'CPA', (199, 222))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('Twist-1', 'Gene', (145, 152))	('cadherin', 'molecular_function', 'GO:0008014', ('108', '116'))	('papilloma', 'Phenotype', 'HP:0012740', (125, 134))	('Twist-1', 'Gene', '7291', (0, 7))	('skin cancer', 'Disease', (18, 29))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cancer', 'Disease', (259, 265))	('tumor', 'Disease', (179, 184))	('high', 'Var', (140, 144))	('cancer', 'Disease', (23, 29))	('Twist-1', 'Gene', (0, 7))	('skin cancer', 'Phenotype', 'HP:0008069', (18, 29))	('Twist-1', 'Gene', '7291', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('Twist-1', 'Gene', '7291', (145, 152))	('benign papilloma', 'Disease', 'MESH:D010212', (118, 134))	('Twist-1', 'Gene', (93, 100))	('cadherin', 'molecular_function', 'GO:0008014', ('159', '167'))	('skin cancer', 'Disease', 'MESH:D012878', (18, 29))
1858	30271576	In CRC cells, the L1-mediated increase in beta-catenin-TCF transactivation results in increased ASCL2, a TF that determines intestinal stem cell fate by regulating various stemness-associated genes .	('beta-catenin', 'Gene', (42, 54))	('ASCL2', 'Gene', (96, 101))	('increased', 'PosReg', (86, 95))	('TCF', 'Gene', (55, 58))	('TCF', 'Gene', '3172', (55, 58))	('beta-catenin', 'Gene', '1499', (42, 54))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('L1', 'Gene', '3897', (18, 20))	('transactivation', 'biological_process', 'GO:2000144', ('59', '74'))	('transactivation', 'Var', (59, 74))	('ASCL2', 'Gene', '430', (96, 101))	('increase', 'PosReg', (30, 38))
1859	30271576	The induction of ASCL2 and NF-kappaB activation by L1 are examples of the means by which changes in cell adhesion during tumorigenesis can induce stemness traits in cancer cells.	('ASCL2', 'Gene', (17, 22))	('L1', 'Gene', '3897', (51, 53))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('27', '47'))	('changes', 'Var', (89, 96))	('tumor', 'Disease', (121, 126))	('NF-kappaB', 'Gene', '4790', (27, 36))	('ASCL2', 'Gene', '430', (17, 22))	('induce', 'Reg', (139, 145))	('cancer', 'Disease', (165, 171))	('stemness traits', 'CPA', (146, 161))	('NF-kappaB', 'Gene', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cell adhesion', 'biological_process', 'GO:0007155', ('100', '113'))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
1862	30271576	For example, the knockdown of integrin alpha6 in glioblastoma cells severely affects a stem cell subpopulation, inhibiting its self-renewal, proliferation, and tumor formation .	('affects', 'Reg', (77, 84))	('integrin alpha6', 'Gene', '3655', (30, 45))	('self-renewal', 'CPA', (127, 139))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('glioblastoma', 'Disease', (49, 61))	('proliferation', 'CPA', (141, 154))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('formation', 'biological_process', 'GO:0009058', ('166', '175'))	('integrin alpha6', 'Gene', (30, 45))	('knockdown', 'Var', (17, 26))	('glioblastoma', 'Disease', 'MESH:D005909', (49, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))	('tumor', 'Disease', (160, 165))	('inhibiting', 'NegReg', (112, 122))
1863	30271576	The expression of integrin beta3 induces various CSC subpopulations in breast, lung, and pancreatic cancer , .	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('lung', 'Disease', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('pancreatic cancer', 'Disease', (89, 106))	('integrin beta3', 'Gene', (18, 32))	('integrin beta3', 'Gene', '3690', (18, 32))	('breast', 'Disease', (71, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('expression', 'Var', (4, 14))	('induces', 'Reg', (33, 40))	('CSC', 'MPA', (49, 52))
1955	29599680	The skin presents lipid disorders (such as lower content of fatty acids: linoleic and linolenic acids), which disrupts the integrity of the dermo-epidermal barrier.	('linolenic acids', 'Var', (86, 101))	('lipid', 'Chemical', 'MESH:D008055', (18, 23))	('lower content of fatty acids', 'Phenotype', 'HP:0040299', (43, 71))	('integrity of the dermo-epidermal barrier', 'CPA', (123, 163))	('disrupts', 'NegReg', (110, 118))	('lipid disorders', 'Disease', (18, 33))	('fatty acids', 'Chemical', 'MESH:D005227', (60, 71))	('linoleic', 'Chemical', '-', (73, 81))	('linolenic acids', 'Chemical', 'MESH:D008042', (86, 101))	('lower', 'NegReg', (43, 48))
1978	29137308	Restoration of ESRP1 rescued the effect of miR-23a on pancreatic cancer cell progression.	('effect', 'MPA', (33, 39))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (54, 71))	('Restoration', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('miR-23a', 'Gene', (43, 50))	('ESRP1', 'Gene', '54845', (15, 20))	('pancreatic cancer', 'Disease', (54, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (54, 71))	('ESRP1', 'Gene', (15, 20))
1981	29137308	In addition, the effect of miR-23a up-regulation was partly reversed by ESRP1 over-expression.	('up-regulation', 'PosReg', (35, 48))	('ESRP1', 'Gene', '54845', (72, 77))	('regulation', 'biological_process', 'GO:0065007', ('38', '48'))	('ESRP1', 'Gene', (72, 77))	('over-expression', 'Var', (78, 93))	('expression', 'Species', '29278', (83, 93))	('miR-23a', 'Gene', (27, 34))
2021	29137308	Compared with the inhibitor NC group, Panc-1 cells transfected with miR-23a inhibitors began to adopt an epithelia-like morphology (Figure 4C), associated with increased E-cadherin expression and reduced N-cadherin and Vimentin expression (Figure 4D).	('Panc-1', 'CellLine', 'CVCL:0480', (38, 44))	('epithelia', 'Disease', (105, 114))	('expression', 'Species', '29278', (228, 238))	('Vimentin', 'cellular_component', 'GO:0045098', ('219', '227'))	('expression', 'MPA', (181, 191))	('Vimentin', 'Gene', '7431', (219, 227))	('E-cadherin', 'Gene', (170, 180))	('increased', 'PosReg', (160, 169))	('E-cadherin', 'Gene', '999', (170, 180))	('inhibitors', 'Var', (76, 86))	('Vimentin', 'Gene', (219, 227))	('reduced', 'NegReg', (196, 203))	('cadherin', 'molecular_function', 'GO:0008014', ('206', '214'))	('Vimentin', 'cellular_component', 'GO:0045099', ('219', '227'))	('epithelia', 'Disease', 'None', (105, 114))	('miR-23a', 'Gene', (68, 75))	('N-cadherin', 'Gene', (204, 214))	('cadherin', 'molecular_function', 'GO:0008014', ('172', '180'))	('N-cadherin', 'Gene', '1000', (204, 214))	('expression', 'Species', '29278', (181, 191))
2025	29137308	To confirm the effect of miR-23a on metastasis in vivo, we established stable Aspc-1 cell line overexpressing miR-23a (miR-23a up) and stable Panc-1 cell line inhibiting miR-23a (miR-23a down).	('miR-23a', 'Var', (110, 117))	('Panc-1', 'CellLine', 'CVCL:0480', (142, 148))	('inhibiting', 'NegReg', (159, 169))
2028	29137308	As shown in Figure 5C, the diameters of the primary splenic tumours in the miR-23a over-expression group mice were significantly increased compared with that in con group mice (Figure 5C; 1.88+-0.48 vs. 0.90+-0.27, P<0.01), and the number of mice with liver metastases in the miR-23a over-expression group was also significantly increased compared with that in con group (Figure 5C; 9/10 vs. 4/10, P<0.05).	('liver metastases', 'Disease', 'MESH:D009362', (252, 268))	('mice', 'Species', '10090', (171, 175))	('miR-23a', 'Gene', (75, 82))	('miR-23a', 'Var', (276, 283))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))	('over-expression', 'PosReg', (83, 98))	('increased', 'PosReg', (129, 138))	('diameters', 'CPA', (27, 36))	('expression', 'Species', '29278', (289, 299))	('expression', 'Species', '29278', (88, 98))	('liver metastases', 'Disease', (252, 268))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('primary splenic tumours', 'Disease', (44, 67))	('increased', 'PosReg', (329, 338))	('mice', 'Species', '10090', (105, 109))	('mice', 'Species', '10090', (242, 246))	('primary splenic tumours', 'Disease', 'MESH:D013160', (44, 67))
2029	29137308	However, the diameters of the primary splenic tumours in the miR-23a down-regulation group mice were significantly decreased compared with that in NC group mice (Figure 5D; 0.64+-0.29 vs. 1.52+-0.26, P<0.01), and the number of mice with liver metastases in the miR-23a down-regulation group was also significantly decreased compared with that in NC group (Figure 5D; 3/10 vs. 8/10, P<0.05).	('liver metastases', 'Disease', (237, 253))	('mice', 'Species', '10090', (91, 95))	('primary splenic tumours', 'Disease', 'MESH:D013160', (30, 53))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('regulation', 'biological_process', 'GO:0065007', ('274', '284'))	('liver metastases', 'Disease', 'MESH:D009362', (237, 253))	('regulation', 'biological_process', 'GO:0065007', ('74', '84'))	('diameters', 'CPA', (13, 22))	('miR-23a', 'Gene', (61, 68))	('decreased', 'NegReg', (115, 124))	('mice', 'Species', '10090', (227, 231))	('mice', 'Species', '10090', (156, 160))	('decreased', 'NegReg', (314, 323))	('primary splenic tumours', 'Disease', (30, 53))	('miR-23a', 'Var', (261, 268))	('down-regulation', 'NegReg', (269, 284))	('down-regulation', 'NegReg', (69, 84))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
2043	29137308	When Aspc-1 cells were co-transfected with wt-ESRP1 3' UTR and either miR-23a mimic or mimic NC, luciferase activity was significantly reduced compared with the transfected control (Figure 7C).	('mimic', 'Var', (78, 83))	('activity', 'MPA', (108, 116))	('luciferase', 'Enzyme', (97, 107))	('luciferase activity', 'molecular_function', 'GO:0045289', ('97', '116'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('97', '116'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('97', '116'))	('ESRP1', 'Gene', '54845', (46, 51))	('luciferase activity', 'molecular_function', 'GO:0050397', ('97', '116'))	('ESRP1', 'Gene', (46, 51))	('reduced', 'NegReg', (135, 142))	('luciferase activity', 'molecular_function', 'GO:0047077', ('97', '116'))	('miR-23a', 'Gene', (70, 77))
2048	29137308	To further determine the role of ESRP1 in the miR-23a-mediated effect on pancreatic cancer cell EMT, rescue experiments were performed.	('miR-23a-mediated', 'Var', (46, 62))	('pancreatic cancer', 'Disease', (73, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ESRP1', 'Gene', '54845', (33, 38))	('EMT', 'biological_process', 'GO:0001837', ('96', '99'))	('ESRP1', 'Gene', (33, 38))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))
2060	29137308	Changes in the expressed CD44 isoforms have been suggested to be associated with EMT.	('EMT', 'Disease', (81, 84))	('CD44', 'Gene', '960', (25, 29))	('associated', 'Reg', (65, 75))	('Changes', 'Var', (0, 7))	('CD44', 'Gene', (25, 29))	('EMT', 'biological_process', 'GO:0001837', ('81', '84'))
2070	29137308	Moreover, patients with higher miR-23a expression levels had significantly reduced disease-free survival and overall survival rates.	('overall survival rates', 'CPA', (109, 131))	('reduced', 'NegReg', (75, 82))	('disease-free survival', 'CPA', (83, 104))	('patients', 'Species', '9606', (10, 18))	('expression', 'MPA', (39, 49))	('expression', 'Species', '29278', (39, 49))	('miR-23a', 'Var', (31, 38))
2075	29137308	Therefore, we concluded that miR-23a was able to promote EMT and the metastasis of pancreatic cancer cells.	('metastasis of', 'CPA', (69, 82))	('pancreatic cancer', 'Disease', (83, 100))	('miR-23a', 'Var', (29, 36))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('promote', 'PosReg', (49, 56))	('EMT', 'CPA', (57, 60))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))	('EMT', 'biological_process', 'GO:0001837', ('57', '60'))
2098	29137308	Thus, the inhibition of ESRP1 expression by miR-23a is essential for pancreatic cancer cell EMT and metastasis.	('pancreatic cancer', 'Disease', (69, 86))	('expression', 'MPA', (30, 40))	('inhibition', 'NegReg', (10, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (69, 86))	('ESRP1', 'Gene', '54845', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('EMT', 'biological_process', 'GO:0001837', ('92', '95'))	('ESRP1', 'Gene', (24, 29))	('miR-23a', 'Var', (44, 51))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (69, 86))	('expression', 'Species', '29278', (30, 40))
2100	29137308	Alternative splicing of CD44 mRNA produces two protein isoform groups: the CD44 variants (CD44v) and the CD44 standard (CD44s).	('CD44', 'Gene', (90, 94))	('CD44', 'Gene', '960', (75, 79))	('CD44', 'Gene', (105, 109))	('CD44', 'Gene', '960', (120, 124))	('CD44', 'Gene', (75, 79))	('CD44', 'Gene', (120, 124))	('CD44', 'Gene', '960', (24, 28))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('variants', 'Var', (80, 88))	('CD44', 'Gene', (24, 28))	('CD44', 'Gene', '960', (90, 94))	('CD44', 'Gene', '960', (105, 109))	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))
2108	29137308	Moreover, restoration of ESRP1 rescued the effect of miR-23a on CD44 splice isoform switching in pancreatic cancer cells.	('effect', 'MPA', (43, 49))	('restoration', 'Var', (10, 21))	('CD44', 'Gene', '960', (64, 68))	('ESRP1', 'Gene', '54845', (25, 30))	('miR-23a', 'Var', (53, 60))	('pancreatic cancer', 'Disease', 'MESH:D010190', (97, 114))	('ESRP1', 'Gene', (25, 30))	('CD44', 'Gene', (64, 68))	('pancreatic cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (97, 114))
2109	29137308	Therefore, miR-23a may affect CD44 splice isoform switching by directly regulating ESRP1, which consequently promoted EMT and metastasis.	('promoted', 'PosReg', (109, 117))	('EMT', 'biological_process', 'GO:0001837', ('118', '121'))	('ESRP1', 'Gene', '54845', (83, 88))	('CD44', 'Gene', '960', (30, 34))	('ESRP1', 'Gene', (83, 88))	('regulating', 'Reg', (72, 82))	('affect', 'Reg', (23, 29))	('CD44', 'Gene', (30, 34))	('miR-23a', 'Var', (11, 18))
2112	29137308	Restoration of ESRP1 rescued the effect of miR-23a on pancreatic cancer cells.	('effect', 'MPA', (33, 39))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (54, 71))	('Restoration', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('ESRP1', 'Gene', '54845', (15, 20))	('pancreatic cancer', 'Disease', (54, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (54, 71))	('ESRP1', 'Gene', (15, 20))
2117	29137308	In summary, we identified a new mechanism by which miR-23a promotes pancreatic cancer cell EMT and metastasis by down-regulating ESRP1.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('promotes', 'PosReg', (59, 67))	('EMT', 'biological_process', 'GO:0001837', ('91', '94'))	('down-regulating', 'NegReg', (113, 128))	('ESRP1', 'Gene', '54845', (129, 134))	('pancreatic cancer', 'Disease', (68, 85))	('ESRP1', 'Gene', (129, 134))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))	('miR-23a', 'Var', (51, 58))
2165	29137308	EMT epithelial-mesenchymal transition ESRP1 Epithelial splicing regulatory protein 1 MET mesenchymal-epithelial transition miRNAs MicroRNAs 3' UTR 3'-untranslated region PDAC pancreatic ductal adenocarcinoma BiNGO Biological Networks Gene Ontology tool GO Gene Ontology CD44v CD44 variants CD44s CD44 standard	('miR', 'Gene', '220972', (123, 126))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('CD44', 'Gene', '960', (296, 300))	('splicing', 'biological_process', 'GO:0045292', ('55', '63'))	('CD44', 'Gene', (296, 300))	('epithelia', 'Disease', 'None', (101, 110))	('CD44', 'Gene', '960', (270, 274))	('variants', 'Var', (281, 289))	('ESRP1', 'Gene', (38, 43))	('CD44', 'Gene', (270, 274))	('miR', 'Gene', (123, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('PDAC', 'Chemical', '-', (170, 174))	('epithelia', 'Disease', 'None', (4, 13))	('Epithelial splicing regulatory protein 1', 'Gene', '54845', (44, 84))	('CD44', 'Gene', '960', (276, 280))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (175, 207))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('4', '37'))	('epithelia', 'Disease', (101, 110))	('PDAC', 'Phenotype', 'HP:0006725', (170, 174))	('Gene Ontology', 'biological_process', 'GO:0003673', ('256', '269'))	('CD44', 'Gene', (276, 280))	('ESRP1', 'Gene', '54845', (38, 43))	('EMT', 'biological_process', 'GO:0001837', ('0', '3'))	('Epithelial splicing regulatory protein 1', 'Gene', (44, 84))	('pancreatic ductal adenocarcinoma', 'Disease', (175, 207))	('epithelia', 'Disease', (4, 13))	('CD44', 'Gene', '960', (290, 294))	('CD44', 'Gene', (290, 294))	('Gene Ontology', 'biological_process', 'GO:0003673', ('234', '247'))	('mesenchymal-epithelial transition', 'biological_process', 'GO:0060231', ('89', '122'))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (175, 207))
2166	29088786	Effect of p53 on pancreatic cancer-glucose tolerance abnormalities by regulating transglutaminase 2 in resistance to glucose metabolic stress Pancreatic ductal adenocarcinoma (PanCa) is an extremely lethal disease characterized by mutations of p53 in up to 70% of cases.	('PanCa', 'Phenotype', 'HP:0006725', (176, 181))	('p53', 'Gene', '7157', (10, 13))	('mutations', 'Var', (231, 240))	('p53', 'Gene', (10, 13))	('Pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (142, 174))	('transglutaminase 2', 'Gene', (81, 99))	('transglutaminase 2', 'Gene', '7052', (81, 99))	('pancreatic cancer-glucose tolerance abnormalities', 'Disease', (17, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('glucose tolerance abnormalities', 'Phenotype', 'HP:0001952', (35, 66))	('cancer-glucose tolerance abnormalities', 'Phenotype', 'HP:0001952', (28, 66))	('p53', 'Gene', '7157', (244, 247))	('glucose metabolic stress', 'Disease', 'MESH:D004194', (117, 141))	('Pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (142, 174))	('p53', 'Gene', (244, 247))	('pancreatic cancer-glucose tolerance abnormalities', 'Disease', 'MESH:D018149', (17, 66))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Pancreatic ductal adenocarcinoma', 'Disease', (142, 174))	('glucose metabolic stress', 'Disease', (117, 141))
2168	29088786	In this article, we showed that targeted knockdown of TG2 or p53 in tumor cells led to decreased cell survival in response to glucose deprivation, while this phenomenon was abolished by combined inhibition of TG2 and p53.	('tumor', 'Disease', (68, 73))	('decreased', 'NegReg', (87, 96))	('TG2', 'Gene', (54, 57))	('cell survival', 'CPA', (97, 110))	('glucose deprivation', 'Disease', 'MESH:D012892', (126, 145))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('glucose deprivation', 'Disease', (126, 145))	('response to glucose', 'biological_process', 'GO:0009749', ('114', '133'))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('p53', 'Gene', (61, 64))	('knockdown', 'Var', (41, 50))
2169	29088786	We observed that inhibition of TG2 or p53 sensitized glucose deprivation resistance through an intracellular reactive oxygen species (ROS) pathway and the induction of Bcl-2.	('glucose deprivation', 'Disease', 'MESH:D012892', (53, 72))	('Bcl-2', 'molecular_function', 'GO:0015283', ('168', '173'))	('p53', 'Gene', (38, 41))	('ROS', 'Chemical', 'MESH:D017382', (134, 137))	('glucose deprivation', 'Disease', (53, 72))	('sensitized', 'NegReg', (42, 52))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (109, 132))	('inhibition', 'Var', (17, 27))	('intracellular', 'cellular_component', 'GO:0005622', ('95', '108'))	('Bcl-2', 'Gene', (168, 173))	('Bcl-2', 'Gene', '596', (168, 173))	('TG2', 'Gene', (31, 34))
2172	29088786	Following the creation of an orthotopic pancreatic cancer mouse model, we revealed glucose tolerance abnormalities in the pancreatic cancer mouse model with TG2 and p53 combined interference, indicating a possible mechanism for damage of betacells in pancreatic cancer.	('glucose tolerance abnormalities in the pancreatic cancer', 'Disease', 'MESH:D018149', (83, 139))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('TG2', 'Gene', (157, 160))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (122, 139))	('pancreatic cancer', 'Disease', (40, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (251, 268))	('glucose tolerance abnormalities', 'Phenotype', 'HP:0001952', (83, 114))	('mouse', 'Species', '10090', (140, 145))	('pancreatic cancer', 'Disease', 'MESH:D010190', (122, 139))	('pancreatic cancer', 'Disease', (251, 268))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('pancreatic cancer', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('p53', 'Gene', (165, 168))	('mouse', 'Species', '10090', (58, 63))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (251, 268))	('combined interference', 'Var', (169, 190))	('pancreatic cancer', 'Disease', 'MESH:D010190', (40, 57))
2192	29088786	Of note, our results demonstrated glucose tolerance abnormalities in an orthotopic pancreatic cancer mouse model with TG2 and p53 combined interference, indicating a possible mechanism for hyperglycemia occurring in pancreatic cancer.	('TG2', 'Gene', (118, 121))	('hyperglycemia', 'Disease', 'MESH:D006943', (189, 202))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (216, 233))	('glucose tolerance abnormalities', 'Phenotype', 'HP:0001952', (34, 65))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('mouse', 'Species', '10090', (101, 106))	('hyperglycemia', 'Phenotype', 'HP:0003074', (189, 202))	('pancreatic cancer', 'Disease', 'MESH:D010190', (216, 233))	('pancreatic cancer', 'Disease', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('glucose tolerance abnormalities', 'Disease', 'MESH:D018149', (34, 65))	('p53', 'Gene', (126, 129))	('rat', 'Species', '10116', (28, 31))	('pancreatic cancer', 'Disease', (216, 233))	('combined interference', 'Var', (130, 151))	('glucose tolerance abnormalities', 'Disease', (34, 65))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('hyperglycemia', 'Disease', (189, 202))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))
2198	29088786	As shown in Figure 1F, the total protein expression levels of p53 in BXPC3, SW1990 and PANC1 cells were higher than in ASPC1 cells.	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('protein expression levels', 'MPA', (33, 58))	('PANC1', 'Gene', '104066', (87, 92))	('PANC1', 'Gene', (87, 92))	('p53', 'Var', (62, 65))	('SW1990', 'CellLine', 'CVCL:1723', (76, 82))	('higher', 'PosReg', (104, 110))
2199	29088786	The total protein expression levels of TG2 in SW1990 cells were higher than in the other cells (Figure 1F).	('higher', 'PosReg', (64, 70))	('TG2', 'Gene', (39, 42))	('protein expression levels', 'MPA', (10, 35))	('SW1990', 'Var', (46, 52))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('SW1990', 'CellLine', 'CVCL:1723', (46, 52))
2206	29088786	As shown in Figure 2C, knockdown of TG2 markedly decreased viability in BXPC3 and PANC1 cells treated with glucose starvation for 48 h. Similar results were obtained using TG2 specific inhibitors in BXPC3 and PANC1 cells (Figure 2D).	('PANC1', 'Gene', '104066', (209, 214))	('PANC1', 'Gene', (209, 214))	('glucose', 'Chemical', 'MESH:D005947', (107, 114))	('inhibitors', 'Var', (185, 195))	('TG2', 'Gene', (172, 175))	('PANC1', 'Gene', '104066', (82, 87))	('PANC1', 'Gene', (82, 87))
2214	29088786	This maybe because that p53 loss determine increased glucose uptake during PDAC progression, so knockdown of p53 by shRNA transfection increased the sensitivity of PDAC cells treated with glucose starvation (Figure 3B).	('knockdown', 'Var', (96, 105))	('p53', 'Gene', (24, 27))	('glucose uptake', 'MPA', (53, 67))	('glucose', 'Chemical', 'MESH:D005947', (53, 60))	('glucose uptake', 'biological_process', 'GO:0046323', ('53', '67'))	('increased', 'PosReg', (135, 144))	('sensitivity', 'MPA', (149, 160))	('increased glucose', 'Phenotype', 'HP:0003074', (43, 60))	('glucose', 'Chemical', 'MESH:D005947', (188, 195))	('p53', 'Gene', (109, 112))	('increased', 'PosReg', (43, 52))	('loss', 'NegReg', (28, 32))
2215	29088786	Surprisingly, combined knockdown of TG2 and p53 did not significantly influence cell survival in response to glucose starvation stress in BXPC3 and PANC1 cells (Figure 3B).	('glucose starvation stress', 'Disease', (109, 134))	('glucose starvation stress', 'Disease', 'MESH:D004194', (109, 134))	('TG2', 'Gene', (36, 39))	('knockdown', 'Var', (23, 32))	('cell survival', 'CPA', (80, 93))	('PANC1', 'Gene', '104066', (148, 153))	('response to glucose', 'biological_process', 'GO:0009749', ('97', '116'))	('PANC1', 'Gene', (148, 153))	('influence', 'Reg', (70, 79))
2217	29088786	These findings suggest that p53 regulates TG2 in resistance to glucose metabolic stress.	('regulates', 'Reg', (32, 41))	('glucose metabolic stress', 'Disease', 'MESH:D004194', (63, 87))	('glucose metabolic stress', 'Disease', (63, 87))	('p53', 'Var', (28, 31))	('TG2', 'Gene', (42, 45))
2219	29088786	Western blot analysis demonstrated that up-regulation of TG2 was reduced after inhibition by p53 shRNA in BXPC3 and PANC1 cells (Figure 3D).	('PANC1', 'Gene', (116, 121))	('regulation', 'biological_process', 'GO:0065007', ('43', '53'))	('reduced', 'NegReg', (65, 72))	('rat', 'Species', '10116', (29, 32))	('TG2', 'Gene', (57, 60))	('inhibition', 'NegReg', (79, 89))	('up-regulation', 'PosReg', (40, 53))	('p53', 'Var', (93, 96))	('PANC1', 'Gene', '104066', (116, 121))
2226	29088786	Moreover, the highest ROS production was acquired in BXPC3-shTG2+shp53 cells when compared to control, shTG2, and shp53 cells, suggesting that higher ROS production was increased after shTG2 and shp53 combined interference (Figure 4A).	('ROS production', 'MPA', (150, 164))	('shp53', 'Gene', (195, 200))	('combined', 'Interaction', (201, 209))	('increased', 'PosReg', (169, 178))	('higher', 'PosReg', (143, 149))	('BXPC3-shTG2+shp53', 'Var', (53, 70))	('ROS', 'Chemical', 'MESH:D017382', (22, 25))	('shTG2', 'Gene', (185, 190))	('ROS', 'Chemical', 'MESH:D017382', (150, 153))
2227	29088786	The higher ROS production was acquired in BXPC3-shTG2 cells when compared to control cells, suggesting that higher ROS production was increased after shTG2 interference (Figure 4A).	('ROS', 'Chemical', 'MESH:D017382', (11, 14))	('interference', 'Var', (156, 168))	('ROS production', 'MPA', (115, 129))	('ROS', 'Chemical', 'MESH:D017382', (115, 118))	('shTG2', 'Gene', (150, 155))	('increased', 'PosReg', (134, 143))	('higher', 'PosReg', (108, 114))
2228	29088786	Total ROS levels were higher in shTG2 and shp53 cells than control under glucose starvation stress (Figure 4A).	('shp53', 'Var', (42, 47))	('higher', 'PosReg', (22, 28))	('ROS levels', 'MPA', (6, 16))	('ROS', 'Chemical', 'MESH:D017382', (6, 9))	('shTG2', 'Gene', (32, 37))	('glucose starvation stress', 'Disease', (73, 98))	('glucose starvation stress', 'Disease', 'MESH:D004194', (73, 98))
2232	29088786	Importantly, Bcl-2 expression levels were increased in BXPC3-shTG2+shp53 cells compared to control, shTG2, and shp53 cells (Figure 4B).	('increased', 'PosReg', (42, 51))	('Bcl-2', 'molecular_function', 'GO:0015283', ('13', '18'))	('BXPC3-shTG2+shp53', 'Var', (55, 72))	('Bcl-2', 'Gene', (13, 18))	('Bcl-2', 'Gene', '596', (13, 18))
2237	29088786	After treatment of cells with ABT, which is a specific inhibitor of Bcl-2, the resistance to glucose starvation was depressed in BXPC3-shTG2+shp53 cells (Figure 4D).	('resistance to glucose starvation', 'MPA', (79, 111))	('Bcl-2', 'molecular_function', 'GO:0015283', ('68', '73'))	('glucose', 'Chemical', 'MESH:D005947', (93, 100))	('ABT', 'Chemical', 'MESH:C002502', (30, 33))	('BXPC3-shTG2+shp53', 'Var', (129, 146))	('depressed', 'NegReg', (116, 125))	('Bcl-2', 'Gene', (68, 73))	('Bcl-2', 'Gene', '596', (68, 73))
2243	29088786	According to the above results, the higher ROS production was acquired in shTG2+shp53 cells and shTG2 when compared to control cells.	('shTG2+shp53', 'Var', (74, 85))	('ROS production', 'MPA', (43, 57))	('higher', 'PosReg', (36, 42))	('ROS', 'Chemical', 'MESH:D017382', (43, 46))
2244	29088786	As oxidative stress and products was responsible for damage in beta cells and diabetes, so we considered that silenced TG2 and p53 combination may provide a specific microenvironment in pancreatic cancer cells.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (186, 203))	('oxidative stress', 'Phenotype', 'HP:0025464', (3, 19))	('TG2', 'Gene', (119, 122))	('pancreatic cancer', 'Disease', (186, 203))	('silenced', 'Var', (110, 118))	('pancreatic cancer', 'Disease', 'MESH:D010190', (186, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('diabetes', 'Disease', (78, 86))	('p53', 'Gene', (127, 130))	('diabetes', 'Disease', 'MESH:D003920', (78, 86))
2249	29088786	These results indicate that silenced p53 and TG2 combination in pancreatic cancer cells may provide a specific microenvironment for adjacent beta cells to reduce their survival.	('combination', 'Var', (49, 60))	('silenced', 'Var', (28, 36))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('reduce', 'NegReg', (155, 161))	('survival', 'CPA', (168, 176))	('p53', 'Gene', (37, 40))	('pancreatic cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('pancreatic cancer', 'Disease', 'MESH:D010190', (64, 81))	('TG2', 'Gene', (45, 48))
2255	29088786	In an effort to identify the effect of shTG2+shp53 pancreatic cancer cells on pancreatic beta cells in vivo, we evaluated glucose and insulin tolerance in vivo.	('insulin', 'molecular_function', 'GO:0016088', ('134', '141'))	('pancreatic', 'Disease', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('glucose and insulin tolerance', 'Disease', 'MESH:D018149', (122, 151))	('pancreatic cancer', 'Disease', (51, 68))	('pancreatic', 'Disease', 'MESH:D010195', (78, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (51, 68))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (51, 68))	('pancreatic', 'Disease', (78, 88))	('shTG2+shp53', 'Var', (39, 50))	('pancreatic', 'Disease', 'MESH:D010195', (51, 61))	('evaluated', 'Reg', (112, 121))
2256	29088786	In the shTG2+shp53 and shTG2 groups, the tumor luminescence was significantly stronger compared to the other two groups (Figure 6A).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('stronger', 'PosReg', (78, 86))	('shTG2+shp53', 'Var', (7, 18))	('shTG2', 'Var', (23, 28))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
2258	29088786	The results demonstrated that glucose tolerance was reduced in the shTG2+shp53-treated pancreatic cancer mouse group during the 4th to 6th week (Figure 6CE).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('pancreatic cancer', 'Disease', (87, 104))	('reduced', 'NegReg', (52, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('shTG2+shp53-treated', 'Var', (67, 86))	('glucose', 'Chemical', 'MESH:D005947', (30, 37))	('rat', 'Species', '10116', (19, 22))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('mouse', 'Species', '10090', (105, 110))	('glucose tolerance', 'CPA', (30, 47))
2259	29088786	Conversely, glucose tolerance of the shTG2 group was eventually reduced without initial changes.	('glucose', 'MPA', (12, 19))	('glucose', 'Chemical', 'MESH:D005947', (12, 19))	('reduced', 'NegReg', (64, 71))	('shTG2', 'Var', (37, 42))
2263	29088786	These results suggest that silenced TG2 may be the cause of changes in the pancreatic cancer cells affecting beta cells in vivo and that silenced p53 could exacerbate this phenomenon.	('silenced', 'Var', (137, 145))	('silenced', 'Var', (27, 35))	('p53', 'Gene', (146, 149))	('TG2', 'Gene', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (75, 92))	('exacerbate', 'PosReg', (156, 166))	('cause', 'Reg', (51, 56))	('pancreatic cancer', 'Disease', (75, 92))	('pancreatic cancer', 'Disease', 'MESH:D010190', (75, 92))
2266	29088786	The mean tumor weight of the shTG2 groups was significantly lighter compared to the other groups (Figure 6F).	('lighter', 'NegReg', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('shTG2', 'Var', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))
2267	29088786	The tumor weight did not differ between the shTG2+shp53, shp53 and control groups (Figure 6F).	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('shp53', 'Var', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('shTG2+shp53', 'Var', (44, 55))
2272	29088786	Our results demonstrated that silenced TG2 combined with p53 in pancreatic cancer cells may cause a specific microenvironment that decreases cell survival in pancreatic beta cells in vitro and reduces glucose tolerance in vivo.	('cause', 'Reg', (92, 97))	('silenced', 'Var', (30, 38))	('glucose', 'Chemical', 'MESH:D005947', (201, 208))	('pancreatic', 'Disease', 'MESH:D010195', (64, 74))	('glucose tolerance', 'CPA', (201, 218))	('pancreatic cancer', 'Disease', 'MESH:D010190', (64, 81))	('decreases', 'NegReg', (131, 140))	('reduces', 'NegReg', (193, 200))	('TG2', 'Gene', (39, 42))	('pancreatic', 'Disease', 'MESH:D010195', (158, 168))	('rat', 'Species', '10116', (19, 22))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('pancreatic', 'Disease', (64, 74))	('pancreatic cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('reduces glucose tolerance', 'Phenotype', 'HP:0040270', (193, 218))	('decreases cell survival in pancreatic beta cells', 'Phenotype', 'HP:0006274', (131, 179))	('pancreatic', 'Disease', (158, 168))
2277	29088786	Interestingly, resistance remained after combined targeted knockdown or inhibition of p53 in the pancreatic cells.	('pancreatic', 'Disease', 'MESH:D010195', (97, 107))	('pancreatic', 'Disease', (97, 107))	('knockdown', 'Var', (59, 68))	('inhibition', 'NegReg', (72, 82))	('p53', 'Gene', (86, 89))
2282	29088786	Moreover, the higher ROS production was acquired in shTG2+shp53 and shTG2 cells when compared to control and shp53 cells.	('ROS', 'Chemical', 'MESH:D017382', (21, 24))	('shTG2+shp53', 'Var', (52, 63))	('ROS production', 'MPA', (21, 35))	('shTG2', 'Var', (68, 73))	('higher', 'PosReg', (14, 20))
2286	29088786	Therefore, the mechanism by which shTG2+shp53 cells remain resistant to glucose starvation may be explained as follows.	('resistant', 'MPA', (59, 68))	('shTG2+shp53', 'Var', (34, 45))	('glucose', 'Chemical', 'MESH:D005947', (72, 79))
2288	29088786	In this context, we then analyzed whether silenced TG2 and p53 combination in pancreatic cancer cells affect adjacent pancreatic beta cells.	('p53', 'Gene', (59, 62))	('pancreatic', 'Disease', 'MESH:D010195', (118, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('pancreatic', 'Disease', (118, 128))	('silenced', 'Var', (42, 50))	('pancreatic', 'Disease', 'MESH:D010195', (78, 88))	('pancreatic', 'Disease', (78, 88))	('pancreatic cancer', 'Disease', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))	('affect', 'Reg', (102, 108))	('TG2', 'Gene', (51, 54))
2289	29088786	We found that the supernatant of shTG2+shp53 pancreatic cancer cells decreased cell survival by approximately 30% in pancreatic beta cells after 72 h and 96 h of treatment.	('cell survival', 'CPA', (79, 92))	('pancreatic', 'Disease', (45, 55))	('pancreatic cancer', 'Disease', (45, 62))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('decreased', 'NegReg', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('pancreatic', 'Disease', 'MESH:D010195', (117, 127))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))	('shTG2+shp53', 'Var', (33, 44))	('pancreatic', 'Disease', 'MESH:D010195', (45, 55))	('pancreatic', 'Disease', (117, 127))
2290	29088786	Inhibition of the ROS pathway played a protective role in beta cells, while ROS higher production in the shTG2+shp53 pancreatic cancer cells may be responsible for damage in beta cells.	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('ROS', 'MPA', (76, 79))	('ROS pathway', 'Pathway', (18, 29))	('pancreatic cancer', 'Disease', (117, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ROS', 'Chemical', 'MESH:D017382', (76, 79))	('shTG2+shp53', 'Var', (105, 116))	('higher', 'PosReg', (80, 86))
2292	29088786	This hypothesis was demonstrated in two ways: 1. shTG2+shp53 cells remained resistant to glucose starvation stress; 2. the highest ROS production was acquired in shTG2+shp53 cells.	('highest', 'PosReg', (123, 130))	('shTG2+shp53', 'Var', (162, 173))	('ROS production', 'MPA', (131, 145))	('ROS', 'Chemical', 'MESH:D017382', (131, 134))	('rat', 'Species', '10116', (27, 30))	('glucose starvation stress', 'Disease', (89, 114))	('glucose starvation stress', 'Disease', 'MESH:D004194', (89, 114))
2294	29088786	The results demonstrated that glucose tolerance was reduced in the shTG2+shp53-treated group during the 4th to 6th week.	('reduced', 'NegReg', (52, 59))	('shTG2+shp53-treated', 'Var', (67, 86))	('rat', 'Species', '10116', (19, 22))	('glucose', 'Chemical', 'MESH:D005947', (30, 37))	('glucose tolerance', 'CPA', (30, 47))
2297	29088786	Taken together, these results suggest that silenced TG2 may be the cause of changes in pancreatic cancer cells affecting beta cells in vivo and that silenced p53 could exacerbate this phenomenon.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('TG2', 'Gene', (52, 55))	('cause', 'Reg', (67, 72))	('pancreatic cancer', 'Disease', (87, 104))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('silenced', 'Var', (149, 157))	('p53', 'Gene', (158, 161))	('silenced', 'Var', (43, 51))
2300	29088786	Inhibition of TG2 and p53 increased intracellular ROS in pancreatic cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (57, 74))	('p53', 'Gene', (22, 25))	('increased intracellular ROS', 'Phenotype', 'HP:0025464', (26, 53))	('intracellular', 'cellular_component', 'GO:0005622', ('36', '49'))	('increased', 'PosReg', (26, 35))	('Inhibition', 'Var', (0, 10))	('intracellular ROS', 'MPA', (36, 53))	('ROS', 'Chemical', 'MESH:D017382', (50, 53))	('pancreatic cancer', 'Disease', (57, 74))	('TG2', 'Gene', (14, 17))	('pancreatic cancer', 'Disease', 'MESH:D010190', (57, 74))
2302	29088786	Glucose tolerance was abnormal for the pancreatic cancer mouse model with TG2 and p53 combined interference.	('abnormal', 'Reg', (22, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (39, 56))	('TG2', 'Gene', (74, 77))	('mouse', 'Species', '10090', (57, 62))	('p53 combined interference', 'Var', (82, 107))	('pancreatic cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('Glucose tolerance', 'Disease', 'MESH:D018149', (0, 17))	('pancreatic cancer', 'Disease', 'MESH:D010190', (39, 56))	('Glucose tolerance', 'Disease', (0, 17))
2306	29088786	Of note, our study demonstrated glucose tolerance abnormalities in vivo with TG2 and p53 combined interference, indicating a possible mechanism for hyperglycemia in pancreatic cancer.	('glucose tolerance abnormalities', 'Phenotype', 'HP:0001952', (32, 63))	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('combined interference', 'Var', (89, 110))	('TG2', 'Gene', (77, 80))	('glucose tolerance abnormalities', 'Disease', 'MESH:D018149', (32, 63))	('hyperglycemia', 'Phenotype', 'HP:0003074', (148, 161))	('rat', 'Species', '10116', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('hyperglycemia', 'Disease', 'MESH:D006943', (148, 161))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('p53', 'Gene', (85, 88))	('hyperglycemia', 'Disease', (148, 161))	('glucose tolerance abnormalities', 'Disease', (32, 63))	('pancreatic cancer', 'Disease', (165, 182))
2327	29088786	F1R1(300-500bp), F2R2(700-900bp) F3R3(2000-2200bp), F4R4(3600-3800bp), F5R5(5000-5200bp), and F6R6(5900-6100bp) were demonstrated as shown in Table 1.	('300-500bp', 'Var', (5, 14))	('2000-2200bp', 'Var', (38, 49))	('rat', 'Species', '10116', (124, 127))	('3600-3800bp', 'Var', (57, 68))	('5900-6100bp', 'Var', (99, 110))	('5000-5200bp', 'Var', (76, 87))	('700-900bp', 'Var', (22, 31))
2440	26943573	Enhanced gemcitabine functionality in tumors is likely the consequence of increased production of the key nucleoside analog metabolizing enzyme, deoxycytidine kinase (dCK) resulting from post-transcriptional regulation of dCK mRNA by HuR.	('dCK', 'Gene', '43828', (222, 225))	('dCK', 'Gene', (222, 225))	('HuR', 'Gene', (234, 237))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('deoxycytidine kinase', 'Gene', '1633', (145, 165))	('HuR', 'Gene', '1994', (234, 237))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('increased', 'PosReg', (74, 83))	('nucleoside', 'Chemical', 'MESH:D009705', (106, 116))	('regulation', 'biological_process', 'GO:0065007', ('208', '218'))	('gemcitabine', 'Chemical', 'MESH:C056507', (9, 20))	('production', 'MPA', (84, 94))	('Enhanced', 'PosReg', (0, 8))	('deoxycytidine kinase', 'Gene', (145, 165))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('dCK', 'Gene', (167, 170))	('dCK', 'Gene', '43828', (167, 170))	('post-transcriptional regulation', 'Var', (187, 218))
2450	26943573	Even when tumors that were scored as + were grouped with ++ and +++ tumors, there was no significant difference in PFS (- and +/-; n=9; median = 8 mo) and (+, ++, +++; n=22; median = 8 mo) (p=0.62).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('- and +/-;', 'Var', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('PFS', 'MPA', (115, 118))
2461	26943573	dCK inhibition resulted in ~80% increase in cell number when cells were treated with 0.005 and 0.01 muM gemcitabine as compared to gemcitabine-treated siCtrl-transfected and untransfected cells (p<0.005) (Figure S2).	('cell number', 'CPA', (44, 55))	('increase', 'PosReg', (32, 40))	('dCK', 'Gene', '43828', (0, 3))	('gemcitabine', 'Chemical', 'MESH:C056507', (104, 115))	('dCK', 'Gene', (0, 3))	('0.01', 'Var', (95, 99))	('0.005', 'Var', (85, 90))	('gemcitabine', 'Chemical', 'MESH:C056507', (131, 142))	('inhibition', 'NegReg', (4, 14))
2522	26943573	A small molecule WEE1 inhibitor, MK-1775, has been shown to enhance antitumor efficacy of p53-deficient tumor cells to DNA-damaging agents including cisplatin, carboplatin, gemcitabine and 5-fluorouracil, and a Phase II clinical trial (NCT02101775) testing MK-1775 in combination with gemcitabine to treat recurrent ovarian cancer is currently recruiting.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('MK-1775', 'Chemical', 'MESH:C549567', (33, 40))	('ovarian cancer', 'Phenotype', 'HP:0100615', (316, 330))	('p53-deficient tumor', 'Disease', 'MESH:D009369', (90, 109))	('p53-deficient tumor', 'Disease', (90, 109))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('carboplatin', 'Chemical', 'MESH:D016190', (160, 171))	('WEE1', 'Gene', (17, 21))	('enhance', 'PosReg', (60, 67))	('tumor', 'Disease', (72, 77))	('MK-1775', 'Var', (33, 40))	('tumor', 'Disease', (104, 109))	('gemcitabine', 'Chemical', 'MESH:C056507', (285, 296))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (306, 330))	('cisplatin', 'Chemical', 'MESH:D002945', (149, 158))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (189, 203))	('ovarian cancer', 'Disease', 'MESH:D010051', (316, 330))	('gemcitabine', 'Chemical', 'MESH:C056507', (173, 184))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('MK-1775', 'Chemical', 'MESH:C549567', (257, 264))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('WEE1', 'Gene', '7465', (17, 21))	('ovarian cancer', 'Disease', (316, 330))
2549	26943573	Human ovarian tumor HuR cytoplasmic staining was scored as -, +/-, ++, or +++.	('Human', 'Species', '9606', (0, 5))	('HuR', 'Gene', '1994', (20, 23))	('+++', 'Var', (74, 77))	('HuR', 'Gene', (20, 23))	('ovarian tumor', 'Disease', (6, 19))	('ovarian tumor', 'Phenotype', 'HP:0100615', (6, 19))	('ovarian tumor', 'Disease', 'MESH:D010051', (6, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
2557	26943573	GAPDH and dCK transcripts were quantified by real-time PCR analysis (#4352024) using specific probes, dCK (#Hs01040726_m), 18S (#Hs99999901_s1), and SUMO-1(#Hs02339312_g1) (A&B Applied Biosystems).	('#Hs01040726_m', 'Var', (107, 120))	('dCK', 'Gene', (102, 105))	('dCK', 'Gene', '43828', (102, 105))	('#Hs99999901_s1', 'Var', (128, 142))	('SUMO-1', 'Gene', (149, 155))	('dCK', 'Gene', '43828', (10, 13))	('dCK', 'Gene', (10, 13))	('SUMO-1', 'Gene', '7341', (149, 155))	('GAPDH', 'Gene', '2597', (0, 5))	('GAPDH', 'Gene', (0, 5))
2562	26317650	One of these anti-EpCAM mAbs, EpAb2-6, was found to induce cancer cell apoptosis in vitro, inhibit tumor growth, and prolong the overall survival of both a pancreatic cancer metastatic mouse model and mice with human colon carcinoma xenografts.	('EpAb2-6', 'Chemical', '-', (30, 37))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('pancreatic cancer', 'Disease', 'MESH:D010190', (156, 173))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('tumor', 'Disease', (99, 104))	('pancreatic cancer', 'Disease', (156, 173))	('mice', 'Species', '10090', (201, 205))	('EpAb2-6', 'Var', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('colon carcinoma xenografts', 'Disease', (217, 243))	('inhibit', 'NegReg', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('colon carcinoma xenografts', 'Disease', 'MESH:D015179', (217, 243))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (156, 173))	('mouse', 'Species', '10090', (185, 190))	('prolong', 'PosReg', (117, 124))	('induce', 'PosReg', (52, 58))	('human', 'Species', '9606', (211, 216))	('cancer', 'Disease', (59, 65))
2564	26317650	Furthermore, EpAb2-6, which binds to positions Y95 and D96 of the EGF-II/TY domain of EpCAM, inhibits production of EpICD, thereby decreasing its translocation and subsequent signal activation.	('EpCAM', 'Gene', (86, 91))	('EGF', 'molecular_function', 'GO:0005154', ('66', '69'))	('production', 'MPA', (102, 112))	('inhibits', 'NegReg', (93, 101))	('EpAb2-6', 'Chemical', '-', (13, 20))	('D96', 'Var', (55, 58))	('translocation', 'MPA', (146, 159))	('Y95', 'Var', (47, 50))	('decreasing', 'NegReg', (131, 141))	('signal activation', 'MPA', (175, 192))
2565	26317650	Collectively, our results indicate that the novel anti-EpCAM mAb can potentially be used for cancer-targeted therapy.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('anti-EpCAM', 'Var', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
2575	26317650	Moreover, subsequent data from clinical trials of other anti-EpCAM antibody-based drug candidates, such as Edrecolomab and Adecatumumab (MT201), suggested that anti-EpCAM monoclonal antibodies have only limited anti-tumor effects, primarily through activation of complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC).	('cytotoxicity', 'Disease', (335, 347))	('activation of complement-dependent cytotoxicity', 'biological_process', 'GO:1903661', ('249', '296'))	('antibody', 'cellular_component', 'GO:0019815', ('307', '315'))	('Adecatumumab', 'Chemical', 'MESH:C460839', (123, 135))	('cytotoxicity', 'Disease', 'MESH:D064420', (335, 347))	('tumor', 'Disease', (216, 221))	('antibody', 'cellular_component', 'GO:0019815', ('67', '75'))	('activation', 'PosReg', (249, 259))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('antibody', 'cellular_component', 'GO:0019814', ('307', '315'))	('anti-EpCAM', 'Var', (160, 170))	('cytotoxicity', 'Disease', (284, 296))	('antibody', 'cellular_component', 'GO:0019814', ('67', '75'))	('cytotoxicity', 'Disease', 'MESH:D064420', (284, 296))	('antibody-dependent cellular cytotoxicity', 'biological_process', 'GO:0001788', ('307', '347'))	('ADCC', 'biological_process', 'GO:0001788', ('349', '353'))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('antibody', 'molecular_function', 'GO:0003823', ('307', '315'))	('antibody', 'cellular_component', 'GO:0042571', ('307', '315'))	('antibody', 'molecular_function', 'GO:0003823', ('67', '75'))	('antibody', 'cellular_component', 'GO:0042571', ('67', '75'))	('Edrecolomab', 'Chemical', 'MESH:C400149', (107, 118))
2594	26317650	2A) revealed a dramatic decrease in EpAb2-6 after EpCAM knockdown, thereby confirming the specificity of EpAb2-6 against EpCAM.	('EpAb2-6', 'Chemical', '-', (105, 112))	('EpAb2-6', 'Chemical', '-', (36, 43))	('EpAb2-6', 'MPA', (36, 43))	('decrease', 'NegReg', (24, 32))	('knockdown', 'Var', (56, 65))
2595	26317650	S1), EpAb2-6 was able to induce apoptosis of SAS, SW620, HCT116, and HCT116 (TP53-/-), but not HCT116/shEpCAM or normal cell lines (NNM) (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (95, 101))	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('apoptosis', 'CPA', (32, 41))	('EpAb2-6', 'Chemical', '-', (5, 12))	('induce', 'PosReg', (25, 31))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('HCT116', 'CellLine', 'CVCL:0291', (69, 75))	('TP53', 'Gene', '7157', (77, 81))	('EpAb2-6', 'Var', (5, 12))	('TP53', 'Gene', (77, 81))	('HCT116', 'CellLine', 'CVCL:0291', (57, 63))
2598	26317650	On the other hand, we found that EpCAM knockdown decreased the viability of untreated cells (data not shown), demonstrating that loss of EpCAM has negative effects on cell survival in HCT116.	('viability', 'CPA', (63, 72))	('negative', 'NegReg', (147, 155))	('knockdown', 'Var', (39, 48))	('decreased', 'NegReg', (49, 58))	('loss', 'Var', (129, 133))	('HCT116', 'CellLine', 'CVCL:0291', (184, 190))	('cell survival', 'CPA', (167, 180))	('EpCAM', 'Gene', (137, 142))
2601	26317650	We previously reported that triggering EpICD cleavage and its subsequent nuclear translocation are involved in cancer initiation in TICs.	('cancer initiation', 'Disease', (111, 128))	('cleavage', 'Var', (45, 53))	('nuclear translocation', 'MPA', (73, 94))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('involved', 'Reg', (99, 107))	('TIC', 'Phenotype', 'HP:0100033', (132, 135))	('TICs', 'Disease', (132, 136))	('TICs', 'Phenotype', 'HP:0100033', (132, 136))	('cancer initiation', 'Disease', 'MESH:D009369', (111, 128))
2605	26317650	Collectively, these results suggest that EpAb2-6 may induce cancer cell cytotoxic activity by inducing an apoptosis pathway, and that EpAb2-6 inhibits EpICD nuclear translocation by blocking the cleavage of EpCAM.	('blocking', 'NegReg', (182, 190))	('EpICD nuclear translocation', 'MPA', (151, 178))	('EpAb2-6', 'Var', (41, 48))	('EpAb2-6', 'Chemical', '-', (134, 141))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('apoptosis', 'CPA', (106, 115))	('inhibits', 'NegReg', (142, 150))	('cleavage', 'MPA', (195, 203))	('cancer', 'Disease', (60, 66))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('EpAb2-6', 'Chemical', '-', (41, 48))	('inducing', 'Reg', (94, 102))	('EpAb2-6', 'Var', (134, 141))	('EpCAM', 'Protein', (207, 212))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('induce', 'PosReg', (53, 59))
2608	26317650	Western blotting was used to determine the reactivity of EpAb2-6 or EpAb3-5 antibodies towards these EpCAM mutants (Fig.	('EpAb', 'Gene', (68, 72))	('EpCAM', 'Gene', (101, 106))	('EpAb2-6', 'Chemical', '-', (57, 64))	('mutants', 'Var', (107, 114))	('EpAb', 'Gene', '381404', (68, 72))	('EpAb', 'Gene', '381404', (57, 61))	('EpAb', 'Gene', (57, 61))
2609	26317650	Amino acid mutations at positions Y95 or D96 in the EGF-II domain of EpCAM caused marked reductions in binding activity of EpAb2-6, but not EpAb3-5 (Fig.	('EpCAM', 'Gene', (69, 74))	('EGF', 'molecular_function', 'GO:0005154', ('52', '55'))	('EpAb', 'Gene', (140, 144))	('binding', 'Interaction', (103, 110))	('binding', 'molecular_function', 'GO:0005488', ('103', '110'))	('EpAb2-6', 'Chemical', '-', (123, 130))	('D96', 'Var', (41, 44))	('reductions', 'NegReg', (89, 99))	('EpAb', 'Gene', '381404', (123, 127))	('EpAb', 'Gene', '381404', (140, 144))	('EpAb', 'Gene', (123, 127))
2610	26317650	However, amino acid mutations at positions Q54, N55, Q89, N90, D92, G93, and L94 had no effect on the binding affinity of EpAb2-6 to EpCAM (Fig.	('D92', 'Var', (63, 66))	('N55', 'Var', (48, 51))	('EpAb2-6', 'Protein', (122, 129))	('N90', 'Var', (58, 61))	('Q89', 'Var', (53, 56))	('binding', 'molecular_function', 'GO:0005488', ('102', '109'))	('Q54', 'Var', (43, 46))	('binding affinity', 'Interaction', (102, 118))	('G93', 'Var', (68, 71))	('EpAb2-6', 'Chemical', '-', (122, 129))	('L94', 'Var', (77, 80))
2622	26317650	At 48 hours after injection, the near-infrared (NIR) fluorescence signal intensity in the tumor tissues of EpAb2-6-HL750-treated mice was significantly higher than that of mice treated with non-conjugated HL750 and NM-IgG-HL750 (Fig.	('higher', 'PosReg', (152, 158))	('EpAb2-6', 'Chemical', '-', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('IgG', 'Gene', (218, 221))	('EpAb2-6-HL750-treated', 'Var', (107, 128))	('mice', 'Species', '10090', (172, 176))	('IgG', 'Gene', '16059', (218, 221))	('mice', 'Species', '10090', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
2625	26317650	These results indicate that EpAb2-6-HL750 exhibits high levels of tumor binding.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('binding', 'molecular_function', 'GO:0005488', ('72', '79'))	('EpAb2-6-HL750', 'Var', (28, 41))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('EpAb2-6', 'Chemical', '-', (28, 35))
2633	26317650	The median overall survival rates for tumor-bearing mice after treatment with PBS, IFL, EpAb2-6, and EpAb2-6 + IFL were 57, 74, 99, and 112 days, respectively (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('EpAb2-6', 'Chemical', '-', (101, 108))	('PBS', 'Disease', (78, 81))	('EpAb2-6', 'Chemical', '-', (88, 95))	('EpAb2-6 +', 'Chemical', '-', (101, 110))	('mice', 'Species', '10090', (52, 56))	('EpAb2-6', 'Var', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('PBS', 'Disease', 'MESH:D011535', (78, 81))	('IFL', 'Chemical', '-', (83, 86))	('IFL', 'Chemical', '-', (111, 114))
2637	26317650	SW620 is p53 mutation and less sensitive to IFL therapy.	('p53', 'Gene', '7157', (9, 12))	('SW620', 'Var', (0, 5))	('IFL', 'Chemical', '-', (44, 47))	('p53', 'Gene', (9, 12))
2642	26317650	The median overall survival of tumor-bearing mice treated with EpAb2-6 (144 days) was significantly higher than that of PBS-treated mice (84 days; Fig.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mice', 'Species', '10090', (45, 49))	('EpAb2-6', 'Var', (63, 70))	('tumor', 'Disease', (31, 36))	('mice', 'Species', '10090', (132, 136))	('higher', 'PosReg', (100, 106))	('PBS', 'Disease', 'MESH:D011535', (120, 123))	('EpAb2-6', 'Chemical', '-', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('PBS', 'Disease', (120, 123))
2652	26317650	We found that EpAb2-6 not only induces AsPC-1 cancer cell apoptosis (Supplementary Fig.	('AsPC-1 cancer', 'Disease', 'MESH:D009369', (39, 52))	('EpAb2-6', 'Var', (14, 21))	('induces', 'PosReg', (31, 38))	('apoptosis', 'biological_process', 'GO:0097194', ('58', '67'))	('apoptosis', 'biological_process', 'GO:0006915', ('58', '67'))	('AsPC-1 cancer', 'Disease', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('EpAb2-6', 'Chemical', '-', (14, 21))
2655	26317650	The median overall survival of tumor-bearing mice treated with EpAb2-6 was significantly higher than that of PBS and isotype-treated mice (Fig.	('mice', 'Species', '10090', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mice', 'Species', '10090', (45, 49))	('EpAb2-6', 'Var', (63, 70))	('tumor', 'Disease', (31, 36))	('PBS', 'Disease', 'MESH:D011535', (109, 112))	('PBS', 'Disease', (109, 112))	('higher', 'PosReg', (89, 95))	('EpAb2-6', 'Chemical', '-', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
2662	26317650	The median overall survival rates of tumor-bearing mice after treatment with PBS, gemcitabine, EpAb2-6, and EpAb2-6 + gemcitabine were 35, 43, 48, and 54 days, respectively (Fig.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mice', 'Species', '10090', (51, 55))	('EpAb2-6', 'Var', (108, 115))	('EpAb2-6', 'Chemical', '-', (95, 102))	('PBS', 'Disease', 'MESH:D011535', (77, 80))	('PBS', 'Disease', (77, 80))	('EpAb2-6 +', 'Chemical', '-', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('gemcitabine', 'Chemical', 'MESH:C056507', (118, 129))	('tumor', 'Disease', (37, 42))	('EpAb2-6', 'Chemical', '-', (108, 115))	('gemcitabine', 'Chemical', 'MESH:C056507', (82, 93))
2672	26317650	The affinities of EpAb2-6 and hEpAb2-6 for EpCAM were analyzed by surface plasmon resonance, and shown to be 0.3491 nM and 0.6773 nM, respectively (Table 1b).	('EpAb2-6', 'Chemical', '-', (31, 38))	('0.6773 nM', 'Var', (123, 132))	('0.3491 nM', 'Var', (109, 118))	('EpAb2-6', 'Chemical', '-', (18, 25))
2677	26317650	We have previously established that EpCAM (specifically the EpICD) promotes tumorigenesis in TICs through up-regulation of reprogramming genes and the epithelial-mesenchymal transition (EMT) process.	('promotes', 'PosReg', (67, 75))	('EpCAM', 'Var', (36, 41))	('regulation', 'biological_process', 'GO:0065007', ('109', '119'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('151', '184'))	('TIC', 'Phenotype', 'HP:0100033', (93, 96))	('reprogramming genes', 'Gene', (123, 142))	('TICs', 'Phenotype', 'HP:0100033', (93, 97))	('up-regulation', 'PosReg', (106, 119))	('EMT', 'biological_process', 'GO:0001837', ('186', '189'))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
2681	26317650	Our results indicate that EpAb2-6 can directly induce apoptosis in cancer cells by increasing cleavage of PARP and decreasing pro-caspase-3 proteins.	('apoptosis', 'CPA', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('induce', 'PosReg', (47, 53))	('pro-caspase-3', 'Gene', (126, 139))	('cancer', 'Disease', (67, 73))	('PARP', 'Gene', (106, 110))	('pro-caspase-3', 'Gene', '836', (126, 139))	('EpAb2-6', 'Chemical', '-', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('EpAb2-6', 'Var', (26, 33))	('cleavage', 'MPA', (94, 102))	('decreasing', 'NegReg', (115, 125))	('increasing', 'PosReg', (83, 93))	('PARP', 'Gene', '1302', (106, 110))
2682	26317650	To our knowledge, this is the first study to describe an anti-EpCAM mAb that directly induces cancer cell death by inhibiting EpCAM signaling, rather than by acting through the ADCC or CDC pathways.	('EpCAM signaling', 'MPA', (126, 141))	('ADCC', 'biological_process', 'GO:0001788', ('177', '181'))	('induces', 'Reg', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('inhibiting', 'NegReg', (115, 125))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('cell death', 'biological_process', 'GO:0008219', ('101', '111'))	('anti-EpCAM', 'Var', (57, 67))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
2688	26317650	No published study has demonstrated direct induction of cancer cell apoptosis by anti-EpCAM antibodies in a clinical setting, and so it remains unclear whether such antibodies can directly inhibit tumor cell proliferation.	('anti-EpCAM antibodies', 'Var', (81, 102))	('antibodies', 'Var', (92, 102))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('apoptosis', 'biological_process', 'GO:0006915', ('68', '77'))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('68', '77'))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('cell proliferation', 'biological_process', 'GO:0008283', ('203', '221'))	('inhibit', 'NegReg', (189, 196))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Disease', (197, 202))	('anti-EpCAM', 'Gene', (81, 91))
2689	26317650	In this study, EpAb2-6 was observed to directly induce apoptosis in HCT116 and HCT116 (TP53-/-) cell lines in vitro (Fig.	('TP53', 'Gene', '7157', (87, 91))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('induce', 'PosReg', (48, 54))	('HCT116', 'CellLine', 'CVCL:0291', (68, 74))	('TP53', 'Gene', (87, 91))	('EpAb2-6', 'Chemical', '-', (15, 22))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('HCT116', 'CellLine', 'CVCL:0291', (79, 85))	('EpAb2-6', 'Var', (15, 22))	('apoptosis', 'CPA', (55, 64))
2691	26317650	Our findings provide direct evidence that our anti-EpCAM antibody is able to inhibit tumor cell proliferation.	('antibody', 'cellular_component', 'GO:0042571', ('57', '65'))	('tumor', 'Disease', (85, 90))	('antibody', 'cellular_component', 'GO:0019815', ('57', '65'))	('inhibit', 'NegReg', (77, 84))	('antibody', 'cellular_component', 'GO:0019814', ('57', '65'))	('cell proliferation', 'biological_process', 'GO:0008283', ('91', '109'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('antibody', 'molecular_function', 'GO:0003823', ('57', '65'))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('anti-EpCAM', 'Var', (46, 56))
2692	26317650	Our study found that p53 expression is increased by EpCAM knockdown.	('EpCAM', 'Gene', (52, 57))	('expression', 'MPA', (25, 35))	('p53', 'Gene', '7157', (21, 24))	('increased', 'PosReg', (39, 48))	('knockdown', 'Var', (58, 67))	('p53', 'Gene', (21, 24))
2693	26317650	Interestingly, EpAb2-6 also kills p53 mutant colon cancer cells (Table 2 and Supplementary Figs S2 and S3), suggesting that this antibody exerts its apoptotic effects through multiple mechanisms, potentially involving both p53-dependent and -independent pathways.	('colon cancer', 'Disease', (45, 57))	('p53', 'Gene', (34, 37))	('mutant', 'Var', (38, 44))	('p53', 'Gene', '7157', (34, 37))	('antibody', 'cellular_component', 'GO:0019814', ('129', '137'))	('p53', 'Gene', (223, 226))	('p53', 'Gene', '7157', (223, 226))	('EpAb2-6', 'Chemical', '-', (15, 22))	('colon cancer', 'Phenotype', 'HP:0003003', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('antibody', 'molecular_function', 'GO:0003823', ('129', '137'))	('colon cancer', 'Disease', 'MESH:D015179', (45, 57))	('apoptotic effects', 'CPA', (149, 166))	('antibody', 'cellular_component', 'GO:0042571', ('129', '137'))	('antibody', 'cellular_component', 'GO:0019815', ('129', '137'))
2694	26317650	Mutation or deletion of the TP53 gene, which is associated with poor prognosis and drug resistance, is observed in over 50 percent of human tumors.	('deletion', 'Var', (12, 20))	('TP53', 'Gene', '7157', (28, 32))	('human', 'Species', '9606', (134, 139))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('drug resistance', 'Phenotype', 'HP:0020174', (83, 98))	('TP53', 'Gene', (28, 32))	('Mutation', 'Var', (0, 8))	('drug resistance', 'biological_process', 'GO:0009315', ('83', '98'))	('drug resistance', 'biological_process', 'GO:0042493', ('83', '98'))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
2704	26317650	EpCAM-positive CTCs are associated with poor prognosis, very low overall survival, and the presence of lymph node metastases.	('metastases', 'Disease', (114, 124))	('EpCAM-positive', 'Var', (0, 14))	('low', 'NegReg', (61, 64))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('CTCs', 'Disease', (15, 19))	('overall survival', 'MPA', (65, 81))
2721	26317650	Our results reveal that administration of EpAb2-6 not only enhances the antitumor activity of IFL against CRC, but it also increases the therapeutic efficacy of gemcitabine against pancreatic cancer.	('therapeutic', 'MPA', (137, 148))	('pancreatic cancer', 'Disease', 'MESH:D010190', (181, 198))	('pancreatic cancer', 'Disease', (181, 198))	('EpAb2-6', 'Var', (42, 49))	('gemcitabine', 'Chemical', 'MESH:C056507', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (181, 198))	('EpAb2-6', 'Chemical', '-', (42, 49))	('IFL', 'Chemical', '-', (94, 97))	('enhances', 'PosReg', (59, 67))	('CRC', 'Disease', (106, 109))	('CRC', 'Phenotype', 'HP:0030731', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('increases', 'PosReg', (123, 132))
2722	26317650	Importantly, EpAb2-6 markedly prolongs the median overall survival of metastatic tumor-bearing mice (Figs 5 and 6).	('mice', 'Species', '10090', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('EpAb2-6', 'Chemical', '-', (13, 20))	('prolongs', 'PosReg', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('EpAb2-6', 'Var', (13, 20))
2723	26317650	Hence, EpAb2-6 may potentially increase the therapeutic index of the current metastatic CRC and pancreatic cancer treatment regimens when used in combination with IFL or gemcitabine.	('therapeutic index', 'MPA', (44, 61))	('pancreatic cancer', 'Disease', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('EpAb2-6', 'Chemical', '-', (7, 14))	('metastatic CRC', 'Disease', (77, 91))	('CRC', 'Phenotype', 'HP:0030731', (88, 91))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))	('gemcitabine', 'Chemical', 'MESH:C056507', (170, 181))	('IFL', 'Chemical', '-', (163, 166))	('EpAb2-6', 'Var', (7, 14))	('increase', 'PosReg', (31, 39))
2724	26317650	To elucidate the exact mechanism underlying the inhibition of tumorigenesis by EpAb2-6, we used phage display to identify the B cell epitope of EpAb2-6: this revealed that positions Y95 and D96 in the EGF-II/thyroglobulin (TY) repeat (EGF-II/TY) domain of EpCAM are recognized by EpAb2-6 (Fig.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('EpAb2-6', 'Chemical', '-', (280, 287))	('D96', 'Var', (190, 193))	('tumor', 'Disease', (62, 67))	('EGF', 'molecular_function', 'GO:0005154', ('235', '238'))	('EpAb2-6', 'Chemical', '-', (144, 151))	('EGF', 'molecular_function', 'GO:0005154', ('201', '204'))	('EpAb2-6', 'Chemical', '-', (79, 86))
2730	26317650	However, we have shown that treatment with sEpEX (soluble EpEX) or transfection with the EpEX gene promotes the cleavage of EpICD and induces activation of reprogramming genes, suggesting that EpEX cleavage may initialize EpCAM signaling, and its release may further activate EpCAM.	('EpEX', 'Gene', (89, 93))	('cleavage', 'MPA', (112, 120))	('EpEX', 'Var', (193, 197))	('reprogramming genes', 'Gene', (156, 175))	('EpICD', 'Gene', (124, 129))	('activation', 'PosReg', (142, 152))	('soluble', 'cellular_component', 'GO:0005625', ('50', '57'))	('EpCAM', 'CPA', (276, 281))	('EpCAM signaling', 'MPA', (222, 237))	('cleavage', 'Var', (198, 206))	('signaling', 'biological_process', 'GO:0023052', ('228', '237'))	('sEpEX', 'Chemical', '-', (43, 48))	('activate', 'PosReg', (267, 275))
2734	26317650	Based on our results, we propose that EpAb2-6 inhibits tumor growth through two pathways.	('two pathways', 'Pathway', (76, 88))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('EpAb2-6', 'Var', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('inhibits', 'NegReg', (46, 54))	('tumor', 'Disease', (55, 60))	('EpAb2-6', 'Chemical', '-', (38, 45))
2735	26317650	The first is direct induction of cancer cell apoptosis or inhibition of EpCAM cleavage into EpICD and EpEX by binding to positions Y95 and D96 of the EGF-II/TY domain (Fig.	('induction', 'Reg', (20, 29))	('binding', 'molecular_function', 'GO:0005488', ('110', '117'))	('cancer', 'Disease', (33, 39))	('D96', 'Var', (139, 142))	('EpCAM', 'Gene', (72, 77))	('cleavage', 'MPA', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('EGF', 'molecular_function', 'GO:0005154', ('150', '153'))	('binding', 'Interaction', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('inhibition', 'NegReg', (58, 68))
2762	26317650	Cells were incubated at room temperature with anti-EpCAM mAbs (1 mug/ml) or anti-EpICD mAb (1:100 dilution; 1144-1; Epitomics, Burlingame, CA), in 1% bovine serum albumin.	('bovine', 'Species', '9913', (150, 156))	('anti-EpCAM', 'Var', (46, 56))	('anti-EpICD', 'Var', (76, 86))	('mug', 'molecular_function', 'GO:0043739', ('65', '68'))
2782	26317650	Site-directed mutagenesis was used to generate EpCAM mutants, using the recombinant expression plasmid pcDNA  3.1/V5-His.	('mutants', 'Var', (53, 60))	('mutagenesis', 'biological_process', 'GO:0006280', ('14', '25'))	('EpCAM', 'Gene', (47, 52))	('His', 'Chemical', 'MESH:D006639', (117, 120))
2783	26317650	HEK293 cells at 80-90% confluency in 6-well plates were transfected with plasmids encoding various EpCAM mutants.	('EpCAM', 'Gene', (99, 104))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('mutants', 'Var', (105, 112))
2787	26317650	EpAb2-6 or NM-IgG (600 mug) were incubated with HEPES solution containing 20 nmole HiLyte Fluor  750 acid NHS ester (HiLyte-750) (AnaSpec) at 4 C overnight, in order to conjugate HiLyte-750 to the mAb via the NHS functional group.	('IgG', 'Gene', '16059', (14, 17))	('HiLyte-750', 'Chemical', '-', (179, 189))	('HEPES', 'Chemical', 'MESH:D006531', (48, 53))	('IgG', 'Gene', (14, 17))	('HiLyte-750', 'Chemical', '-', (117, 127))	('HiLyte Fluor  750 acid NHS ester', 'Chemical', '-', (83, 115))	('EpAb2-6', 'Chemical', '-', (0, 7))	('conjugate', 'Reg', (169, 178))	('mug', 'molecular_function', 'GO:0043739', ('23', '26'))	('HiLyte-750', 'Var', (179, 189))
2812	26317650	Humanized EpAb2-6 VH consisted of the modified FR1 to FR4 from the accession DI164282 gene, and the CDR1 to CDR3 of EpAb2-6 VH, respectively.	('Human', 'Species', '9606', (0, 5))	('EpAb2-6', 'Chemical', '-', (10, 17))	('CDR3', 'Gene', '8163', (108, 112))	('CDR1', 'Gene', '1038', (100, 104))	('CDR1', 'Gene', (100, 104))	('EpAb2-6', 'Chemical', '-', (116, 123))	('modified', 'Var', (38, 46))	('FR1 to FR4', 'Gene', (47, 57))	('CDR3', 'Gene', (108, 112))
2823	25993003	In Capan-1 cells, PPIs inhibited recovery of intracellular pH from acidosis.	('acidosis', 'Disease', 'MESH:D000138', (67, 75))	('PPIs', 'Var', (18, 22))	('pH', 'Gene', '2821', (59, 61))	('inhibited', 'NegReg', (23, 32))	('acidosis', 'Disease', (67, 75))	('acidosis', 'Phenotype', 'HP:0001941', (67, 75))	('intracellular', 'cellular_component', 'GO:0005622', ('45', '58'))	('Capan-1', 'CellLine', 'CVCL:0237', (3, 10))
2824	25993003	Furthermore, in rats treated with PPIs, pancreatic secretion was inhibited but concentrations of major ions in secretion follow similar excretory curves in control and PPI treated animals.	('pancreatic secretion', 'Disease', 'MESH:D010195', (40, 60))	('rat', 'Species', '10116', (16, 19))	('secretion', 'biological_process', 'GO:0046903', ('111', '120'))	('PPI', 'biological_process', 'GO:0060134', ('168', '171'))	('secretion', 'biological_process', 'GO:0046903', ('51', '60'))	('rats', 'Species', '10116', (16, 20))	('inhibited', 'NegReg', (65, 74))	('PPIs', 'Var', (34, 38))	('rat', 'Species', '10116', (86, 89))	('pancreatic secretion', 'Disease', (40, 60))
2837	25993003	In addition to NBCs and NHE, earlier studies have shown vacuolar H+ ATPase (V-ATPase) activity on the basolateral membrane of pancreatic ducts by intracellular pH (pHi) measurements and use of the V-ATPase inhibitor bafilomycin A1 Nevertheless, whether the V-ATPase plays a significant role in pancreatic HCO3 - secretion is not clarified, as for example in guinea pig pancreatic ducts bafilomycin A1 could not inhibit agonist-stimulated HCO3 - and fluid secretion.	('V-ATPase', 'cellular_component', 'GO:0008245', ('257', '265'))	('ATPase', 'Gene', (68, 74))	('pancreatic', 'Disease', 'MESH:D010195', (369, 379))	('V-ATPase', 'cellular_component', 'GO:0000219', ('197', '205'))	('bafilomycin A1', 'Var', (386, 400))	('V-ATPase', 'cellular_component', 'GO:0000219', ('257', '265'))	('intracellular', 'cellular_component', 'GO:0005622', ('146', '159'))	('ATPase', 'Gene', '1769', (68, 74))	('V-ATPase', 'cellular_component', 'GO:0000219', ('76', '84'))	('pancreatic duct', 'Disease', 'MESH:D021441', (126, 141))	('pHi', 'Gene', '2821', (164, 167))	('ATPase', 'Gene', (199, 205))	('pancreatic', 'Disease', (369, 379))	('ATPase) activity', 'molecular_function', 'GO:0016887', ('78', '94'))	('V-ATPase', 'cellular_component', 'GO:0008245', ('197', '205'))	('inhibit', 'NegReg', (411, 418))	('pH', 'Gene', '2821', (160, 162))	('ATPase', 'Gene', '1769', (199, 205))	('bafilomycin', 'Chemical', '-', (386, 397))	('pancreatic duct', 'Disease', (126, 141))	('secretion', 'biological_process', 'GO:0046903', ('455', '464'))	('pancreatic', 'Disease', 'MESH:D010195', (126, 136))	('pancreatic', 'Disease', 'MESH:D010195', (294, 304))	('ATPase', 'Gene', (259, 265))	('pancreatic duct', 'Disease', 'MESH:D021441', (369, 384))	('membrane', 'cellular_component', 'GO:0016020', ('114', '122'))	('HCO3', 'Chemical', 'MESH:D001639', (305, 309))	('secretion', 'biological_process', 'GO:0046903', ('312', '321'))	('pH', 'Gene', '2821', (164, 166))	('ATPase', 'Gene', (78, 84))	('bafilomycin', 'Chemical', '-', (216, 227))	('ATPase', 'Gene', '1769', (259, 265))	('pHi', 'Gene', (164, 167))	('HCO3', 'Chemical', 'MESH:D001639', (438, 442))	('guinea pig', 'Species', '10141', (358, 368))	('V-ATPase', 'cellular_component', 'GO:0008245', ('76', '84'))	('pancreatic duct', 'Disease', (369, 384))	('ATPase', 'Gene', '1769', (78, 84))	('pancreatic', 'Disease', (126, 136))	('pancreatic', 'Disease', (294, 304))
2861	25993003	Briefly, Capan-1 cells grown on standard Ibidi mu-Dish35mm were loaded with 2 muM BCECF/AM (Invitrogen) for 20-30 min; thereafter they were superfused at 2 ml/min, at 37 C. Control perfusate had the following composition (in mM): Na+ 145, Cl- 145, K+ 4, Ca2+ 1.5, Mg2+ 1, phosphate 2, HEPES 10 glucose 5; pH was 7.4.	('muM', 'Gene', (78, 81))	('Ca2+', 'Chemical', 'MESH:D000069285', (254, 258))	('Capan-1', 'CellLine', 'CVCL:0237', (9, 16))	('Na+ 145', 'Var', (230, 237))	('BCECF', 'Chemical', 'MESH:C043829', (82, 87))	('glucose', 'Chemical', 'MESH:D005947', (294, 301))	('pH', 'Gene', '2821', (305, 307))	('Mg2', 'Chemical', '-', (264, 267))	('HEPES', 'Chemical', 'MESH:D006531', (285, 290))	('muM', 'Gene', '56925', (78, 81))	('K+ 4', 'Var', (248, 252))	('phosphate', 'Chemical', 'MESH:D010710', (272, 281))
2867	25993003	Tissues were exposed to ammonium pulses (2-3 min), then ammonium was removed, and pHi recovery rates from acidosis were determined from the initial slopes of pHi changes and expressed as dpH/dt (i.e.	('ammonium', 'Chemical', 'MESH:D064751', (24, 32))	('pHi', 'Gene', '2821', (158, 161))	('ammonium', 'Chemical', 'MESH:D064751', (56, 64))	('pHi', 'Gene', '2821', (82, 85))	('pHi', 'Gene', (158, 161))	('acidosis', 'Disease', 'MESH:D000138', (106, 114))	('rat', 'Species', '10116', (95, 98))	('pHi', 'Gene', (82, 85))	('dpH', 'Chemical', 'MESH:D010672', (187, 190))	('acidosis', 'Phenotype', 'HP:0001941', (106, 114))	('acidosis', 'Disease', (106, 114))	('changes', 'Var', (162, 169))	('dt', 'Chemical', 'MESH:D013936', (191, 193))
2913	25993003	Capan-1 and PANC-1 cells express functional CFTR, while CFPAC-1 cells have F508 deletion in CFTR and thus the protein expression and function are defect.	('function', 'MPA', (133, 141))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('protein', 'Protein', (110, 117))	('PANC-1', 'CellLine', 'CVCL:0480', (12, 18))	('F508 deletion', 'Var', (75, 88))	('CFTR', 'Gene', '1080', (44, 48))	('CFTR', 'Gene', '1080', (92, 96))	('CFPAC-1', 'CellLine', 'CVCL:1119', (56, 63))	('defect', 'NegReg', (146, 152))	('Capan-1', 'CellLine', 'CVCL:0237', (0, 7))	('CFTR', 'Gene', (44, 48))	('CFTR', 'Gene', (92, 96))
2936	25993003	The gastric H+/K+ pump inhibitor omeprazole inhibited 75% of the Na+ independent pHi recovery (n = 6), while SCH28080 reduced the Na+ independent pHi recovery by 52% (n = 5).	('SCH28080', 'Var', (109, 117))	('pHi', 'Gene', (81, 84))	('SCH28080', 'Chemical', 'MESH:C035235', (109, 117))	('inhibited', 'NegReg', (44, 53))	('pHi', 'Gene', '2821', (146, 149))	('omeprazole', 'Chemical', 'MESH:D009853', (33, 43))	('pHi', 'Gene', '2821', (81, 84))	('pHi', 'Gene', (146, 149))
2937	25993003	In addition, PPIs also reduced pHi recovery when cells were returned to control Na+ containing buffer (Fig 4 phase III vs.	('PPIs', 'Var', (13, 17))	('pHi', 'Gene', '2821', (31, 34))	('reduced', 'NegReg', (23, 30))	('pHi', 'Gene', (31, 34))
2953	25993003	In order to check the possible contribution of non-gastric H+/K+ pump to pancreatic secretion, the acute effects of SCH28080 were tested.	('SCH28080', 'Var', (116, 124))	('SCH28080', 'Chemical', 'MESH:C035235', (116, 124))	('pancreatic secretion', 'Disease', 'MESH:D010195', (73, 93))	('pancreatic secretion', 'Disease', (73, 93))	('secretion', 'biological_process', 'GO:0046903', ('84', '93'))
2954	25993003	SCH28080 inhibits gastric pump and it has been reported that in high doses it can also inhibit non-gastric H+/K+ pumps.	('SCH28080', 'Var', (0, 8))	('non-gastric H+/K+ pumps', 'MPA', (95, 118))	('gastric pump', 'MPA', (18, 30))	('inhibits', 'NegReg', (9, 17))	('SCH28080', 'Chemical', 'MESH:C035235', (0, 8))	('inhibit', 'NegReg', (87, 94))
2956	25993003	There seems to be more pronounced inhibition of secretion with SCH28080 than with omeprazole compared to their respective controls.	('inhibition of secretion', 'biological_process', 'GO:0051048', ('34', '57'))	('omeprazole', 'Chemical', 'MESH:D009853', (82, 92))	('secretion', 'MPA', (48, 57))	('inhibition', 'NegReg', (34, 44))	('SCH28080', 'Var', (63, 71))	('SCH28080', 'Chemical', 'MESH:C035235', (63, 71))
2957	25993003	Interestingly, given the dose of inhibitors used in our studies, we would have expected weaker inhibition by SCH28080, due to higher expected ED50 values.	('SCH28080', 'Var', (109, 117))	('SCH28080', 'Chemical', 'MESH:C035235', (109, 117))	('higher', 'PosReg', (126, 132))	('ED50 values', 'MPA', (142, 153))	('weaker', 'NegReg', (88, 94))
2969	25993003	Also with SCH28080, HCO3 - concentrations decreased in low secretory rates.	('decreased', 'NegReg', (42, 51))	('SCH28080', 'Var', (10, 18))	('HCO3', 'Chemical', 'MESH:D001639', (20, 24))	('low secretory rates', 'MPA', (55, 74))	('SCH28080', 'Chemical', 'MESH:C035235', (10, 18))	('rat', 'Species', '10116', (34, 37))	('HCO3 - concentrations', 'MPA', (20, 41))	('rat', 'Species', '10116', (69, 72))
3004	25993003	Additionally, several mucin genes have been identified in pancreatic duct cells and pancreatic mucins would be relevant in epithelial protection, and altered expression pattern of mucins is one of the important factors in development and drug resistance in pancreatic cancer.	('pancreatic', 'Disease', 'MESH:D010195', (84, 94))	('pancreatic cancer', 'Disease', (257, 274))	('expression', 'MPA', (158, 168))	('pancreatic', 'Disease', (84, 94))	('pancreatic cancer', 'Disease', 'MESH:D010190', (257, 274))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('drug resistance', 'Phenotype', 'HP:0020174', (238, 253))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (257, 274))	('pancreatic', 'Disease', 'MESH:D010195', (58, 68))	('pancreatic', 'Disease', 'MESH:D010195', (257, 267))	('drug resistance', 'biological_process', 'GO:0009315', ('238', '253'))	('altered', 'Var', (150, 157))	('drug resistance', 'biological_process', 'GO:0042493', ('238', '253'))	('pancreatic', 'Disease', (58, 68))	('pancreatic duct', 'Disease', (58, 73))	('pancreatic duct', 'Disease', 'MESH:D021441', (58, 73))	('pancreatic', 'Disease', (257, 267))
3007	25993003	The observation that PPIs and P-CABs inhibit secretin-evoked pancreatic secretion in in vivo rat studies shows that H+/K+-pumps are in general involved in pancreatic duct secretion.	('secretin', 'molecular_function', 'GO:0008565', ('45', '53'))	('pancreatic secretion', 'Disease', 'MESH:D010195', (61, 81))	('secretion', 'biological_process', 'GO:0046903', ('171', '180'))	('P-CABs', 'Var', (30, 36))	('pancreatic secretion', 'Disease', (61, 81))	('inhibit', 'NegReg', (37, 44))	('pancreatic duct secretion', 'Disease', 'MESH:D021441', (155, 180))	('secretin', 'molecular_function', 'GO:0046659', ('45', '53'))	('secretion', 'biological_process', 'GO:0046903', ('72', '81'))	('PPIs', 'Var', (21, 25))	('pancreatic duct secretion', 'Disease', (155, 180))	('rat', 'Species', '10116', (93, 96))
3009	25993003	Omeprazole, the acid-activated pro-drug, would inhibit the gastric pump, while SCH28080, which competitively binds to the K+ site, could, most likely, inhibit both gastric and non-gastric pumps and seems more effective given the dose used in our experiments and published ED50 values.	('Omeprazole', 'Chemical', 'MESH:D009853', (0, 10))	('gastric pump', 'MPA', (59, 71))	('inhibit', 'NegReg', (47, 54))	('SCH28080', 'Var', (79, 87))	('SCH28080', 'Chemical', 'MESH:C035235', (79, 87))	('inhibit', 'NegReg', (151, 158))
3010	25993003	In pHi studies, we acidified the pro-drug and thus the activated form of omeprazole would be formed.	('pHi', 'Gene', (3, 6))	('pHi', 'Gene', '2821', (3, 6))	('omeprazole', 'Chemical', 'MESH:D009853', (73, 83))	('acidified', 'Var', (19, 28))
3013	25993003	Clearly, the first was the case and pancreatic secretion was further reduced by long-term PPI treatment.	('reduced', 'NegReg', (69, 76))	('secretion', 'biological_process', 'GO:0046903', ('47', '56'))	('PPI', 'Var', (90, 93))	('pancreatic secretion', 'Disease', 'MESH:D010195', (36, 56))	('pancreatic secretion', 'Disease', (36, 56))	('PPI', 'biological_process', 'GO:0060134', ('90', '93'))
3027	25993003	Our acute and long-term experiments on rats show that pancreatic secretion is significantly inhibited by PPIs.	('rats', 'Species', '10116', (39, 43))	('inhibited', 'NegReg', (92, 101))	('PPIs', 'Var', (105, 109))	('pancreatic secretion', 'Disease', 'MESH:D010195', (54, 74))	('secretion', 'biological_process', 'GO:0046903', ('65', '74'))	('pancreatic secretion', 'Disease', (54, 74))
3036	25988180	Methylation of cell-free circulating DNA in the diagnosis of cancer A range of molecular alterations found in tumor cells, such as DNA mutations and DNA methylation, is reflected in cell-free circulating DNA (circDNA) released from the tumor into the blood, thereby making circDNA an ideal candidate for the basis of a blood-based cancer diagnosis test.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('DNA', 'Gene', (131, 134))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))	('DNA', 'cellular_component', 'GO:0005574', ('149', '152'))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('mutations', 'Var', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('DNA', 'Gene', (149, 152))	('cancer', 'Disease', (61, 67))	('DNA methylation', 'biological_process', 'GO:0006306', ('149', '164'))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('methylation', 'Var', (153, 164))	('cancer', 'Disease', (331, 337))	('DNA', 'cellular_component', 'GO:0005574', ('204', '207'))	('tumor', 'Disease', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('tumor', 'Disease', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
3037	25988180	In many cancer types, mutations driving tumor development and progression are present in a wide range of oncogenes and tumor suppressor genes.	('tumor', 'Disease', (119, 124))	('cancer', 'Disease', (8, 14))	('tumor suppressor', 'biological_process', 'GO:0051726', ('119', '135'))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('119', '135'))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mutations', 'Var', (22, 31))	('men', 'Species', '9606', (53, 56))	('tumor', 'Disease', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
3041	25988180	Aberrant circDNA methylation has been described in most cancer types and is actively being investigated for clinical applications.	('described', 'Reg', (38, 47))	('clinical', 'Species', '191496', (108, 116))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
3042	25988180	A commercial blood test for colorectal cancer based on the methylation of the SEPT9 promoter region in circDNA is under review for approval by the Federal Drug Administration (FDA) for clinical use.	('clinical', 'Species', '191496', (185, 193))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('SEPT9', 'Gene', (78, 83))	('colorectal cancer', 'Disease', (28, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('methylation', 'Var', (59, 70))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('SEPT9', 'Gene', '10801', (78, 83))
3045	25988180	One of the surprising aspects of cancer biology that emerged from The Cancer Genome Atlas (TCGA) sequencing projects was the wide diversity of mutations that give rise to cancer (Vogelstein et al.,).	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('rise to cancer', 'Disease', 'MESH:D009369', (163, 177))	('cancer', 'Disease', (171, 177))	('rise to cancer', 'Disease', (163, 177))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Cancer Genome Atlas', 'Disease', (70, 89))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (70, 89))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('mutations', 'Var', (143, 152))
3050	25988180	For example, TP53 is one of the most consistently altered genes in high grade serous ovarian cancer (HGSOC), with around 95% of tumors harboring a mutation (Ahmed et al.,; Cancer Genome Atlas Research Network,).	('TP53', 'Gene', (13, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (85, 99))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (172, 191))	('mutation', 'Var', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Cancer', 'Phenotype', 'HP:0002664', (172, 178))	('GS', 'Disease', 'MESH:D011125', (102, 104))	('altered', 'Reg', (50, 57))	('Cancer Genome Atlas', 'Disease', (172, 191))	('tumors', 'Disease', (128, 134))	('serous ovarian cancer', 'Disease', (78, 99))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('TP53', 'Gene', '7157', (13, 17))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (78, 99))
3051	25988180	However, as predicted for a tumor suppressor gene (Vogelstein et al.,), the mutations show minimal clustering and are spread over several exons (Hollstein et al.,; Cancer Genome Atlas Research Network,), which span nearly 20 kilobases of sequence.	('mutations', 'Var', (76, 85))	('tumor', 'Disease', (28, 33))	('Cancer Genome Atlas', 'Disease', (164, 183))	('Cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (164, 183))	('tumor suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
3053	25988180	This diversity of mutations provides a challenge for the development of cancer diagnosis tests based on DNA sequence changes, as very large proportions of the genome would need to be interrogated to provide a test of adequate sensitivity (Schmidt and Diehl,).	('cancer', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('men', 'Species', '9606', (64, 67))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('changes', 'Var', (117, 124))	('mutations', 'Var', (18, 27))
3055	25988180	The 14-3-3 sigma promoter has been found to be methylated in 96% of breast carcinomas, and unmethylated in the breast epithelium of individuals without cancer (Umbricht et al.,).	('methylated', 'Var', (47, 57))	('breast carcinomas', 'Disease', (68, 85))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('breast carcinomas', 'Phenotype', 'HP:0003002', (68, 85))	('14-3-3 sigma', 'Gene', '2810', (4, 16))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('14-3-3 sigma', 'Gene', (4, 16))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast carcinomas', 'Disease', 'MESH:D001943', (68, 85))
3059	25988180	In individuals with cancer a proportion of circDNA is derived from tumor cells, and not only contains the same mutations as tumor cells, but also the same methylation pattern (Schwarzenbach et al.,).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('methylation', 'MPA', (155, 166))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (124, 129))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Disease', (20, 26))	('tumor', 'Disease', (67, 72))	('methylation', 'biological_process', 'GO:0032259', ('155', '166'))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
3073	25988180	However, in the course of the PRESEPT trial a simple technical change to the assay, designating a patient sample as positive when 1 of 3 rather than 1 of 2 PCR reactions showed methylated SEPT9 amplification, was identified as giving better sensitivity and incorporated into the trial.	('patient', 'Species', '9606', (98, 105))	('SEPT9', 'Gene', (188, 193))	('SEPT9', 'Gene', '10801', (188, 193))	('methylated', 'Var', (177, 187))
3088	25988180	used bisulphite conversion and methylation-specific PCR of circDNA to show that the CST6 promoter was methylated in two separate cohorts of breast cancer patients, with methylation found in 14/73 patients (19.2%) in the first cohort, and in 49/123 patients (39.8%) in the second cohort, while none of the 37 healthy individuals tested showed methylation.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('CST6', 'Gene', '1474', (84, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('bisulphite', 'Chemical', 'MESH:C042345', (5, 15))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (196, 204))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('methylation', 'biological_process', 'GO:0032259', ('169', '180'))	('methylation', 'Var', (169, 180))	('methylation', 'biological_process', 'GO:0032259', ('342', '353'))	('CST6', 'Gene', (84, 88))	('patients', 'Species', '9606', (248, 256))
3112	25988180	A recent study by Nones et al., as part of the Australian Pancreatic Cancer Genome Initiative (APGI), found high levels of aberrant methylation in crucial signaling pathways, suggesting its feasibility as a biomarker for disease.	('crucial signaling pathways', 'Pathway', (147, 173))	('aberrant', 'Var', (123, 131))	('methylation', 'MPA', (132, 143))	('Pancreatic Cancer', 'Disease', (58, 75))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('methylation', 'biological_process', 'GO:0032259', ('132', '143'))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (58, 75))	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (58, 75))
3114	25988180	One of the first studies identified PENK and CDKN2A methylation in the plasma of 21.4 and 45.4% of patients with localized pancreatic cancer, however, this study did not include a cancer-free control group (Jiao et al.,).	('localized pancreatic cancer', 'Disease', (113, 140))	('PENK', 'Gene', (36, 40))	('localized pancreatic cancer', 'Disease', 'MESH:D010190', (113, 140))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('patients', 'Species', '9606', (99, 107))	('PENK', 'Gene', '5179', (36, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (123, 140))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('methylation', 'Var', (52, 63))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('CDKN2A', 'Gene', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (180, 186))	('CDKN2A', 'Gene', '1029', (45, 51))
3117	25988180	This technique has been used to identify promoters that are hypomethylated in the plasma of pancreatic cancer patients relative to controls.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('hypomethylated', 'Var', (60, 74))	('pancreatic cancer', 'Disease', (92, 109))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))	('patients', 'Species', '9606', (110, 118))
3121	25988180	On the other hand, lack of detectable methylation is potentially useful in distinguishing cancer from conditions which present with similar symptoms.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('methylation', 'Var', (38, 49))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))
3122	25988180	The MethDet56 method described above was used to differentiate between healthy controls, pancreatic cancer patients and patients with chronic pancreatitis, with sequences that were methylated in chronic pancreatitis but unmethylated in pancreatic cancer contributing to the specificity of the biomarker (Liggett et al.,).	('pancreatitis', 'Phenotype', 'HP:0001733', (142, 154))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (195, 215))	('pancreatic cancer', 'Disease', 'MESH:D010190', (236, 253))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('pancreatitis', 'Disease', 'MESH:D010195', (142, 154))	('methylated', 'Var', (181, 191))	('pancreatitis', 'Disease', (142, 154))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('pancreatitis', 'Phenotype', 'HP:0001733', (203, 215))	('patients', 'Species', '9606', (107, 115))	('pancreatic cancer', 'Disease', (236, 253))	('pancreatitis', 'Disease', 'MESH:D010195', (203, 215))	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (236, 253))	('pancreatitis', 'Disease', (203, 215))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (134, 154))	('patients', 'Species', '9606', (120, 128))	('pancreatic cancer', 'Disease', (89, 106))
3129	25988180	While many studies have reported aberrent methylation in ovarian cancer (reviewed in Gloss and Samimi,), there are relatively few reports of ovarian cancer plasma methylation biomarkers.	('ovarian cancer', 'Disease', 'MESH:D010051', (57, 71))	('methylation', 'MPA', (42, 53))	('ovarian cancer', 'Disease', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('ovarian cancer', 'Phenotype', 'HP:0100615', (141, 155))	('methylation', 'biological_process', 'GO:0032259', ('163', '174'))	('aberrent', 'Var', (33, 41))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('ovarian cancer', 'Disease', 'MESH:D010051', (141, 155))	('ovarian cancer', 'Phenotype', 'HP:0100615', (57, 71))	('ovarian cancer', 'Disease', (141, 155))
3130	25988180	found methylation of RASSF1A and BRCA1 promoters in plasma or serum in 25/50 (50%) and 9/50 (18%) of ovarian cancer samples, respectively, with neither promoter methylated in any of 20 controls.	('RASSF1A', 'Gene', (21, 28))	('ovarian cancer', 'Disease', (101, 115))	('RASSF1A', 'Gene', '11186', (21, 28))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('BRCA1', 'Gene', '672', (33, 38))	('methylation', 'Var', (6, 17))	('BRCA1', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('ovarian cancer', 'Disease', 'MESH:D010051', (101, 115))
3133	25988180	In a cohort of 30 patients with ovarian cancer, 30 patients with benign ovarian disease and 30 healthy controls, methylation of RASSF1A, CACLA, and EP300 combined differentiated between patients with ovarian cancer and healthy controls with 90% sensitivity and 87% specificity, while methylation of RASSF1A and PGR differentiated between patients with ovarian cancer and patients with benign ovarian disease with 80.0% sensitivity and 73.3% specificity (Liggett et al.,).	('benign ovarian disease', 'Disease', 'MESH:D010049', (65, 87))	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('RASSF1A', 'Gene', (299, 306))	('patients', 'Species', '9606', (371, 379))	('methylation', 'biological_process', 'GO:0032259', ('284', '295'))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('benign ovarian disease', 'Disease', (385, 407))	('ovarian cancer', 'Disease', 'MESH:D010051', (200, 214))	('patients', 'Species', '9606', (338, 346))	('ovarian cancer', 'Disease', 'MESH:D010051', (352, 366))	('differentiated', 'Reg', (163, 177))	('PGR', 'Gene', '5241', (311, 314))	('patients', 'Species', '9606', (51, 59))	('ovarian disease', 'Phenotype', 'HP:0000137', (392, 407))	('benign ovarian disease', 'Disease', (65, 87))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ovarian cancer', 'Disease', 'MESH:D010051', (32, 46))	('patients', 'Species', '9606', (186, 194))	('RASSF1A', 'Gene', '11186', (128, 135))	('ovarian cancer', 'Disease', (200, 214))	('ovarian cancer', 'Disease', (352, 366))	('ovarian disease', 'Phenotype', 'HP:0000137', (72, 87))	('RASSF1A', 'Gene', (128, 135))	('ovarian cancer', 'Phenotype', 'HP:0100615', (200, 214))	('ovarian cancer', 'Phenotype', 'HP:0100615', (352, 366))	('patients', 'Species', '9606', (18, 26))	('benign ovarian disease', 'Disease', 'MESH:D010049', (385, 407))	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('methylation', 'Var', (113, 124))	('ovarian cancer', 'Disease', (32, 46))	('PGR', 'Gene', (311, 314))	('ovarian cancer', 'Phenotype', 'HP:0100615', (32, 46))	('RASSF1A', 'Gene', '11186', (299, 306))
3157	25988180	The problems associated with a requirement for very high sensitivity can be to some extent overcome by targeting the screening test to at-risk populations with higher prevalence of the cancer, e.g., BRCA1/2 mutation carriers for ovarian cancer screening.	('men', 'Species', '9606', (38, 41))	('ovarian cancer', 'Disease', 'MESH:D010051', (229, 243))	('BRCA1', 'Gene', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutation', 'Var', (207, 215))	('ovarian cancer', 'Disease', (229, 243))	('BRCA1', 'Gene', '672', (199, 204))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('ovarian cancer', 'Phenotype', 'HP:0100615', (229, 243))	('cancer', 'Disease', (237, 243))	('cancer', 'Disease', (185, 191))
3183	25884642	Moreover, motility of cancer cells and ECs in response to HGF was reduced upon treatment with INC280.	('reduced', 'NegReg', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('INC280', 'Var', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('INC280', 'Chemical', 'MESH:C000613976', (94, 100))
3199	25884642	With regards to pancreatic cancer, expression of cMET has been associated with poor survival and phosphorylation of cMET has been described in patients with early distant metastases even after complete surgical resection.	('cMET', 'Gene', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('phosphorylation', 'Var', (97, 112))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (16, 33))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))	('patients', 'Species', '9606', (143, 151))	('metastases', 'Disease', (171, 181))	('described', 'Reg', (130, 139))	('pancreatic cancer', 'Disease', (16, 33))	('pancreatic cancer', 'Disease', 'MESH:D010190', (16, 33))	('cMET', 'Gene', (116, 120))	('poor', 'NegReg', (79, 83))	('metastases', 'Disease', 'MESH:D009362', (171, 181))	('expression', 'Var', (35, 45))
3205	25884642	Currently, phase I and II studies for patients with advanced solid malignancies (NCT01911507, NCT01546428, NCT01324479), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), renal cell carcinoma and melanoma have been launched (NCT01737827, NCT01610336, NCT01820364).	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (153, 179))	('NSCLC', 'Disease', 'MESH:D002289', (181, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('hepatocellular carcinoma', 'Disease', (121, 145))	('NCT01546428', 'Var', (94, 105))	('patients', 'Species', '9606', (38, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('NSCLC', 'Disease', (181, 186))	('non-small cell lung cancer', 'Disease', (153, 179))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('melanoma', 'Disease', (214, 222))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('NCT01911507', 'Var', (81, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (181, 186))	('solid malignancies', 'Disease', 'MESH:D009369', (61, 79))	('solid malignancies', 'Disease', (61, 79))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (189, 209))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (121, 145))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (157, 179))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (153, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('NCT01324479', 'Var', (107, 118))	('HCC', 'Phenotype', 'HP:0001402', (147, 150))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (121, 145))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('NCT01820364', 'Var', (269, 280))	('renal cell carcinoma', 'Disease', (189, 209))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (189, 209))	('NCT01737827', 'Var', (243, 254))
3209	25884642	Evaluation of INC280 in combination with gemcitabine on tumour growth in these experimental murine models provide in vivo evidence that targeting cMET has potential that could be applied to improve outcomes in patients with pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (224, 241))	('cMET', 'Gene', (146, 150))	('pancreatic cancer', 'Disease', (224, 241))	('targeting', 'Var', (136, 145))	('gemcitabine', 'Chemical', 'MESH:C056507', (41, 52))	('murine', 'Species', '10090', (92, 98))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour growth', 'Disease', (56, 69))	('tumour growth', 'Disease', 'MESH:D006130', (56, 69))	('patients', 'Species', '9606', (210, 218))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (224, 241))	('INC280', 'Chemical', 'MESH:C000613976', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('improve', 'PosReg', (190, 197))
3226	25884642	Unless otherwise indicated, cells were incubated with increasing doses of INC280 (100, 500, 1000 nM) for 4 or 24 hours before stimulation with HGF (50 ng/ml) for 15 minutes.	('INC280', 'Chemical', 'MESH:C000613976', (74, 80))	('INC280', 'Gene', (74, 80))	('100', 'Var', (82, 85))
3277	25884642	Incubation of HPAF-II cells with INC280 for 4 hours or 24 hours did not affect constitutive Akt, ERK or FAK phosphorylation.	('INC280', 'Chemical', 'MESH:C000613976', (33, 39))	('ERK', 'Gene', (97, 100))	('constitutive', 'MPA', (79, 91))	('Akt', 'Gene', '207', (92, 95))	('phosphorylation', 'biological_process', 'GO:0016310', ('108', '123'))	('FAK', 'molecular_function', 'GO:0004717', ('104', '107'))	('Akt', 'Gene', (92, 95))	('ERK', 'molecular_function', 'GO:0004707', ('97', '100'))	('INC280', 'Var', (33, 39))	('FAK', 'Gene', '5747', (104, 107))	('FAK', 'Gene', (104, 107))	('ERK', 'Gene', '5594', (97, 100))
3282	25884642	Taken together, our results show that treatment with INC280 efficiently abrogates HGF-induced motility and oncogenic signaling in pancreatic cancer cell lines in vitro.	('abrogates', 'NegReg', (72, 81))	('INC280', 'Chemical', 'MESH:C000613976', (53, 59))	('oncogenic signaling', 'CPA', (107, 126))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('HGF-induced', 'Gene', (82, 93))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (130, 147))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))	('INC280', 'Var', (53, 59))	('pancreatic cancer', 'Disease', (130, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (130, 147))
3290	25884642	In MiaPaCa2(G250) HGF led to a more than 6-fold increase in motility which was abrogated by cMET blockade (Figure 2E).	('MiaPaCa2', 'Gene', (3, 11))	('MiaPaCa2(G250)', 'CellLine', 'CVCL:0428', (3, 17))	('G250) HGF', 'Var', (12, 21))	('motility', 'CPA', (60, 68))	('increase', 'PosReg', (48, 56))
3291	25884642	Finally, Western blotting from MiaPaCa2(par) showed only modest phosphorylation of ERK and Akt upon HGF stimulation and INC280 had only minor effects on Akt but impaired ERK phosphorylation (Figure 2F).	('INC280', 'Var', (120, 126))	('Akt', 'Gene', '207', (91, 94))	('phosphorylation', 'MPA', (64, 79))	('Akt', 'Gene', '207', (153, 156))	('ERK', 'Gene', (83, 86))	('ERK', 'Gene', '5594', (170, 173))	('ERK', 'molecular_function', 'GO:0004707', ('83', '86'))	('phosphorylation', 'biological_process', 'GO:0016310', ('64', '79'))	('Akt', 'Gene', (91, 94))	('ERK', 'Gene', (170, 173))	('Akt', 'Gene', (153, 156))	('MiaPaCa2(par)', 'Gene', '8856', (31, 44))	('INC280', 'Chemical', 'MESH:C000613976', (120, 126))	('phosphorylation', 'biological_process', 'GO:0016310', ('174', '189'))	('ERK', 'molecular_function', 'GO:0004707', ('170', '173'))	('impaired', 'NegReg', (161, 169))	('ERK', 'Gene', '5594', (83, 86))	('MiaPaCa2(par', 'Gene', (31, 43))
3301	25884642	Nonetheless, INC280 had no effect on constitutive secretion of both factors in MiaPaCa2(par) or in MiaPaCa2(G250), suggesting that other cMET-independent mechanisms are involved in this up-regulation (Figure 3B, Additional file 2: Figure S2D).	('INC280', 'Var', (13, 19))	('secretion', 'biological_process', 'GO:0046903', ('50', '59'))	('MiaPaCa2(par)', 'Gene', '8856', (79, 92))	('up-regulation', 'PosReg', (186, 199))	('MiaPaCa2(G250)', 'CellLine', 'CVCL:0428', (99, 113))	('constitutive secretion', 'MPA', (37, 59))	('INC280', 'Chemical', 'MESH:C000613976', (13, 19))	('regulation', 'biological_process', 'GO:0065007', ('189', '199'))	('MiaPaCa2(par', 'Gene', (79, 91))
3302	25884642	Finally, we assessed the effect of cMET inhibition on hypoxia-induced VEGF-A secretion in MiaPaCa2(G250) since INC280 led to inhibition of HIF-1alpha in these cells.	('hypoxia', 'Disease', (54, 61))	('hypoxia', 'Disease', 'MESH:D000860', (54, 61))	('INC280', 'Var', (111, 117))	('HIF-1alpha', 'Gene', (139, 149))	('VEGF-A', 'Gene', '7422', (70, 76))	('VEGF-A', 'Gene', (70, 76))	('INC280', 'Chemical', 'MESH:C000613976', (111, 117))	('secretion', 'biological_process', 'GO:0046903', ('77', '86'))	('MiaPaCa2(G250)', 'CellLine', 'CVCL:0428', (90, 104))	('HIF-1alpha', 'Gene', '3091', (139, 149))	('inhibition', 'NegReg', (125, 135))
3303	25884642	Results showed a strong DFX-induced increase in VEGF-A secretion that was significantly impaired by cMET blockade (Figure 3C).	('VEGF-A', 'Gene', '7422', (48, 54))	('DFX', 'Chemical', '-', (24, 27))	('increase', 'PosReg', (36, 44))	('VEGF-A', 'Gene', (48, 54))	('secretion', 'biological_process', 'GO:0046903', ('55', '64'))	('DFX-induced', 'Var', (24, 35))
3311	25884642	Regarding activation of signaling pathways, treatment with INC280 strongly inhibited HGF-induced activation of Akt and ERK whereas no effects on constitutive Akt and ERK phosphorylation were found (Figure 4B).	('ERK', 'Gene', '5594', (166, 169))	('activation', 'PosReg', (97, 107))	('Akt', 'Gene', (111, 114))	('phosphorylation', 'biological_process', 'GO:0016310', ('170', '185'))	('Akt', 'Gene', '207', (158, 161))	('ERK', 'Gene', (166, 169))	('signaling pathways', 'Pathway', (24, 42))	('inhibited', 'NegReg', (75, 84))	('INC280', 'Var', (59, 65))	('ERK', 'Gene', '5594', (119, 122))	('ERK', 'molecular_function', 'GO:0004707', ('166', '169'))	('ERK', 'Gene', (119, 122))	('HGF-induced', 'Gene', (85, 96))	('ERK', 'molecular_function', 'GO:0004707', ('119', '122'))	('INC280', 'Chemical', 'MESH:C000613976', (59, 65))	('Akt', 'Gene', (158, 161))	('Akt', 'Gene', '207', (111, 114))	('signaling', 'biological_process', 'GO:0023052', ('24', '33'))
3312	25884642	Taken together, these results show that INC280 affects ECs only when these cells are stimulated with HGF.	('affects', 'Reg', (47, 54))	('INC280', 'Var', (40, 46))	('ECs', 'MPA', (55, 58))	('INC280', 'Chemical', 'MESH:C000613976', (40, 46))
3315	25884642	In contrast to ECs, stimulation with HGF upon serum-starved conditions had no effect on VSMC growth and, accordingly, INC280 did not have a further growth inhibitory effect in MTT assays (Additional file 3: Figure S3D).	('INC280', 'Chemical', 'MESH:C000613976', (118, 124))	('VSMC growth', 'CPA', (88, 99))	('VSMC', 'Chemical', '-', (88, 92))	('INC280', 'Var', (118, 124))	('not', 'NegReg', (129, 132))	('MTT', 'Chemical', 'MESH:C070243', (176, 179))
3355	25884642	Results from this model showed that INC280 alone has no effect on advanced tumour growth, and gemcitabine significantly improves survival as expected.	('tumour growth', 'Disease', (75, 88))	('INC280', 'Chemical', 'MESH:C000613976', (36, 42))	('survival', 'CPA', (129, 137))	('tumour growth', 'Disease', 'MESH:D006130', (75, 88))	('gemcitabine', 'Chemical', 'MESH:C056507', (94, 105))	('improves', 'PosReg', (120, 128))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('INC280', 'Var', (36, 42))
3370	25884642	Hence, phosphorylation of oncogenic signaling cascades in pancreatic cancer cells via paracrine activation of the cMET receptor might contribute to pancreatic cancer aggressiveness.	('pancreatic cancer', 'Disease', (58, 75))	('pancreatic cancer', 'Disease', 'MESH:D010190', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('contribute', 'Reg', (134, 144))	('pancreatic cancer', 'Disease', 'MESH:D010190', (148, 165))	('pancreatic cancer aggressiveness', 'Disease', 'MESH:D010190', (148, 180))	('signaling', 'biological_process', 'GO:0023052', ('36', '45'))	('pancreatic cancer aggressiveness', 'Disease', (148, 180))	('phosphorylation', 'biological_process', 'GO:0016310', ('7', '22'))	('phosphorylation', 'Var', (7, 22))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (58, 75))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (148, 165))	('cMET receptor', 'Gene', (114, 127))	('activation', 'PosReg', (96, 106))	('aggressiveness', 'Phenotype', 'HP:0000718', (166, 180))
3380	25884642	This is of particular importance since expression of MDR-1 and its encoding protein P-gp have been implicated in reduced drug up-take, thereby mediating resistance to chemotherapy.	('P-gp', 'Gene', (84, 88))	('MDR-1', 'Gene', (53, 58))	('expression', 'Var', (39, 49))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('MDR-1', 'Gene', '5243', (53, 58))	('mediating', 'Reg', (143, 152))	('drug up-take', 'MPA', (121, 133))	('MDR', 'molecular_function', 'GO:0004745', ('53', '56'))	('reduced', 'NegReg', (113, 120))	('P-gp', 'Gene', '283871', (84, 88))
3389	25884642	Regarding apoptosis, a study by Hage and coworkers described a significant increase in vitro when pancreatic cancer cell lines were treated with a cMET inhibitor in combination with gemcitabine.	('pancreatic cancer', 'Disease', 'MESH:D010190', (98, 115))	('gemcitabine', 'Chemical', 'MESH:C056507', (182, 193))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (98, 115))	('apoptosis', 'CPA', (10, 19))	('inhibitor', 'Var', (152, 161))	('apoptosis', 'biological_process', 'GO:0097194', ('10', '19'))	('apoptosis', 'biological_process', 'GO:0006915', ('10', '19'))	('increase', 'PosReg', (75, 83))	('pancreatic cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cMET', 'Gene', (147, 151))	('vitro', 'CPA', (87, 92))
3398	25884642	In summary, the present study shows that targeting cMET may lead to an effective inhibition of tumour growth in pancreatic cancer, even in advanced tumour stages.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumour', 'Disease', (148, 154))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('tumour growth in pancreatic cancer', 'Disease', (95, 129))	('inhibition', 'NegReg', (81, 91))	('tumour', 'Disease', (95, 101))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('tumour growth in pancreatic cancer', 'Disease', 'MESH:D010190', (95, 129))	('targeting', 'Var', (41, 50))	('tumour', 'Disease', 'MESH:D009369', (148, 154))	('cMET', 'Gene', (51, 55))
3399	25884642	Particularly, inhibition of gemcitabine-resistance in tumour cells by cMET inhibitors may improve current anti-neoplastic therapy strategies for the treatment of pancreatic cancer patients.	('gemcitabine-resistance', 'MPA', (28, 50))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('inhibitors', 'Var', (75, 85))	('tumour', 'Disease', (54, 60))	('cMET', 'Gene', (70, 74))	('pancreatic cancer', 'Disease', (162, 179))	('pancreatic cancer', 'Disease', 'MESH:D010190', (162, 179))	('gemcitabine', 'Chemical', 'MESH:C056507', (28, 39))	('improve', 'PosReg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (162, 179))	('patients', 'Species', '9606', (180, 188))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('inhibition', 'NegReg', (14, 24))
3472	25427073	Furthermore, targeted therapies have been shown to have marginal activity in clinical trials of pancreatic cancer.	('pancreatic cancer', 'Disease', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))	('targeted', 'Var', (13, 21))
3626	25228990	After 6 h of treatment with different doses of sodium hydroxybutyrate, lithium acetoacetate, and S-hydroxybutyrate on S2-013, Capan1, HPNE, and RAPAN cells, we observed significant decrease in intracellular pH (0.2 to 0.4 units) in all the cell lines (Additional file 5).	('sodium hydroxybutyrate', 'Chemical', '-', (47, 69))	('HPNE', 'Chemical', '-', (134, 138))	('intracellular', 'cellular_component', 'GO:0005622', ('193', '206'))	('decrease', 'NegReg', (181, 189))	('S-hydroxybutyrate', 'Chemical', 'MESH:D006885', (97, 114))	('S-hydroxybutyrate', 'Var', (97, 114))	('lithium acetoacetate', 'Chemical', 'MESH:C016635', (71, 91))
3641	25228990	Overall, our results indicate that ketone bodies diminish the overall energetic health of pancreatic cancer cells by reducing glucose uptake, lactate release, glutamine uptake, cellular ATP content, and ROS levels.	('ketone bodies', 'Phenotype', 'HP:0001946', (35, 48))	('lactate release', 'MPA', (142, 157))	('glucose', 'Chemical', 'MESH:D005947', (126, 133))	('lactate', 'Chemical', 'MESH:D019344', (142, 149))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('energetic', 'MPA', (70, 79))	('glutamine uptake', 'MPA', (159, 175))	('ATP', 'Chemical', 'MESH:D000255', (186, 189))	('ketone', 'Var', (35, 41))	('diminish', 'NegReg', (49, 57))	('ROS levels', 'MPA', (203, 213))	('glutamine', 'Chemical', 'MESH:D005973', (159, 168))	('uptake', 'biological_process', 'GO:0098657', ('169', '175'))	('reducing', 'NegReg', (117, 125))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('glucose uptake', 'biological_process', 'GO:0046323', ('126', '140'))	('cellular ATP content', 'MPA', (177, 197))	('ketone bodies', 'Chemical', 'MESH:D007657', (35, 48))	('uptake', 'biological_process', 'GO:0098739', ('169', '175'))	('pancreatic cancer', 'Disease', (90, 107))	('ROS', 'Chemical', 'MESH:D017382', (203, 206))	('glucose uptake', 'MPA', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
3661	25228990	Of note, beta-hydroxybutyrate improves body weight, while reducing proteolysis in muscle cells.	('beta-hydroxybutyrate', 'Chemical', 'MESH:D020155', (9, 29))	('proteolysis', 'biological_process', 'GO:0006508', ('67', '78'))	('reducing', 'NegReg', (58, 66))	('improves', 'PosReg', (30, 38))	('body', 'MPA', (39, 43))	('beta-hydroxybutyrate', 'Var', (9, 29))	('proteolysis in muscle cells', 'MPA', (67, 94))
3683	25228990	Importantly, 13C6-glucose highlighted metabolite changes associated with glycolytic flux in tumor cells.	('13C6-glucose', 'Chemical', '-', (13, 25))	('metabolite changes', 'MPA', (38, 56))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('13C6-glucose', 'Var', (13, 25))
3704	25228990	We also assayed conditioned medium from GLUT1 knockdown S2-013 cells (S2-013-shGLUT1) for cachectic potential.	('GLUT1', 'Gene', (40, 45))	('knockdown', 'Var', (46, 55))	('GLUT1', 'Gene', '6513', (40, 45))	('GLUT1', 'Gene', (79, 84))	('cachectic potential', 'CPA', (90, 109))	('GLUT1', 'Gene', '6513', (79, 84))
3705	25228990	Treatment with conditioned medium generated from ketone bodies or glycolytic inhibitor-pretreated S2-013 cells, or GLUT1 knockdown S2-013 cells, demonstrated a significant protection against myotube degradation (Figure 7A,B) and adipocyte fat depletion (Figure 7C,D) in comparison to controls.	('knockdown', 'Var', (121, 130))	('myotube degradation', 'Disease', 'MESH:D055959', (191, 210))	('ketone bodies', 'Chemical', 'MESH:D007657', (49, 62))	('ketone bodies', 'Phenotype', 'HP:0001946', (49, 62))	('myotube degradation', 'Disease', (191, 210))	('adipocyte fat depletion', 'MPA', (229, 252))	('protection', 'NegReg', (172, 182))	('degradation', 'biological_process', 'GO:0009056', ('199', '210'))	('GLUT1', 'Gene', (115, 120))	('GLUT1', 'Gene', '6513', (115, 120))
3743	25228990	Inhibition of histone deacetylase activity can suppress or prevent cancer growth as indicated by several studies with histone deacetylase inhibitors that are currently being evaluated for cancer prevention.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', (67, 73))	('histone deacetylase activity', 'molecular_function', 'GO:0004407', ('14', '42'))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('prevent', 'NegReg', (59, 66))	('suppress', 'NegReg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Inhibition of histone deacetylase activity', 'biological_process', 'GO:1901726', ('0', '42'))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (188, 194))
3747	25228990	Inhibition of GLUT1, which is the main transporter of glucose in cancer cells, is currently being considered for cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('GLUT1', 'Gene', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('glucose', 'Chemical', 'MESH:D005947', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (113, 119))	('GLUT1', 'Gene', '6513', (14, 19))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
3760	25228990	Our results with the cell culture-based models indicate that ketone bodies significantly inhibit myotube degradation and adipolysis.	('ketone', 'Var', (61, 67))	('myotube degradation', 'Disease', (97, 116))	('ketone bodies', 'Chemical', 'MESH:D007657', (61, 74))	('inhibit', 'NegReg', (89, 96))	('ketone bodies', 'Phenotype', 'HP:0001946', (61, 74))	('degradation', 'biological_process', 'GO:0009056', ('105', '116'))	('adipolysis', 'MPA', (121, 131))	('myotube degradation', 'Disease', 'MESH:D055959', (97, 116))
3772	25228990	Our results indicate that the inhibition of either glucose uptake by GLUT1 knockdown or chemical inhibition of glycolysis by utilizing BPA in cancer cells diminished myotube degradation and depletion of adipose deposits.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('depletion of adipose deposits', 'MPA', (190, 219))	('myotube degradation', 'Disease', (166, 185))	('glucose uptake', 'CPA', (51, 65))	('inhibition', 'NegReg', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('glucose', 'Chemical', 'MESH:D005947', (51, 58))	('glucose uptake', 'biological_process', 'GO:0046323', ('51', '65'))	('GLUT1', 'Gene', (69, 74))	('knockdown', 'Var', (75, 84))	('inhibition', 'NegReg', (30, 40))	('BPA', 'Chemical', 'MESH:C017092', (135, 138))	('inhibition of glycolysis', 'biological_process', 'GO:0045820', ('97', '121'))	('degradation', 'biological_process', 'GO:0009056', ('174', '185'))	('GLUT1', 'Gene', '6513', (69, 74))	('diminished', 'NegReg', (155, 165))	('myotube degradation', 'Disease', 'MESH:D055959', (166, 185))	('cancer', 'Disease', (142, 148))
3783	25228990	While high-calorie and high-fat diets are associated with increased incidence of cancer, several epidemiological studies have demonstrated a direct relationship between low-sugar diet and a lower incidence of cancer.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (209, 215))	('sugar', 'Chemical', 'MESH:D000073893', (173, 178))	('low-sugar', 'Var', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('incidence', 'MPA', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
3793	25228990	This work was supported in part by funding from the National Institutes of Health grants (P20 RR-17675, P30 GM103335, R01 CA163649) to PKS and RP, American Association for Cancer Research (AACR):Pancreatic Cancer Action Network (PanCAN) Career Development Award (30-20-25-SING) to PKS, the Specialized Programs for Research Excellence (SPORE, P50 CA127297, NCI) Career Development Award to PKS, SPORE (P50 CA127297, NCI) Developmental Research Project Award to PKS, Pancreatic Tumor Microenvironment Research Network (U54, CA163120, NCI) to PKS, LB506 (2014-37, DHHS-NE) to PKS, and Cancer Prevention and Control Nutrition seed grant (15618, GSCN) to PKS.	('PKS', 'cellular_component', 'GO:0034081', ('574', '577'))	('P50', 'Gene', (402, 405))	('Tumor', 'Phenotype', 'HP:0002664', (477, 482))	('Cancer', 'Phenotype', 'HP:0002664', (583, 589))	('Cancer', 'Disease', (172, 178))	('PKS', 'cellular_component', 'GO:0034081', ('390', '393'))	('PKS', 'cellular_component', 'GO:0034081', ('651', '654'))	('Pancreatic Tumor', 'Disease', 'MESH:D010190', (466, 482))	('Cancer', 'Disease', 'MESH:D009369', (206, 212))	('P30', 'Gene', '201161', (104, 107))	('P30', 'Gene', (104, 107))	('Pancreatic Cancer', 'Disease', (195, 212))	('Cancer', 'Disease', (583, 589))	('CA163120', 'Var', (523, 531))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (195, 212))	('Cancer', 'Disease', 'MESH:D009369', (172, 178))	('Pancreatic Tumor', 'Disease', (466, 482))	('PKS', 'cellular_component', 'GO:0034081', ('135', '138'))	('P50', 'Gene', (343, 346))	('PKS', 'cellular_component', 'GO:0034081', ('461', '464'))	('Cancer', 'Disease', 'MESH:D009369', (583, 589))	('P50', 'Gene', '4790', (402, 405))	('Pancreatic Tumor', 'Phenotype', 'HP:0002894', (466, 482))	('Cancer', 'Phenotype', 'HP:0002664', (206, 212))	('PKS', 'cellular_component', 'GO:0034081', ('541', '544'))	('PKS', 'cellular_component', 'GO:0034081', ('281', '284'))	('Cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Cancer', 'Disease', (206, 212))	('P20', 'Gene', '51673', (90, 93))	('P20', 'Gene', (90, 93))	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (195, 212))	('P50', 'Gene', '4790', (343, 346))
3794	24058792	TLR7 inhibition Pancreatic ductal adenocarcinoma is associated with a poor prognosis: For local disease, the 5-y survival rate is approximately 20% and median survival in locally advanced disease is only about 10 mo.	('Pancreatic ductal adenocarcinoma', 'Disease', (16, 48))	('inhibition', 'Var', (5, 15))	('Pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (16, 48))	('Pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (16, 48))	('TLR7', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('rat', 'Species', '10116', (122, 125))	('TLR7', 'Gene', '51284', (0, 4))
3797	24058792	Of note, inhibition of TLR7 signaling in a mouse p48Cre;KrasG12D pancreatic cancer model protected against tumor progression thus paving the road for TLR-blocking strategies to combat tumors.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('pancreatic cancer', 'Disease', (65, 82))	('tumor', 'Disease', (107, 112))	('rat', 'Species', '10116', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('TLR7 signaling', 'MPA', (23, 37))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Disease', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('signaling', 'biological_process', 'GO:0023052', ('28', '37'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('mouse', 'Species', '10090', (43, 48))	('inhibition', 'Var', (9, 19))
3810	24058792	TLR agonists have also been reported to be beneficial in models of mouse mammary tumors and leukemia to name a few.	('leukemia', 'Disease', (92, 100))	('leukemia', 'Phenotype', 'HP:0001909', (92, 100))	('leukemia', 'Disease', 'MESH:D007938', (92, 100))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('beneficial', 'PosReg', (43, 53))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mouse', 'Species', '10090', (67, 72))	('agonists', 'Var', (4, 12))	('TLR', 'Gene', (0, 3))
3823	24058792	To gain insights into the functional role of TLR7 in pancreatic cancer, the authors treated p48Cre;KrasG12D mice with ssRNA40, a synthetic ligand for TLR7.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (53, 70))	('ligand', 'molecular_function', 'GO:0005488', ('139', '145'))	('mice', 'Species', '10090', (108, 112))	('ssRNA40', 'Var', (118, 125))	('pancreatic cancer', 'Disease', (53, 70))	('pancreatic cancer', 'Disease', 'MESH:D010190', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
3825	24058792	Conversely, TLR7 blockade using an inhibitory oligonucleotide prevented malignant progression when administered together with cancer progression accelerator caerulein in Kras mutant mice.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('TLR7', 'Gene', (12, 16))	('caerulein', 'Chemical', 'MESH:D002108', (157, 166))	('mice', 'Species', '10090', (182, 186))	('cancer', 'Disease', (126, 132))	('prevented', 'NegReg', (62, 71))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('rat', 'Species', '10116', (151, 154))	('malignant progression', 'CPA', (72, 93))	('oligonucleotide', 'Chemical', 'MESH:D009841', (46, 61))	('mutant', 'Var', (175, 181))
3826	24058792	On the molecular level, TLR7 ligation in Kras mutated mice caused a dysregulation of proteins involved in cell cycle regulation including p53, p21, p27, cyclin D1 and cyclin B1 in the pancreata.	('p21', 'Gene', (143, 146))	('cyclin D1', 'Gene', '12443', (153, 162))	('proteins', 'Protein', (85, 93))	('p53', 'Gene', (138, 141))	('p27', 'Gene', '12576', (148, 151))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('106', '127'))	('ligation', 'Var', (29, 37))	('cyclin B1', 'Gene', '268697', (167, 176))	('p21', 'Gene', '12575', (143, 146))	('cyclin D1', 'Gene', (153, 162))	('cyclin', 'molecular_function', 'GO:0016538', ('153', '159'))	('p53', 'Gene', '22060', (138, 141))	('TLR7', 'Gene', (24, 28))	('dysregulation', 'MPA', (68, 81))	('p27', 'Gene', (148, 151))	('cyclin B1', 'Gene', (167, 176))	('mice', 'Species', '10090', (54, 58))	('cyclin', 'molecular_function', 'GO:0016538', ('167', '173'))
3827	24058792	Furthermore, ssRNA40 administration interfered with multiple signaling pathways including MAPK, NFkappaB and Notch activation and induced loss of PTEN expression.	('Notch', 'Gene', '4851;4853', (109, 114))	('loss', 'NegReg', (138, 142))	('PTEN', 'Gene', (146, 150))	('MAPK', 'Pathway', (90, 94))	('ssRNA40', 'Var', (13, 20))	('Notch', 'Gene', (109, 114))	('PTEN', 'Gene', '5728', (146, 150))	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('NFkappaB', 'Protein', (96, 104))	('MAPK', 'molecular_function', 'GO:0004707', ('90', '94'))	('expression', 'MPA', (151, 161))	('rat', 'Species', '10116', (29, 32))	('interfered', 'NegReg', (36, 46))
3835	24058792	For example, silencing of STAT3 sensitized A549 lung carcinoma cells to DNA damaging chemotherapeutics, potentially by downregulation of Bcl-xl, but did not affect TNF- and natural killer cell-mediated cytotoxicity.	('Bcl-xl', 'Gene', '598', (137, 143))	('natural killer cell-mediated cytotoxicity', 'biological_process', 'GO:0042267', ('173', '214'))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('TNF', 'Gene', '7124', (164, 167))	('A549 lung carcinoma', 'Disease', (43, 62))	('downregulation', 'NegReg', (119, 133))	('A549 lung carcinoma', 'Disease', 'MESH:D008175', (43, 62))	('STAT3', 'Gene', '6774', (26, 31))	('cytotoxicity', 'Disease', 'MESH:D064420', (202, 214))	('cytotoxicity', 'Disease', (202, 214))	('Bcl-xl', 'Gene', (137, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('DNA damaging', 'MPA', (72, 84))	('STAT3', 'Gene', (26, 31))	('sensitized', 'Reg', (32, 42))	('TNF', 'Gene', (164, 167))	('silencing', 'Var', (13, 22))
3837	24058792	Using bone-marrow chimeric mice, the authors further show that TLR7 expression in the inflammatory stromal cells was required for pancreatic cancer progression as p48Cre;KrasG12D-TLR7-/- chimeric mice were protected from caerulein-induced accelerated neoplasia.	('p48Cre;KrasG12D-TLR7-/-', 'Var', (163, 186))	('neoplasia', 'Phenotype', 'HP:0002664', (251, 260))	('mice', 'Species', '10090', (196, 200))	('caerulein', 'Chemical', 'MESH:D002108', (221, 230))	('mice', 'Species', '10090', (27, 31))	('rat', 'Species', '10116', (245, 248))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('neoplasia', 'Disease', 'MESH:D009369', (251, 260))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (130, 147))	('neoplasia', 'Disease', (251, 260))	('pancreatic cancer', 'Disease', (130, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (130, 147))
3839	24058792	Thus, the authors conclude that carcinogenic changes seen in these cells in vivo after TLR7 ligation are secondary to direct effects of TLR7 activation on the stromal inflammatory cells.	('TLR7', 'Gene', (136, 140))	('ligation', 'Var', (92, 100))	('TLR7', 'Gene', (87, 91))	('carcinogenic', 'Disease', 'MESH:D063646', (32, 44))	('carcinogenic', 'Disease', (32, 44))
3851	24058792	They observed a strong upregulation of TLR2 and blockade or genetic deletion of TLR2 resulted in a decrease of epithelial proliferation and a parallel increase of apoptosis.	('TLR2', 'Gene', '7097', (80, 84))	('apoptosis', 'CPA', (163, 172))	('apoptosis', 'biological_process', 'GO:0006915', ('163', '172'))	('epithelial proliferation', 'CPA', (111, 135))	('TLR2', 'Gene', (80, 84))	('TLR2', 'Gene', '7097', (39, 43))	('rat', 'Species', '10116', (129, 132))	('upregulation', 'PosReg', (23, 35))	('TLR2', 'Gene', (39, 43))	('decrease', 'NegReg', (99, 107))	('apoptosis', 'biological_process', 'GO:0097194', ('163', '172'))	('increase', 'PosReg', (151, 159))	('genetic deletion', 'Var', (60, 76))
3863	24058792	However, although the paper presented here demonstrated that inhibition of TLR7-mediated signaling could prevent pancreatic cancer progression, it is not yet clear if TLR7 antagonism alone is sufficient to induce regression of established adenocarcinoma.	('prevent', 'NegReg', (105, 112))	('adenocarcinoma', 'Disease', (239, 253))	('inhibition', 'Var', (61, 71))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('rat', 'Species', '10116', (50, 53))	('adenocarcinoma', 'Disease', 'MESH:D000230', (239, 253))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('pancreatic cancer', 'Disease', (113, 130))	('pancreatic cancer', 'Disease', 'MESH:D010190', (113, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))
3864	24058792	It is rather likely that alleviation of pro-inflammatory tumor microenvironment by TLR7 blockade could be used in conjunction with classical anti-proliferative chemotherapeutics.	('blockade', 'Var', (88, 96))	('rat', 'Species', '10116', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('TLR7', 'Gene', (83, 87))	('rat', 'Species', '10116', (6, 9))	('tumor', 'Disease', (57, 62))
3886	20714789	Although metastases can have a clonal origin, genetic instability results in rapid biological diversification and the regeneration of heterogeneous subpopulations of cells.	('metastases', 'Disease', (9, 19))	('genetic instability', 'Var', (46, 65))	('regeneration', 'CPA', (118, 130))	('metastases', 'Disease', 'MESH:D009362', (9, 19))	('regeneration', 'biological_process', 'GO:0031099', ('118', '130'))	('results in', 'Reg', (66, 76))
3911	20714789	EGCG and ECG were found to inhibit melanoma cell adhesion in the culture medium.	('ECG', 'Var', (9, 12))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('ECG', 'Chemical', 'MESH:C062669', (9, 12))	('cell adhesion', 'biological_process', 'GO:0007155', ('44', '57'))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('EGCG', 'Var', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('inhibit', 'NegReg', (27, 34))	('melanoma', 'Disease', (35, 43))
3923	20714789	Additionally, on treatment of cells with a combination of EGCG and TRAIL, there was decrease in the activity and protein expression of MMP-2, -3, and -9 and upregulation of TIMP1.	('decrease', 'NegReg', (84, 92))	('TIMP1', 'Gene', (173, 178))	('protein expression', 'MPA', (113, 131))	('MMP-2, -3, and -9', 'Gene', '17390;17392;17395', (135, 152))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('men', 'Species', '9606', (22, 25))	('upregulation', 'PosReg', (157, 169))	('EGCG', 'Chemical', 'MESH:C045651', (58, 62))	('TIMP1', 'Gene', '21857', (173, 178))	('MMP-2', 'molecular_function', 'GO:0004228', ('135', '140'))	('EGCG', 'Var', (58, 62))	('activity', 'MPA', (100, 108))
3980	20714789	Pulmonary colonization was reduced by 63% in mice receiving nutrient mixture in diet, whereas, it was reduced by 86% in mice receiving nutrient mixture by intraperitoneal and intravenous injections and completely inhibited in mice injected with melanoma cells pretreated with nutrient mixture.	('reduced', 'NegReg', (27, 34))	('mice', 'Species', '10090', (120, 124))	('mice', 'Species', '10090', (45, 49))	('mice', 'Species', '10090', (226, 230))	('Pulmonary colonization', 'CPA', (0, 22))	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('melanoma', 'Disease', (245, 253))	('reduced', 'NegReg', (102, 109))	('nutrient mixture', 'Var', (60, 76))
3998	20714789	There was much higher inhibition of hepatocellular carcinoma SMMC-7721 cell proliferation and migration by mixture of EGCG and ascorbic acid as compared with EGCG or ascorbic acid alone.	('EGCG', 'Chemical', 'MESH:C045651', (118, 122))	('cell proliferation', 'biological_process', 'GO:0008283', ('71', '89'))	('SMMC-7721', 'CellLine', 'CVCL:0534', (61, 70))	('EGCG', 'Var', (118, 122))	('migration', 'CPA', (94, 103))	('inhibition', 'NegReg', (22, 32))	('EGCG', 'Chemical', 'MESH:C045651', (158, 162))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (36, 60))	('ascorbic acid', 'Chemical', 'MESH:D001205', (127, 140))	('hepatocellular carcinoma', 'Disease', (36, 60))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (36, 60))	('mixture', 'Interaction', (107, 114))	('ascorbic acid', 'Chemical', 'MESH:D001205', (166, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
4013	20714789	EGCG was also found to inhibit intestinal tumor formation in APC (Min/+) mice, compared with vehicle-treated mice, in association with reduced bFGF expression.	('formation', 'biological_process', 'GO:0009058', ('48', '57'))	('bFGF', 'Gene', (143, 147))	('APC', 'cellular_component', 'GO:0005680', ('61', '64'))	('mice', 'Species', '10090', (73, 77))	('inhibit', 'NegReg', (23, 30))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('intestinal tumor', 'Disease', 'MESH:D007414', (31, 47))	('reduced', 'NegReg', (135, 142))	('EGCG', 'Var', (0, 4))	('expression', 'MPA', (148, 158))	('intestinal tumor', 'Disease', (31, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('bFGF', 'Gene', '14173', (143, 147))	('mice', 'Species', '10090', (109, 113))
4022	20714789	There was reduction in Ki-67, PCNA, Von Willebrand factor, VEGF, CD31, VEGFR-2, ERK1/2, JNK1/2, p38, MMP-2, MMP-7, MMP-9, and MMP-12 and induction of apoptosis, caspase-3 activity, and p21/WAF1 in tumors of athymic nude mice implanted with human pancreatic cancer AsPC-1 cells suggesting that EGCG inhibited pancreatic cancer growth, invasion, metastasis, and angiogenesis.	('VEGFR-2', 'Gene', (71, 78))	('AsPC-1', 'CellLine', 'CVCL:0152', (264, 270))	('Ki-67', 'Gene', '17345', (23, 28))	('p21', 'Gene', (185, 188))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('human', 'Species', '9606', (240, 245))	('angiogenesis', 'biological_process', 'GO:0001525', ('360', '372'))	('MMP-12', 'molecular_function', 'GO:0004234', ('126', '132'))	('angiogenesis', 'CPA', (360, 372))	('pancreatic cancer', 'Disease', (246, 263))	('CD31', 'Gene', (65, 69))	('pancreatic cancer', 'Disease', (308, 325))	('EGCG', 'Chemical', 'MESH:C045651', (293, 297))	('tumors of athymic', 'Disease', (197, 214))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('ERK1', 'molecular_function', 'GO:0004707', ('80', '84'))	('caspase-3', 'Gene', '12367', (161, 170))	('inhibited', 'NegReg', (298, 307))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('161', '179'))	('nude mice', 'Species', '10090', (215, 224))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('invasion', 'CPA', (334, 342))	('Ki-67', 'Gene', (23, 28))	('reduction', 'NegReg', (10, 19))	('Von Willebrand factor', 'Gene', (36, 57))	('PCNA', 'Gene', '18538', (30, 34))	('p38', 'Gene', (96, 99))	('VEGFR-2', 'Gene', '16542', (71, 78))	('WAF1', 'Gene', '12575', (189, 193))	('Von Willebrand factor', 'Gene', '22371', (36, 57))	('MMP-12', 'Gene', '17381', (126, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (246, 263))	('p21', 'Gene', '12575', (185, 188))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (308, 325))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('137', '159'))	('WAF1', 'Gene', (189, 193))	('MMP-7', 'molecular_function', 'GO:0004235', ('108', '113'))	('tumors of athymic', 'Disease', 'MESH:D009369', (197, 214))	('JNK', 'molecular_function', 'GO:0004705', ('88', '91'))	('MMP-9', 'molecular_function', 'GO:0004229', ('115', '120'))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('161', '179'))	('MMP-12', 'Gene', (126, 132))	('p38', 'Gene', '26416', (96, 99))	('PCNA', 'Gene', (30, 34))	('metastasis', 'CPA', (344, 354))	('JNK1/2', 'Gene', '26419;26420', (88, 94))	('MMP-2', 'molecular_function', 'GO:0004228', ('101', '106'))	('PCNA', 'molecular_function', 'GO:0003892', ('30', '34'))	('MMP-7', 'Gene', '17393', (108, 113))	('CD31', 'Gene', '18613', (65, 69))	('caspase-3', 'Gene', (161, 170))	('pancreatic cancer', 'Disease', 'MESH:D010190', (246, 263))	('pancreatic cancer', 'Disease', 'MESH:D010190', (308, 325))	('JNK1/2', 'Gene', (88, 94))	('MMP-7', 'Gene', (108, 113))	('EGCG', 'Var', (293, 297))
4034	20714789	A molecular epidemiologic study was conducted at Jiangsu Province of China, on histologically confirmed esophageal squamous cell carcinoma patients to investigate the association between aberrant hypermethylation of MGMT gene and clinical characteristics as well as MTHFR C677T genetic polymorphisms in esophageal squamous cell carcinoma.	('MGMT', 'molecular_function', 'GO:0003908', ('216', '220'))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (303, 337))	('patients', 'Species', '9606', (139, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (314, 337))	('C677T', 'Mutation', 'rs1801133', (272, 277))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (104, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('esophageal squamous cell carcinoma', 'Disease', (303, 337))	('esophageal squamous cell carcinoma', 'Disease', (104, 138))	('MGMT', 'Gene', (216, 220))	('aberrant hypermethylation', 'Var', (187, 212))
4037	20714789	Variant allele of MTHFR C677T was found to be associated with hypermethylation of MGMT gene after adjusting by potential confounders.	('C677T', 'Mutation', 'rs1801133', (24, 29))	('C677T', 'Var', (24, 29))	('MTHFR', 'Gene', (18, 23))	('MGMT gene', 'Gene', (82, 91))	('associated', 'Reg', (46, 56))	('hypermethylation', 'MPA', (62, 78))
4047	20714789	EGCG suppressed the gelatin-degrading activities due to MMP-2 and MMP-9 in the culture medium of human fibrosarcoma HT1080 cells which were consistent with the decreased levels of MMP-2 and MMP-9 mRNAs.	('MMP-9', 'molecular_function', 'GO:0004229', ('66', '71'))	('gelatin-degrading activities', 'MPA', (20, 48))	('fibrosarcoma', 'Disease', 'MESH:D005354', (103, 115))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (103, 115))	('MMP-2', 'Var', (56, 61))	('suppressed', 'NegReg', (5, 15))	('HT1080', 'CellLine', 'CVCL:0317', (116, 122))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('MMP-2', 'molecular_function', 'GO:0004228', ('180', '185'))	('human', 'Species', '9606', (97, 102))	('MMP-9', 'molecular_function', 'GO:0004229', ('190', '195'))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('MMP-2', 'molecular_function', 'GO:0004228', ('56', '61'))	('fibrosarcoma', 'Disease', (103, 115))	('MMP-9', 'Var', (66, 71))
4063	33298240	Hypermethylation-mediated silencing of NDRG4 promotes pancreatic ductal adenocarcinoma by regulating mitochondrial function The N-myc downstream regulated gene (NDRG) family members are dysregulated in several tumors.	('NDRG4', 'Gene', '65009', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('pancreatic ductal adenocarcinoma', 'Disease', (54, 86))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (54, 86))	('tumors', 'Disease', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (54, 86))	('Hypermethylation-mediated', 'Var', (0, 25))	('promotes', 'PosReg', (45, 53))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('silencing', 'Var', (26, 35))	('regulating', 'Reg', (90, 100))	('mitochondrial function', 'MPA', (101, 123))	('NDRG4', 'Gene', (39, 44))
4067	33298240	Here, we firstly report that epigenetic-mediated silencing of NDRG4 promotes PDAC by regulating mitochondrial function.	('promotes', 'PosReg', (68, 76))	('PDAC', 'Disease', (77, 81))	('PDAC', 'Phenotype', 'HP:0006725', (77, 81))	('regulating', 'Reg', (85, 95))	('epigenetic-mediated silencing', 'Var', (29, 58))	('NDRG4', 'Gene', (62, 67))	('mitochondrial function', 'MPA', (96, 118))	('PDAC', 'Chemical', '-', (77, 81))
4072	33298240	These results indicate that hypermethylation-driven silencing of NDRG4 can promote PDAC by regulating mitochondrial function and that NDRG4 could be as a potential biomarker for PDAC patients.	('mitochondrial function', 'MPA', (102, 124))	('promote', 'PosReg', (75, 82))	('silencing', 'Var', (52, 61))	('regulating', 'Reg', (91, 101))	('PDAC', 'Chemical', '-', (83, 87))	('PDAC', 'Chemical', '-', (178, 182))	('NDRG4', 'Gene', (65, 70))	('hypermethylation-driven', 'Var', (28, 51))	('PDAC', 'Disease', (83, 87))	('PDAC', 'Phenotype', 'HP:0006725', (178, 182))	('PDAC', 'Phenotype', 'HP:0006725', (83, 87))	('patients', 'Species', '9606', (183, 191))
4093	33298240	Interestingly, NDRG4 promoter methylation had been found in gastric cancer, colorectal cancer, and breast cancer, resulting in decreased NDRG4 expression.	('NDRG4', 'Gene', (15, 20))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('decreased', 'NegReg', (127, 136))	('methylation', 'Var', (30, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('expression', 'MPA', (143, 153))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (99, 112))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('NDRG4', 'Gene', (137, 142))	('gastric cancer', 'Disease', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('colorectal cancer', 'Disease', (76, 93))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
4099	33298240	To better illuminate the role of aberrant expression of NDRG family member in the prognosis of PDAC, data mining was carried out according to cross results of online analysis between Kaplan-Meier plotter (http://kmplot.com/analysis/) and oncolnc (http://www.oncolnc.org/).	('PDAC', 'Disease', (95, 99))	('PDAC', 'Phenotype', 'HP:0006725', (95, 99))	('NDRG', 'Gene', (56, 60))	('aberrant', 'Var', (33, 41))	('PDAC', 'Chemical', '-', (95, 99))
4102	33298240	To unveil the expression pattern of NDRG4 in PDAC, the following analysis was performed with two GEO datasets (GSE28735 and GSE62452), including matched tumor and corresponding non-tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('PDAC', 'Chemical', '-', (45, 49))	('NDRG4', 'Gene', (36, 41))	('tumor', 'Disease', (181, 186))	('GSE28735', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('PDAC', 'Phenotype', 'HP:0006725', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
4122	33298240	Results showed that NDRG4 overexpression resulted in decreased ATP production in SW1990 and Canpan1 cells (Fig.	('SW1990', 'CellLine', 'CVCL:1723', (81, 87))	('ATP production', 'MPA', (63, 77))	('NDRG4', 'Gene', (20, 25))	('ATP', 'Chemical', 'MESH:D000255', (63, 66))	('overexpression', 'Var', (26, 40))	('decreased', 'NegReg', (53, 62))
4130	33298240	Results showed that abnormal NDRG4 expression was associated with patients' outcome.	('NDRG4', 'Gene', (29, 34))	('abnormal', 'Var', (20, 28))	('expression', 'MPA', (35, 45))	('associated', 'Reg', (50, 60))	('patients', 'Species', '9606', (66, 74))
4134	33298240	Hyper-methylation of CpG islands in the promoter region of suppressor is considered to be an important inducer of cancer progression, including colorectal cancer, gastric cancer, esophageal cancer, and PDAC.	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('gastric cancer', 'Phenotype', 'HP:0012126', (163, 177))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('colorectal cancer', 'Disease', 'MESH:D015179', (144, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('PDAC', 'Chemical', '-', (202, 206))	('cancer', 'Disease', (190, 196))	('colorectal cancer', 'Disease', (144, 161))	('PDAC', 'Phenotype', 'HP:0006725', (202, 206))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('gastric cancer', 'Disease', (163, 177))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Hyper-methylation', 'Var', (0, 17))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (155, 161))	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('gastric cancer', 'Disease', 'MESH:D013274', (163, 177))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (114, 120))	('PDAC', 'Disease', (202, 206))	('up', 'Gene', '7378', (60, 62))
4136	33298240	More importantly, we firstly reported that NDRG4 was epigenetic silenced by hypermethylation of its promoter in PDAC, consistent with previous reports about its role in other pathological processes.	('NDRG4', 'Gene', (43, 48))	('hypermethylation', 'Var', (76, 92))	('PDAC', 'Disease', (112, 116))	('PDAC', 'Phenotype', 'HP:0006725', (112, 116))	('PDAC', 'Chemical', '-', (112, 116))
4137	33298240	Therefore, reactivating NDRG4 expression with a demethylation agent might have potential value for PDAC therapy.	('PDAC', 'Chemical', '-', (99, 103))	('PDAC', 'Phenotype', 'HP:0006725', (99, 103))	('reactivating', 'Var', (11, 23))	('demethylation', 'biological_process', 'GO:0070988', ('48', '61'))	('NDRG4', 'Gene', (24, 29))
4141	33298240	Overexpression of NDRG4 in PDAC cells inhibited cell proliferation and invasion in vitro.	('PDAC', 'Chemical', '-', (27, 31))	('cell proliferation', 'CPA', (48, 66))	('NDRG4', 'Gene', (18, 23))	('inhibited', 'NegReg', (38, 47))	('PDAC', 'Phenotype', 'HP:0006725', (27, 31))	('Overexpression', 'Var', (0, 14))	('invasion in vitro', 'CPA', (71, 88))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))
4143	33298240	Results showed that NDRG4 overexpression could weaken the mitochondrial function in PDAC cells, including decreased ATP production, increased depolarization, and fragmented mitochondria.	('decreased', 'NegReg', (106, 115))	('fragmented mitochondria', 'CPA', (162, 185))	('PDAC', 'Chemical', '-', (84, 88))	('PDAC', 'Phenotype', 'HP:0006725', (84, 88))	('weaken', 'NegReg', (47, 53))	('ATP', 'Chemical', 'MESH:D000255', (116, 119))	('NDRG4', 'Gene', (20, 25))	('increased', 'PosReg', (132, 141))	('mitochondrial function', 'MPA', (58, 80))	('depolarization', 'MPA', (142, 156))	('mitochondria', 'cellular_component', 'GO:0005739', ('173', '185'))	('ATP production', 'MPA', (116, 130))	('overexpression', 'Var', (26, 40))
4144	33298240	Meanwhile, NDRG4 overexpression weakened expression levels of Tom20, a mitochondrial marker.	('expression levels', 'MPA', (41, 58))	('overexpression', 'Var', (17, 31))	('Tom20', 'Gene', '9804', (62, 67))	('NDRG4', 'Gene', (11, 16))	('Tom20', 'Gene', (62, 67))	('weakened', 'NegReg', (32, 40))
4146	33298240	This is the first report demonstrating that hypermethylation-driven NDRG4 silencing can promote PDAC by regulating mitochondrial function.	('hypermethylation-driven', 'Var', (44, 67))	('PDAC', 'Chemical', '-', (96, 100))	('promote', 'PosReg', (88, 95))	('silencing', 'NegReg', (74, 83))	('NDRG4', 'Gene', (68, 73))	('PDAC', 'Disease', (96, 100))	('PDAC', 'Phenotype', 'HP:0006725', (96, 100))	('regulating', 'Reg', (104, 114))	('mitochondrial function', 'MPA', (115, 137))
4163	32314446	Combination of KRAS and SMAD4 mutations in formalin-fixed paraffin-embedded tissues as a biomarker for pancreatic cancer Formalin-fixed paraffin-embedded (FFPE) tissues used for routine pathological diagnosis are valuable for cancer genomic analysis; however, the association between mutation status derived from these specimens and prognosis in pancreatic ductal adenocarcinoma (PDAC) remains unclear.	('pancreatic cancer', 'Disease', (103, 120))	('pancreatic ductal adenocarcinoma', 'Disease', (346, 378))	('formalin', 'Chemical', 'MESH:D005557', (43, 51))	('PDAC', 'Phenotype', 'HP:0006725', (380, 384))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('SMAD4', 'Gene', '4089', (24, 29))	('Formalin', 'Chemical', 'MESH:D005557', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (346, 378))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (103, 120))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('paraffin', 'Chemical', 'MESH:D010232', (58, 66))	('mutations', 'Var', (30, 39))	('KRAS', 'Gene', '3845', (15, 19))	('paraffin', 'Chemical', 'MESH:D010232', (136, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (369, 378))	('KRAS', 'Gene', (15, 19))	('cancer', 'Disease', (114, 120))	('pancreatic cancer', 'Disease', 'MESH:D010190', (103, 120))	('cancer', 'Disease', (226, 232))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (346, 378))	('SMAD4', 'Gene', (24, 29))	('PDAC', 'Chemical', '-', (380, 384))
4167	32314446	The prevalence of driver gene mutations was as follows: 84% for KRAS, 62% for TP53, 32% for SMAD4, and 18% for CDKN2A.	('mutations', 'Var', (30, 39))	('TP53', 'Gene', '7157', (78, 82))	('CDKN2A', 'Gene', (111, 117))	('TP53', 'Gene', (78, 82))	('CDKN2A', 'Gene', '1029', (111, 117))
4169	32314446	The combination of KRAS and SMAD4 mutations resulted in significantly shorter relapse-free survival (RFS; median survival time [MST], 12.3 vs. 28.9 months, P = .014) and overall survival (OS; MST, 22.3 months vs. not reached, P = .048).	('relapse-free survival', 'CPA', (78, 99))	('shorter', 'NegReg', (70, 77))	('overall survival', 'CPA', (170, 186))	('KRAS', 'Gene', (19, 23))	('RFS', 'Gene', (101, 104))	('RFS', 'Gene', '65211', (101, 104))	('SMAD4', 'Gene', (28, 33))	('mutations', 'Var', (34, 43))
4170	32314446	On multivariate analysis, the combination of KRAS and SMAD4 mutations was an independent prognostic factor for RFS (hazard ratio [HR] 4.218; 95% confidence interval [CI], 1.77-10.08; P = .001) and OS (HR 6.730; 95% CI, 1.93-23.43; P = .003).	('RFS', 'Gene', '65211', (111, 114))	('SMAD4', 'Gene', (54, 59))	('RFS', 'Gene', (111, 114))	('mutations', 'Var', (60, 69))	('KRAS', 'Gene', (45, 49))
4171	32314446	The combination of KRAS and SMAD4 mutations in DNA obtained from FFPE tissues is an independent poor prognostic factor in PDAC.	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('PDAC', 'Chemical', '-', (122, 126))	('KRAS', 'Gene', (19, 23))	('PDAC', 'Disease', (122, 126))	('PDAC', 'Phenotype', 'HP:0006725', (122, 126))	('SMAD4', 'Gene', (28, 33))	('mutations', 'Var', (34, 43))
4173	32314446	First, the detection of KRAS and SMAD4 mutations in the resected specimen implied an increase in tumor recurrence with a poor chance of survival.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('SMAD4', 'Gene', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', (97, 102))	('increase', 'PosReg', (85, 93))	('KRAS', 'Gene', (24, 28))
4181	32314446	Recently, gene mutations have been reported to be effective biomarkers for the determination of therapeutic strategies in various cancers, 5 ,  6  and some druggable gene mutations have been reported to improve survival rates.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('mutations', 'Var', (15, 24))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('survival rates', 'CPA', (211, 225))	('improve', 'PosReg', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('mutations', 'Var', (171, 180))
4182	32314446	7 ,  8  In advanced PDAC patients with distant metastasis, germline BRCA mutations have been reported to be druggable genes 9 ; however, biomarkers have not yet been established for therapeutic targets or precision medicine in resected PDAC.	('PDAC', 'Chemical', '-', (20, 24))	('PDAC', 'Phenotype', 'HP:0006725', (236, 240))	('patients', 'Species', '9606', (25, 33))	('PDAC', 'Phenotype', 'HP:0006725', (20, 24))	('BRCA', 'Gene', '672', (68, 72))	('PDAC', 'Chemical', '-', (236, 240))	('BRCA', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))
4183	32314446	Genomic biomarkers for PDAC have been identified by analyzing the association between somatic gene mutations and their clinicopathological variables.	('PDAC', 'Chemical', '-', (23, 27))	('mutations', 'Var', (99, 108))	('PDAC', 'Disease', (23, 27))	('PDAC', 'Phenotype', 'HP:0006725', (23, 27))
4185	32314446	13  However, we also previously reported that the survival rate of IPMC patients with a genetic heterogeneous primary tumor containing more than 2 types of KRAS mutation, was better than that of IPMC patients with genetic homogenous primary tumors with only 1 type of KRAS mutation.	('better', 'PosReg', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('patients', 'Species', '9606', (200, 208))	('tumor', 'Disease', (241, 246))	('KRAS', 'Gene', (156, 160))	('IPMC', 'Chemical', '-', (195, 199))	('mutation', 'Var', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Disease', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('tumor', 'Disease', (118, 123))	('IPMC', 'Chemical', '-', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('survival', 'CPA', (50, 58))	('patients', 'Species', '9606', (72, 80))
4225	32314446	Other variants detected in 1 case included hotspot mutations in APC, ATM, GNAS, HRAS, JAK2, JAK3, NRAS, PTEN, RB1, SMARCB1, SRC, and STK11.	('mutations', 'Var', (51, 60))	('RB1', 'Gene', (110, 113))	('STK11', 'Gene', '6794', (133, 138))	('APC', 'Disease', 'MESH:D011125', (64, 67))	('APC', 'cellular_component', 'GO:0005680', ('64', '67'))	('APC', 'Disease', (64, 67))	('NRAS', 'Gene', (98, 102))	('ATM', 'Gene', '472', (69, 72))	('SMARCB1', 'Gene', '6598', (115, 122))	('STK11', 'molecular_function', 'GO:0033868', ('133', '138'))	('SMARCB1', 'Gene', (115, 122))	('RB1', 'Gene', '5925', (110, 113))	('JAK2', 'Gene', '3717', (86, 90))	('SRC', 'Gene', '6714', (124, 127))	('PTEN', 'Gene', (104, 108))	('JAK', 'molecular_function', 'GO:0004713', ('86', '89'))	('JAK3', 'Gene', (92, 96))	('ATM', 'Gene', (69, 72))	('NRAS', 'Gene', '4893', (98, 102))	('STK11', 'Gene', (133, 138))	('SRC', 'Gene', (124, 127))	('JAK2', 'Gene', (86, 90))	('PTEN', 'Gene', '5728', (104, 108))	('GNAS', 'Gene', (74, 78))	('HRAS', 'Gene', '3265', (80, 84))	('JAK3', 'Gene', '3718', (92, 96))	('JAK', 'molecular_function', 'GO:0004713', ('92', '95'))	('HRAS', 'Gene', (80, 84))	('GNAS', 'Gene', '2778', (74, 78))
4227	32314446	Mutations were observed in 2 driver genes, KRAS/TP53 in 15 cases (30.0%) and KRAS/SMAD4, KRAS/CDKN2A, TP53/SMAD4, and TP53/CDKN2A in 4 (8.0%), 3 (6.0%), 1 (2.0%), and 1 (2.0%) cases, respectively.	('KRAS/SMAD4', 'Var', (77, 87))	('TP53', 'Gene', (102, 106))	('TP53', 'Gene', '7157', (48, 52))	('CDKN2A', 'Gene', '1029', (94, 100))	('TP53', 'Gene', (48, 52))	('TP53', 'Gene', '7157', (118, 122))	('Mutations', 'Var', (0, 9))	('CDKN2A', 'Gene', (123, 129))	('TP53', 'Gene', (118, 122))	('TP53', 'Gene', '7157', (102, 106))	('CDKN2A', 'Gene', '1029', (123, 129))	('CDKN2A', 'Gene', (94, 100))
4229	32314446	Ten mutations were found in the druggable genes ATM, NOTCH1, PIK3CA, PTEN, and RET; however, these mutations were detected in only 8 cases (16.0%).	('PIK3CA', 'Gene', (61, 67))	('RET', 'Gene', '5979', (79, 82))	('NOTCH1', 'Gene', (53, 59))	('NOTCH1', 'Gene', '4851', (53, 59))	('PIK3CA', 'Gene', '5290', (61, 67))	('PTEN', 'Gene', '5728', (69, 73))	('ATM', 'Gene', '472', (48, 51))	('RET', 'Gene', (79, 82))	('mutations', 'Var', (4, 13))	('ATM', 'Gene', (48, 51))	('PTEN', 'Gene', (69, 73))
4235	32314446	Patients with SMAD4 mutations had significantly poorer RFS than those with WT SMAD4 (MST, 12.3 vs. 23.4 months, respectively; 1- and 3-year RFS, 54.7%, 13.0% vs. 69.0%, 33.2%, respectively, P = .034; Figure 2A).	('RFS', 'Gene', (140, 143))	('RFS', 'Gene', '65211', (55, 58))	('RFS', 'Gene', (55, 58))	('poorer', 'NegReg', (48, 54))	('Patients', 'Species', '9606', (0, 8))	('SMAD4', 'Gene', (14, 19))	('RFS', 'Gene', '65211', (140, 143))	('mutations', 'Var', (20, 29))
4236	32314446	Patients with SMAD4 mutations had poorer OS than those with WT SMAD4 (MST, 22.3 months vs. not reached, respectively; 1- and 3-year OS, 87.1%, 30.5% vs. 93.8%, 70.9%, respectively, P = .063; Figure 2B).	('Patients', 'Species', '9606', (0, 8))	('SMAD4', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))
4238	32314446	Patients with a combination of KRAS and SMAD4 mutations had significantly poorer RFS than those with WT KRAS or SMAD4 (MST, 12.3 vs. 28.9 months; 1- and 3-year RFS, 51.4%, 11.4% vs. 69.9%, 33.8%, P = .014; Figure 3A).	('poorer', 'NegReg', (74, 80))	('KRAS', 'Gene', (31, 35))	('mutations', 'Var', (46, 55))	('WT KRAS', 'Disease', 'MESH:C536751', (101, 108))	('RFS', 'Gene', '65211', (81, 84))	('SMAD4', 'Gene', (40, 45))	('RFS', 'Gene', '65211', (160, 163))	('Patients', 'Species', '9606', (0, 8))	('RFS', 'Gene', (81, 84))	('WT KRAS', 'Disease', (101, 108))	('RFS', 'Gene', (160, 163))
4239	32314446	Patients with a combination of KRAS and SMAD4 mutations also had significantly poorer OS than those with WT KRAS or SMAD4 (MST, 22.3 months vs. not reached, respectively; 1- and 3-year OS, 78.3%, 27.4% vs. 94.2%, 71.4%, respectively, P = .048; Figure 3B).	('KRAS', 'Gene', (31, 35))	('mutations', 'Var', (46, 55))	('SMAD4', 'Gene', (40, 45))	('poorer', 'NegReg', (79, 85))	('WT KRAS', 'Disease', 'MESH:C536751', (105, 112))	('Patients', 'Species', '9606', (0, 8))	('WT KRAS', 'Disease', (105, 112))
4240	32314446	On univariate Cox regression analysis, SMAD4 mutation, a combination of KRAS and SMAD4 mutations, lymphatic and intrapancreatic nerve infiltration, serosal, extrapancreatic nerve plexus invasion, pathological T status, pathological N status, and successfully completed adjuvant treatment were identified as significant predictive factors for RFS (Table 3).	('SMAD4', 'Gene', (39, 44))	('KRAS', 'Gene', (72, 76))	('SMAD4', 'Gene', (81, 86))	('mutation', 'Var', (45, 53))	('RFS', 'Gene', '65211', (342, 345))	('RFS', 'Gene', (342, 345))	('mutations', 'Var', (87, 96))
4241	32314446	On multivariate Cox regression analysis, a combination of KRAS and SMAD4 mutations (HR = 4.218; 95% CI, 1.77-10.08; P = .001) and successfully completed adjuvant treatment (HR = 0.226; 95% CI, 0.10-0.52; P < .001) were independent predictive factors for RFS (Table 3), whereas a combination of KRAS and SMAD4 mutations (HR = 6.730; 95% CI, 1.93-23.43; P = .003) and successfully completed adjuvant treatment (HR = 0.068; 95% CI, 0.02-0.27; P < .001) were identified as independent predictive factors for OS (Table 3).	('RFS', 'Gene', (254, 257))	('SMAD4', 'Gene', (67, 72))	('RFS', 'Gene', '65211', (254, 257))	('mutations', 'Var', (73, 82))	('SMAD4', 'Gene', (303, 308))
4242	32314446	Among the 4 driver genes, SMAD4 mutations were recognized as a prognostic factor for RFS.	('SMAD4', 'Gene', (26, 31))	('mutations', 'Var', (32, 41))	('RFS', 'Gene', (85, 88))	('RFS', 'Gene', '65211', (85, 88))
4243	32314446	Furthermore, the combination of KRAS and SMAD4 mutations was found to be an independent prognostic factor for RFS and OS.	('RFS', 'Gene', (110, 113))	('KRAS', 'Gene', (32, 36))	('mutations', 'Var', (47, 56))	('SMAD4', 'Gene', (41, 46))	('RFS', 'Gene', '65211', (110, 113))
4245	32314446	17 ,  18 ,  20  Among these genes, SMAD4 mutations were found to be an independent prognostic factor for RFS.	('mutations', 'Var', (41, 50))	('RFS', 'Gene', '65211', (105, 108))	('SMAD4', 'Gene', (35, 40))	('RFS', 'Gene', (105, 108))
4246	32314446	Furthermore, the combination of KRAS and SMAD4 mutations was an independent prognostic factor for both RFS and OS.	('RFS', 'Gene', '65211', (103, 106))	('KRAS', 'Gene', (32, 36))	('RFS', 'Gene', (103, 106))	('mutations', 'Var', (47, 56))	('SMAD4', 'Gene', (41, 46))
4248	32314446	Although KRAS mutations in PDAC occur too frequently to be considered appropriate prognostic factors, previous reports mention that the KRAS mutant subtype G12V or G12D is associated with poor prognosis 31 ,  32 ; however, which exact subtype is associated with a worse prognosis is controversial.	('PDAC', 'Chemical', '-', (27, 31))	('G12V', 'Var', (156, 160))	('G12V', 'Mutation', 'rs121913529', (156, 160))	('PDAC', 'Gene', (27, 31))	('PDAC', 'Phenotype', 'HP:0006725', (27, 31))	('G12D', 'Var', (164, 168))	('G12D', 'Mutation', 'rs121913529', (164, 168))
4250	32314446	33 ,  34  Loss of heterozygosity or the homozygous deletion of SMAD4 was first reported in PDAC, 35  but has since been identified in various types of cancer.	('homozygous deletion', 'Var', (40, 59))	('PDAC', 'Chemical', '-', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('PDAC', 'Disease', (91, 95))	('PDAC', 'Phenotype', 'HP:0006725', (91, 95))	('SMAD4', 'Gene', (63, 68))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('Loss', 'Var', (10, 14))
4252	32314446	14 ,  38 ,  39 ,  40  In NGS, SMAD4 mutations are considered a poor prognostic factor in the analysis of DNA extracts from resected PDAC cells purified from cell lines or xenografts, 21  whereas they were not a prognostic factor in the analysis of DNA extracts from FFPE or fresh-frozen specimens.	('SMAD4', 'Gene', (30, 35))	('PDAC', 'Chemical', '-', (132, 136))	('mutations', 'Var', (36, 45))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('DNA', 'cellular_component', 'GO:0005574', ('248', '251'))	('PDAC', 'Phenotype', 'HP:0006725', (132, 136))
4253	32314446	To our knowledge, the current study is the first to report SMAD4 mutations as a prognostic factor for PDAC in NGS analysis using DNA extracts from FFPE.	('PDAC', 'Chemical', '-', (102, 106))	('DNA', 'cellular_component', 'GO:0005574', ('129', '132'))	('PDAC', 'Disease', (102, 106))	('PDAC', 'Phenotype', 'HP:0006725', (102, 106))	('SMAD4', 'Gene', (59, 64))	('mutations', 'Var', (65, 74))
4254	32314446	Wilentz et al reported that SMAD4 mutations could be detected at a rate of 30% in high-grade PanIN, a precancerous lesion of pancreatic cancer.	('high-grade PanIN', 'Disease', (82, 98))	('precancerous lesion of pancreatic cancer', 'Disease', 'MESH:D010190', (102, 142))	('detected', 'Reg', (53, 61))	('SMAD4', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('precancerous lesion of pancreatic cancer', 'Disease', (102, 142))	('mutations', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))
4255	32314446	41  In a mouse model, KRAS mutations alone could slow the progression of PanIN to cancer; however, combining KRAS mutations and SMAD4 deletions was found to cause the rapid progression of tumors.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cause', 'Reg', (157, 162))	('tumors', 'Disease', (188, 194))	('deletions', 'Var', (134, 143))	('SMAD4', 'Gene', (128, 133))	('mutations', 'Var', (114, 123))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('mouse', 'Species', '10090', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cancer', 'Disease', (82, 88))	('KRAS', 'Gene', (109, 113))	('slow', 'NegReg', (49, 53))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('PanIN', 'Disease', (73, 78))
4256	32314446	42  In the examination of autopsy cases, SMAD4 gene mutations were found to be a predictor of multiple distant metastases.	('mutations', 'Var', (52, 61))	('metastases', 'Disease', (111, 121))	('SMAD4', 'Gene', (41, 46))	('metastases', 'Disease', 'MESH:D009362', (111, 121))
4257	32314446	43  These previous reports suggest that SMAD4 mutations could lead to cancer progression and, therefore, poor prognosis; this supports the results of the current study.	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SMAD4', 'Gene', (40, 45))	('lead to', 'Reg', (62, 69))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
4258	32314446	18 ,  20  Cancer Hotspot Panel version 2 does not contain BRCA mutations, which have been reported to be effective targets for treatment with a poly (adenosine diphosphate-ribose) polymerase inhibitor.	('mutations', 'Var', (63, 72))	('BRCA', 'Gene', '672', (58, 62))	('BRCA', 'Gene', (58, 62))	('Cancer', 'Phenotype', 'HP:0002664', (10, 16))	('Cancer', 'Disease', (10, 16))	('adenosine', 'Chemical', 'MESH:D000241', (150, 159))	('Cancer', 'Disease', 'MESH:D009369', (10, 16))
4261	32314446	In conclusion, based on NGS analysis using the FFPE tissue of resected PDAC, the current study revealed that the combination of KRAS and SMAD4 mutations is an independent poor prognostic factor for recurrence and survival.	('KRAS', 'Gene', (128, 132))	('recurrence', 'CPA', (198, 208))	('PDAC', 'Phenotype', 'HP:0006725', (71, 75))	('survival', 'CPA', (213, 221))	('SMAD4', 'Gene', (137, 142))	('PDAC', 'Chemical', '-', (71, 75))	('mutations', 'Var', (143, 152))
4306	31849832	For example, in several cancers including endocrine pancreatic cancer cells, loss of fructose-1,6-bisphosphatase (FBP1) that catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate, is associated with increased cancer stem cell like phenotype and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', (24, 30))	('metastasis', 'CPA', (269, 279))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('FBP1', 'Gene', '2203', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('loss', 'Var', (77, 81))	('cancers', 'Disease', (24, 31))	('cancer', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('endocrine pancreatic cancer', 'Disease', (42, 69))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('fructose 1,6-bisphosphate', 'Chemical', 'MESH:C029063', (153, 178))	('increased', 'PosReg', (223, 232))	('FBP1', 'Gene', (114, 118))	('endocrine pancreatic cancer', 'Disease', 'MESH:D010190', (42, 69))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('fructose 6-phosphate', 'Chemical', 'MESH:C027618', (182, 202))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (52, 69))
4312	31849832	Similarly, Glut3 expression in non-small cell lung cancer is associated with increased glucose uptake, activation of EMT-TFs and tumor cell invasiveness.	('glucose', 'Chemical', 'MESH:D005947', (87, 94))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (31, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('increased', 'PosReg', (77, 86))	('tumor', 'Disease', (129, 134))	('lung cancer', 'Disease', (46, 57))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (35, 57))	('EMT', 'biological_process', 'GO:0001837', ('117', '120'))	('Glut3', 'Gene', (11, 16))	('glucose uptake', 'CPA', (87, 101))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('activation', 'PosReg', (103, 113))	('EMT-TFs', 'CPA', (117, 124))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('glucose uptake', 'biological_process', 'GO:0046323', ('87', '101'))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('expression', 'Var', (17, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))	('Glut3', 'Gene', '6515', (11, 16))	('increased glucose', 'Phenotype', 'HP:0003074', (77, 94))
4315	31849832	In intestinal-type gastric cancer cell lines, silencing LDHa downregulates Zeb2 and the synergistic decrease of LDHa and Zeb2 decreased cancer invasion, metastasis and poor prognosis.	('LDHa', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('downregulates', 'NegReg', (61, 74))	('silencing', 'Var', (46, 55))	('gastric cancer', 'Phenotype', 'HP:0012126', (19, 33))	('decrease', 'NegReg', (100, 108))	('cancer', 'Disease', (136, 142))	('intestinal-type gastric cancer', 'Disease', 'MESH:D013274', (3, 33))	('poor prognosis', 'CPA', (168, 182))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('Zeb2', 'Gene', (75, 79))	('Zeb2', 'Gene', '9839', (75, 79))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('Zeb2', 'Gene', '9839', (121, 125))	('Zeb2', 'Gene', (121, 125))	('decreased', 'NegReg', (126, 135))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('intestinal-type gastric cancer', 'Disease', (3, 33))	('LDHa', 'Gene', '3939', (112, 116))	('metastasis', 'CPA', (153, 163))	('LDHa', 'Gene', (112, 116))	('LDHa', 'Gene', '3939', (56, 60))	('cancer', 'Disease', (27, 33))
4316	31849832	Also, in bladder cell lines, high levels of LDHa stimulated EMT leading to migration and invasion of the tumor cells and silencing Ldha inhibited tumorogenecity in pancreatic cells in vivo.	('stimulated', 'PosReg', (49, 59))	('Ldha', 'Gene', (131, 135))	('silencing', 'Var', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('inhibited', 'NegReg', (136, 145))	('LDHa', 'Gene', (44, 48))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('Ldha', 'Gene', '3939', (131, 135))	('pancreatic', 'Disease', 'MESH:D010195', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('EMT', 'biological_process', 'GO:0001837', ('60', '63'))	('EMT', 'CPA', (60, 63))	('migration', 'CPA', (75, 84))	('tumor', 'Disease', (105, 110))	('pancreatic', 'Disease', (164, 174))	('LDHa', 'Gene', '3939', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
4322	31849832	For example, mutation of mtDNA encoding Complex I subunits of the ETC increases the propensity of oncocytic thyroid cancers.	('oncocytic thyroid cancers', 'Disease', 'MESH:D013964', (98, 123))	('mtDNA', 'cellular_component', 'GO:0000262', ('25', '30'))	('mutation', 'Var', (13, 21))	('oncocytic thyroid cancers', 'Disease', (98, 123))	('increases', 'PosReg', (70, 79))	('Complex I', 'cellular_component', 'GO:0030964', ('40', '49'))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('mtDNA', 'Gene', (25, 30))
4323	31849832	The importance of mtDNA mutations to metastasis is highlighted by experiments using cybrid technology, to distinguish the contribution of mitochondrial genome to cancer metastasis.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('mtDNA', 'cellular_component', 'GO:0000262', ('18', '23'))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('mitochondrial genome', 'cellular_component', 'GO:0000262', ('138', '158'))	('mutations', 'Var', (24, 33))	('mtDNA', 'Gene', (18, 23))
4325	31849832	ROS, a mitochondrial byproduct of the ETC, which can damage and mutate mtDNA, was also shown to induce metastasis of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutate', 'Var', (64, 70))	('mtDNA', 'cellular_component', 'GO:0000262', ('71', '76'))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('tumor', 'Disease', (117, 122))	('induce', 'PosReg', (96, 102))	('mtDNA', 'Gene', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
4336	31849832	Silencing Pgc-1alpha impaired the invasion and metastasis without affecting the proliferation of the primary tumor.	('Pgc-1alpha', 'Gene', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('impaired', 'NegReg', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('Pgc-1alpha', 'Gene', '10891', (10, 20))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', (109, 114))
4338	31849832	Evident in endocrine cancers are mutations of TCA cycle operational enzymes, which are linked to EMT.	('TCA cycle operational enzymes', 'Enzyme', (46, 75))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('endocrine cancers', 'Disease', (11, 28))	('EMT', 'biological_process', 'GO:0001837', ('97', '100'))	('linked', 'Reg', (87, 93))	('mutations', 'Var', (33, 42))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('endocrine cancer', 'Phenotype', 'HP:0100568', (11, 27))	('TCA', 'Chemical', 'MESH:D014233', (46, 49))	('endocrine cancers', 'Disease', 'MESH:D004701', (11, 28))	('TCA cycle', 'biological_process', 'GO:0006099', ('46', '55'))
4339	31849832	The neuroendocrine tumors, pheochromocytoma and paragangliomas are associated with mutation of succinate dehydrogenase (SDH) that converts succinate to fumarate.	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (4, 25))	('paragangliomas', 'Disease', 'MESH:D010235', (48, 62))	('paraganglioma', 'Phenotype', 'HP:0002668', (48, 61))	('paragangliomas', 'Phenotype', 'HP:0002668', (48, 62))	('mutation', 'Var', (83, 91))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (27, 61))	('SDH', 'Gene', '6390', (120, 123))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (4, 25))	('succinate', 'Chemical', 'MESH:D019802', (95, 104))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (27, 43))	('succinate dehydrogenase', 'Gene', (95, 118))	('SDH', 'Gene', (120, 123))	('paragangliomas', 'Disease', (48, 62))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('associated', 'Reg', (67, 77))	('neuroendocrine tumors', 'Disease', (4, 25))	('endocrine tumor', 'Phenotype', 'HP:0100568', (9, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('succinate', 'Chemical', 'MESH:D019802', (139, 148))	('fumarate', 'Chemical', 'MESH:D005650', (152, 160))	('succinate dehydrogenase', 'Gene', '6390', (95, 118))
4340	31849832	In particular, a mutation of SDHb a subunit of SDH, is thought to alter glucose and glutamine utilization and cause epigenetic modifications that results in EMT.	('SDHb', 'Gene', '6390', (29, 33))	('results in', 'Reg', (146, 156))	('glucose', 'Chemical', 'MESH:D005947', (72, 79))	('SDH', 'Gene', (47, 50))	('mutation', 'Var', (17, 25))	('glutamine', 'Chemical', 'MESH:D005973', (84, 93))	('epigenetic modifications', 'MPA', (116, 140))	('EMT', 'biological_process', 'GO:0001837', ('157', '160'))	('alter', 'Reg', (66, 71))	('SDH', 'Gene', '6390', (29, 32))	('cause', 'Reg', (110, 115))	('EMT', 'CPA', (157, 160))	('SDH', 'Gene', '6390', (47, 50))	('SDHb', 'Gene', (29, 33))	('SDH', 'Gene', (29, 32))
4341	31849832	Moreover, SDH mutation is hypothesized to cause consumption of extracellular pyruvate to maintain the Warburg effect conducive for cell growth and thus EMT potential.	('cell growth', 'biological_process', 'GO:0016049', ('131', '142'))	('SDH', 'Gene', '6390', (10, 13))	('pyruvate', 'Chemical', 'MESH:D019289', (77, 85))	('EMT potential', 'CPA', (152, 165))	('SDH', 'Gene', (10, 13))	('cause', 'Reg', (42, 47))	('Warburg effect', 'MPA', (102, 116))	('extracellular', 'cellular_component', 'GO:0005576', ('63', '76'))	('mutation', 'Var', (14, 22))	('EMT', 'biological_process', 'GO:0001837', ('152', '155'))	('consumption of extracellular pyruvate', 'MPA', (48, 85))
4344	31849832	SDHb mutations cause upregulation of metastatic genes and epigenetic silencing of cell adhesion protein, keratin 19, leading to EMT and rendering the tumor cells more aggressive and invasive.	('keratin 19', 'Gene', (105, 115))	('EMT', 'CPA', (128, 131))	('epigenetic silencing', 'Var', (58, 78))	('SDHb', 'Gene', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('SDHb', 'Gene', '6390', (0, 4))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('EMT', 'biological_process', 'GO:0001837', ('128', '131'))	('metastatic genes', 'Gene', (37, 53))	('upregulation', 'PosReg', (21, 33))	('keratin 19', 'Gene', '3880', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cell adhesion', 'biological_process', 'GO:0007155', ('82', '95'))	('aggressive', 'CPA', (167, 177))	('more', 'PosReg', (162, 166))	('invasive', 'CPA', (182, 190))	('tumor', 'Disease', (150, 155))
4345	31849832	Mutation of another important enzyme of the TCA cycle, fumarate hydratase (FH), which converts fumarate to malate, is also implicated in metastasis of pheochromocytoma and paraganglioma.	('TCA', 'Chemical', 'MESH:D014233', (44, 47))	('paraganglioma', 'Phenotype', 'HP:0002668', (172, 185))	('TCA cycle', 'biological_process', 'GO:0006099', ('44', '53'))	('Mutation', 'Var', (0, 8))	('fumarate', 'Chemical', 'MESH:D005650', (95, 103))	('fumarate hydratase', 'Gene', '2271', (55, 73))	('implicated', 'Reg', (123, 133))	('fumarate', 'Chemical', 'MESH:D005650', (55, 63))	('FH', 'Gene', '2271', (75, 77))	('metastasis of pheochromocytoma and paraganglioma', 'Disease', 'MESH:D009362', (137, 185))	('malate', 'Chemical', 'MESH:C030298', (107, 113))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (151, 167))	('fumarate hydratase', 'Gene', (55, 73))
4348	31849832	Recently, fumarate buildup in renal cancers has been shown to cause EMT by inhibiting Tet dioxygenase mediated demethyation of antimetastatic miR-200 which is a known activator of metastasis and EMT.	('renal cancers', 'Disease', (30, 43))	('inhibiting', 'NegReg', (75, 85))	('Tet', 'Chemical', 'MESH:C010349', (86, 89))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('EMT', 'Disease', (68, 71))	('EMT', 'biological_process', 'GO:0001837', ('68', '71'))	('fumarate', 'Chemical', 'MESH:D005650', (10, 18))	('cause', 'Reg', (62, 67))	('miR-200', 'Chemical', '-', (142, 149))	('Tet dioxygenase mediated demethyation', 'MPA', (86, 123))	('renal cancers', 'Disease', 'MESH:D007680', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('fumarate buildup', 'Var', (10, 26))	('oxygen', 'Chemical', 'MESH:D010100', (92, 98))	('EMT', 'biological_process', 'GO:0001837', ('195', '198'))
4350	31849832	An oncometabolite formed due to mutation of isocitrate dehydrogenase, 2D hydroxyglutarate, induced metastasis and EMT in colorectal cancers by increasing Zeb1 expression.	('Zeb1', 'Gene', '6935', (154, 158))	('EMT', 'CPA', (114, 117))	('Zeb1', 'Gene', (154, 158))	('isocitrate dehydrogenase', 'Gene', (44, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('colorectal cancers', 'Disease', 'MESH:D015179', (121, 139))	('2D hydroxyglutarate', 'Chemical', '-', (70, 89))	('increasing', 'PosReg', (143, 153))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('isocitrate dehydrogenase', 'Gene', '3417', (44, 68))	('colorectal cancers', 'Disease', (121, 139))	('expression', 'MPA', (159, 169))	('metastasis', 'CPA', (99, 109))	('induced', 'PosReg', (91, 98))	('mutation', 'Var', (32, 40))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('EMT', 'biological_process', 'GO:0001837', ('114', '117'))
4368	31849832	High FASN expression levels in pancreatic cancer and papillary thyroid carcinoma patients is associated with poor survival rate, but its importance to EMT is unknown.	('survival', 'MPA', (114, 122))	('FASN', 'Gene', '2194', (5, 9))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (63, 80))	('EMT', 'biological_process', 'GO:0001837', ('151', '154'))	('papillary thyroid carcinoma', 'Disease', (53, 80))	('High', 'Var', (0, 4))	('poor', 'NegReg', (109, 113))	('expression levels', 'MPA', (10, 27))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('pancreatic cancer', 'Disease', (31, 48))	('patients', 'Species', '9606', (81, 89))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (53, 80))	('pancreatic cancer', 'Disease', 'MESH:D010190', (31, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (53, 80))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (31, 48))	('FASN', 'Gene', (5, 9))
4374	31849832	Importantly, inhibition of SCD in prostate cancer blocked tumor gowth and survival.	('survival', 'CPA', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('SCD', 'Gene', (27, 30))	('blocked', 'NegReg', (50, 57))	('inhibition', 'Var', (13, 23))	('prostate cancer', 'Disease', (34, 49))	('SCD', 'Gene', '6319', (27, 30))	('tumor gowth', 'Disease', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('prostate cancer', 'Disease', 'MESH:D011471', (34, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (34, 49))	('tumor gowth', 'Disease', 'MESH:D009369', (58, 69))
4379	31849832	The importance of PM composition affecting EMT is also reinforced by the influence of cholesterol, whereby altering cholesterol content of plasma membrane is associated with increased mesenchymal stem cell like phenotype.	('cholesterol content', 'MPA', (116, 135))	('mesenchymal stem cell like phenotype', 'CPA', (184, 220))	('cholesterol', 'Chemical', 'MESH:D002784', (116, 127))	('altering', 'Var', (107, 115))	('cholesterol', 'Chemical', 'MESH:D002784', (86, 97))	('EMT', 'biological_process', 'GO:0001837', ('43', '46'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('139', '154'))	('increased', 'PosReg', (174, 183))
4393	30358104	Comparing serum levels of WASF2,ARF6,SNORA74A,SNORA25, and CA19-9 revealed that levels of WASF2 were the most highly correlated with the risk of pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (145, 162))	('ARF6', 'Gene', (32, 36))	('SNORA25', 'Gene', '684959', (46, 53))	('WASF2', 'Gene', '10163', (90, 95))	('SNORA74A', 'Gene', (37, 45))	('ARF6', 'Gene', '382', (32, 36))	('pancreatic cancer', 'Disease', (145, 162))	('correlated with', 'Reg', (117, 132))	('levels', 'Var', (80, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (145, 162))	('WASF2', 'Gene', '10163', (26, 31))	('WASF2', 'Gene', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('SNORA25', 'Gene', (46, 53))	('SNORA74A', 'Gene', '26821', (37, 45))	('WASF2', 'Gene', (26, 31))
4408	30358104	SNORA42 is frequently overexpressed in lung cancer and colorectal cancer, and knockdown of SNORA42 slows the growth of cancer cells, indicating that SNORA42 is a putative oncogene (Mei et al., 2012).	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (55, 72))	('SNORA42', 'Gene', (91, 98))	('lung cancer', 'Disease', (39, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('SNORA42', 'Gene', '677823', (0, 7))	('colorectal cancer', 'Disease', 'MESH:D015179', (55, 72))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('SNORA42', 'Gene', '677823', (149, 156))	('colorectal cancer', 'Disease', (55, 72))	('SNORA42', 'Gene', (0, 7))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('SNORA42', 'Gene', (149, 156))	('knockdown', 'Var', (78, 87))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('overexpressed', 'PosReg', (22, 35))	('SNORA42', 'Gene', '677823', (91, 98))	('slows', 'NegReg', (99, 104))	('cancer', 'Disease', (66, 72))
4455	30358104	The levels of WASF2, ARF6, SNORA74A, SNORA25, and CA19-9 in serum samples from patients in the early stages of PDAC (stages 0, I, and IIA) were significantly higher than the level in controls (Fig.	('WASF2', 'Gene', (14, 19))	('ARF6', 'Gene', '382', (21, 25))	('CA19-9', 'Var', (50, 56))	('SNORA25', 'Gene', '684959', (37, 44))	('SNORA74A', 'Gene', '26821', (27, 35))	('ARF6', 'Gene', (21, 25))	('higher', 'PosReg', (158, 164))	('PDAC', 'Chemical', '-', (111, 115))	('WASF2', 'Gene', '10163', (14, 19))	('SNORA74A', 'Gene', (27, 35))	('patients', 'Species', '9606', (79, 87))	('SNORA25', 'Gene', (37, 44))	('PDAC', 'Disease', (111, 115))	('PDAC', 'Phenotype', 'HP:0006725', (111, 115))
4459	30358104	Receiver operating characteristic curve analysis of the combinations returned AUC values of 0.960 (95% CI, 0.910-1.000) for the combination of WASF2 with CA19-9; 0.980 (95% CI, 0.946-1.000) for the combination of ARF6 with CA19-9; 0.946 (95% CI, 0.879-1.000) for the combination of SNORA74A with CA19-9; and 0.940 (95% CI, 0.871-1.000) for the combination of SNORA25 with CA19-9 (Fig.	('ARF6', 'Gene', '382', (213, 217))	('WASF2', 'Gene', (143, 148))	('SNORA25', 'Gene', (359, 366))	('SNORA74A', 'Gene', '26821', (282, 290))	('ARF6', 'Gene', (213, 217))	('WASF2', 'Gene', '10163', (143, 148))	('SNORA25', 'Gene', '684959', (359, 366))	('CA19-9', 'Var', (372, 378))	('SNORA74A', 'Gene', (282, 290))
4475	30358104	Suppression of YKT6 reduces exosome release from lung cancer cells (Ruiz-Martinez et al., 2016).	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('YKT6', 'Gene', '10652', (15, 19))	('exosome', 'cellular_component', 'GO:0070062', ('28', '35'))	('reduces', 'NegReg', (20, 27))	('Suppression', 'Var', (0, 11))	('exosome release', 'MPA', (28, 43))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('YKT6', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
4487	30358104	Serum concentrations of the snoRNA SNORD91B are decreased in PDAC patients (Liu et al., 2014), and to date, there is no evidence indicating upregulation of snoRNA expression in PDAC development.	('snoRNA', 'Gene', (156, 162))	('snoRNA', 'Gene', '85388', (156, 162))	('PDAC', 'Disease', (61, 65))	('PDAC', 'Phenotype', 'HP:0006725', (177, 181))	('PDAC', 'Phenotype', 'HP:0006725', (61, 65))	('decreased', 'NegReg', (48, 57))	('snoRNA', 'cellular_component', 'GO:0005733', ('156', '162'))	('SNORD91B', 'Var', (35, 43))	('snoRNA', 'Gene', (28, 34))	('snoRNA', 'Gene', '85388', (28, 34))	('snoRNA', 'cellular_component', 'GO:0005733', ('28', '34'))	('PDAC', 'Chemical', '-', (177, 181))	('PDAC', 'Chemical', '-', (61, 65))	('patients', 'Species', '9606', (66, 74))	('Serum concentrations', 'MPA', (0, 20))
4494	30358104	Toward this end, we have started two prospective clinical validation studies (UMIN #000021938 and UMIN #000031970) at the Kochi Medical School Hospital, Kochi Health Sciences Center, Hata Prefectural Hospital, and Kanagawa Cancer Center to assess the utility of SNORA74A, SNORA25, WASF2, and ARF6 as potential diagnostic markers for the early detection of PDAC in comparison with CA19-9.	('PDAC', 'Chemical', '-', (356, 360))	('UMIN #000031970', 'Var', (98, 113))	('UMIN #000021938', 'Var', (78, 93))	('SNORA25', 'Gene', (272, 279))	('SNORA74A', 'Gene', '26821', (262, 270))	('WASF2', 'Gene', '10163', (281, 286))	('Cancer', 'Disease', 'MESH:D009369', (223, 229))	('PDAC', 'Disease', (356, 360))	('Cancer', 'Disease', (223, 229))	('SNORA25', 'Gene', '684959', (272, 279))	('PDAC', 'Phenotype', 'HP:0006725', (356, 360))	('Cancer', 'Phenotype', 'HP:0002664', (223, 229))	('SNORA74A', 'Gene', (262, 270))	('ARF6', 'Gene', (292, 296))	('WASF2', 'Gene', (281, 286))	('ARF6', 'Gene', '382', (292, 296))
4544	30136592	However, CM from curcumin-treated CAFs had little effect on pancreatic cancer cell migration, suggesting that inactivating CAFs, instead of deleting them, suppressed pancreatic cancer migration.	('CAFs', 'Gene', (123, 127))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('pancreatic cancer', 'Disease', (166, 183))	('curcumin', 'Chemical', 'MESH:D003474', (17, 25))	('cell migration', 'biological_process', 'GO:0016477', ('78', '92'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (166, 183))	('suppressed', 'NegReg', (155, 165))	('pancreatic cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (166, 183))	('inactivating', 'Var', (110, 122))
4556	30136592	Similarly, Hendrayani et al also tested the effect of low concentrations of curcumin on patient-derived primary breast CAF cells and showed that curcumin treatment suppressed the paracrine proinvasive/migratory effects of CAFs on breast cancer cells.	('curcumin', 'Var', (145, 153))	('patient', 'Species', '9606', (88, 95))	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('curcumin', 'Chemical', 'MESH:D003474', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('suppressed', 'NegReg', (164, 174))	('breast cancer', 'Disease', (230, 243))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('paracrine proinvasive/migratory', 'MPA', (179, 210))	('curcumin', 'Chemical', 'MESH:D003474', (76, 84))
4557	30136592	These results, combined with ours, demonstrate that active stromal fibroblasts can be inactivated (reeducated to a normal state) and provide proof of principle that the application of natural products such as curcumin might be used to normalize CAFs and suppress their procarcinogenic effects.	('suppress', 'NegReg', (254, 262))	('procarcinogenic effects', 'CPA', (269, 292))	('CAFs', 'Disease', (245, 249))	('curcumin', 'Chemical', 'MESH:D003474', (209, 217))	('normalize', 'Var', (235, 244))
4594	30419905	Silencing TNS2 expression may increase the activities of Akt, Mek, and IRS-1 in lung and cervical cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Akt', 'Gene', '207', (57, 60))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('lung and cervical cancers', 'Disease', 'MESH:D008175', (80, 105))	('TNS2', 'Gene', (10, 14))	('IRS-1', 'Gene', '3667', (71, 76))	('expression', 'Species', '29278', (15, 25))	('Mek', 'Pathway', (62, 65))	('IRS-1', 'Gene', (71, 76))	('increase', 'PosReg', (30, 38))	('activities', 'MPA', (43, 53))	('Akt', 'Gene', (57, 60))	('Silencing', 'Var', (0, 9))	('TNS2', 'Gene', '23371', (10, 14))
4614	30419905	The site-directed mutagenesis for the generation of Myc-TNS2 (C231S) and Myc-TNS2 (Y483S) was performed with a KOH Hotstar DNA polymerase kit (Merck Millipore, Darmstadt, Germany) using the following primers: Cells were transfected as aforementioned and grown in 10-cm dishes.	('Myc', 'Gene', (73, 76))	('mutagenesis', 'biological_process', 'GO:0006280', ('18', '29'))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('TNS2', 'Gene', '23371', (56, 60))	('C231S', 'Mutation', 'p.C231S', (62, 67))	('Myc', 'Gene', '4609', (73, 76))	('Y483S', 'Var', (83, 88))	('Myc', 'Gene', '4609', (52, 55))	('Myc', 'Gene', (52, 55))	('TNS2', 'Gene', (56, 60))	('C231S', 'Var', (62, 67))	('TNS2', 'Gene', '23371', (77, 81))	('Y483S', 'Mutation', 'p.Y483S', (83, 88))	('TNS2', 'Gene', (77, 81))
4616	30419905	The lysates were incubated, respectively, with 2 mug of IP antibodies to Myc (9E10) (#05419, Millipore) or Axl (C-20) (#sc-1096, Santa Cruz) at 4  C overnight with constant rotation.	('mug', 'molecular_function', 'GO:0043739', ('49', '52'))	('#05419', 'Var', (85, 91))	('#sc-1096', 'Var', (119, 127))	('Myc', 'Gene', '4609', (73, 76))	('Axl', 'Gene', '558', (107, 110))	('Myc', 'Gene', (73, 76))	('Axl', 'Gene', (107, 110))
4621	30419905	To generate an antibody against p-Axl, the synthetic phospho-oligopeptide Asp-Gly-Leu-(phospho)Tyr-Ala-Leu-Met-Ser-Arg-Cys was used as an antigen for the generation of rabbit immune serum using a commercial service (GenTex Inc., California).	('Ser', 'cellular_component', 'GO:0005790', ('111', '114'))	('antibody', 'cellular_component', 'GO:0042571', ('15', '23'))	('Axl', 'Gene', '558', (34, 37))	('Asp-Gly-Leu', 'Chemical', '-', (74, 85))	('antibody', 'cellular_component', 'GO:0019815', ('15', '23'))	('(phospho)Tyr-Ala-Leu-Met-Ser-Arg-Cys', 'Chemical', '-', (86, 122))	('Axl', 'Gene', (34, 37))	('Asp-Gly-Leu-', 'Var', (74, 86))	('antibody', 'cellular_component', 'GO:0019814', ('15', '23'))	('antibody', 'molecular_function', 'GO:0003823', ('15', '23'))	('rabbit', 'Species', '9986', (168, 174))
4626	30419905	R428 is a specific Axl inhibitor.	('Axl', 'Gene', '558', (19, 22))	('R428', 'Chemical', '-', (0, 4))	('R428', 'Var', (0, 4))	('Axl', 'Gene', (19, 22))
4640	30419905	For Axl, p-Axl and p-TNS2 detection, the sections were incubated overnight at 4  C with anti-AXL (1:50, ab72069, Abcam, Eugene, OR), anti-pAxl-Y779 (1:100 AF2228, R&D, MN, USA) and anti-p-TNS2 (1:100, ab138414, Abcam, Eugene, OR), respectively.	('1:50', 'Var', (98, 102))	('TNS2', 'Gene', (21, 25))	('TNS2', 'Gene', '23371', (188, 192))	('Axl', 'Gene', (139, 142))	('Axl', 'Gene', '558', (11, 14))	('Axl', 'Gene', '558', (4, 7))	('AXL', 'Gene', (93, 96))	('MN', 'CellLine', 'CVCL:U508', (168, 170))	('Axl', 'Gene', (11, 14))	('Axl', 'Gene', (4, 7))	('AXL', 'Gene', '558', (93, 96))	('Axl', 'Gene', '558', (139, 142))	('ab72069', 'Var', (104, 111))	('TNS2', 'Gene', (188, 192))	('TNS2', 'Gene', '23371', (21, 25))
4642	30419905	PDAC cases were categorized into 3 groups based on H-score: low expression (H-score 0:100), moderate expression (H-score 101:200), and high expression (H-score 201:300).	('H-score 201:300', 'Var', (152, 167))	('expression', 'Species', '29278', (140, 150))	('PDAC', 'Chemical', '-', (0, 4))	('H-score 101:200', 'Var', (113, 128))	('PDAC', 'Disease', (0, 4))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('expression', 'Species', '29278', (101, 111))	('expression', 'Species', '29278', (64, 74))
4651	30419905	When Axl and the Myc-tagged TNS2 expression constructs were co-transfected into Mia PaCa-2 cells, the levels of both TNS2 and p-TNS2 were significantly increased by Axl transfection in a dose-dependent manner (0 to 1.5 mug of Axl plasmid DNA) (Fig.	('transfection', 'Var', (169, 181))	('TNS2', 'Gene', '23371', (128, 132))	('TNS2', 'Gene', (117, 121))	('Myc', 'Gene', '4609', (17, 20))	('Axl', 'Gene', '558', (165, 168))	('TNS2', 'Gene', (28, 32))	('Mia PaCa-2', 'CellLine', 'CVCL:0428', (80, 90))	('Axl', 'Gene', (165, 168))	('mug', 'molecular_function', 'GO:0043739', ('219', '222'))	('levels', 'MPA', (102, 108))	('Axl', 'Gene', '558', (5, 8))	('Axl', 'Gene', '558', (226, 229))	('TNS2', 'Gene', '23371', (117, 121))	('increased', 'PosReg', (152, 161))	('Axl', 'Gene', (5, 8))	('TNS2', 'Gene', (128, 132))	('expression', 'Species', '29278', (33, 43))	('Axl', 'Gene', (226, 229))	('TNS2', 'Gene', '23371', (28, 32))	('Myc', 'Gene', (17, 20))	('DNA', 'cellular_component', 'GO:0005574', ('238', '241'))
4656	30419905	Similarly, levels of p-Erk were downregulated by shAxl co-transfection.	('downregulated', 'NegReg', (32, 45))	('Axl', 'Gene', '558', (51, 54))	('Erk', 'molecular_function', 'GO:0004707', ('23', '26'))	('p-Erk', 'Gene', '9451', (21, 26))	('p-Erk', 'Gene', (21, 26))	('Axl', 'Gene', (51, 54))	('co-transfection', 'Var', (55, 70))	('levels', 'MPA', (11, 17))
4663	30419905	Consistently, knockdown of Axl expression abrogated TNS2 expression and significantly decreased cellular glucose import (Fig.	('expression', 'MPA', (57, 67))	('abrogated', 'NegReg', (42, 51))	('Axl', 'Gene', '558', (27, 30))	('TNS2', 'Gene', '23371', (52, 56))	('TNS2', 'Gene', (52, 56))	('expression', 'Species', '29278', (31, 41))	('glucose', 'Chemical', 'MESH:D005947', (105, 112))	('Axl', 'Gene', (27, 30))	('decreased', 'NegReg', (86, 95))	('cellular glucose import', 'MPA', (96, 119))	('knockdown', 'Var', (14, 23))	('glucose import', 'biological_process', 'GO:0046323', ('105', '119'))	('expression', 'Species', '29278', (57, 67))
4666	30419905	Axl has three auto-phosphorylation sites: Y779, Y821, and Y886.	('phosphorylation', 'biological_process', 'GO:0016310', ('19', '34'))	('Y886', 'Var', (58, 62))	('Axl', 'Gene', '558', (0, 3))	('Y821', 'Var', (48, 52))	('Axl', 'Gene', (0, 3))	('Y779', 'Var', (42, 46))
4667	30419905	Y779 is important in Axl kinase activity.	('Axl', 'Gene', (21, 24))	('Axl', 'Gene', '558', (21, 24))	('kinase activity', 'molecular_function', 'GO:0016301', ('25', '40'))	('Y779', 'Var', (0, 4))
4668	30419905	We verified whether Y779 regulates phosphorylation of TNS2.	('TNS2', 'Gene', '23371', (54, 58))	('phosphorylation', 'MPA', (35, 50))	('regulates', 'Reg', (25, 34))	('Y779', 'Var', (20, 24))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('TNS2', 'Gene', (54, 58))
4670	30419905	The Y886F/Y821F double mutation did not affect the interaction between Axl and TNS2, whereas the kinase-death (KD) mutation (K567R) significantly abolished the interaction (Fig.	('Y886F', 'Var', (4, 9))	('Axl', 'Gene', (71, 74))	('Y821F', 'SUBSTITUTION', 'None', (10, 15))	('TNS2', 'Gene', '23371', (79, 83))	('K567R', 'Mutation', 'p.K567R', (125, 130))	('TNS2', 'Gene', (79, 83))	('interaction', 'Interaction', (51, 62))	('abolished', 'NegReg', (146, 155))	('Y821F', 'Var', (10, 15))	('Axl', 'Gene', '558', (71, 74))	('Y886F', 'SUBSTITUTION', 'None', (4, 9))	('interaction', 'Interaction', (160, 171))	('K567R', 'Var', (125, 130))
4678	30419905	According our data, the dysregulation of the Axl kinase is involved in phosphorylation of TNS2.	('phosphorylation', 'MPA', (71, 86))	('Axl', 'Gene', '558', (45, 48))	('TNS2', 'Gene', '23371', (90, 94))	('dysregulation', 'Var', (24, 37))	('involved', 'Reg', (59, 67))	('TNS2', 'Gene', (90, 94))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))	('Axl', 'Gene', (45, 48))
4679	30419905	To determine the certain phosphorylation site of TNS2, we constructed two candidate mutations of TNS2, TNS2-Cysteine 231 (C231S) and TNS2-tyrosine 483 (Y483F).	('TNS2', 'Gene', (133, 137))	('TNS2', 'Gene', '23371', (103, 107))	('Cys', 'Chemical', 'MESH:D003545', (108, 111))	('tyrosine', 'Chemical', 'MESH:D014443', (138, 146))	('Y483F', 'Mutation', 'p.Y483F', (152, 157))	('C231S', 'Mutation', 'p.C231S', (122, 127))	('TNS2', 'Gene', '23371', (49, 53))	('TNS2', 'Gene', '23371', (97, 101))	('phosphorylation', 'biological_process', 'GO:0016310', ('25', '40'))	('TNS2', 'Gene', (49, 53))	('TNS2', 'Gene', (103, 107))	('C231S', 'Var', (122, 127))	('TNS2', 'Gene', '23371', (133, 137))	('TNS2', 'Gene', (97, 101))	('Y483F', 'Var', (152, 157))
4682	30419905	According to the previous study, C231S is a phosphatase-dead mutant of TNS2 and Y483F is a phosphorylation-dead mutant of TNS2.	('TNS2', 'Gene', (122, 126))	('C231S', 'Var', (33, 38))	('phosphatase-dead', 'MPA', (44, 60))	('Y483F', 'Mutation', 'p.Y483F', (80, 85))	('TNS2', 'Gene', '23371', (122, 126))	('TNS2', 'Gene', '23371', (71, 75))	('Y483F', 'Var', (80, 85))	('C231S', 'Mutation', 'p.C231S', (33, 38))	('TNS2', 'Gene', (71, 75))
4684	30419905	Phosphorylation of TNS2 was abolished in the Y483F mutant but not in the C231S mutant (Fig.	('abolished', 'NegReg', (28, 37))	('Y483F', 'Mutation', 'p.Y483F', (45, 50))	('TNS2', 'Gene', '23371', (19, 23))	('Phosphorylation', 'MPA', (0, 15))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('Y483F', 'Var', (45, 50))	('C231S', 'Mutation', 'p.C231S', (73, 78))	('TNS2', 'Gene', (19, 23))
4685	30419905	We further measured the IRS1-associated signaling during dysregulation of TNS2.	('measured', 'Reg', (11, 19))	('IRS1', 'Gene', '3667', (24, 28))	('IRS1', 'Gene', (24, 28))	('dysregulation', 'Var', (57, 70))	('TNS2', 'Gene', '23371', (74, 78))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('TNS2', 'Gene', (74, 78))
4687	30419905	More importantly, the mutant Y483 site of TNS2 reflected less colony formation (Fig.	('colony formation', 'CPA', (62, 78))	('TNS2', 'Gene', '23371', (42, 46))	('less', 'NegReg', (57, 61))	('TNS2', 'Gene', (42, 46))	('Y483', 'Var', (29, 33))
4700	30419905	These results suggested that the expression of TNS2 may involved in pancreatic cnacer metabolism, proliferation, angiogenesis, and epithelial-mesenchymal transition (EMT) process.	('TNS2', 'Gene', (47, 51))	('EMT', 'biological_process', 'GO:0001837', ('166', '169'))	('expression', 'Var', (33, 43))	('involved in', 'Reg', (56, 67))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('131', '164'))	('angiogenesis', 'CPA', (113, 125))	('expression', 'Species', '29278', (33, 43))	('pancreatic', 'Disease', 'MESH:D010195', (68, 78))	('epithelial-mesenchymal transition', 'CPA', (131, 164))	('TNS2', 'Gene', '23371', (47, 51))	('metabolism', 'biological_process', 'GO:0008152', ('86', '96'))	('pancreatic', 'Disease', (68, 78))	('angiogenesis', 'biological_process', 'GO:0001525', ('113', '125'))	('proliferation', 'CPA', (98, 111))
4705	30419905	The results of our present study suggest that knockdown of Axl expression reduces glucose uptake and that Axl is related to high expression of glucose metabolism molecules, IRS-1, Glut4 and PDK1 in cancer tissues.	('expression', 'Species', '29278', (63, 73))	('IRS-1', 'Gene', (173, 178))	('reduces', 'NegReg', (74, 81))	('glucose metabolism molecules', 'MPA', (143, 171))	('cancer', 'Disease', (198, 204))	('expression', 'MPA', (129, 139))	('Glut4', 'Gene', (180, 185))	('glucose uptake', 'biological_process', 'GO:0046323', ('82', '96'))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('PDK1', 'Gene', '5163', (190, 194))	('Glut4', 'Gene', '6517', (180, 185))	('IRS-1', 'Gene', '3667', (173, 178))	('Axl', 'Gene', '558', (59, 62))	('glucose metabolism', 'biological_process', 'GO:0006006', ('143', '161'))	('glucose', 'Chemical', 'MESH:D005947', (82, 89))	('Axl', 'Gene', (59, 62))	('expression', 'Species', '29278', (129, 139))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('glucose', 'MPA', (82, 89))	('knockdown', 'Var', (46, 55))	('Axl', 'Gene', '558', (106, 109))	('PDK1', 'molecular_function', 'GO:0004740', ('190', '194'))	('Axl', 'Gene', (106, 109))	('glucose', 'Chemical', 'MESH:D005947', (143, 150))	('PDK1', 'Gene', (190, 194))
4708	30419905	TNS2 region contains both an SH2 domain and a PTB domain, suggesting that an interaction with Axl might be mediated by phosphotyrosine.	('TNS2', 'Gene', (0, 4))	('PTB', 'Gene', (46, 49))	('Axl', 'Gene', '558', (94, 97))	('PTB', 'Gene', '5725', (46, 49))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (119, 134))	('phosphotyrosine', 'Var', (119, 134))	('mediated', 'Reg', (107, 115))	('interaction', 'Interaction', (77, 88))	('TNS2', 'Gene', '23371', (0, 4))	('Axl', 'Gene', (94, 97))
4710	30419905	2a and kinase-dead of Axl abrogates TNS2 expression in Fig.	('expression', 'Species', '29278', (41, 51))	('Axl', 'Gene', '558', (22, 25))	('Axl', 'Gene', (22, 25))	('expression', 'MPA', (41, 51))	('TNS2', 'Gene', '23371', (36, 40))	('abrogates', 'NegReg', (26, 35))	('kinase-dead', 'Var', (7, 18))	('TNS2', 'Gene', (36, 40))
4727	30419905	Several proteins have been found to interact with TNS2 through its C231 site of the PTPase domain; this C231 mutation may abolish the tumorigenicity of breast and colon cancer cells.	('abolish', 'NegReg', (122, 129))	('TNS2', 'Gene', '23371', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('TNS2', 'Gene', (50, 54))	('colon cancer', 'Phenotype', 'HP:0003003', (163, 175))	('breast and colon cancer', 'Disease', 'MESH:D001943', (152, 175))	('C231 mutation', 'Var', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
4730	30419905	In this study, however, we demonstrate for the first time that Axl directly binds to and phosphorylates TNS2 at Y483.	('Y483', 'Var', (112, 116))	('TNS2', 'Gene', '23371', (104, 108))	('TNS2', 'Gene', (104, 108))	('binds', 'Interaction', (76, 81))	('Axl', 'Gene', '558', (63, 66))	('phosphorylates', 'MPA', (89, 103))	('Axl', 'Gene', (63, 66))
4731	30419905	The Y483 site is close to the PTPase domain of TNS2.	('TNS2', 'Gene', (47, 51))	('Y483', 'Var', (4, 8))	('TNS2', 'Gene', '23371', (47, 51))
4734	30419905	Our results show that the Y483 site is more important than the C231 site of TNS2 for regulation of IRS-1 expression and IRS-1-mediated signaling.	('regulation', 'biological_process', 'GO:0065007', ('85', '95'))	('Y483', 'Var', (26, 30))	('signaling', 'biological_process', 'GO:0023052', ('135', '144'))	('TNS2', 'Gene', '23371', (76, 80))	('IRS-1', 'Gene', '3667', (120, 125))	('IRS-1', 'Gene', '3667', (99, 104))	('expression', 'Species', '29278', (105, 115))	('TNS2', 'Gene', (76, 80))	('IRS-1', 'Gene', (120, 125))	('IRS-1', 'Gene', (99, 104))
4735	30419905	By using tissue microarrays of pancreatic patients, we also demonstrate that in comparison to the adjacent normal parts of pancreaatic patients, cancer cells highly express both Axl (total form and the Y799-phosphorylated form) and TNS2 (total form and the Y483-phosphorylated form), as well as other molecules involved in glucose metabolism and cancer progression.	('cancer', 'Disease', (145, 151))	('patients', 'Species', '9606', (135, 143))	('pancreatic', 'Disease', (31, 41))	('glucose', 'Chemical', 'MESH:D005947', (323, 330))	('cancer', 'Disease', (346, 352))	('cancer', 'Disease', 'MESH:D009369', (346, 352))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Axl', 'Gene', (178, 181))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('TNS2', 'Gene', '23371', (232, 236))	('Y799-phosphorylated', 'Var', (202, 221))	('patients', 'Species', '9606', (42, 50))	('pancreatic', 'Disease', 'MESH:D010195', (31, 41))	('glucose metabolism', 'biological_process', 'GO:0006006', ('323', '341'))	('TNS2', 'Gene', (232, 236))	('Axl', 'Gene', '558', (178, 181))
4736	30419905	In the future, it will be interesting to investigate whether Y483 phosphorylation of TNS2 plays a role in regulating IRS-1 and glucose metabolism with respect to the Warburg effect.	('IRS-1', 'Gene', (117, 122))	('TNS2', 'Gene', (85, 89))	('Y483 phosphorylation', 'Var', (61, 81))	('regulating', 'Reg', (106, 116))	('glucose metabolism', 'biological_process', 'GO:0006006', ('127', '145'))	('glucose', 'Chemical', 'MESH:D005947', (127, 134))	('phosphorylation', 'biological_process', 'GO:0016310', ('66', '81'))	('IRS-1', 'Gene', '3667', (117, 122))	('TNS2', 'Gene', '23371', (85, 89))	('glucose metabolism', 'MPA', (127, 145))
4739	30419905	Dysregulated phosphorylation of tyrosine and serine/threonine in IRS-1 may lead to the pathologic state of insulin resistance.	('IRS-1', 'Gene', (65, 70))	('insulin', 'Gene', '3630', (107, 114))	('lead to', 'Reg', (75, 82))	('threonine', 'Chemical', 'MESH:D013912', (52, 61))	('phosphorylation', 'MPA', (13, 28))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('serine', 'Chemical', 'MESH:D012694', (45, 51))	('tyrosine', 'Chemical', 'MESH:D014443', (32, 40))	('insulin', 'molecular_function', 'GO:0016088', ('107', '114'))	('serine/threonine', 'MPA', (45, 61))	('Dysregulated', 'Var', (0, 12))	('IRS-1', 'Gene', '3667', (65, 70))	('insulin resistance', 'Phenotype', 'HP:0000855', (107, 125))	('insulin', 'Gene', (107, 114))
4740	30419905	Recent studies indicate that phosphorylation of IRS-1 at S307 and/or at certain tyrosine residues can serve as a biomarker in peripheral exosomes, in both DM2 and AD patients.	('AD', 'Disease', (163, 165))	('IRS-1', 'Gene', (48, 53))	('tyrosine', 'Chemical', 'MESH:D014443', (80, 88))	('at S307', 'Var', (54, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('29', '44'))	('DM2', 'Gene', (155, 158))	('IRS-1', 'Gene', '3667', (48, 53))	('DM2', 'Gene', '28508', (155, 158))	('patients', 'Species', '9606', (166, 174))	('AD', 'Disease', 'MESH:D000544', (163, 165))	('phosphorylation', 'MPA', (29, 44))
4754	29945294	The receiver operating characteristic curve analysis revealed that the performance of CA19.9 in the validation group were improved by the marker panel composed of CA19.9, POSTN, and CA242, to discriminate early stage PDAC not only from healthy controls (area under the curve [AUC]CA19.9 = 0.94 vs AUCCA19.9 + POSTN + CA242 = 0.98, P < .05) but also from benign conditions (AUCCA19.9 = 0.87 vs AUCCA19.9 + POSTN + CA242 = 0.90, P < .05).	('POSTN', 'Gene', '10631', (171, 176))	('CA19.9', 'Chemical', 'MESH:C086528', (376, 382))	('CA19.9', 'Chemical', 'MESH:C086528', (280, 286))	('PDAC', 'Disease', (217, 221))	('POSTN', 'Gene', (405, 410))	('POSTN', 'Gene', (309, 314))	('CA19.9', 'Chemical', 'MESH:C086528', (300, 306))	('CA19.9', 'Chemical', 'MESH:C086528', (86, 92))	('PDAC', 'Chemical', '-', (217, 221))	('CA19.9', 'Chemical', 'MESH:C086528', (396, 402))	('POSTN', 'Gene', '10631', (405, 410))	('improved', 'PosReg', (122, 130))	('performance', 'MPA', (71, 82))	('POSTN', 'Gene', '10631', (309, 314))	('PDAC', 'Phenotype', 'HP:0006725', (217, 221))	('CA19.9', 'Chemical', 'MESH:C086528', (163, 169))	('POSTN', 'Gene', (171, 176))	('CA19.9', 'Var', (163, 169))	('CA242', 'Var', (182, 187))
4756	29945294	This study suggested that POSTN and CA242 are potential diagnostic serum biomarkers complementing CA19.9 in detecting early pancreatic cancer.	('pancreatic cancer', 'Disease', (124, 141))	('POSTN', 'Gene', '10631', (26, 31))	('pancreatic cancer', 'Disease', 'MESH:D010190', (124, 141))	('CA242', 'Var', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('POSTN', 'Gene', (26, 31))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (124, 141))	('CA19.9', 'Chemical', 'MESH:C086528', (98, 104))
4767	29945294	We also developed a biomarker panel consisting of CA19.9, CA242, and POSTN, and validated its improved performance compared with CA19.9 alone.	('CA19.9', 'Var', (50, 56))	('CA19.9', 'Chemical', 'MESH:C086528', (129, 135))	('CA19.9', 'Chemical', 'MESH:C086528', (50, 56))	('POSTN', 'Gene', '10631', (69, 74))	('CA242', 'Var', (58, 63))	('POSTN', 'Gene', (69, 74))
4788	29945294	Because of the wide distribution of CA19.9, CA242, and CEA levels, values were plotted on a logarithmic scale.	('CEA', 'Gene', (55, 58))	('CA19.9', 'Var', (36, 42))	('CEA', 'Gene', '5670', (55, 58))	('CA19.9', 'Chemical', 'MESH:C086528', (36, 42))	('CA242', 'Var', (44, 49))
4793	29945294	As shown in Figure 1, serum levels of POSTN and CA242, with analogous expression patterns of CA19.9, were significantly increased in PDAC patients compared with those with benign disease and healthy controls in both the training and validation cohorts.	('PDAC', 'Chemical', '-', (133, 137))	('PDAC', 'Disease', (133, 137))	('PDAC', 'Phenotype', 'HP:0006725', (133, 137))	('CA19.9', 'Chemical', 'MESH:C086528', (93, 99))	('POSTN', 'Gene', '10631', (38, 43))	('serum levels', 'MPA', (22, 34))	('increased', 'PosReg', (120, 129))	('POSTN', 'Gene', (38, 43))	('patients', 'Species', '9606', (138, 146))	('CA242', 'Var', (48, 53))
4807	29945294	As shown in Table 2 and Figure 2, AUCs for CA242 to discriminate PDAC early stage from healthy controls were comparable with CA19.9 in the training set (AUCCA19.9 = 0.94, AUCCA242 = 0.89) and in the validation set (AUCCA19.9 = 0.94, AUCCA242 = 0.83).	('CA19.9', 'Chemical', 'MESH:C086528', (125, 131))	('PDAC', 'Chemical', '-', (65, 69))	('CA242', 'Var', (43, 48))	('CA19.9', 'Chemical', 'MESH:C086528', (156, 162))	('CA19.9', 'Chemical', 'MESH:C086528', (218, 224))	('PDAC', 'Phenotype', 'HP:0006725', (65, 69))	('PDAC', 'Disease', (65, 69))
4812	29945294	As illustrated in Figure 3, no correlation was found between serum CA19.9 and POSTN (R = 0.219, P < .001) or CA242 and POSTN (R = 0.295, P < .001).	('POSTN', 'Gene', '10631', (78, 83))	('CA242', 'Var', (109, 114))	('POSTN', 'Gene', (78, 83))	('POSTN', 'Gene', '10631', (119, 124))	('CA19.9', 'Chemical', 'MESH:C086528', (67, 73))	('POSTN', 'Gene', (119, 124))
4813	29945294	However, there was a significant positive correlation between serum levels of CA19.9 and CA242 (R = 0.617, P < .001).	('CA19.9', 'Chemical', 'MESH:C086528', (78, 84))	('CA19.9', 'Var', (78, 84))	('CA242', 'Var', (89, 94))
4814	29945294	To estimate whether the discrimination ability of CA19.9 could be improved by POSTN and CA242, marker panel models were constructed.	('POSTN', 'Gene', (78, 83))	('CA19.9', 'Chemical', 'MESH:C086528', (50, 56))	('POSTN', 'Gene', '10631', (78, 83))	('CA242', 'Var', (88, 93))
4815	29945294	As shown in Figures 4 and S6 and Tables 2 and S1, the three-marker panels composed of CA19.9, POSTN, and CA242 were observed with significantly improved AUCs than CA19.9 alone in all of the analysis groups (healthy vs all PDAC, healthy vs PDAC early-stage, benign disease vs all PDAC, and benign disease vs PDAC early stage).	('improved', 'PosReg', (144, 152))	('CA19.9', 'Chemical', 'MESH:C086528', (86, 92))	('POSTN', 'Gene', (94, 99))	('CA19.9', 'Chemical', 'MESH:C086528', (163, 169))	('PDAC', 'Chemical', '-', (307, 311))	('PDAC', 'Chemical', '-', (279, 283))	('CA242', 'Var', (105, 110))	('CA19.9', 'Var', (86, 92))	('PDAC', 'Phenotype', 'HP:0006725', (307, 311))	('PDAC', 'Phenotype', 'HP:0006725', (222, 226))	('PDAC', 'Phenotype', 'HP:0006725', (239, 243))	('benign disease', 'Disease', (257, 271))	('PDAC', 'Phenotype', 'HP:0006725', (279, 283))	('PDAC', 'Chemical', '-', (222, 226))	('PDAC', 'Chemical', '-', (239, 243))	('POSTN', 'Gene', '10631', (94, 99))	('AUCs', 'MPA', (153, 157))
4820	29945294	As shown in Figure 5 and Table 3, POSTN retained significant ability to discriminate PDAC CA19.9-negative from healthy controls in the training set (AUCPOSTN = 0.89), the validation set (AUCPOSTN = 0.85), and the whole set (AUCPOSTN = 0.87).	('POSTN', 'Gene', '10631', (190, 195))	('POSTN', 'Gene', (152, 157))	('PDAC', 'Chemical', '-', (85, 89))	('CA19.9-negative', 'Var', (90, 105))	('POSTN', 'Gene', (190, 195))	('CA19.9', 'Chemical', 'MESH:C086528', (90, 96))	('PDAC', 'Phenotype', 'HP:0006725', (85, 89))	('POSTN', 'Gene', '10631', (34, 39))	('POSTN', 'Gene', '10631', (227, 232))	('POSTN', 'Gene', (34, 39))	('POSTN', 'Gene', (227, 232))	('POSTN', 'Gene', '10631', (152, 157))
4825	29945294	As an important strategy to improve the diagnosis of PDAC, marker panel studies have gained increased attention in recent years.9, 10 In the present study, we identified that POSTN and CA242 could be potential diagnostic serum biomarkers complementing CA19.9 in detecting early pancreatic cancer.	('pancreatic cancer', 'Disease', (278, 295))	('PDAC', 'Phenotype', 'HP:0006725', (53, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (278, 295))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('POSTN', 'Gene', '10631', (175, 180))	('POSTN', 'Gene', (175, 180))	('CA19.9', 'Chemical', 'MESH:C086528', (252, 258))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (278, 295))	('CA242', 'Var', (185, 190))	('PDAC', 'Chemical', '-', (53, 57))
4842	29945294	Although there is a high correlation between serum CA19.9 and CA242, our study indicated that the discriminating capabilities of CA19.9 for PDAC could be significantly improved by CA242, especially to make up for the shortcomings of CA19.9 in the diagnosis of early stage PDAC.	('CA242', 'Var', (180, 185))	('early stage PDAC', 'Disease', (260, 276))	('PDAC', 'Chemical', '-', (140, 144))	('PDAC', 'Chemical', '-', (272, 276))	('CA19.9', 'Chemical', 'MESH:C086528', (51, 57))	('improved', 'PosReg', (168, 176))	('discriminating', 'MPA', (98, 112))	('PDAC', 'Disease', (140, 144))	('PDAC', 'Phenotype', 'HP:0006725', (140, 144))	('PDAC', 'Phenotype', 'HP:0006725', (272, 276))	('CA19.9', 'Chemical', 'MESH:C086528', (129, 135))	('CA19.9', 'Chemical', 'MESH:C086528', (233, 239))
4844	29945294	One possible reason is that there is no correlation between the expression of POSTN and CA19.9, but CA242 and CA19.9 do have a correlation of expression.12 Patients with PDAC missed by CA19.9 tend to be those with lower CA242 levels.	('CA19.9', 'Var', (185, 191))	('CA19.9', 'Chemical', 'MESH:C086528', (185, 191))	('Patients', 'Species', '9606', (156, 164))	('POSTN', 'Gene', '10631', (78, 83))	('CA19.9', 'Chemical', 'MESH:C086528', (110, 116))	('CA242 levels', 'MPA', (220, 232))	('PDAC', 'Chemical', '-', (170, 174))	('POSTN', 'Gene', (78, 83))	('CA19.9', 'Chemical', 'MESH:C086528', (88, 94))	('lower', 'NegReg', (214, 219))	('PDAC', 'Phenotype', 'HP:0006725', (170, 174))
4850	29945294	A marker panel composed of CA19.9, POSTN, and CA242 showed significantly improved performance compared with CA19.9 alone, especially to distinguish patients with early stage PDAC from control subjects.	('POSTN', 'Gene', (35, 40))	('patients', 'Species', '9606', (148, 156))	('CA19.9', 'Chemical', 'MESH:C086528', (27, 33))	('CA242', 'Var', (46, 51))	('PDAC', 'Chemical', '-', (174, 178))	('CA19.9', 'Chemical', 'MESH:C086528', (108, 114))	('improved', 'PosReg', (73, 81))	('PDAC', 'Phenotype', 'HP:0006725', (174, 178))	('CA19.9', 'Var', (27, 33))	('POSTN', 'Gene', '10631', (35, 40))	('performance', 'MPA', (82, 93))
4851	29945294	The data presented in our study could provide valuable information for the early diagnosis of PDAC using CA19.9, POSTN, and CA242 as a marker panel in clinical work.	('CA242', 'Var', (124, 129))	('PDAC', 'Chemical', '-', (94, 98))	('POSTN', 'Gene', '10631', (113, 118))	('POSTN', 'Gene', (113, 118))	('CA19.9', 'Chemical', 'MESH:C086528', (105, 111))	('PDAC', 'Disease', (94, 98))	('PDAC', 'Phenotype', 'HP:0006725', (94, 98))
4852	29945294	In conclusion, the present study suggested that POSTN and CA242 were potential diagnostic serum biomarkers complementing CA19.9 in detecting pancreatic cancer.	('CA19.9', 'Chemical', 'MESH:C086528', (121, 127))	('pancreatic cancer', 'Disease', (141, 158))	('pancreatic cancer', 'Disease', 'MESH:D010190', (141, 158))	('POSTN', 'Gene', '10631', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('CA242', 'Var', (58, 63))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (141, 158))	('POSTN', 'Gene', (48, 53))
4895	30092011	The validity of signature was further established using ROC analysis on 2 separate pancreatic microarray datasets in the GEO data repository, GSE57495 (63 samples, 12 Survival-/17 Survival+) and GSE71729 (357 samples, 41 Survival-/15 Survival+).	('pancreatic', 'Disease', (83, 93))	('GSE71729', 'Var', (195, 203))	('pancreatic', 'Disease', 'MESH:D010195', (83, 93))
4902	30092011	The anti-ADM antibody (1:20, R&D Biosystems, AF6108), anti-ASPM antibody (1:500; Novus Biologicals, NB100-2278), anti-DCBLD2 antibody (1:50, Sigma-Aldrich, HPA016909), anti-E2F7 antibody (1:500, Abcam, ab56022), or anti-KRT6a antibody (1:100, Sigma-Aldrich, SAB2700299) was applied and incubated at 4c overnight followed by staining with appropriate biotinylated secondary antibodies (1:200, Jackson ImmunoResearch).	('antibody', 'cellular_component', 'GO:0019814', ('226', '234'))	('DCBLD2', 'Gene', (118, 124))	('antibody', 'cellular_component', 'GO:0019815', ('13', '21'))	('antibody', 'molecular_function', 'GO:0003823', ('125', '133'))	('ASPM', 'Gene', (59, 63))	('antibody', 'cellular_component', 'GO:0019814', ('178', '186'))	('antibody', 'cellular_component', 'GO:0019815', ('64', '72'))	('E2F7', 'Gene', (173, 177))	('DCBLD2', 'Gene', '131566', (118, 124))	('antibody', 'cellular_component', 'GO:0042571', ('125', '133'))	('ASPM', 'Gene', '259266', (59, 63))	('antibody', 'molecular_function', 'GO:0003823', ('226', '234'))	('KRT6a', 'Gene', (220, 225))	('KRT6a', 'Gene', '3853', (220, 225))	('antibody', 'cellular_component', 'GO:0042571', ('226', '234'))	('antibody', 'cellular_component', 'GO:0019814', ('13', '21'))	('antibody', 'cellular_component', 'GO:0019814', ('64', '72'))	('antibody', 'molecular_function', 'GO:0003823', ('178', '186'))	('antibody', 'cellular_component', 'GO:0042571', ('178', '186'))	('antibody', 'cellular_component', 'GO:0019815', ('125', '133'))	('E2F7', 'Gene', '144455', (173, 177))	('antibody', 'molecular_function', 'GO:0003823', ('13', '21'))	('antibody', 'cellular_component', 'GO:0019815', ('226', '234'))	('antibody', 'Var', (125, 133))	('antibody', 'molecular_function', 'GO:0003823', ('64', '72'))	('antibody', 'cellular_component', 'GO:0042571', ('13', '21'))	('antibody', 'cellular_component', 'GO:0042571', ('64', '72'))	('antibody', 'cellular_component', 'GO:0019815', ('178', '186'))	('antibody', 'cellular_component', 'GO:0019814', ('125', '133'))	('antibody', 'Var', (226, 234))
4942	30092011	This was not surprising considering that our signature was derived using the ICGC cohort, so we also performed ROC analysis on 2 separate pancreatic microarray datasets in the GEO data repository, GSE57495 (63 samples, 12 Survival-/17 Survival+) and GSE71729 (357 samples, 41 Survival-/15 Survival+), which have been used previously to predict survival in PDAC.	('PDAC', 'Chemical', '-', (356, 360))	('pancreatic', 'Disease', (138, 148))	('PDAC', 'Disease', (356, 360))	('PDAC', 'Phenotype', 'HP:0006725', (356, 360))	('GSE57495', 'Var', (197, 205))	('pancreatic', 'Disease', 'MESH:D010195', (138, 148))
4985	28961214	Elevated exposure to cadmium is associated with reduced pulmonary function, obstructive lung disease, bronchogenic carcinoma, cardiovascular diseases including myocardial infarction, peripheral arterial disease, prostate cancer, cervical cancer, pancreatic cancer, and various oral pathologies.	('obstructive lung disease', 'Disease', (76, 100))	('bronchogenic carcinoma', 'Disease', 'MESH:D002283', (102, 124))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('bronchogenic carcinoma', 'Disease', (102, 124))	('peripheral arterial disease', 'Disease', 'MESH:D058729', (183, 210))	('myocardial infarction', 'Disease', (160, 181))	('pancreatic cancer', 'Disease', (246, 263))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (126, 148))	('myocardial infarction', 'Phenotype', 'HP:0001658', (160, 181))	('cervical cancer', 'Disease', (229, 244))	('cervical cancer', 'Disease', 'MESH:D002583', (229, 244))	('cardiovascular diseases', 'Disease', (126, 149))	('reduced pulmonary function', 'Phenotype', 'HP:0005952', (48, 74))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (126, 149))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('lung disease', 'Phenotype', 'HP:0002088', (88, 100))	('myocardial infarction', 'Disease', 'MESH:D009203', (160, 181))	('cadmium', 'Var', (21, 28))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (246, 263))	('reduced', 'NegReg', (48, 55))	('oral pathologies', 'Disease', (277, 293))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('obstructive lung disease', 'Phenotype', 'HP:0006536', (76, 100))	('prostate cancer', 'Disease', 'MESH:D011471', (212, 227))	('cadmium', 'Chemical', 'MESH:D002104', (21, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (212, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (126, 149))	('pulmonary function', 'Disease', (56, 74))	('prostate cancer', 'Disease', (212, 227))	('peripheral arterial disease', 'Phenotype', 'HP:0004950', (183, 210))	('pancreatic cancer', 'Disease', 'MESH:D010190', (246, 263))	('peripheral arterial disease', 'Disease', (183, 210))	('obstructive lung disease', 'Disease', 'MESH:D008173', (76, 100))
4999	28961214	Strong evidence exists supporting cadmium as an inducer of proinflammatory cytokines, as a carcinogen, and as a substance that causes disease in many tissues in the body including the lungs and the kidneys.	('cadmium', 'Chemical', 'MESH:D002104', (34, 41))	('causes', 'Reg', (127, 133))	('proinflammatory cytokines', 'MPA', (59, 84))	('disease', 'Disease', (134, 141))	('cadmium', 'Var', (34, 41))
5003	28961214	In addition to inhibiting DNA repair enzymes, cadmium exposure causes an inflammatory response by stimulating reactive oxygen species production by human polymorphonuclear leukocytes and phagocytic cells.	('DNA repair', 'biological_process', 'GO:0006281', ('26', '36'))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('inflammatory response', 'CPA', (73, 94))	('stimulating', 'PosReg', (98, 109))	('cadmium', 'Var', (46, 53))	('human', 'Species', '9606', (148, 153))	('inflammatory response', 'biological_process', 'GO:0006954', ('73', '94'))	('cadmium', 'Chemical', 'MESH:D002104', (46, 53))	('reactive oxygen species production', 'MPA', (110, 144))	('causes', 'Reg', (63, 69))	('inhibiting', 'NegReg', (15, 25))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (110, 133))
5086	28961214	They concluded that cadmium exposure is a risk factor for cardiovascular disease with 1084 cardiovascular events, including 400 deaths among 3348 study subjects.	('deaths', 'Disease', (128, 134))	('cardiovascular disease', 'Disease', (58, 80))	('cadmium', 'Chemical', 'MESH:D002104', (20, 27))	('deaths', 'Disease', 'MESH:D003643', (128, 134))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (58, 80))	('cardiovascular', 'Disease', (91, 105))	('cardiovascular disease', 'Disease', 'MESH:D002318', (58, 80))	('cardiovascular events', 'Phenotype', 'HP:0001626', (91, 112))	('cadmium', 'Var', (20, 27))
5157	28961214	Both changes facilitate angiogenesis and cell migratory properties and are likely indicative of cell transformation to an early stage of cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('facilitate', 'PosReg', (13, 23))	('changes', 'Var', (5, 12))	('cell migratory properties', 'CPA', (41, 66))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('angiogenesis', 'biological_process', 'GO:0001525', ('24', '36'))	('angiogenesis', 'CPA', (24, 36))
5187	28961214	Collectively these factors are consistent with cadmium exposure as a risk factor for pancreatic cancer and for smoking as the most commonly associated risk factor for pancreatic cancer.	('pancreatic cancer', 'Disease', (85, 102))	('pancreatic cancer', 'Disease', 'MESH:D010190', (167, 184))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (167, 184))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('cadmium', 'Var', (47, 54))	('pancreatic cancer', 'Disease', (167, 184))	('cadmium', 'Chemical', 'MESH:D002104', (47, 54))
5225	28961214	Some studies suggest that cadmium exposure may increase the risk of vascular and heart disease.	('cadmium', 'Chemical', 'MESH:D002104', (26, 33))	('cadmium', 'Var', (26, 33))	('heart disease', 'Disease', 'MESH:D006331', (81, 94))	('heart disease', 'Disease', (81, 94))
5278	28440066	Importantly, GPC1+ crExos showed a nearly 100% sensitivity and specificity even for early stage PDAC, indicating its outstanding potential for early detection of the disease 7.	('PDAC', 'Phenotype', 'HP:0006725', (96, 100))	('early stage PDAC', 'Disease', (84, 100))	('PDAC', 'Chemical', '-', (96, 100))	('GPC1+', 'Var', (13, 18))
5321	28440066	Kaplan-Meier survival analysis indicated a significant correlation between positive GPC1 staining and a shorter overall survival time in the PDAC patients (P = 0.0028; Fig.	('positive', 'Var', (75, 83))	('PDAC', 'Phenotype', 'HP:0006725', (141, 145))	('GPC1', 'Gene', (84, 88))	('shorter', 'NegReg', (104, 111))	('PDAC', 'Chemical', '-', (141, 145))	('overall survival', 'MPA', (112, 128))	('patients', 'Species', '9606', (146, 154))	('staining', 'Var', (89, 97))
5327	28440066	This result suggests that promoter hypomethylation and gene amplification of GPC1 are frequent in PDAC.	('PDAC', 'Disease', (98, 102))	('GPC1', 'Gene', (77, 81))	('PDAC', 'Phenotype', 'HP:0006725', (98, 102))	('gene amplification', 'Var', (55, 73))	('frequent', 'Reg', (86, 94))	('PDAC', 'Chemical', '-', (98, 102))	('promoter', 'MPA', (26, 34))
5328	28440066	In addition, we found that GPC1 expression was associated with worse biological behaviors of PDAC, such as poorer differentiation and larger tumor diameters, indicating that aberrantly expressed GPC1 may play important roles in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('play', 'Reg', (204, 208))	('expression', 'Var', (32, 42))	('PDAC', 'Chemical', '-', (93, 97))	('tumor', 'Disease', (141, 146))	('poorer differentiation', 'CPA', (107, 129))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('GPC1', 'Gene', (27, 31))	('aberrantly', 'Var', (174, 184))	('associated', 'Reg', (47, 57))	('tumor', 'Disease', (228, 233))	('PDAC', 'Disease', (93, 97))	('PDAC', 'Phenotype', 'HP:0006725', (93, 97))
5329	28440066	Previous studies had shown that GPC1 strengthened the mitogenic responses of PDAC cells to fibroblast growth factor 2 (FGF2), heparin binding EGF-like growth factor (HB-EGF), and hepatocyte growth factor (HGF) as a growth factor coreceptor 12, 17, 18.	('fibroblast growth factor 2', 'Gene', '2247', (91, 117))	('HB-EGF', 'Gene', '1839', (166, 172))	('EGF', 'molecular_function', 'GO:0005154', ('169', '172'))	('heparin binding', 'molecular_function', 'GO:0008201', ('126', '141'))	('hepatocyte growth factor', 'Gene', '3082', (179, 203))	('PDAC', 'Chemical', '-', (77, 81))	('heparin binding EGF-like growth factor', 'Gene', (126, 164))	('FGF2', 'Gene', (119, 123))	('hepatocyte growth factor', 'Gene', (179, 203))	('PDAC', 'Phenotype', 'HP:0006725', (77, 81))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('91', '115'))	('HB-EGF', 'Gene', (166, 172))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('179', '203'))	('HGF', 'Gene', '3082', (205, 208))	('GPC1', 'Var', (32, 36))	('fibroblast growth factor 2', 'Gene', (91, 117))	('heparin binding EGF-like growth factor', 'Gene', '1839', (126, 164))	('HGF', 'Gene', (205, 208))	('mitogenic', 'MPA', (54, 63))	('FGF2', 'Gene', '2247', (119, 123))	('strengthened', 'PosReg', (37, 49))	('EGF', 'molecular_function', 'GO:0005154', ('142', '145'))
5332	28440066	Therefore, it is understandable that GPC1 is an independent unfavorable prognostic factor for PDAC.	('GPC1', 'Var', (37, 41))	('PDAC', 'Disease', (94, 98))	('PDAC', 'Phenotype', 'HP:0006725', (94, 98))	('PDAC', 'Chemical', '-', (94, 98))
5340	28440066	In endothelial cells, GPC1 induces metaphase arrest and centrosome overproduction, and it mediates flow-induced NO synthase (eNOS) activation to protect endothelial function 30, 31, 32.	('eNOS', 'Gene', (125, 129))	('arrest', 'Disease', (45, 51))	('arrest', 'Disease', 'MESH:D006323', (45, 51))	('induces', 'Reg', (27, 34))	('GPC1', 'Var', (22, 26))	('eNOS', 'Gene', '4846', (125, 129))	('metaphase', 'biological_process', 'GO:0051323', ('35', '44'))	('centrosome', 'cellular_component', 'GO:0005813', ('56', '66'))	('centrosome overproduction', 'CPA', (56, 81))
5344	28440066	In ESCC, high levels of GPC1 were also significantly associated with chemoresistance to cisplatin 33.	('chemoresistance', 'CPA', (69, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('associated with', 'Reg', (53, 68))	('GPC1', 'Var', (24, 28))
5353	28440066	GPC1 could serve as an independent unfavorable prognostic factor in PDAC.	('PDAC', 'Phenotype', 'HP:0006725', (68, 72))	('PDAC', 'Disease', (68, 72))	('PDAC', 'Chemical', '-', (68, 72))	('GPC1', 'Var', (0, 4))
5360	28440235	Patients with a dilated PD had a significantly higher incidence of pancreatic malignancy than those with a normal PD diameter (106/239, 44.4% vs. 32/236, 13.6%, P < 0.001).	('pancreatic malignancy', 'Disease', (67, 88))	('pancreatic malignancy', 'Phenotype', 'HP:0002894', (67, 88))	('pancreatic malignancy', 'Disease', 'MESH:D010190', (67, 88))	('dilated', 'Var', (16, 23))	('PD', 'Disease', 'MESH:D010300', (24, 26))	('Patients', 'Species', '9606', (0, 8))	('PD', 'Disease', 'MESH:D010300', (114, 116))
5412	28440235	Patients with a dilated PD had a significantly higher incidence of pancreatic malignancy than those with a normal PD diameter (106/239, 44.4% vs. 32/236, 13.6%; P < 0.001) [Table 1].	('pancreatic malignancy', 'Disease', (67, 88))	('pancreatic malignancy', 'Phenotype', 'HP:0002894', (67, 88))	('pancreatic malignancy', 'Disease', 'MESH:D010190', (67, 88))	('dilated', 'Var', (16, 23))	('PD', 'Disease', 'MESH:D010300', (24, 26))	('Patients', 'Species', '9606', (0, 8))	('PD', 'Disease', 'MESH:D010300', (114, 116))
5427	28440235	Twenty-three (67.6%) patients with masses measuring in the 1st quartile had dilated a PD whereas 28 (77.8%), 30 (91.0%), and 25 (71.4%) of those with masses measuring in the 2nd, 3rd, and 4th quartiles, respectively, had a dilated PD.	('PD', 'Disease', 'MESH:D010300', (231, 233))	('dilated', 'MPA', (76, 83))	('patients', 'Species', '9606', (21, 29))	('PD', 'Disease', 'MESH:D010300', (86, 88))	('masses', 'Var', (35, 41))	('dilated', 'MPA', (223, 230))
5482	26918939	Furthermore, heterospheroids of Panc-1 and hPSCs attained smaller size with hPSCs transfected with anti-miR-199a/-214 compared to control anti-miR.	('smaller', 'NegReg', (58, 65))	('anti-miR-199a/-214', 'Var', (99, 117))	('Panc-1', 'CellLine', 'CVCL:0480', (32, 38))	('hPSC', 'Gene', (43, 47))	('hPSC', 'Gene', '100653366', (43, 47))	('hPSC', 'Gene', '100653366', (76, 80))	('hPSC', 'Gene', (76, 80))
5484	26918939	Interestingly, these inductions were abrogated in hPSCs transfected with anti-miR-199a or miR-214.	('hPSC', 'Gene', (50, 54))	('hPSC', 'Gene', '100653366', (50, 54))	('miR-214', 'Gene', '406996', (90, 97))	('abrogated', 'NegReg', (37, 46))	('anti-miR-199a', 'Var', (73, 86))	('miR-214', 'Gene', (90, 97))
5485	26918939	Moreover, IPA analyses revealed signaling pathways related to miR-199a (TP53, mTOR, Smad1) and miR-214 (PTEN, Bax, ING4).	('Bax', 'Gene', (110, 113))	('TP53', 'Gene', '7157', (72, 76))	('Smad1', 'Gene', '4086', (84, 89))	('ING4', 'Gene', (115, 119))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('miR-214', 'Gene', (95, 102))	('Bax', 'Gene', '581', (110, 113))	('TP53', 'Gene', (72, 76))	('mTOR', 'Gene', (78, 82))	('ING4', 'Gene', '51147', (115, 119))	('mTOR', 'Gene', '2475', (78, 82))	('miR-214', 'Gene', '406996', (95, 102))	('PTEN', 'Gene', '5728', (104, 108))	('miR-199a', 'Var', (62, 70))	('signaling pathways', 'Pathway', (32, 50))	('PTEN', 'Gene', (104, 108))	('Smad1', 'Gene', (84, 89))
5496	26918939	Silencing of CAF pro-tumorigenic activities, instead of their depletion, might be the right direction to develop anti-stromal therapies to treat pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (145, 162))	('tumor', 'Disease', (21, 26))	('CAF', 'Gene', (13, 16))	('pancreatic cancer', 'Disease', (145, 162))	('pancreatic cancer', 'Disease', 'MESH:D010190', (145, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CAF', 'Gene', '8850', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('Silencing', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
5500	26918939	Blockade of PSC activation might, therefore, be an interesting approach to inhibit their tumor-inducing actions.	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('Blockade', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('PSC', 'Gene', '100653366', (12, 15))	('PSC', 'Gene', (12, 15))	('tumor', 'Disease', (89, 94))
5502	26918939	Dysregulation of miRNA in stromal cells has received a huge attention for the potential therapeutic and diagnostic targets in cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('miRNA', 'Protein', (17, 22))
5507	26918939	Then, we investigated the effect of inhibition of either miR-199a or miR-214 on the differentiation, cell growth and migration of hPSCs and also on the hPSC-induced paracrine effects on human pancreatic tumor cells and endothelial cells in vitro.	('hPSC', 'Gene', '100653366', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('miR-199a', 'Var', (57, 65))	('hPSC', 'Gene', (130, 134))	('hPSC', 'Gene', '100653366', (130, 134))	('miR-214', 'Gene', '406996', (69, 76))	('pancreatic tumor', 'Disease', (192, 208))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (192, 208))	('cell growth', 'biological_process', 'GO:0016049', ('101', '112'))	('human', 'Species', '9606', (186, 191))	('rat', 'Species', '10116', (120, 123))	('pancreatic tumor', 'Disease', 'MESH:D010190', (192, 208))	('hPSC', 'Gene', (152, 156))	('miR-214', 'Gene', (69, 76))
5508	26918939	To confirm that miR-199a and miR-214 are expressed in the stromal region of human pancreatic cancer, we first performed an in-situ hybridization (ISH) assay to detect the presence of miR-199a and miR-214 (Figure 1A).	('miR-214', 'Gene', '406996', (196, 203))	('miR-214', 'Gene', (29, 36))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('human', 'Species', '9606', (76, 81))	('miR-214', 'Gene', (196, 203))	('miR-214', 'Gene', '406996', (29, 36))	('pancreatic cancer', 'Disease', (82, 99))	('pancreatic cancer', 'Disease', 'MESH:D010190', (82, 99))	('miR-199a', 'Var', (183, 191))
5510	26918939	The expression levels of miR-199a and miR-214 were also confirmed in CAFs, which were isolated from three different patients (Figure 1B).	('miR-214', 'Gene', '406996', (38, 45))	('patients', 'Species', '9606', (116, 124))	('miR-199a', 'Var', (25, 33))	('CAF', 'Gene', (69, 72))	('CAF', 'Gene', '8850', (69, 72))	('miR-214', 'Gene', (38, 45))
5521	26918939	Pretreatment of hPSCs with anti-miR-199a or -214 led to a significant inhibition of the closure of the wound (scratch gap) compared to the control cells.	('inhibition', 'NegReg', (70, 80))	('hPSC', 'Gene', '100653366', (16, 20))	('hPSC', 'Gene', (16, 20))	('rat', 'Species', '10116', (112, 115))	('anti-miR-199a', 'Var', (27, 40))
5524	26918939	We found that anti-miR-199a reduced the cell growth significantly whereas anti-miR-214 showed only moderate inhibitory effects (Figure 4C).	('reduced', 'NegReg', (28, 35))	('rat', 'Species', '10116', (103, 106))	('cell growth', 'CPA', (40, 51))	('miR-214', 'Gene', '406996', (79, 86))	('anti-miR-199a', 'Var', (14, 27))	('cell growth', 'biological_process', 'GO:0016049', ('40', '51'))	('miR-214', 'Gene', (79, 86))
5525	26918939	These data demonstrate that both miR-199a and miR-214 are involved in regulation of hPSC migration while miR-199a is also involved in the proliferation of hPSCs.	('rat', 'Species', '10116', (18, 21))	('hPSC', 'Gene', '100653366', (84, 88))	('miR-199a', 'Var', (105, 113))	('regulation', 'biological_process', 'GO:0065007', ('70', '80'))	('involved', 'Reg', (122, 130))	('hPSC', 'Gene', (84, 88))	('miR-214', 'Gene', (46, 53))	('involved', 'Reg', (58, 66))	('rat', 'Species', '10116', (92, 95))	('miR-199a', 'Gene', (33, 41))	('hPSC', 'Gene', '100653366', (155, 159))	('miR-214', 'Gene', '406996', (46, 53))	('rat', 'Species', '10116', (145, 148))	('hPSC', 'Gene', (155, 159))
5531	26918939	Interestingly, treatment with anti-miR-199a or -214 reduced PSC-induced proliferation of tumor cells compared with that of negative control miR treated hPSCs (Figure 5C).	('PSC', 'Gene', (153, 156))	('hPSC', 'Gene', '100653366', (152, 156))	('PSC', 'Gene', (60, 63))	('PSC', 'Gene', '100653366', (60, 63))	('reduced', 'NegReg', (52, 59))	('anti-miR-199a', 'Var', (30, 43))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('rat', 'Species', '10116', (79, 82))	('PSC', 'Gene', '100653366', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('hPSC', 'Gene', (152, 156))
5536	26918939	Although we observe a much decrease in the tube formation with conditioned medium from anti-miR-199a treated PSCs, we observed no cell death in endothelial cells microscopically after staining with calcein-red.	('PSC', 'Gene', (109, 112))	('decrease', 'NegReg', (27, 35))	('PSC', 'Gene', '100653366', (109, 112))	('cell death', 'biological_process', 'GO:0008219', ('130', '140'))	('anti-miR-199a', 'Var', (87, 100))	('tube formation', 'CPA', (43, 57))	('tube formation', 'biological_process', 'GO:0035148', ('43', '57'))	('calcein-red', 'Chemical', '-', (198, 209))
5537	26918939	These data indicate that inhibition of miR-199a and -214 in PSCs inhibits TGF-beta-activated PSC-induced endothelial cell activation.	('PSC', 'Gene', (60, 63))	('inhibits', 'NegReg', (65, 73))	('TGF-beta', 'Gene', '7040', (74, 82))	('PSC', 'Gene', '100653366', (93, 96))	('endothelial cell activation', 'biological_process', 'GO:0042118', ('105', '132'))	('inhibition', 'Var', (25, 35))	('miR-199a and -214', 'Gene', '406996', (39, 56))	('TGF-beta', 'Gene', (74, 82))	('PSC', 'Gene', (93, 96))	('PSC', 'Gene', '100653366', (60, 63))
5545	26918939	Furthermore, we demonstrated that inactivation of hPSCs with miR inhibitors significantly reduced the hPSC-induced paracrine pro-tumorigenic effects on tumor cell proliferation and endothelial cells.	('hPSC', 'Gene', (50, 54))	('hPSC', 'Gene', '100653366', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('reduced', 'NegReg', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('inactivation', 'Var', (34, 46))	('rat', 'Species', '10116', (170, 173))	('hPSC', 'Gene', (102, 106))	('rat', 'Species', '10116', (23, 26))	('hPSC', 'Gene', '100653366', (102, 106))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('cell proliferation', 'biological_process', 'GO:0008283', ('158', '176'))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))
5548	26918939	Since there are no markers to distinguish these differential CAF phenotypes, normalization of CAFs, in general, might be a right strategy to inhibit their paracrine signals.	('CAF', 'Gene', '8850', (94, 97))	('rat', 'Species', '10116', (131, 134))	('CAF', 'Gene', (61, 64))	('paracrine signals', 'MPA', (155, 172))	('normalization', 'Var', (77, 90))	('CAF', 'Gene', '8850', (61, 64))	('CAF', 'Gene', (94, 97))	('inhibit', 'NegReg', (141, 148))
5555	26918939	Interestingly, induction of both miR-199a and miR-214 was also established in these cells, indicating a relationship of these miRNAs with PSC differentiation.	('miR-199a', 'Var', (33, 41))	('miR-214', 'Gene', (46, 53))	('PSC', 'Gene', '100653366', (138, 141))	('PSC', 'Gene', (138, 141))	('miR-214', 'Gene', '406996', (46, 53))
5557	26918939	Interestingly, TGF-beta-induced activation and differentiation as well as migration and cell growth of hPSCs was inhibited by anti-miR-199a or anti-miR-214, confirming the significance of these miRs in controlling PSCs' phenotypic behavior.	('miR-214', 'Gene', (148, 155))	('differentiation', 'CPA', (47, 62))	('PSC', 'Gene', (214, 217))	('rat', 'Species', '10116', (77, 80))	('inhibited', 'NegReg', (113, 122))	('cell growth', 'biological_process', 'GO:0016049', ('88', '99'))	('activation', 'PosReg', (32, 42))	('TGF-beta', 'Gene', '7040', (15, 23))	('anti-miR-199a', 'Var', (126, 139))	('TGF-beta', 'Gene', (15, 23))	('migration', 'CPA', (74, 83))	('cell growth', 'CPA', (88, 99))	('miR-214', 'Gene', '406996', (148, 155))	('hPSC', 'Gene', '100653366', (103, 107))	('PSC', 'Gene', '100653366', (104, 107))	('PSC', 'Gene', (104, 107))	('hPSC', 'Gene', (103, 107))	('PSC', 'Gene', '100653366', (214, 217))
5560	26918939	Treatment of hPSCs with anti-miR-199a or anti-miR-214 abrogated hPSC-induced Panc-1 tumor cell growth, spheroid formation and inhibited endothelial cells activation.	('spheroid formation', 'CPA', (103, 121))	('formation', 'biological_process', 'GO:0009058', ('112', '121'))	('hPSC', 'Gene', (64, 68))	('hPSC', 'Gene', '100653366', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Panc-1 tumor', 'Disease', (77, 89))	('abrogated', 'NegReg', (54, 63))	('hPSC', 'Gene', (13, 17))	('inhibited', 'NegReg', (126, 135))	('miR-214', 'Gene', (46, 53))	('hPSC', 'Gene', '100653366', (13, 17))	('anti-miR-199a', 'Var', (24, 37))	('cell growth', 'biological_process', 'GO:0016049', ('90', '101'))	('endothelial cells activation', 'CPA', (136, 164))	('Panc-1 tumor', 'Disease', 'MESH:D009369', (77, 89))	('miR-214', 'Gene', '406996', (46, 53))
5561	26918939	These data signify that inhibition of miR-199a and miR-214 in hPSCs leads to inhibition of PSC-induced pro-tumorigenic effects in vitro, representing them interesting miRNAs to develop for potential gene therapy.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('PSC', 'Gene', '100653366', (63, 66))	('miR-214', 'Gene', '406996', (51, 58))	('inhibition', 'NegReg', (77, 87))	('PSC', 'Gene', (63, 66))	('inhibition', 'Var', (24, 34))	('hPSC', 'Gene', (62, 66))	('hPSC', 'Gene', '100653366', (62, 66))	('PSC', 'Gene', '100653366', (91, 94))	('miR-199a', 'Var', (38, 46))	('miR-214', 'Gene', (51, 58))	('PSC', 'Gene', (91, 94))
5564	26918939	These studies have shown pro-tumoral effects of p53 inactivation in the stromal fibroblasts, as well as that genetic inactivation of PTEN in CAFs, potentiate both onset and progression of carcinomas.	('genetic inactivation', 'Var', (109, 129))	('p53', 'Gene', (48, 51))	('CAF', 'Gene', '8850', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('p53', 'Gene', '7157', (48, 51))	('potentiate', 'PosReg', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('inactivation', 'NegReg', (52, 64))	('PTEN', 'Gene', (133, 137))	('tumor', 'Disease', (29, 34))	('PTEN', 'Gene', '5728', (133, 137))	('CAF', 'Gene', (141, 144))	('progression', 'CPA', (173, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('carcinomas', 'Disease', (188, 198))	('carcinomas', 'Disease', 'MESH:D002277', (188, 198))
5567	26918939	BAX (Bcl-2-associated X protein) is a pro-apoptotic gene, and its alteration modulates fibroblasts function by disrupting apoptosis pathway.	('Bcl-2-associated X protein', 'Gene', '581', (5, 31))	('rat', 'Species', '10116', (70, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('BAX', 'Gene', (0, 3))	('Bcl-2', 'molecular_function', 'GO:0015283', ('5', '10'))	('BAX', 'Gene', '581', (0, 3))	('alteration', 'Var', (66, 76))	('apoptosis pathway', 'Pathway', (122, 139))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('disrupting', 'NegReg', (111, 121))	('fibroblasts function', 'CPA', (87, 107))	('Bcl-2-associated X protein', 'Gene', (5, 31))	('modulates', 'Reg', (77, 86))
5573	26918939	Nevertheless, silencing of miR-199a or miR-214 in hPSCs/CAFs may represent a novel therapeutic option for the development of novel therapies for this devastating disease.	('hPSC', 'Gene', (50, 54))	('silencing', 'Var', (14, 23))	('miR-199a', 'Gene', (27, 35))	('hPSC', 'Gene', '100653366', (50, 54))	('CAF', 'Gene', '8850', (56, 59))	('miR-214', 'Gene', (39, 46))	('CAF', 'Gene', (56, 59))	('miR-214', 'Gene', '406996', (39, 46))
5600	26918939	After 18 h, cells were incubated in serum-free media and transfected with anti-miR-199a and anti-miR-214 (50 nM).	('anti-miR-199a', 'Var', (74, 87))	('miR-214', 'Gene', '406996', (97, 104))	('miR-214', 'Gene', (97, 104))
5603	26918939	hPSCs were seeded in a 24-well plate (4 x 104 cells/well) for 18 h and transfected with anti-miR-199a and anti-miR-214 hairpin inhibitors and allowed them to become confluent.	('anti-miR-199a', 'Var', (88, 101))	('miR-214', 'Gene', (111, 118))	('hPSC', 'Gene', '100653366', (0, 4))	('hPSC', 'Gene', (0, 4))	('miR-214', 'Gene', '406996', (111, 118))
5607	26918939	hPSCs transfected with anti-miRs are trypsinized and suspended in culture medium to a concentration of 3 x 105 cells/ml.	('hPSC', 'Gene', (0, 4))	('anti-miRs', 'Var', (23, 32))	('hPSC', 'Gene', '100653366', (0, 4))	('rat', 'Species', '10116', (93, 96))
5622	27216187	Notably, in PDAC cells Mito-Met10 potently inhibited mitochondrial complex I, stimulating superoxide and AMPK activation, but had no effect in non-transformed control cells.	('complex I', 'cellular_component', 'GO:0030964', ('67', '76'))	('superoxide', 'Chemical', 'MESH:D013481', (90, 100))	('Mito-Met10', 'Var', (23, 33))	('AMPK', 'Gene', '5562', (105, 109))	('PDAC', 'Phenotype', 'HP:0006725', (12, 16))	('inhibited', 'NegReg', (43, 52))	('AMPK', 'Gene', (105, 109))	('stimulating', 'Reg', (78, 89))	('AMPK', 'molecular_function', 'GO:0050405', ('105', '109'))	('AMPK', 'molecular_function', 'GO:0004691', ('105', '109'))	('-Met10', 'Chemical', '-', (27, 33))	('AMPK', 'molecular_function', 'GO:0047322', ('105', '109'))	('mitochondrial complex I', 'Enzyme', (53, 76))	('PDAC', 'Chemical', '-', (12, 16))
5623	27216187	Moreover, Mito-Met10 potently triggered G1 cell cycle phase arrest in PDAC cells, enhanced their radiosensitivity and more potently abrogated PDAC growth in preclinical mouse models, compared to Met.	('PDAC', 'Phenotype', 'HP:0006725', (70, 74))	('enhanced', 'PosReg', (82, 90))	('PDAC', 'Chemical', '-', (142, 146))	('abrogated', 'NegReg', (132, 141))	('Met', 'Chemical', 'MESH:D008687', (195, 198))	('cell cycle phase', 'biological_process', 'GO:0022403', ('43', '59'))	('PDAC', 'Chemical', '-', (70, 74))	('radiosensitivity', 'MPA', (97, 113))	('Mito-Met10', 'Var', (10, 20))	('triggered', 'Reg', (30, 39))	('mouse', 'Species', '10090', (169, 174))	('-Met10', 'Chemical', '-', (14, 20))	('PDAC', 'Phenotype', 'HP:0006725', (142, 146))	('G1 cell cycle phase arrest', 'CPA', (40, 66))	('Met', 'Chemical', 'MESH:D008687', (15, 18))	('PDAC', 'Disease', (142, 146))
5628	27216187	A prevailing view is that Met exerts antitumor effects by elevating cellular AMP/ATP ratio and activating the 5'-AMP-activated protein kinase (AMPK)/mTOR pathway and/or by decreasing the circulating insulin and the blood glucose levels.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('blood glucose levels', 'MPA', (215, 235))	('mTOR', 'Gene', '2475', (149, 153))	('AMPK', 'Gene', '5562', (143, 147))	('AMP', 'Gene', '353', (77, 80))	('glucose', 'Chemical', 'MESH:D005947', (221, 228))	('decreasing', 'NegReg', (172, 182))	('AMPK', 'molecular_function', 'GO:0004691', ('143', '147'))	('activating', 'PosReg', (95, 105))	('AMP', 'Gene', (113, 116))	('ATP', 'Chemical', 'MESH:D000255', (81, 84))	('elevating', 'PosReg', (58, 67))	('AMPK', 'molecular_function', 'GO:0047322', ('143', '147'))	('AMP', 'Gene', (143, 146))	('tumor', 'Disease', (41, 46))	('circulating insulin', 'MPA', (187, 206))	('AMPK', 'Gene', (143, 147))	('AMP', 'Gene', '353', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('AMP', 'Gene', (77, 80))	('Met', 'Chemical', 'MESH:D008687', (26, 29))	('Met', 'Var', (26, 29))	('mTOR', 'Gene', (149, 153))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('insulin', 'molecular_function', 'GO:0016088', ('199', '206'))	('AMP', 'Gene', '353', (143, 146))	('AMPK', 'molecular_function', 'GO:0050405', ('143', '147'))
5630	27216187	Met suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase.	('inhibiting', 'NegReg', (34, 44))	('gluconeogenesis', 'MPA', (15, 30))	('Met', 'Chemical', 'MESH:D008687', (0, 3))	('Met', 'Var', (0, 3))	('gluconeogenesis', 'biological_process', 'GO:0006094', ('15', '30'))	('suppresses', 'NegReg', (4, 14))	('mitochondrial glycerophosphate dehydrogenase', 'Enzyme', (45, 89))	('suppresses gluconeogenesis', 'Phenotype', 'HP:0005959', (4, 30))
5636	27216187	For example, conjugating a nitroxide, quinone, a chromanol moiety of alpha-tocopherol to the triphenylphosphonium (TPP+) group via an aliphatic linker increased their antiproliferative effect in tumor cells.	('increased', 'PosReg', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('nitroxide', 'Chemical', 'MESH:D019811', (27, 36))	('quinone', 'Chemical', 'MESH:C004532', (38, 45))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (69, 85))	('TPP', 'molecular_function', 'GO:0004294', ('115', '118'))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('chromanol', 'Chemical', 'MESH:C029141', (49, 58))	('triphenylphosphonium', 'Chemical', '-', (93, 113))	('TPP+', 'Chemical', 'MESH:C016136', (115, 119))	('conjugating', 'Var', (13, 24))
5641	27216187	To this end, we synthesized and characterized several Met analogs (e.g., Mito-Met2, Mito-Met6, Mito-Met10, Mito-Met12, Fig.	('Met', 'Chemical', 'MESH:D008687', (54, 57))	('Mito-Met10', 'Var', (95, 105))	('-Met10', 'Chemical', '-', (99, 105))	('Met', 'Chemical', 'MESH:D008687', (89, 92))	('Met', 'Chemical', 'MESH:D008687', (78, 81))	('Met', 'Chemical', 'MESH:D008687', (112, 115))	('Mito-Met2', 'Var', (73, 82))	('Met', 'Chemical', 'MESH:D008687', (100, 103))	('Mito-Met6', 'Var', (84, 93))	('Mito-Met12', 'Var', (107, 117))
5643	27216187	The present results show that Mito-Met10 is nearly 1,000-fold more effective than Met in inhibiting pancreatic ductal adenoma cell (PDAC) proliferation in vitro and more effective than Met in abrogating PDAC tumor growth in vivo.	('Mito-Met10', 'Var', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('-Met10', 'Chemical', '-', (34, 40))	('Met', 'Chemical', 'MESH:D008687', (82, 85))	('inhibiting', 'NegReg', (89, 99))	('PDAC', 'Chemical', '-', (203, 207))	('pancreatic ductal adenoma', 'Disease', (100, 125))	('PDAC', 'Chemical', '-', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('Met', 'Chemical', 'MESH:D008687', (185, 188))	('abrogating', 'NegReg', (192, 202))	('Met', 'Chemical', 'MESH:D008687', (35, 38))	('pancreatic ductal adenoma', 'Disease', 'MESH:C538110', (100, 125))	('tumor', 'Disease', (208, 213))	('PDAC', 'Disease', (203, 207))	('PDAC', 'Phenotype', 'HP:0006725', (203, 207))	('PDAC', 'Phenotype', 'HP:0006725', (132, 136))
5644	27216187	Mito-Met10 inhibited mitochondrial complex I, stimulating superoxide generation and AMPK activation, more potently than Met in MiaPaCa-2 cells.	('AMPK', 'Gene', '5562', (84, 88))	('AMPK', 'molecular_function', 'GO:0050405', ('84', '88'))	('AMPK', 'molecular_function', 'GO:0004691', ('84', '88'))	('Met', 'Chemical', 'MESH:D008687', (5, 8))	('superoxide generation', 'MPA', (58, 79))	('stimulating', 'Reg', (46, 57))	('mitochondrial complex I', 'Enzyme', (21, 44))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (127, 136))	('AMPK', 'Gene', (84, 88))	('Met', 'Chemical', 'MESH:D008687', (120, 123))	('AMPK', 'molecular_function', 'GO:0047322', ('84', '88'))	('Mito-Met10', 'Var', (0, 10))	('complex I', 'cellular_component', 'GO:0030964', ('35', '44'))	('inhibited', 'NegReg', (11, 20))	('superoxide', 'Chemical', 'MESH:D013481', (58, 68))
5646	27216187	In this study, we show that Mito-Met10 enhanced radiation sensitivity in PDAC to the same extent as did Met (1 mM) but at a 1,000-fold lower concentration (1 muM).	('Met', 'Chemical', 'MESH:D008687', (33, 36))	('muM', 'Gene', (158, 161))	('Mito-Met10', 'Var', (28, 38))	('radiation', 'MPA', (48, 57))	('PDAC', 'Chemical', '-', (73, 77))	('Met', 'Chemical', 'MESH:D008687', (104, 107))	('PDAC', 'Phenotype', 'HP:0006725', (73, 77))	('-Met10', 'Chemical', '-', (32, 38))	('muM', 'Gene', '56925', (158, 161))	('enhanced', 'PosReg', (39, 47))
5662	27216187	Stimulations with Met or Mito-Met10 were performed for 30 min in serum-free medium (AMPK) or for 24 h in full growth media (FOXM1).	('AMPK', 'Gene', '5562', (84, 88))	('AMPK', 'molecular_function', 'GO:0004691', ('84', '88'))	('AMPK', 'molecular_function', 'GO:0050405', ('84', '88'))	('Met', 'Chemical', 'MESH:D008687', (30, 33))	('AMPK', 'Gene', (84, 88))	('AMPK', 'molecular_function', 'GO:0047322', ('84', '88'))	('Mito-Met10', 'Var', (25, 35))	('Met', 'Chemical', 'MESH:D008687', (18, 21))	('-Met10', 'Chemical', '-', (29, 35))
5671	27216187	An orthotopic syngeneic engraftment model was used to assess metastatic homing and tumor progression following treatment with Met or Mito-Met10.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Mito-Met10', 'Var', (133, 143))	('tumor', 'Disease', (83, 88))	('Met', 'Chemical', 'MESH:D008687', (126, 129))	('metastatic homing', 'CPA', (61, 78))	('Met', 'Var', (126, 129))	('Met', 'Chemical', 'MESH:D008687', (138, 141))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
5680	27216187	To compare the antiproliferative effects of Met and Mito-Met10, human MiaPaCa-2 cells were treated with Met (0.1 - 2 mM) or Mito-Met10 (0.1-1 muM).	('Met', 'Chemical', 'MESH:D008687', (129, 132))	('human', 'Species', '9606', (64, 69))	('Met', 'Chemical', 'MESH:D008687', (44, 47))	('Met', 'Chemical', 'MESH:D008687', (57, 60))	('muM', 'Gene', '56925', (142, 145))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (70, 79))	('-Met10', 'Chemical', '-', (128, 134))	('Met', 'Chemical', 'MESH:D008687', (104, 107))	('-Met10', 'Chemical', '-', (56, 62))	('muM', 'Gene', (142, 145))	('Mito-Met10', 'Var', (124, 134))
5684	27216187	Mito-Met10 was also significantly more potent than Met in inhibiting proliferation of mouse pancreatic cells, FC-1242 (Suppl.	('proliferation', 'CPA', (69, 82))	('Met', 'Chemical', 'MESH:D008687', (5, 8))	('mouse', 'Species', '10090', (86, 91))	('inhibiting', 'NegReg', (58, 68))	('Mito-Met10', 'Var', (0, 10))	('-Met10', 'Chemical', '-', (4, 10))	('Met', 'Chemical', 'MESH:D008687', (51, 54))
5686	27216187	Almost no colony formation was detected in cells treated with 3 muM of Mito-Met10 and 3 mM of Met (Fig.	('Mito-Met10', 'Var', (71, 81))	('-Met10', 'Chemical', '-', (75, 81))	('muM', 'Gene', (64, 67))	('formation', 'biological_process', 'GO:0009058', ('17', '26'))	('Met', 'Chemical', 'MESH:D008687', (94, 97))	('muM', 'Gene', '56925', (64, 67))	('Met', 'Chemical', 'MESH:D008687', (76, 79))	('colony formation', 'CPA', (10, 26))
5687	27216187	1C right) showed that the IC50 values determined for Met and Mito-Met10 were 1.3 mM and 1.1 muM, respectively.	('Mito-Met10', 'Var', (61, 71))	('muM', 'Gene', (92, 95))	('Met', 'Chemical', 'MESH:D008687', (53, 56))	('Met', 'Var', (53, 56))	('Met', 'Chemical', 'MESH:D008687', (66, 69))	('-Met10', 'Chemical', '-', (65, 71))	('muM', 'Gene', '56925', (92, 95))
5688	27216187	Thus, results from two independent cell growth assays revealed that Mito-Met10 is nearly 1,000-fold more potent than Met in inhibiting MiaPaCa-2 cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('145', '163'))	('MiaPaCa-2 cell proliferation', 'CPA', (135, 163))	('Mito-Met10', 'Var', (68, 78))	('cell growth', 'biological_process', 'GO:0016049', ('35', '46'))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (135, 144))	('inhibiting', 'NegReg', (124, 134))	('Met', 'Chemical', 'MESH:D008687', (73, 76))	('Met', 'Chemical', 'MESH:D008687', (117, 120))
5689	27216187	To compare the cytotoxic effects of Met, Mito-Met10 and selected other TPP+-linked compounds, MiaPaCa-2 cells were treated with Mito-Met10 (100 muM) or Met (30-100 mM) and other TPP+-linked compounds for 24 h and cell death was monitored in real time using the Sytox Green assay (Suppl.	('muM', 'Gene', '56925', (144, 147))	('TPP+', 'Chemical', 'MESH:C016136', (71, 75))	('Met', 'Chemical', 'MESH:D008687', (133, 136))	('TPP', 'molecular_function', 'GO:0004294', ('71', '74'))	('cell death', 'biological_process', 'GO:0008219', ('213', '223'))	('Sytox Green', 'Chemical', 'MESH:C402795', (261, 272))	('-Met10', 'Chemical', '-', (45, 51))	('muM', 'Gene', (144, 147))	('TPP', 'molecular_function', 'GO:0004294', ('178', '181'))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (94, 103))	('TPP+', 'Chemical', 'MESH:C016136', (178, 182))	('Mito-Met10', 'Var', (128, 138))	('-Met10', 'Chemical', '-', (132, 138))	('Met', 'Chemical', 'MESH:D008687', (46, 49))	('Met', 'Chemical', 'MESH:D008687', (152, 155))	('Met', 'Chemical', 'MESH:D008687', (36, 39))
5691	27216187	In contrast, other mitochondria-targeted agents (e.g., Mito-CP, Mito-Q, Mito-CP-Ac, Mito-Tempol, and Mito-Chromanol) were considerably more cytotoxic to MiaPaCa-2 cells under these conditions.	('Mito', 'Species', '262676', (55, 59))	('Mito-Tempol', 'Var', (84, 95))	('cytotoxic', 'CPA', (140, 149))	('Mito-Q', 'Var', (64, 70))	('Mito', 'Species', '262676', (101, 105))	('Mito', 'Species', '262676', (72, 76))	('mitochondria', 'cellular_component', 'GO:0005739', ('19', '31'))	('Mito', 'Species', '262676', (64, 68))	('Mito-CP-Ac', 'Var', (72, 82))	('Mito', 'Species', '262676', (84, 88))	('Mito-CP', 'Var', (55, 62))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (153, 162))
5693	27216187	We also tested the antiproliferative effects of Mito-Met10 and Met in the multicellular tumor spheroid model.	('tested', 'Reg', (8, 14))	('Met', 'Chemical', 'MESH:D008687', (53, 56))	('antiproliferative effects', 'CPA', (19, 44))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('Mito-Met10', 'Var', (48, 58))	('Met', 'Chemical', 'MESH:D008687', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Met', 'Var', (63, 66))	('tumor', 'Disease', (88, 93))
5695	27216187	Thus, both 2D and 3D cell growth assays indicate that Mito-Met10 is 1,000- to 10,000-fold more effective than Met in inhibiting PDAC proliferation.	('PDAC proliferation', 'CPA', (128, 146))	('Mito-Met10', 'Var', (54, 64))	('PDAC', 'Chemical', '-', (128, 132))	('Met', 'Chemical', 'MESH:D008687', (59, 62))	('inhibiting', 'NegReg', (117, 127))	('Met', 'Chemical', 'MESH:D008687', (110, 113))	('PDAC', 'Phenotype', 'HP:0006725', (128, 132))	('cell growth', 'biological_process', 'GO:0016049', ('21', '32'))
5697	27216187	Figure 3A compares the antiproliferative effects of Mito-Met10 (left) and Met (right) in MiaPaCa-2 and PANC-1 and in nonmalignant control cells, HPNE, IEC-6, and N27 cells.	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (89, 98))	('Met', 'Chemical', 'MESH:D008687', (74, 77))	('Met', 'Chemical', 'MESH:D008687', (57, 60))	('antiproliferative effects', 'CPA', (23, 48))	('N27', 'CellLine', 'CVCL:D584', (162, 165))	('Mito-Met10', 'Var', (52, 62))	('-Met10', 'Chemical', '-', (56, 62))	('HPNE', 'Chemical', '-', (145, 149))	('PANC-1', 'CellLine', 'CVCL:0480', (103, 109))
5698	27216187	Mito-Met10 and Met more potently inhibited proliferation of MiaPaCa-2 and PANC-1 cells as compared to normal cells (HPNE, IEC-6 and N27) (Fig.	('HPNE', 'Chemical', '-', (116, 120))	('Met', 'Chemical', 'MESH:D008687', (5, 8))	('Met', 'Var', (15, 18))	('N27', 'CellLine', 'CVCL:D584', (132, 135))	('Mito-Met10', 'Var', (0, 10))	('-Met10', 'Chemical', '-', (4, 10))	('PANC-1', 'CellLine', 'CVCL:0480', (74, 80))	('proliferation', 'CPA', (43, 56))	('Met', 'Chemical', 'MESH:D008687', (15, 18))	('inhibited', 'NegReg', (33, 42))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (60, 69))
5700	27216187	Over a wide range of concentrations and incubation times, Dec-TPP+ did not show any selectivity with regard to inhibition of cell viability in PDAC versus nonmalignant cells.	('cell viability', 'CPA', (125, 139))	('TPP', 'molecular_function', 'GO:0004294', ('62', '65'))	('PDAC', 'Disease', (143, 147))	('PDAC', 'Phenotype', 'HP:0006725', (143, 147))	('Dec-TPP+', 'Var', (58, 66))	('Dec-TPP+', 'Chemical', '-', (58, 66))	('PDAC', 'Chemical', '-', (143, 147))
5701	27216187	However, Met conjugated to TPP+ (e.g., Mito-Met10) more potently inhibited pancreatic cancer cell viability as compared to normal cell viability, with significantly lower IC50values in MiaPaCa-2 and PANC-1 cells as compared to HPNE and IEC-6 cells (Suppl.	('PANC-1', 'CellLine', 'CVCL:0480', (199, 205))	('lower', 'NegReg', (165, 170))	('Met', 'Chemical', 'MESH:D008687', (44, 47))	('Met', 'Chemical', 'MESH:D008687', (9, 12))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (185, 194))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (75, 92))	('TPP+', 'Chemical', 'MESH:C016136', (27, 31))	('HPNE', 'Chemical', '-', (227, 231))	('inhibited', 'NegReg', (65, 74))	('Mito-Met10', 'Var', (39, 49))	('pancreatic cancer', 'Disease', (75, 92))	('pancreatic cancer', 'Disease', 'MESH:D010190', (75, 92))	('IC50values', 'MPA', (171, 181))	('TPP', 'molecular_function', 'GO:0004294', ('27', '30'))
5702	27216187	Figure 3B shows the relative potencies of Mito-Met analogs (Mito-Met2, Mito-Met6, and Mito-Met10, phenformin, and Met) in inhibiting MiaPaCa-2 colony formation.	('inhibiting', 'NegReg', (122, 132))	('-Met6', 'Chemical', '-', (75, 80))	('Met', 'Chemical', 'MESH:D008687', (47, 50))	('MiaPaCa-2 colony formation', 'CPA', (133, 159))	('Met', 'Chemical', 'MESH:D008687', (65, 68))	('-Met2', 'Chemical', '-', (64, 69))	('Met', 'Chemical', 'MESH:D008687', (91, 94))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (133, 142))	('Mito-Met10', 'Var', (86, 96))	('formation', 'biological_process', 'GO:0009058', ('150', '159'))	('Mito-Met6', 'Var', (71, 80))	('Met', 'Chemical', 'MESH:D008687', (76, 79))	('Met', 'Chemical', 'MESH:D008687', (114, 117))	('phenformin', 'Chemical', 'MESH:D010629', (98, 108))
5703	27216187	Mito-Met2 and Mito-Met6 were relatively less potent than Mito-Met10 in inhibiting MiaPaCa-2 cell proliferation (Fig.	('inhibiting', 'NegReg', (71, 81))	('Mito-Met6', 'Var', (14, 23))	('MiaPaCa-2 cell proliferation', 'CPA', (82, 110))	('-Met6', 'Chemical', '-', (18, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('-Met2', 'Chemical', '-', (4, 9))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (82, 91))
5704	27216187	Next we investigated the relative uptake of different Mito-Met analogs (Mito-Met2, Mito-Met6, and Mito-Met10) and phenformin in MiaPaCa-2 cells by LC-MS (Fig.	('uptake', 'biological_process', 'GO:0098739', ('34', '40'))	('Mito-Met6', 'Var', (83, 92))	('-Met10', 'Chemical', '-', (102, 108))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (128, 137))	('phenformin', 'Chemical', 'MESH:D010629', (114, 124))	('Mito-Met10', 'Var', (98, 108))	('uptake', 'biological_process', 'GO:0098657', ('34', '40'))
5714	27216187	Next we monitored the mitochondrial respiration rates in MiaPaCa-2 cells after longer treatment (24 h) with Met, Mito-Mets, and phenformin followed by a washout and replenishment with fresh assay media.	('Mito-Mets', 'Var', (113, 122))	('mitochondrial respiration', 'MPA', (22, 47))	('respiration', 'biological_process', 'GO:0007585', ('36', '47'))	('respiration', 'biological_process', 'GO:0045333', ('36', '47'))	('phenformin', 'Chemical', 'MESH:D010629', (128, 138))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (57, 66))	('Met', 'Chemical', 'MESH:D008687', (108, 111))	('Met', 'Chemical', 'MESH:D008687', (118, 121))
5716	27216187	These results demonstrate that the extent of OCR inhibition was dependent on the alkyl chain length with Mito-Met2, Mito-Met6 and Mito-Met10 showing similar effects at the concentrations of 25, 16 and 1 muM, respectively (Fig.	('muM', 'Gene', '56925', (203, 206))	('Mito-Met2', 'Var', (105, 114))	('-Met6', 'Chemical', '-', (120, 125))	('Mito-Met10', 'Var', (130, 140))	('-Met10', 'Chemical', '-', (134, 140))	('OCR', 'Chemical', '-', (45, 48))	('OCR', 'MPA', (45, 48))	('muM', 'Gene', (203, 206))	('-Met2', 'Chemical', '-', (109, 114))	('Mito-Met6', 'Var', (116, 125))
5718	27216187	As shown in Figure 5A, Met pretreatment decreased MiaPaCa-2 cell growth after irradiation, in agreement with previous reports indicating radiosensitizing effects of Met in PDAC.	('Met', 'Chemical', 'MESH:D008687', (23, 26))	('PDAC', 'Chemical', '-', (172, 176))	('Met', 'Var', (23, 26))	('MiaPaCa-2 cell growth', 'CPA', (50, 71))	('cell growth', 'biological_process', 'GO:0016049', ('60', '71'))	('Met', 'Chemical', 'MESH:D008687', (165, 168))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (50, 59))	('PDAC', 'Phenotype', 'HP:0006725', (172, 176))	('decreased', 'NegReg', (40, 49))
5719	27216187	Radiation dose-response results show that 1 muM Mito-Met was as effective as 1 mM Met in radiosensitization (Fig.	('muM', 'Gene', (44, 47))	('Met', 'Chemical', 'MESH:D008687', (53, 56))	('Met', 'Chemical', 'MESH:D008687', (82, 85))	('Mito-Met', 'Var', (48, 56))	('radiosensitization', 'CPA', (89, 107))	('muM', 'Gene', '56925', (44, 47))
5721	27216187	Enhanced radiosensitivity in MiaPaCa-2 cells could be attributed to an increased uptake and retention of Mito-Met10 in these cells, as compared to normal (MCF-10A) cells (Suppl.	('Mito-Met10', 'Var', (105, 115))	('uptake', 'MPA', (81, 87))	('MCF-10A', 'CellLine', 'CVCL:0598', (155, 162))	('retention', 'MPA', (92, 101))	('retention', 'biological_process', 'GO:0051235', ('92', '101'))	('radiosensitivity', 'CPA', (9, 25))	('Enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (0, 25))	('uptake', 'biological_process', 'GO:0098739', ('81', '87'))	('increased', 'PosReg', (71, 80))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (29, 38))	('uptake', 'biological_process', 'GO:0098657', ('81', '87'))	('Enhanced', 'PosReg', (0, 8))
5722	27216187	Detailed cell cycle analysis showed that treatment with Mito-Met10, but not Met, arrested PANC-1 cell growth in the G1 phase with a concomitant decrease in cyclin D1 levels (Fig.	('G1 phase', 'biological_process', 'GO:0051318', ('116', '124'))	('cyclin D1', 'Gene', (156, 165))	('Met', 'Chemical', 'MESH:D008687', (61, 64))	('cell growth', 'biological_process', 'GO:0016049', ('97', '108'))	('decrease', 'NegReg', (144, 152))	('cell cycle', 'biological_process', 'GO:0007049', ('9', '19'))	('cyclin', 'molecular_function', 'GO:0016538', ('156', '162'))	('Mito-Met10', 'Var', (56, 66))	('PANC-1', 'CellLine', 'CVCL:0480', (90, 96))	('Met', 'Chemical', 'MESH:D008687', (76, 79))	('cyclin D1', 'Gene', '595', (156, 165))
5723	27216187	Next we investigated whether treatment with Mito-Met10 or Met would have an effect on the FOXM1 pathway.	('Mito-Met10', 'Var', (44, 54))	('FOXM1 pathway', 'Pathway', (90, 103))	('effect', 'Reg', (76, 82))	('Met', 'Chemical', 'MESH:D008687', (58, 61))	('-Met10', 'Chemical', '-', (48, 54))	('Met', 'Chemical', 'MESH:D008687', (49, 52))
5725	27216187	Treatment of MiaPaCa-2 cells with Mito-Met10, but not Met, resulted in a significant decrease in FOXM1 levels (Fig 5C, left).	('Met', 'Chemical', 'MESH:D008687', (54, 57))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (13, 22))	('Met', 'Chemical', 'MESH:D008687', (39, 42))	('Mito-Met10', 'Var', (34, 44))	('-Met10', 'Chemical', '-', (38, 44))	('decrease', 'NegReg', (85, 93))	('FOXM1 levels', 'MPA', (97, 109))
5729	27216187	5C, middle) and a ~four-fold increase in pAMPK in murine FC-1242 PDAC cells treated with Mito-Met10 and Met (Fig.	('PDAC', 'Chemical', '-', (65, 69))	('murine', 'Species', '10090', (50, 56))	('Mito-Met10', 'Var', (89, 99))	('increase', 'PosReg', (29, 37))	('PDAC', 'Phenotype', 'HP:0006725', (65, 69))	('AMPK', 'Gene', '5562', (42, 46))	('Met', 'Chemical', 'MESH:D008687', (104, 107))	('AMPK', 'Gene', (42, 46))	('Met', 'Chemical', 'MESH:D008687', (94, 97))	('Met', 'Var', (104, 107))
5739	27216187	The IC50 values for Met and Mito-Met10 to inhibit complex I-mediated oxygen consumption upon injection to permeabilized cells were determined to be 0.8 mM and 2 muM, respectively (Suppl.	('complex I-mediated oxygen consumption', 'MPA', (50, 87))	('Met', 'Chemical', 'MESH:D008687', (33, 36))	('muM', 'Gene', (161, 164))	('Mito-Met10', 'Var', (28, 38))	('Met', 'Chemical', 'MESH:D008687', (20, 23))	('complex I', 'cellular_component', 'GO:0030964', ('50', '59'))	('oxygen', 'Chemical', 'MESH:D010100', (69, 75))	('Met', 'Var', (20, 23))	('inhibit', 'NegReg', (42, 49))	('-Met10', 'Chemical', '-', (32, 38))	('muM', 'Gene', '56925', (161, 164))
5740	27216187	Next, we tested the effects of a 24 h pretreatment of intact cells with Mito-Met10 or Met on complex I activity.	('Met', 'Chemical', 'MESH:D008687', (86, 89))	('complex I', 'cellular_component', 'GO:0030964', ('93', '102'))	('Mito-Met10', 'Var', (72, 82))	('tested', 'Reg', (9, 15))	('Met', 'Chemical', 'MESH:D008687', (77, 80))
5743	27216187	This increased potency of Mito-Met10 to inhibit complex I activity is consistent with the >1,000-fold enhanced antiproliferative effect of Mito-Met10 versus Met.	('enhanced', 'PosReg', (102, 110))	('activity', 'MPA', (58, 66))	('complex I', 'Enzyme', (48, 57))	('inhibit', 'NegReg', (40, 47))	('-Met10', 'Chemical', '-', (30, 36))	('Met', 'Chemical', 'MESH:D008687', (157, 160))	('antiproliferative effect', 'MPA', (111, 135))	('-Met10', 'Chemical', '-', (143, 149))	('Met', 'Chemical', 'MESH:D008687', (144, 147))	('Met', 'Chemical', 'MESH:D008687', (31, 34))	('complex I', 'cellular_component', 'GO:0030964', ('48', '57'))	('Mito-Met10', 'Var', (139, 149))
5747	27216187	Results indicate that Mito-Met10 treatment of MiaPaCa-2 cells increased the formation of 2-hydroxyethidium (2-OH-E+), a diagnostic marker product of HE/superoxide reaction (Fig.	('increased', 'PosReg', (62, 71))	('Mito-Met10', 'Var', (22, 32))	('-Met10', 'Chemical', '-', (26, 32))	('formation of', 'MPA', (76, 88))	('superoxide', 'Chemical', 'MESH:D013481', (152, 162))	('2-hydroxyethidium', 'Chemical', 'MESH:C506392', (89, 106))	('2-OH-E+', 'Chemical', '-', (108, 115))	('HE', 'Chemical', 'MESH:C058428', (149, 151))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (46, 55))	('formation', 'biological_process', 'GO:0009058', ('76', '85'))
5749	27216187	6B, middle), indicating that Mito-Met10 also induced generation of one-electron oxidants.	('-Met10', 'Chemical', '-', (33, 39))	('Mito-Met10', 'Var', (29, 39))	('generation of one-electron oxidants', 'MPA', (53, 88))	('induced', 'Reg', (45, 52))
5750	27216187	Under these conditions, Mito-Met10 did not stimulate O2 - formation in control HPNE cells (Fig.	('O2', 'Chemical', '-', (53, 55))	('O2 - formation', 'MPA', (53, 67))	('HPNE', 'Chemical', '-', (79, 83))	('Mito-Met10', 'Var', (24, 34))	('formation', 'biological_process', 'GO:0009058', ('58', '67'))
5752	27216187	A proposed model for Mito-Met10-induced antiproliferative effect in PDAC via inhibition of mitochondrial complex I activity, enhanced O2 - generation, and AMPK activation is shown in Figure 6C.	('AMPK', 'Gene', (155, 159))	('AMPK', 'molecular_function', 'GO:0047322', ('155', '159'))	('AMPK', 'molecular_function', 'GO:0050405', ('155', '159'))	('PDAC', 'Phenotype', 'HP:0006725', (68, 72))	('Mito-Met10-induced', 'Var', (21, 39))	('O2', 'Chemical', '-', (134, 136))	('activity', 'MPA', (115, 123))	('antiproliferative effect', 'MPA', (40, 64))	('inhibition', 'NegReg', (77, 87))	('AMPK', 'Gene', '5562', (155, 159))	('enhanced', 'PosReg', (125, 133))	('PDAC', 'Chemical', '-', (68, 72))	('complex I', 'cellular_component', 'GO:0030964', ('105', '114'))	('mitochondrial complex I', 'Enzyme', (91, 114))	('O2 - generation', 'MPA', (134, 149))	('AMPK', 'molecular_function', 'GO:0004691', ('155', '159'))
5753	27216187	In vivo data show that Mito-Met suppresses tumor growth in a preclinical mouse model (Fig.	('Mito-Met', 'Var', (23, 31))	('suppresses', 'NegReg', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mouse', 'Species', '10090', (73, 78))	('tumor', 'Disease', (43, 48))
5756	27216187	Consistent with the cell culture data, Mito-Met10 was considerably more effective than Met in mitigating PDAC growth (Fig.	('PDAC growth', 'Disease', (105, 116))	('PDAC', 'Phenotype', 'HP:0006725', (105, 109))	('Met', 'Chemical', 'MESH:D008687', (44, 47))	('Met', 'Chemical', 'MESH:D008687', (87, 90))	('PDAC', 'Chemical', '-', (105, 109))	('mitigating', 'NegReg', (94, 104))	('Mito-Met10', 'Var', (39, 49))
5760	27216187	Over time, PDAC tumor bearing mice treated with Mito-Met10 had lower tumor burden when assessed at early, middle, and later time points as visualized by bioluminescent imaging, with smaller tumors at the completion of the study (Fig.	('smaller', 'NegReg', (182, 189))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mice', 'Species', '10090', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('lower', 'NegReg', (63, 68))	('PDAC', 'Chemical', '-', (11, 15))	('Mito-Met10', 'Var', (48, 58))	('tumor', 'Disease', (190, 195))	('-Met10', 'Chemical', '-', (52, 58))	('tumor', 'Disease', (16, 21))	('PDAC', 'Phenotype', 'HP:0006725', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
5778	27216187	In this study we showed and characterized, for the first time, that fine-tuning of Met structure by attaching a TPP+ group tethered to different alkyl chain lengths is synthetically feasible, and that these modified analogs increasingly target tumor mitochondria.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('mitochondria', 'cellular_component', 'GO:0005739', ('250', '262'))	('tumor', 'Disease', (244, 249))	('TPP+', 'Chemical', 'MESH:C016136', (112, 116))	('increasingly', 'PosReg', (224, 236))	('target', 'Reg', (237, 243))	('Met', 'Chemical', 'MESH:D008687', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('TPP', 'molecular_function', 'GO:0004294', ('112', '115'))	('modified', 'Var', (207, 215))
5779	27216187	Consistent with enhanced intracellular uptake, Mito-Met analogs were more potent than Met in their ability to inhibit PDAC proliferation.	('analogs', 'Var', (56, 63))	('PDAC', 'Phenotype', 'HP:0006725', (118, 122))	('intracellular uptake', 'MPA', (25, 45))	('PDAC proliferation', 'CPA', (118, 136))	('Mito-Met', 'Gene', (47, 55))	('intracellular', 'cellular_component', 'GO:0005622', ('25', '38'))	('Met', 'Chemical', 'MESH:D008687', (86, 89))	('PDAC', 'Chemical', '-', (118, 122))	('uptake', 'biological_process', 'GO:0098739', ('39', '45'))	('uptake', 'biological_process', 'GO:0098657', ('39', '45'))	('Met', 'Chemical', 'MESH:D008687', (52, 55))	('inhibit', 'NegReg', (110, 117))	('enhanced', 'PosReg', (16, 24))
5780	27216187	The antiproliferative potency of Mito-Met analogs increased with increasing length of the alkyl linker (Mito-Met10 > Mito-Met6 > Mito-Met2) (Fig.	('Mito-Met10', 'Var', (104, 114))	('-Met2', 'Chemical', '-', (133, 138))	('increased', 'PosReg', (50, 59))	('antiproliferative potency', 'MPA', (4, 29))
5785	27216187	Mito-Met10 activated AMPK in MiaPaCa-2 cells nearly 1,000-fold more potently than did Met (Fig.	('Met', 'Chemical', 'MESH:D008687', (5, 8))	('AMPK', 'molecular_function', 'GO:0004691', ('21', '25'))	('Mito-Met10', 'Var', (0, 10))	('AMPK', 'molecular_function', 'GO:0050405', ('21', '25'))	('AMPK', 'Gene', '5562', (21, 25))	('Met', 'Chemical', 'MESH:D008687', (86, 89))	('AMPK', 'Gene', (21, 25))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (29, 38))	('AMPK', 'molecular_function', 'GO:0047322', ('21', '25'))
5787	27216187	Under conditions wherein intracellular ATP levels are decreased along with a concomitant increase in AMP (enhanced AMP/ATP ratio), AMPK is activated via phosphorylation of its threonine-172 residue.	('AMP', 'Gene', (101, 104))	('ATP', 'Chemical', 'MESH:D000255', (119, 122))	('AMPK', 'Gene', (131, 135))	('ATP', 'Chemical', 'MESH:D000255', (39, 42))	('phosphorylation', 'Var', (153, 168))	('AMPK', 'Gene', '5562', (131, 135))	('AMP', 'Gene', '353', (115, 118))	('threonine', 'Chemical', 'MESH:D013912', (176, 185))	('AMP', 'Gene', '353', (101, 104))	('AMP', 'Gene', '353', (131, 134))	('phosphorylation', 'biological_process', 'GO:0016310', ('153', '168'))	('intracellular', 'cellular_component', 'GO:0005622', ('25', '38'))	('AMPK', 'molecular_function', 'GO:0050405', ('131', '135'))	('AMP', 'Gene', (131, 134))	('AMP', 'Gene', (115, 118))	('AMPK', 'molecular_function', 'GO:0004691', ('131', '135'))	('increase', 'PosReg', (89, 97))	('AMPK', 'molecular_function', 'GO:0047322', ('131', '135'))
5792	27216187	We propose that Mito-Met10-mediated inhibition of complex I and superoxide generation, accompanied by activation of AMPK, play an important role in inhibiting PDAC proliferation (Fig.	('Mito-Met10-mediated', 'Var', (16, 35))	('PDAC proliferation', 'CPA', (159, 177))	('-Met10', 'Chemical', '-', (20, 26))	('complex I', 'Enzyme', (50, 59))	('AMPK', 'molecular_function', 'GO:0050405', ('116', '120'))	('inhibition', 'NegReg', (36, 46))	('AMPK', 'Gene', '5562', (116, 120))	('complex I', 'cellular_component', 'GO:0030964', ('50', '59'))	('AMPK', 'Gene', (116, 120))	('PDAC', 'Chemical', '-', (159, 163))	('activation', 'PosReg', (102, 112))	('AMPK', 'molecular_function', 'GO:0004691', ('116', '120'))	('superoxide', 'Chemical', 'MESH:D013481', (64, 74))	('AMPK', 'molecular_function', 'GO:0047322', ('116', '120'))	('superoxide generation', 'MPA', (64, 85))	('inhibiting', 'NegReg', (148, 158))	('PDAC', 'Phenotype', 'HP:0006725', (159, 163))
5795	27216187	Prevailing views suggest that the antiproliferative effects of Met are mediated by activation of the AMPK pathway and/or improved tumor oxygenation (i.e., decreased hypoxia) due to inhibition of mitochondria, leading to decreased tumor cell respiration in irradiated tumors.	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('improved', 'PosReg', (121, 129))	('Met', 'Chemical', 'MESH:D008687', (63, 66))	('mitochondria', 'MPA', (195, 207))	('inhibition', 'NegReg', (181, 191))	('Met', 'Var', (63, 66))	('tumor', 'Disease', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('activation', 'PosReg', (83, 93))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('decreased hypoxia', 'Disease', 'MESH:D000860', (155, 172))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('AMPK', 'Gene', '5562', (101, 105))	('irradiated tumors', 'Disease', (256, 273))	('tumor', 'Disease', (230, 235))	('decreased', 'NegReg', (220, 229))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('irradiated tumors', 'Disease', 'MESH:D012793', (256, 273))	('antiproliferative', 'CPA', (34, 51))	('oxygen', 'Chemical', 'MESH:D010100', (136, 142))	('decreased hypoxia', 'Disease', (155, 172))	('tumor', 'Disease', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('AMPK', 'Gene', (101, 105))
5796	27216187	The enhanced radiosensitivity upon treatment with Mito-Met analogs may be attributed to increased tumor oxygenation (i.e., decreased hypoxia).	('decreased hypoxia', 'Disease', 'MESH:D000860', (123, 140))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (4, 29))	('enhanced', 'PosReg', (4, 12))	('Mito-Met', 'Gene', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('decreased hypoxia', 'Disease', (123, 140))	('oxygen', 'Chemical', 'MESH:D010100', (104, 110))	('increased', 'PosReg', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('analogs', 'Var', (59, 66))	('tumor', 'Disease', (98, 103))	('radiosensitivity', 'MPA', (13, 29))
5800	27216187	The present results show that Mito-Met10 decreases mitochondrial respiration in MiaPaCa-2 cells after 24 h (Fig.	('Mito-Met10', 'Var', (30, 40))	('decreases', 'NegReg', (41, 50))	('respiration', 'biological_process', 'GO:0007585', ('65', '76'))	('mitochondrial respiration', 'MPA', (51, 76))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (80, 89))	('respiration', 'biological_process', 'GO:0045333', ('65', '76'))
5802	27216187	It is likely that Mito-Met10 stimulates tumor oxygenation at concentrations 1,000-fold lower than that of Met.	('Met', 'Chemical', 'MESH:D008687', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Met', 'Chemical', 'MESH:D008687', (106, 109))	('Mito-Met10', 'Var', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('oxygen', 'Chemical', 'MESH:D010100', (46, 52))	('stimulates', 'PosReg', (29, 39))
5803	27216187	A plausible mechanism by which Mito-Met10 decreased mitochondrial respiration may be due to increased accumulation of Mito-Met10 in mitochondria, leading to enhanced inhibition of complex I in the mitochondrial electron transport chain.	('mitochondrial electron transport chain', 'Enzyme', (197, 235))	('mitochondrial electron transport', 'biological_process', 'GO:0042775', ('197', '229'))	('electron transport chain', 'biological_process', 'GO:0022900', ('211', '235'))	('respiration', 'biological_process', 'GO:0007585', ('66', '77'))	('decreased', 'NegReg', (42, 51))	('complex I', 'Enzyme', (180, 189))	('enhanced', 'PosReg', (157, 165))	('inhibition', 'NegReg', (166, 176))	('-Met10', 'Chemical', '-', (122, 128))	('mitochondrial electron transport chain', 'cellular_component', 'GO:0005746', ('197', '235'))	('mitochondrial respiration', 'MPA', (52, 77))	('-Met10', 'Chemical', '-', (35, 41))	('Mito-Met10', 'Var', (31, 41))	('respiration', 'biological_process', 'GO:0045333', ('66', '77'))	('increased accumulation', 'PosReg', (92, 114))	('mitochondria', 'cellular_component', 'GO:0005739', ('132', '144'))	('Mito-Met10', 'Gene', (118, 128))	('complex I', 'cellular_component', 'GO:0030964', ('180', '189'))
5808	27216187	Although Met inhibits growth of glioblastoma cells and mammalian target of rapamycin (mTOR) pathway, the effects were found to be independent of AMPK.	('AMPK', 'Gene', '5562', (145, 149))	('glioblastoma', 'Phenotype', 'HP:0012174', (32, 44))	('AMPK', 'Gene', (145, 149))	('mTOR', 'Gene', '2475', (86, 90))	('AMPK', 'molecular_function', 'GO:0050405', ('145', '149'))	('Met', 'Var', (9, 12))	('mTOR', 'Gene', (86, 90))	('AMPK', 'molecular_function', 'GO:0004691', ('145', '149'))	('AMPK', 'molecular_function', 'GO:0047322', ('145', '149'))	('mammalian target of rapamycin', 'Gene', '2475', (55, 84))	('growth', 'CPA', (22, 28))	('mammalian target of rapamycin', 'Gene', (55, 84))	('glioblastoma', 'Disease', (32, 44))	('Met', 'Chemical', 'MESH:D008687', (9, 12))	('glioblastoma', 'Disease', 'MESH:D005909', (32, 44))	('inhibits', 'NegReg', (13, 21))
5811	27216187	Clearly, the antiproliferative mechanism of action of Met and Mito-Met may also be related to other mechanisms (i.e., activation of PRAS40/RAPTOR association).	('antiproliferative', 'CPA', (13, 30))	('Met', 'Chemical', 'MESH:D008687', (54, 57))	('activation', 'PosReg', (118, 128))	('PRAS40/RAPTOR', 'Protein', (132, 145))	('Met', 'Var', (54, 57))	('association', 'Interaction', (146, 157))	('Met', 'Chemical', 'MESH:D008687', (67, 70))	('Mito-Met', 'Gene', (62, 70))
5813	27216187	Mito-Met10, at concentrations 1,000-fold lower than Met, inhibited mitochondrial respiration, activated AMPK, and significantly decreased FOXM1 (Fig.	('AMPK', 'molecular_function', 'GO:0047322', ('104', '108'))	('respiration', 'biological_process', 'GO:0045333', ('81', '92'))	('Met', 'Chemical', 'MESH:D008687', (5, 8))	('inhibited', 'NegReg', (57, 66))	('Mito-Met10', 'Var', (0, 10))	('-Met10', 'Chemical', '-', (4, 10))	('decreased', 'NegReg', (128, 137))	('AMPK', 'molecular_function', 'GO:0004691', ('104', '108'))	('AMPK', 'molecular_function', 'GO:0050405', ('104', '108'))	('Met', 'Chemical', 'MESH:D008687', (52, 55))	('respiration', 'biological_process', 'GO:0007585', ('81', '92'))	('AMPK', 'Gene', (104, 108))	('FOXM1', 'Gene', (138, 143))	('mitochondrial respiration', 'MPA', (67, 92))	('activated', 'PosReg', (94, 103))	('AMPK', 'Gene', '5562', (104, 108))
5830	26242412	In addition, genetic alterations and dysfunctional signaling pathways in pancreatic tumor cells also lead to intrinsic drug resistance.	('intrinsic drug resistance', 'MPA', (109, 134))	('dysfunctional', 'Var', (37, 50))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('pancreatic tumor', 'Disease', 'MESH:D010190', (73, 89))	('drug resistance', 'biological_process', 'GO:0009315', ('119', '134'))	('drug resistance', 'biological_process', 'GO:0042493', ('119', '134'))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('pancreatic tumor', 'Disease', (73, 89))	('genetic alterations', 'Var', (13, 32))	('drug resistance', 'Phenotype', 'HP:0020174', (119, 134))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (73, 89))	('lead to', 'Reg', (101, 108))
5879	26242412	Since a high level of IGF1R was uniformly expressed in almost all pancreatic cancer cells and its level was further increased in chemoresistant tumor cells, targeting IGF1R has an advantage for efficient drug delivery into tumor cells by receptor-mediated endocytosis over drug delivery using uPAR targeting developed previously.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('drug delivery', 'MPA', (204, 217))	('uPAR', 'Gene', (293, 297))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (66, 83))	('IGF1R', 'Gene', (167, 172))	('uPAR', 'molecular_function', 'GO:0030377', ('293', '297'))	('receptor-mediated endocytosis', 'biological_process', 'GO:0006898', ('238', '267'))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', (223, 228))	('targeting', 'Var', (157, 166))	('uPAR', 'Gene', '5329', (293, 297))	('pancreatic cancer', 'Disease', 'MESH:D010190', (66, 83))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('high level of IGF1R', 'Phenotype', 'HP:0030269', (8, 27))	('IGF1R', 'Gene', (22, 27))	('pancreatic cancer', 'Disease', (66, 83))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
5885	26242412	Examination of the hydrodynamic size of IGF1-IONPs by dynamic light scattering (DLS) revealed that a polymer-coated IONP was 14.5 nm and conjugation of IGF1 increased its size to 17.2 nm (Figure 2d).	('conjugation', 'Var', (137, 148))	('IGF1 increased', 'Phenotype', 'HP:0030269', (152, 166))	('conjugation', 'biological_process', 'GO:0000746', ('137', '148'))	('IONP', 'Chemical', '-', (116, 120))	('IONP', 'Chemical', '-', (45, 49))	('increased', 'PosReg', (157, 166))	('polymer', 'Chemical', 'MESH:D011108', (101, 108))	('IGF1', 'Gene', (152, 156))
5890	26242412	There was only a slight change in zeta-potentials following IGF1 conjugation and Dox encapsulation.	('IGF1', 'Protein', (60, 64))	('zeta-potentials', 'MPA', (34, 49))	('Dox', 'Chemical', 'MESH:D004317', (81, 84))	('conjugation', 'Var', (65, 76))	('conjugation', 'biological_process', 'GO:0000746', ('65', '76'))
5900	26242412	Since the binding of the receptor-targeted nanoparticles to tumor cells will likely lead to receptor-mediated internalization of the nanoparticle-receptor complexes, we hypothesized that conjugation of a growth factor to nanoparticles will attenuate its cell growth promotion effect.	('attenuate', 'NegReg', (240, 249))	('lead to', 'Reg', (84, 91))	('cell growth promotion effect', 'CPA', (254, 282))	('binding', 'Interaction', (10, 17))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('receptor-mediated internalization', 'MPA', (92, 125))	('cell growth', 'biological_process', 'GO:0016049', ('254', '265'))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('conjugation', 'Var', (187, 198))	('conjugation', 'biological_process', 'GO:0000746', ('187', '198'))	('binding', 'molecular_function', 'GO:0005488', ('10', '17'))	('tumor', 'Disease', (60, 65))
5905	26242412	Cells were then incubated with IGF1-IONPs or BSA-IONPs for 4 h. Following washing and fixing cells, Prussian blue staining showed a high level of IONP-bound cells treated with IGF1-IONP but not with BSA-conjugated-IONP (Figure 3b).	('IONP', 'Chemical', '-', (214, 218))	('Prussian blue', 'Chemical', 'MESH:C000170', (100, 113))	('IONP-bound', 'MPA', (146, 156))	('IONP', 'Chemical', '-', (181, 185))	('IGF1-IONP', 'Var', (176, 185))	('IONP', 'Chemical', '-', (49, 53))	('IONP', 'Chemical', '-', (146, 150))	('IONP', 'Chemical', '-', (36, 40))
5912	26242412	Results of the cell proliferation assay showed a Dox dose-dependent cytotoxicity in tumor cells treated with conventional Dox, IONP-Dox, and IGF1-IONP-Dox (Figure 3e).	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('IONP-Dox', 'Chemical', '-', (146, 154))	('cytotoxicity', 'Disease', (68, 80))	('Dox', 'Chemical', 'MESH:D004317', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cell proliferation', 'biological_process', 'GO:0008283', ('15', '33'))	('tumor', 'Disease', (84, 89))	('IONP-Dox', 'Var', (127, 135))	('IONP-Dox', 'Chemical', '-', (127, 135))	('IGF1-IONP-Dox', 'Var', (141, 154))	('cytotoxicity', 'Disease', 'MESH:D064420', (68, 80))	('Dox', 'Chemical', 'MESH:D004317', (122, 125))	('Dox', 'Chemical', 'MESH:D004317', (151, 154))	('Dox', 'Chemical', 'MESH:D004317', (49, 52))
5913	26242412	In vitro results indicated that Dox and IGF1-IONP-Dox had a comparable cytotoxic effect.	('IGF1-IONP-Dox', 'Var', (40, 53))	('Dox', 'Chemical', 'MESH:D004317', (32, 35))	('Dox', 'Chemical', 'MESH:D004317', (50, 53))	('IONP-Dox', 'Chemical', '-', (45, 53))	('cytotoxic effect', 'CPA', (71, 87))
5916	26242412	Therefore, similar cytotoxic effects were seen in cancer cells treated with Dox and IGF1-IONP-Dox.	('IGF1-IONP-Dox', 'Var', (84, 97))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('Dox', 'Chemical', 'MESH:D004317', (94, 97))	('Dox', 'Chemical', 'MESH:D004317', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('IONP-Dox', 'Chemical', '-', (89, 97))
5919	26242412	As a representative example shown in Figure 4a, the mean signal intensities of the tumor area in the mice that received IGF1-IONPs were 996 (left side image of the mouse) and 1301 (mouse front image), compared to 319 (left side image) and 371 (front image) in the mouse that received BSA-IONPs.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('IONP', 'Chemical', '-', (288, 292))	('mouse', 'Species', '10090', (264, 269))	('mouse', 'Species', '10090', (164, 169))	('tumor', 'Disease', (83, 88))	('mice', 'Species', '10090', (101, 105))	('IGF1-IONPs', 'Var', (120, 130))	('IONP', 'Chemical', '-', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('mouse', 'Species', '10090', (181, 186))
5920	26242412	Representative ex vivo images of tumors and normal organs showed the presence of high levels of optical signal in tumors injected with IGF1-IONPs (mean signal intensity: 898) but not BSA-IONPs (mean signal intensity: 398) (Figure 4b).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('IGF1-IONPs', 'Var', (135, 145))	('IONP', 'Chemical', '-', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('IONP', 'Chemical', '-', (187, 191))	('tumors', 'Disease', (33, 39))	('optical signal', 'MPA', (96, 110))
5932	26242412	Orthotopic pancreatic PDX tumors obtained from the mice that received IGF1-IONPs had a 4.2-fold higher iron concentration than that of the tumor treated with BSA-IONPs.	('IGF1-IONPs', 'Var', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('IONP', 'Chemical', '-', (162, 166))	('mice', 'Species', '10090', (51, 55))	('iron', 'Chemical', 'MESH:D007501', (103, 107))	('iron concentration', 'MPA', (103, 121))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('IONP', 'Chemical', '-', (75, 79))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('higher', 'PosReg', (96, 102))	('pancreatic PDX tumors', 'Disease', (11, 32))	('pancreatic PDX tumors', 'Disease', 'MESH:D010190', (11, 32))
5934	26242412	Since we consistently observed a low level of optical signals in the liver and spleen in mouse whole body and ex vivo optical imaging, it is likely that uptake of IONPs conjugated with NIR830 dye labeled IGF1 into macrophages led to degradation of NIR830-IGF1 on IONPs.	('degradation', 'biological_process', 'GO:0009056', ('233', '244'))	('uptake', 'biological_process', 'GO:0098657', ('153', '159'))	('IONP', 'Chemical', '-', (163, 167))	('uptake', 'biological_process', 'GO:0098739', ('153', '159'))	('IONP', 'Chemical', '-', (263, 267))	('NIR830-IGF1', 'Var', (248, 259))	('degradation', 'MPA', (233, 244))	('mouse', 'Species', '10090', (89, 94))	('IGF1', 'Gene', (204, 208))
5939	26242412	However, a significant MRI signal decrease was found in the tumor 24 h after administration of IGF1-IONPs, indicating the accumulation of IONPs in the tumor.	('accumulation', 'PosReg', (122, 134))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('IONPs', 'MPA', (138, 143))	('tumor', 'Disease', (151, 156))	('decrease', 'NegReg', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('IONP', 'Chemical', '-', (100, 104))	('IGF1-IONPs', 'Var', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('IONP', 'Chemical', '-', (138, 142))	('tumor', 'Disease', (60, 65))	('MRI signal', 'MPA', (23, 33))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
5940	26242412	There was a 37.3% MRI signal decrease in the tumor of the mice that received IGF-1-IONPs (Figure 4c).	('IGF-1-IONPs', 'Var', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('MRI signal', 'MPA', (18, 28))	('tumor', 'Disease', (45, 50))	('mice', 'Species', '10090', (58, 62))	('IONP', 'Chemical', '-', (83, 87))	('decrease', 'NegReg', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
5946	26242412	When comparing T2-weighted MR images of the mice treated with IGF1-IONP-Dox or nontargeted IONP-Dox, a remarkable signal decrease was detected in the tumor area of the mouse that received IGF1-IONP-Dox but not the one that received nontargeted IONP-Dox, suggesting selective accumulation of IGF1R-targeted IONP-Dox in the orthotopic pancreatic PDX tumor (Figure 5a).	('IGF1-IONP-Dox', 'Var', (188, 201))	('IONP-Dox', 'Chemical', '-', (306, 314))	('IONP-Dox', 'Chemical', '-', (193, 201))	('mouse', 'Species', '10090', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('accumulation', 'PosReg', (275, 287))	('IONP-Dox', 'Chemical', '-', (91, 99))	('IONP-Dox', 'Chemical', '-', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('pancreatic PDX tumor', 'Disease', 'MESH:D010190', (333, 353))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('mice', 'Species', '10090', (44, 48))	('decrease', 'NegReg', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (348, 353))	('pancreatic PDX tumor', 'Disease', (333, 353))	('IONP-Dox', 'Chemical', '-', (244, 252))	('tumor', 'Disease', (150, 155))
5947	26242412	Additionally, the mice receiving IGF1-IONP-Dox also showed a significant reduction in tumor size compared with tumors in the mice receiving Dox, nontargeted IONP-Dox, or no-treatment control (Figure 5a).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('Dox', 'Chemical', 'MESH:D004317', (162, 165))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('IONP-Dox', 'Chemical', '-', (38, 46))	('mice', 'Species', '10090', (18, 22))	('tumors', 'Disease', (111, 117))	('mice', 'Species', '10090', (125, 129))	('tumor', 'Disease', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('IONP-Dox', 'Chemical', '-', (157, 165))	('Dox', 'Chemical', 'MESH:D004317', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('reduction', 'NegReg', (73, 82))	('Dox', 'Chemical', 'MESH:D004317', (140, 143))	('IGF1-IONP-Dox', 'Var', (33, 46))
5954	26242412	In contrast, PDX tumors collected from the mice that were treated with IGF1-IONP-Dox were significantly smaller than those from the control groups of no treatment or the Dox- or IONP-Dox-treated group.	('mice', 'Species', '10090', (43, 47))	('PDX tumors', 'Disease', (13, 23))	('IGF1-IONP-Dox', 'Var', (71, 84))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('Dox', 'Chemical', 'MESH:D004317', (183, 186))	('IONP-Dox', 'Chemical', '-', (76, 84))	('smaller', 'NegReg', (104, 111))	('Dox', 'Chemical', 'MESH:D004317', (81, 84))	('Dox', 'Chemical', 'MESH:D004317', (170, 173))	('IONP-Dox', 'Chemical', '-', (178, 186))	('PDX tumors', 'Disease', 'MESH:D009369', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
5960	26242412	In contrast, there was no systemic toxicity observed in the mice that received 15 mg/kg of Dox equivalent doses of IGF1-IONP-Dox (Figure S8).	('toxicity', 'Disease', 'MESH:D064420', (35, 43))	('Dox', 'Chemical', 'MESH:D004317', (125, 128))	('toxicity', 'Disease', (35, 43))	('Dox', 'Chemical', 'MESH:D004317', (91, 94))	('IONP-Dox', 'Chemical', '-', (120, 128))	('mice', 'Species', '10090', (60, 64))	('IGF1-IONP-Dox', 'Var', (115, 128))
5965	26242412	After IGF1-IONP-Dox treatment, tumor cell density was further decreased with tumor cells forming large ductal-like structures that were surrounded by extensive stroma with central necrosis (Figure 6a).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('decreased', 'NegReg', (62, 71))	('necrosis', 'Disease', (180, 188))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('IGF1-IONP-Dox', 'Var', (6, 19))	('necrosis', 'biological_process', 'GO:0070265', ('180', '188'))	('necrosis', 'biological_process', 'GO:0008219', ('180', '188'))	('necrosis', 'biological_process', 'GO:0001906', ('180', '188'))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('necrosis', 'biological_process', 'GO:0019835', ('180', '188'))	('necrosis', 'biological_process', 'GO:0008220', ('180', '188'))	('necrosis', 'Disease', 'MESH:D009336', (180, 188))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('IONP-Dox', 'Chemical', '-', (11, 19))
5969	26242412	A marked decrease in the number of Ki-67 positive proliferating cells was observed in the tumor treated with IGF1-IONP-Dox compared with the tumor without treatment.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('Ki-67', 'Protein', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('IGF1-IONP-Dox', 'Var', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('decrease', 'NegReg', (9, 17))	('IONP-Dox', 'Chemical', '-', (114, 122))
5971	26242412	These results suggested that targeted therapy using IGF1-IONP-Dox had a stronger inhibitory effect on tumor cell proliferation compared with unconjugated Dox or nontargeted IONP-Dox (Figure 7a and b).	('inhibitory effect', 'NegReg', (81, 98))	('IONP-Dox', 'Chemical', '-', (173, 181))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('IONP-Dox', 'Chemical', '-', (57, 65))	('cell proliferation', 'biological_process', 'GO:0008283', ('108', '126'))	('IGF1-IONP-Dox', 'Var', (52, 65))	('Dox', 'Chemical', 'MESH:D004317', (154, 157))	('Dox', 'Chemical', 'MESH:D004317', (178, 181))	('tumor', 'Disease', (102, 107))	('Dox', 'Chemical', 'MESH:D004317', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
5972	26242412	Additionally, results from the TUNEL assay indicated that IGF1-IONP-Dox treatment induced 2-fold higher numbers of apoptotic cell death compared with no treatment or unconjugated Dox-treated controls (Figure 7a and c).	('apoptotic cell death', 'CPA', (115, 135))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('115', '135'))	('higher', 'PosReg', (97, 103))	('IGF1-IONP-Dox', 'Var', (58, 71))	('IONP-Dox', 'Chemical', '-', (63, 71))	('Dox', 'Chemical', 'MESH:D004317', (68, 71))	('Dox', 'Chemical', 'MESH:D004317', (179, 182))
5974	26242412	We found that the number of active caspase-3-positive cells in IGF1-IONP-Dox-treated tumor tissues was 6.1- to 8.5-fold higher than that in control no-treatment or Dox-treated tumors (Figure 7a and d).	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('active', 'MPA', (28, 34))	('Dox', 'Chemical', 'MESH:D004317', (73, 76))	('higher', 'PosReg', (120, 126))	('tumor', 'Disease', (176, 181))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('IGF1-IONP-Dox-treated', 'Var', (63, 84))	('IONP-Dox', 'Chemical', '-', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Dox', 'Chemical', 'MESH:D004317', (164, 167))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
5978	26242412	Although nonspecific uptake of IGF1-IONP-Dox was detected in the spleen (Figure S6), active caspase 3 was not found in the spleen tissues, suggesting that nonproliferating macrophages may have a low sensitivity to DNA-damaging drugs.	('IONP-Dox', 'Chemical', '-', (36, 44))	('uptake', 'biological_process', 'GO:0098739', ('21', '27'))	('caspase 3', 'Gene', (92, 101))	('uptake', 'biological_process', 'GO:0098657', ('21', '27'))	('IGF1-IONP-Dox', 'Var', (31, 44))	('caspase 3', 'Gene', '836', (92, 101))	('DNA', 'cellular_component', 'GO:0005574', ('214', '217'))
6011	26242412	Recombinant human IGF-1 was expressed in an E. coli strain as a 8.1 kDa precursor protein (pro-IGF1) containing the N-terminal-fused pentapeptide Met(M)-Lys(K)-Lys(K)-Ile (I)-Met (M) as a leader sequence that facilitates the expression and folding of the protein.	('folding', 'MPA', (240, 247))	('facilitates', 'PosReg', (209, 220))	('Met', 'Var', (146, 149))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('E. coli', 'Species', '562', (44, 51))	('human', 'Species', '9606', (12, 17))	('protein', 'cellular_component', 'GO:0003675', ('255', '262'))	('IGF-1', 'Gene', (18, 23))	('expression', 'MPA', (225, 235))
6054	26242412	Nude mice bearing orthotopic pancreatic PDX tumors derived from patient #1 tumor were randomized into four experimental groups with six mice in each group, including no-treatment control, unconjugated Dox, IONP-Dox, and IGF1-IONP-Dox.	('IONP-Dox', 'Chemical', '-', (225, 233))	('IGF1-IONP-Dox', 'Var', (220, 233))	('mice', 'Species', '10090', (5, 9))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', (75, 80))	('patient', 'Species', '9606', (64, 71))	('Dox', 'Chemical', 'MESH:D004317', (211, 214))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('IONP-Dox', 'Chemical', '-', (206, 214))	('orthotopic pancreatic PDX tumors', 'Disease', (18, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('Dox', 'Chemical', 'MESH:D004317', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('IONP-Dox', 'Var', (206, 214))	('orthotopic pancreatic PDX tumors', 'Disease', 'MESH:D010190', (18, 50))	('mice', 'Species', '10090', (136, 140))	('Nude mice', 'Species', '10090', (0, 9))	('Dox', 'Chemical', 'MESH:D004317', (230, 233))
6079	25918719	Subsequently, the autophosphorylation of FAK on Tyr397 creates a high-affinity binding site for Src homology 2 (SH2) domain-containing proteins, such as Src family kinases, phosphoinositide 3-kinase, phospholipase C, and growth factor receptor-bound protein 7 (Grb7), thereby relying the upstream signal on versatile downstream signaling pathways.	('Tyr397', 'Chemical', '-', (48, 54))	('Src', 'Gene', (153, 156))	('Src', 'Gene', '6714', (153, 156))	('signaling', 'biological_process', 'GO:0023052', ('328', '337'))	('growth factor receptor-bound protein 7', 'Gene', (221, 259))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('binding', 'Interaction', (79, 86))	('FAK', 'molecular_function', 'GO:0004717', ('41', '44'))	('Src', 'Gene', (96, 99))	('Src', 'Gene', '6714', (96, 99))	('protein', 'cellular_component', 'GO:0003675', ('250', '257'))	('Grb7', 'Gene', (261, 265))	('growth factor receptor-bound protein 7', 'Gene', '2886', (221, 259))	('Grb7', 'Gene', '2886', (261, 265))	('Tyr397', 'Var', (48, 54))
6080	25918719	Moreover, the binding of Src family kinases onto the phospho-Tyr397 of FAK contributes to the promotion of FAK kinase activity and signaling as a result of additional tyrosine phosphorylations on several tyrosine sites, including Tyr407, Tyr576, Tyr577, and Tyr925 of FAK.	('Tyr576', 'Chemical', '-', (238, 244))	('binding', 'Interaction', (14, 21))	('Src', 'Gene', '6714', (25, 28))	('FAK', 'molecular_function', 'GO:0004717', ('268', '271'))	('Tyr925', 'Var', (258, 264))	('Tyr577', 'Var', (246, 252))	('kinase activity', 'molecular_function', 'GO:0016301', ('111', '126'))	('activity', 'MPA', (118, 126))	('tyrosine', 'Chemical', 'MESH:D014443', (204, 212))	('Tyr407', 'Var', (230, 236))	('Tyr576', 'Var', (238, 244))	('FAK', 'Gene', (71, 74))	('Tyr577', 'Chemical', '-', (246, 252))	('promotion', 'PosReg', (94, 103))	('additional', 'PosReg', (156, 166))	('tyrosine', 'Chemical', 'MESH:D014443', (167, 175))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('FAK', 'molecular_function', 'GO:0004717', ('71', '74'))	('tyrosine phosphorylations', 'MPA', (167, 192))	('binding', 'molecular_function', 'GO:0005488', ('14', '21'))	('Src', 'Gene', (25, 28))	('Tyr925', 'Chemical', '-', (258, 264))	('signaling', 'MPA', (131, 140))	('Tyr397', 'Chemical', '-', (61, 67))	('FAK', 'molecular_function', 'GO:0004717', ('107', '110'))	('Tyr407', 'Chemical', '-', (230, 236))	('FAK kinase', 'Enzyme', (107, 117))
6081	25918719	In fact, the phosphorylation of FAK on Tyr576 and Tyr577 by Src leads to a steric effect on preventing an intramolecular interaction between the aminoterminal FERM domain and the kinase domain within FAK.	('FAK', 'molecular_function', 'GO:0004717', ('32', '35'))	('Src', 'Gene', '6714', (60, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('phosphorylation', 'MPA', (13, 28))	('Src', 'Gene', (60, 63))	('Tyr577', 'Chemical', '-', (50, 56))	('Tyr576', 'Chemical', '-', (39, 45))	('preventing', 'NegReg', (92, 102))	('FAK', 'molecular_function', 'GO:0004717', ('200', '203'))	('Tyr577', 'Var', (50, 56))	('Tyr576', 'Var', (39, 45))	('intramolecular interaction', 'MPA', (106, 132))
6082	25918719	On the other hand, phospho-Tyr925 of FAK provides a docking site for growth factor receptor-bound protein 2 (Grb2), leading to activation of a RAS-MEK/ERK cascade.	('Grb2', 'Gene', '2885', (109, 113))	('FAK', 'Gene', (37, 40))	('MEK', 'Gene', (147, 150))	('growth factor receptor-bound protein 2', 'Gene', '2885', (69, 107))	('MEK', 'Gene', '5609', (147, 150))	('phospho-Tyr925', 'Var', (19, 33))	('ERK cascade', 'biological_process', 'GO:0070371', ('151', '162'))	('growth factor receptor-bound protein 2', 'Gene', (69, 107))	('Tyr925', 'Chemical', '-', (27, 33))	('ERK', 'Gene', '5594', (151, 154))	('ERK', 'molecular_function', 'GO:0004707', ('151', '154'))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('activation', 'PosReg', (127, 137))	('Grb2', 'Gene', (109, 113))	('ERK', 'Gene', (151, 154))	('FAK', 'molecular_function', 'GO:0004717', ('37', '40'))
6094	25918719	In addition, several other upstream signals also contribute to FAK-mediated anoikis resistance in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('FAK', 'molecular_function', 'GO:0004717', ('63', '66'))	('FAK-mediated', 'Var', (63, 75))	('cancer', 'Disease', (98, 104))	('contribute', 'Reg', (49, 59))	('anoikis', 'biological_process', 'GO:0043276', ('76', '83'))
6095	25918719	For example, transforming growth factor-beta (TGF-beta) induces the activation of FAK and AKT via SMAD3 and p38 MAPK, respectively, which, in turn, results in anoikis resistance and tumor promotion.	('FAK', 'Pathway', (82, 85))	('results in', 'Reg', (148, 158))	('activation', 'PosReg', (68, 78))	('anoikis', 'biological_process', 'GO:0043276', ('159', '166'))	('p38', 'Var', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('SMAD3', 'Gene', (98, 103))	('transforming growth factor-beta', 'Gene', '7040', (13, 44))	('anoikis resistance', 'CPA', (159, 177))	('TGF-beta', 'Gene', '7040', (46, 54))	('transforming growth factor-beta', 'molecular_function', 'GO:0005160', ('13', '44'))	('AKT', 'Gene', (90, 93))	('FAK', 'molecular_function', 'GO:0004717', ('82', '85'))	('transforming growth factor-beta', 'Gene', (13, 44))	('tumor', 'Disease', (182, 187))	('TGF-beta', 'Gene', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('SMAD3', 'Gene', '4088', (98, 103))	('AKT', 'Gene', '207', (90, 93))	('MAPK', 'molecular_function', 'GO:0004707', ('112', '116'))
6097	25918719	As expected, disruption of the organized fibronectin structure enables anoikis of SCC, presumably losing FAK phosphorylation and ERK activation.	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('ERK', 'molecular_function', 'GO:0004707', ('129', '132'))	('fibronectin', 'Gene', (41, 52))	('SCC', 'Gene', '6317', (82, 85))	('FAK', 'molecular_function', 'GO:0004717', ('105', '108'))	('disruption', 'Var', (13, 23))	('ERK', 'Gene', '5594', (129, 132))	('losing', 'NegReg', (98, 104))	('FAK phosphorylation', 'MPA', (105, 124))	('fibronectin', 'Gene', '2335', (41, 52))	('anoikis', 'biological_process', 'GO:0043276', ('71', '78'))	('ERK', 'Gene', (129, 132))	('SCC', 'Gene', (82, 85))	('phosphorylation', 'biological_process', 'GO:0016310', ('109', '124'))
6098	25918719	Moreover, overexpression of FAK has been shown to block the caspase-3-mediated apoptosis; conversely, inhibition of FAK leads to apoptosis in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('leads to', 'Reg', (120, 128))	('FAK', 'molecular_function', 'GO:0004717', ('28', '31'))	('FAK', 'molecular_function', 'GO:0004717', ('116', '119'))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('apoptosis', 'CPA', (129, 138))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('inhibition', 'Var', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('FAK', 'Gene', (116, 119))	('caspase-3', 'Gene', (60, 69))	('block', 'NegReg', (50, 55))	('caspase-3', 'Gene', '836', (60, 69))	('cancer', 'Disease', (142, 148))
6099	25918719	Hence, knockdown of FAK expression by RNA interference promotes anoikis and further inhibits pancreatic cancer metastasis in vivo.	('RNA interference', 'biological_process', 'GO:0016246', ('38', '54'))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('pancreatic cancer metastasis', 'Disease', (93, 121))	('pancreatic cancer metastasis', 'Disease', 'MESH:D009362', (93, 121))	('RNA', 'cellular_component', 'GO:0005562', ('38', '41'))	('promotes', 'PosReg', (55, 63))	('FAK', 'Gene', (20, 23))	('RNA interference', 'MPA', (38, 54))	('anoikis', 'biological_process', 'GO:0043276', ('64', '71'))	('FAK', 'molecular_function', 'GO:0004717', ('20', '23'))	('inhibits', 'NegReg', (84, 92))	('anoikis', 'CPA', (64, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (93, 110))	('knockdown', 'Var', (7, 16))
6103	25918719	Moreover, FAK also reportedly binds to the death domain kinase receptor-interacting protein (RIP), a component of death receptor complex in the programmed cell death, by which FAK is capable of suppressing apoptosis by blocking the function of death domain of RIP.	('blocking', 'NegReg', (219, 227))	('death domain', 'MPA', (244, 256))	('FAK', 'molecular_function', 'GO:0004717', ('10', '13'))	('apoptosis', 'CPA', (206, 215))	('function', 'MPA', (232, 240))	('receptor-interacting protein', 'Gene', (63, 91))	('RIP', 'Gene', '8737', (260, 263))	('programmed cell death', 'biological_process', 'GO:0012501', ('144', '165'))	('FAK', 'molecular_function', 'GO:0004717', ('176', '179'))	('RIP', 'Gene', '8737', (93, 96))	('suppressing', 'NegReg', (194, 205))	('receptor complex', 'cellular_component', 'GO:0043235', ('120', '136'))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('RIP', 'Gene', (260, 263))	('FAK', 'Var', (176, 179))	('apoptosis', 'biological_process', 'GO:0097194', ('206', '215'))	('apoptosis', 'biological_process', 'GO:0006915', ('206', '215'))	('RIP', 'Gene', (93, 96))	('receptor-interacting protein', 'Gene', '8737', (63, 91))
6109	25918719	Consistently, the promotion of cell cycle progression by FAK is mediated by enhanced expression of cyclin D1 and cyclin E in concert with reduced expression of CDK inhibitors p27Kip1 and p21Waf1.	('reduced', 'NegReg', (138, 145))	('cell cycle progression', 'CPA', (31, 53))	('promotion', 'PosReg', (18, 27))	('cyclin', 'molecular_function', 'GO:0016538', ('99', '105'))	('p27Kip1', 'Gene', (175, 182))	('cyclin D1', 'Gene', '595', (99, 108))	('FAK', 'molecular_function', 'GO:0004717', ('57', '60'))	('cyclin', 'molecular_function', 'GO:0016538', ('113', '119'))	('expression', 'MPA', (146, 156))	('p27Kip1', 'Gene', '1027', (175, 182))	('p21', 'Gene', (187, 190))	('CDK', 'molecular_function', 'GO:0004693', ('160', '163'))	('p21', 'Gene', '644914', (187, 190))	('cyclin', 'Protein', (113, 119))	('FAK', 'Var', (57, 60))	('expression', 'MPA', (85, 95))	('cell cycle', 'biological_process', 'GO:0007049', ('31', '41'))	('enhanced', 'PosReg', (76, 84))	('cyclin D1', 'Gene', (99, 108))
6119	25918719	Through the FAK/Src complex formation and kinase activity, cell migration is profoundly affected by the subsequent phosphorylated p130Cas in promoting the formation of Cas/Crk complex, myosin light-chain kinase- (MLCK-) mediated focal adhesion disassembly, c-Jun N-terminal kinase- (JNK-) mediated phosphorylation of paxillin in facilitating cytoskeleton reorganization, interactions with PI3-kinase and/or Grb7 in governing intracellular signaling related to cell motility, and so on.	('c-Jun N-terminal kinase- (JNK-)', 'Gene', '5599', (257, 288))	('signaling', 'biological_process', 'GO:0023052', ('439', '448'))	('JNK', 'molecular_function', 'GO:0004705', ('283', '286'))	('Grb7', 'Gene', '2886', (407, 411))	('promoting', 'PosReg', (141, 150))	('p130Cas', 'Gene', (130, 137))	('phosphorylated', 'Var', (115, 129))	('FAK', 'molecular_function', 'GO:0004717', ('12', '15'))	('Cas', 'cellular_component', 'GO:0005650', ('134', '137'))	('Cas', 'Gene', (168, 171))	('Src', 'Gene', '6714', (16, 19))	('Cas', 'Gene', '9564', (168, 171))	('paxillin', 'Gene', '5829', (317, 325))	('cell migration', 'CPA', (59, 73))	('Crk', 'Gene', '1398', (172, 175))	('intracellular', 'cellular_component', 'GO:0005622', ('425', '438'))	('p130Cas', 'Gene', '9564', (130, 137))	('MLCK', 'molecular_function', 'GO:0004687', ('213', '217'))	('Grb7', 'Gene', (407, 411))	('governing intracellular signaling', 'MPA', (415, 448))	('myosin light-chain kinase-', 'Gene', '4638', (185, 211))	('paxillin', 'Gene', (317, 325))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('342', '354'))	('Cas', 'cellular_component', 'GO:0005650', ('168', '171'))	('MLCK', 'Gene', (213, 217))	('formation', 'biological_process', 'GO:0009058', ('28', '37'))	('focal adhesion disassembly', 'biological_process', 'GO:0120181', ('229', '255'))	('Cas', 'Gene', (134, 137))	('cell migration', 'biological_process', 'GO:0016477', ('59', '73'))	('kinase activity', 'molecular_function', 'GO:0016301', ('42', '57'))	('cell motility', 'biological_process', 'GO:0048870', ('460', '473'))	('Crk', 'Gene', (172, 175))	('interactions', 'Interaction', (371, 383))	('c-Jun N-terminal kinase- (JNK-', 'Gene', (257, 287))	('Cas', 'Gene', '9564', (134, 137))	('MLCK', 'Gene', '4638', (213, 217))	('focal adhesion', 'cellular_component', 'GO:0005925', ('229', '243'))	('formation', 'biological_process', 'GO:0009058', ('155', '164'))	('phosphorylation', 'biological_process', 'GO:0016310', ('298', '313'))	('myosin light-chain kinase', 'molecular_function', 'GO:0004687', ('185', '210'))	('cytoskeleton reorganization', 'CPA', (342, 369))	('Src', 'Gene', (16, 19))	('myosin light-chain kinase-', 'Gene', (185, 211))
6133	25918719	Reportedly, the phosphorylation of FAK at Tyr407 and Tyr861 by the FAK/Src complex drives the interruption of E-cadherin-mediated epithelial adherent junctions.	('FAK', 'molecular_function', 'GO:0004717', ('35', '38'))	('Tyr861', 'Chemical', '-', (53, 59))	('FAK', 'molecular_function', 'GO:0004717', ('67', '70'))	('phosphorylation', 'biological_process', 'GO:0016310', ('16', '31'))	('cadherin', 'molecular_function', 'GO:0008014', ('112', '120'))	('interruption', 'NegReg', (94, 106))	('Tyr861', 'Var', (53, 59))	('Src', 'Gene', (71, 74))	('Tyr407', 'Chemical', '-', (42, 48))	('Src', 'Gene', '6714', (71, 74))	('E-cadherin', 'Gene', (110, 120))	('E-cadherin', 'Gene', '999', (110, 120))
6140	25918719	Accordingly, suppression of FAK expression and signaling by RNA interference (RNAi) or dominant-negative mutants of FAK (i.e., FAK-related nonkinase, FRNK) generally enables inhibiting FAK-triggered cancer metastasis.	('FAK', 'molecular_function', 'GO:0004717', ('116', '119'))	('FAK', 'Gene', (116, 119))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('FAK', 'molecular_function', 'GO:0004717', ('185', '188'))	('FRNK', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('FAK', 'molecular_function', 'GO:0004717', ('28', '31'))	('RNA interference', 'biological_process', 'GO:0016246', ('60', '76'))	('RNA', 'MPA', (60, 63))	('mutants', 'Var', (105, 112))	('RNAi', 'biological_process', 'GO:0016246', ('78', '82'))	('expression', 'MPA', (32, 42))	('suppression', 'NegReg', (13, 24))	('signaling', 'MPA', (47, 56))	('cancer metastasis', 'Disease', (199, 216))	('FAK', 'Protein', (28, 31))	('inhibiting', 'NegReg', (174, 184))	('RNA', 'cellular_component', 'GO:0005562', ('60', '63'))	('cancer metastasis', 'Disease', 'MESH:D009362', (199, 216))	('FRNK', 'Gene', '5747', (150, 154))	('FAK', 'molecular_function', 'GO:0004717', ('127', '130'))
6144	25918719	Additionally, although a synergistic effect of FAK and epidermal growth factor receptor (EGFR) is highlighted for their cooperation in the promotion of non-small cell lung cancer metastasis, knockdown of FAK and EGFR expression using short hairpin RNA (shRNA) significantly inhibits cancer metastasis.	('FAK', 'molecular_function', 'GO:0004717', ('204', '207'))	('FAK', 'Gene', (204, 207))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (156, 178))	('epidermal growth factor receptor', 'Gene', (55, 87))	('epidermal growth factor receptor', 'Gene', '1956', (55, 87))	('EGFR', 'Gene', '1956', (212, 216))	('cancer metastasis', 'Disease', 'MESH:D009362', (283, 300))	('cancer metastasis', 'Disease', 'MESH:D009362', (172, 189))	('inhibits', 'NegReg', (274, 282))	('EGFR', 'Gene', (89, 93))	('EGFR', 'molecular_function', 'GO:0005006', ('212', '216'))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('non-small cell lung cancer metastasis', 'Disease', 'MESH:D002289', (152, 189))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('FAK', 'molecular_function', 'GO:0004717', ('47', '50'))	('EGFR', 'Gene', (212, 216))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('55', '78'))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('RNA', 'cellular_component', 'GO:0005562', ('248', '251'))	('knockdown', 'Var', (191, 200))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (152, 178))	('cancer metastasis', 'Disease', (283, 300))	('EGFR', 'Gene', '1956', (89, 93))	('non-small cell lung cancer metastasis', 'Disease', (152, 189))
6149	25918719	Recently, deletion of FAK in mammary epithelial cells (MaECs) has been reported to affect breast cancer development, that is, suppression of mammary tumor formation and progression, in the mammary tumor mouse MMTV-PyMV model.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('MMTV', 'Species', '11757', (209, 213))	('suppression', 'NegReg', (126, 137))	('affect', 'Reg', (83, 89))	('mouse', 'Species', '10090', (203, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('FAK', 'Gene', (22, 25))	('formation', 'biological_process', 'GO:0009058', ('155', '164'))	('FAK', 'molecular_function', 'GO:0004717', ('22', '25'))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('breast cancer', 'Disease', (90, 103))	('tumor', 'Disease', (149, 154))	('deletion', 'Var', (10, 18))	('progression', 'CPA', (169, 180))	('tumor', 'Disease', (197, 202))
6150	25918719	In that study, impairment of the cancer stem cell maintenance in FAK ablated MaECs has been taken into account for the decreased tumorigenicity and metastasis of mammary tumors.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('decreased', 'NegReg', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('FAK', 'molecular_function', 'GO:0004717', ('65', '68'))	('FAK', 'Var', (65, 68))	('metastasis', 'CPA', (148, 158))	('impairment of the cancer', 'Disease', 'MESH:D009422', (15, 39))	('tumor', 'Disease', (170, 175))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('impairment of the cancer', 'Disease', (15, 39))	('tumor', 'Disease', (129, 134))	('tumors', 'Disease', (170, 176))
6151	25918719	Indeed, loss of FAK leads to less activation of the PI3K-AKT signaling and, therefore, impedes MaCSC self-renewal and tumorigenicity although a compensatory activity by Pyk2, a nonreceptor tyrosine kinase of the FAK family, might appear.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tyrosine kinase', 'Gene', (189, 204))	('loss', 'Var', (8, 12))	('activation', 'PosReg', (34, 44))	('tyrosine kinase', 'Gene', '7294', (189, 204))	('MaCSC self-renewal', 'CPA', (95, 113))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('AKT', 'Gene', '207', (57, 60))	('AKT signaling', 'biological_process', 'GO:0043491', ('57', '70'))	('FAK', 'molecular_function', 'GO:0004717', ('16', '19'))	('FAK', 'Gene', (16, 19))	('PI3K', 'molecular_function', 'GO:0016303', ('52', '56'))	('impedes', 'NegReg', (87, 94))	('FAK', 'molecular_function', 'GO:0004717', ('212', '215'))	('Pyk2', 'Gene', (169, 173))	('AKT', 'Gene', (57, 60))	('less', 'NegReg', (29, 33))	('tumor', 'Disease', (118, 123))	('Pyk2', 'Gene', '2185', (169, 173))
6161	25918719	As mentioned above, in light of tumor microenvironmental cues, activation of FAK is capable of driving the integrin- and growth factor receptor-mediated signaling inside of a cell to ignite tyrosine phosphorylation cascades and reorganize cytoskeleton of tumor cells.	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('tyrosine phosphorylation cascades', 'MPA', (190, 223))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('driving', 'PosReg', (95, 102))	('FAK', 'Gene', (77, 80))	('ignite', 'Reg', (183, 189))	('activation', 'Var', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tyrosine', 'Chemical', 'MESH:D014443', (190, 198))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('FAK', 'molecular_function', 'GO:0004717', ('77', '80'))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('239', '251'))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Disease', (32, 37))	('phosphorylation', 'biological_process', 'GO:0016310', ('199', '214'))
6168	25918719	In response to the increment of tumor matrix-stiffness, activation of FAK is also correlated with the clustering of beta1 integrin encountering with the stiffen matrices and then elicits PI3K/AKT signaling.	('AKT', 'Gene', (192, 195))	('elicits', 'Reg', (179, 186))	('FAK', 'Enzyme', (70, 73))	('FAK', 'molecular_function', 'GO:0004717', ('70', '73'))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('AKT', 'Gene', '207', (192, 195))	('PI3K', 'molecular_function', 'GO:0016303', ('187', '191'))	('beta1 integrin', 'Gene', '3688', (116, 130))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('AKT signaling', 'biological_process', 'GO:0043491', ('192', '205'))	('tumor', 'Disease', (32, 37))	('activation', 'PosReg', (56, 66))	('clustering', 'Var', (102, 112))	('beta1 integrin', 'Gene', (116, 130))
6178	25918719	Moreover, FAK-deleted endothelial cells reduce tumor angiogenesis, which is caused by reduction of VEGF-mediated AKT phosphorylation.	('reduction', 'NegReg', (86, 95))	('FAK-deleted', 'Var', (10, 21))	('VEGF', 'Gene', '7422', (99, 103))	('reduce', 'NegReg', (40, 46))	('FAK', 'molecular_function', 'GO:0004717', ('10', '13'))	('AKT', 'Gene', '207', (113, 116))	('angiogenesis', 'biological_process', 'GO:0001525', ('53', '65'))	('phosphorylation', 'biological_process', 'GO:0016310', ('117', '132'))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('AKT', 'Gene', (113, 116))	('VEGF', 'Gene', (99, 103))	('tumor', 'Disease', (47, 52))
6184	25918719	Importantly, inhibition of FAK signaling reduces the infiltration of macrophages into tumor tissues.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('reduces', 'NegReg', (41, 48))	('tumor', 'Disease', (86, 91))	('inhibition', 'Var', (13, 23))	('FAK', 'molecular_function', 'GO:0004717', ('27', '30'))	('FAK', 'Protein', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
6194	25918719	In addition to establishment of a favorable microenvironment, TAMs also inhibit the antitumor immune responses through the suppression of cytotoxic functions and the induction of apoptosis in T cells and NK cells.	('cytotoxic functions', 'CPA', (138, 157))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('TAMs', 'Chemical', '-', (62, 66))	('apoptosis', 'CPA', (179, 188))	('TAMs', 'Var', (62, 66))	('induction', 'Reg', (166, 175))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('inhibit', 'NegReg', (72, 79))	('suppression', 'NegReg', (123, 134))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('166', '188'))
6201	25918719	Moreover, inhibition of FAK leads to impairing the phosphorylation of AKT as well as the reduction of the expression of alpha-SMA.	('AKT', 'Gene', '207', (70, 73))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('FAK', 'molecular_function', 'GO:0004717', ('24', '27'))	('alpha-SMA', 'Protein', (120, 129))	('expression', 'MPA', (106, 116))	('AKT', 'Gene', (70, 73))	('impairing', 'NegReg', (37, 46))	('phosphorylation', 'MPA', (51, 66))	('reduction', 'NegReg', (89, 98))	('FAK', 'Gene', (24, 27))	('inhibition', 'Var', (10, 20))
6204	25918719	Indeed, loss of FAK in the epidermis had been reported to reduce the malignant progression of skin cancers by enhancing the apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('skin cancers', 'Disease', 'MESH:D012878', (94, 106))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('FAK', 'Protein', (16, 19))	('malignant progression of', 'CPA', (69, 93))	('reduce', 'NegReg', (58, 64))	('loss', 'Var', (8, 12))	('enhancing', 'PosReg', (110, 119))	('skin cancers', 'Phenotype', 'HP:0008069', (94, 106))	('apoptosis', 'CPA', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('skin cancers', 'Disease', (94, 106))	('FAK', 'molecular_function', 'GO:0004717', ('16', '19'))
6206	25918719	In PDA mouse model, inhibition of FAK impairs cancer cells proliferation and leads to the decreased CAFs recruitment.	('inhibition', 'Var', (20, 30))	('mouse', 'Species', '10090', (7, 12))	('PDA', 'Phenotype', 'HP:0006725', (3, 6))	('impairs cancer', 'Disease', (38, 52))	('decreased', 'NegReg', (90, 99))	('impairs cancer', 'Disease', 'MESH:D009422', (38, 52))	('FAK', 'molecular_function', 'GO:0004717', ('34', '37'))	('FAK', 'Gene', (34, 37))	('CAFs recruitment', 'CPA', (100, 116))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
6211	25918719	Eventually, several approaches have been developed to modulate the expression or activation of FAK, including small chemical inhibitors, PF-573,228 and VS-4718, in capable of blocking the autophosphorylation of FAK on Tyr397.	('FAK', 'Gene', (95, 98))	('VS-4718', 'Var', (152, 159))	('FAK', 'molecular_function', 'GO:0004717', ('95', '98'))	('modulate', 'Reg', (54, 62))	('autophosphorylation', 'MPA', (188, 207))	('FAK', 'Protein', (211, 214))	('activation', 'PosReg', (81, 91))	('Tyr397', 'Chemical', '-', (218, 224))	('expression', 'MPA', (67, 77))	('blocking', 'NegReg', (175, 183))	('FAK', 'molecular_function', 'GO:0004717', ('211', '214'))
6217	25918719	Moreover, gains in copy number of fak gene in invasive squamous cell carcinomas also revealed in correlation with elevation of FAK protein and tumorigenesis.	('copy number', 'Var', (19, 30))	('elevation', 'PosReg', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('tumor', 'Disease', (143, 148))	('invasive squamous cell carcinomas', 'Disease', 'MESH:D002294', (46, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('fak', 'molecular_function', 'GO:0004717', ('34', '37'))	('invasive squamous cell carcinomas', 'Disease', (46, 79))	('fak', 'Gene', '5747', (34, 37))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (55, 79))	('FAK', 'molecular_function', 'GO:0004717', ('127', '130'))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('FAK protein', 'Protein', (127, 138))	('gains', 'PosReg', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('fak', 'Gene', (34, 37))
6220	25918719	For example, in human head and neck squamous cell carcinoma, not all cases with an amplification of the fak gene displayed FAK protein overexpression, implicating a sophisticated posttranscriptional regulation involved in FAK expression and functions.	('FAK', 'molecular_function', 'GO:0004717', ('222', '225'))	('neck', 'cellular_component', 'GO:0044326', ('31', '35'))	('fak', 'Gene', (104, 107))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (22, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('neck squamous cell carcinoma', 'Disease', (31, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (31, 59))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('FAK', 'molecular_function', 'GO:0004717', ('123', '126'))	('regulation', 'biological_process', 'GO:0065007', ('199', '209'))	('FAK protein', 'Protein', (123, 134))	('human', 'Species', '9606', (16, 21))	('fak', 'molecular_function', 'GO:0004717', ('104', '107'))	('amplification', 'Var', (83, 96))	('fak', 'Gene', '5747', (104, 107))	('overexpression', 'PosReg', (135, 149))
6224	25918719	In human breast and colon cancers, FAK expression is significantly increased in tumors containing p53 mutations in comparison to tumors bearing wild-type p53.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('tumors', 'Disease', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('human', 'Species', '9606', (3, 8))	('FAK', 'molecular_function', 'GO:0004717', ('35', '38'))	('p53', 'Gene', (98, 101))	('tumors', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('FAK expression', 'MPA', (35, 49))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('increased', 'PosReg', (67, 76))	('mutations', 'Var', (102, 111))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('p53', 'Gene', '7157', (154, 157))	('colon cancers', 'Phenotype', 'HP:0003003', (20, 33))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('colon cancer', 'Phenotype', 'HP:0003003', (20, 32))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (98, 101))	('breast and colon cancers', 'Disease', 'MESH:D001943', (9, 33))
6225	25918719	Moreover, missense p53 mutations in its DNA-binding domain, that is, V173M, R249M, and R282M, also confer to promote the FAK promoter activity.	('R249M', 'Var', (76, 81))	('missense', 'Var', (10, 18))	('promote', 'PosReg', (109, 116))	('R249M', 'Mutation', 'rs587782329', (76, 81))	('R282M', 'Mutation', 'p.R282M', (87, 92))	('V173M', 'Var', (69, 74))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('R282M', 'Var', (87, 92))	('FAK promoter activity', 'MPA', (121, 142))	('V173M', 'Mutation', 'rs876660754', (69, 74))	('DNA-binding', 'molecular_function', 'GO:0003677', ('40', '51'))	('FAK', 'molecular_function', 'GO:0004717', ('121', '124'))
6231	25918719	Moreover, the overexpression of FAK and phosphorylation of FAK on Tyr397 is frequently associated with tumor metastasis as well as poor patient prognosis, indicating a critical role for FAK in tumor progression and malignancy.	('Tyr397', 'Var', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('patient', 'Species', '9606', (136, 143))	('FAK', 'Protein', (32, 35))	('FAK', 'Gene', (59, 62))	('overexpression', 'PosReg', (14, 28))	('malignancy', 'Disease', (215, 225))	('Tyr397', 'Chemical', '-', (66, 72))	('FAK', 'molecular_function', 'GO:0004717', ('186', '189'))	('tumor', 'Disease', (193, 198))	('FAK', 'molecular_function', 'GO:0004717', ('59', '62'))	('FAK', 'molecular_function', 'GO:0004717', ('32', '35'))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor metastasis', 'Disease', 'MESH:D009362', (103, 119))	('phosphorylation', 'Var', (40, 55))	('associated with', 'Reg', (87, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('malignancy', 'Disease', 'MESH:D009369', (215, 225))	('tumor metastasis', 'Disease', (103, 119))
6232	25918719	These studies suggest that FAK could be functioned as a potential prognostic marker and anticancer candidate.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('FAK', 'Var', (27, 30))	('FAK', 'molecular_function', 'GO:0004717', ('27', '30'))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
6238	25918719	TAE226 inhibits the phosphorylation of FAK and the FAK-mediated signaling, such as AKT, ERK, and S6 ribosomal protein in glioma.	('AKT', 'Gene', '207', (83, 86))	('S6 ribosomal protein', 'Protein', (97, 117))	('TAE226', 'Chemical', 'MESH:C524632', (0, 6))	('glioma', 'Disease', (121, 127))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('ERK', 'Gene', '5594', (88, 91))	('inhibits', 'NegReg', (7, 15))	('FAK', 'Protein', (39, 42))	('FAK-mediated', 'MPA', (51, 63))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('100', '117'))	('FAK', 'molecular_function', 'GO:0004717', ('39', '42'))	('TAE226', 'Var', (0, 6))	('AKT', 'Gene', (83, 86))	('ERK', 'Gene', (88, 91))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('FAK', 'molecular_function', 'GO:0004717', ('51', '54'))	('phosphorylation', 'biological_process', 'GO:0016310', ('20', '35'))	('phosphorylation', 'MPA', (20, 35))	('ERK', 'molecular_function', 'GO:0004707', ('88', '91'))	('signaling', 'biological_process', 'GO:0023052', ('64', '73'))
6240	25918719	TAE226 also impairs glioma tumor adhesion, migration, and invasion.	('impairs glioma tumor', 'Disease', 'MESH:D005910', (12, 32))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('TAE226', 'Var', (0, 6))	('invasion', 'CPA', (58, 66))	('migration', 'CPA', (43, 52))	('impairs glioma tumor', 'Disease', (12, 32))	('TAE226', 'Chemical', 'MESH:C524632', (0, 6))
6241	25918719	Besides glioblastomas, TAE226 is capable of accomplishing the detachment and apoptosis of breast cancers but no effects on MCF-10A normal breast epithelial cells.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('glioblastomas', 'Disease', 'MESH:D005909', (8, 21))	('MCF-10A', 'CellLine', 'CVCL:0598', (123, 130))	('glioblastoma', 'Phenotype', 'HP:0012174', (8, 20))	('apoptosis', 'CPA', (77, 86))	('glioblastomas', 'Disease', (8, 21))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('breast cancers', 'Phenotype', 'HP:0003002', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('detachment', 'CPA', (62, 72))	('TAE226', 'Chemical', 'MESH:C524632', (23, 29))	('breast cancers', 'Disease', (90, 104))	('breast cancers', 'Disease', 'MESH:D001943', (90, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('glioblastomas', 'Phenotype', 'HP:0012174', (8, 21))	('TAE226', 'Var', (23, 29))
6242	25918719	In animal models, TAE226 prolongs the survival rate with breast cancer bone metastasis.	('TAE226', 'Chemical', 'MESH:C524632', (18, 24))	('breast cancer bone metastasis', 'Disease', 'MESH:D009362', (57, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('survival rate', 'CPA', (38, 51))	('breast cancer bone metastasis', 'Disease', (57, 86))	('TAE226', 'Var', (18, 24))	('prolongs', 'PosReg', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
6243	25918719	TAE226 also suppresses the growth and angiogenesis of oral squamous cell carcinoma in a xenograft mouse model.	('suppresses', 'NegReg', (12, 22))	('TAE226', 'Var', (0, 6))	('oral squamous cell carcinoma', 'Disease', (54, 82))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))	('angiogenesis', 'biological_process', 'GO:0001525', ('38', '50'))	('mouse', 'Species', '10090', (98, 103))	('angiogenesis', 'CPA', (38, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('TAE226', 'Chemical', 'MESH:C524632', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
6248	25918719	Not only reduction in cell migration but also PND-1186 triggers cancer apoptosis in a 3D environment via blockage of the FAK/p130Cas tyrosine phosphorylation cascade and induction of caspase-3 activation.	('p130Cas', 'Gene', (125, 132))	('caspase-3', 'Gene', '836', (183, 192))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('tyrosine', 'Chemical', 'MESH:D014443', (133, 141))	('PND-1186', 'Chemical', 'MESH:C559284', (46, 54))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('blockage', 'NegReg', (105, 113))	('caspase-3', 'Gene', (183, 192))	('activation', 'PosReg', (193, 203))	('cancer', 'Disease', (64, 70))	('phosphorylation', 'biological_process', 'GO:0016310', ('142', '157'))	('p130Cas', 'Gene', '9564', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('reduction', 'NegReg', (9, 18))	('triggers', 'Reg', (55, 63))	('FAK', 'molecular_function', 'GO:0004717', ('121', '124'))	('cell migration', 'biological_process', 'GO:0016477', ('22', '36'))	('Cas', 'cellular_component', 'GO:0005650', ('129', '132'))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('PND-1186', 'Var', (46, 54))	('cell migration', 'CPA', (22, 36))
6267	25918719	In addition, ectopic expressions of miR-138 and miR-135 targeting the FAK 3'UTR reportedly suppress FAK-mediated tumor growth and invasion as well as drug sensitivity.	('tumor', 'Disease', (113, 118))	('miR-138', 'Var', (36, 43))	('FAK', 'molecular_function', 'GO:0004717', ('100', '103'))	('drug sensitivity', 'Phenotype', 'HP:0020174', (150, 166))	('suppress', 'NegReg', (91, 99))	('invasion', 'CPA', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('miR-135', 'Gene', (48, 55))	('drug sensitivity', 'CPA', (150, 166))	('FAK', 'molecular_function', 'GO:0004717', ('70', '73'))
6271	25918719	Moreover, the multifunctional characteristics of FAK have been highlighted to modulate numerous signal transductions in governing the activities and functions of the tumor microenvironment, cancer cells, and/or cancer stem cells (Figure 1).	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('FAK', 'molecular_function', 'GO:0004717', ('49', '52'))	('cancer', 'Disease', (211, 217))	('tumor', 'Disease', (166, 171))	('FAK', 'Var', (49, 52))	('modulate', 'Reg', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('activities', 'MPA', (134, 144))
6273	25918719	In lines of clinical observations, overexpression of FAK at both transcriptional and translational levels in human varied cancers implies that FAK could be a prognostic marker and a potential anticancer candidate for target therapies.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('human', 'Species', '9606', (109, 114))	('FAK', 'Var', (143, 146))	('cancer', 'Disease', (122, 128))	('FAK', 'Gene', (53, 56))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Disease', (196, 202))	('cancers', 'Disease', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('overexpression', 'PosReg', (35, 49))	('FAK', 'molecular_function', 'GO:0004717', ('53', '56'))	('FAK', 'molecular_function', 'GO:0004717', ('143', '146'))
6289	23293934	For example, elevated levels of miR-142-3p were detected in the sera of patients with systemic sclerosis and these levels were correlated with the severity of the disease (Makino et al.	('elevated', 'PosReg', (13, 21))	('miR-142-3p', 'Var', (32, 42))	('systemic sclerosis', 'Disease', 'MESH:D012595', (86, 104))	('correlated', 'Reg', (127, 137))	('systemic sclerosis', 'Disease', (86, 104))	('sera', 'molecular_function', 'GO:0004617', ('64', '68'))	('patients', 'Species', '9606', (72, 80))
6292	23293934	investigated the expression of several miRNAs in newly diagnosed type 2 diabetic (nT2D) and pre-diabetic patients and observed that seven miRNAs, i.e., miR-9, miR-29a, miR-30d, miR-34a, miR-124a, miR-146a and miR-375, were elevated significantly in nT2D compared to pre-diabetes.	('pre', 'molecular_function', 'GO:0003904', ('92', '95'))	('miR-124a', 'Gene', (186, 194))	('diabetic', 'Disease', 'MESH:D003920', (96, 104))	('diabetes', 'Disease', (270, 278))	('diabetic', 'Disease', (96, 104))	('miR-124a', 'Gene', '406907', (186, 194))	('miR-30d', 'Gene', (168, 175))	('miR-146a', 'Gene', (196, 204))	('miR-34a', 'Gene', (177, 184))	('miR-29a', 'Gene', (159, 166))	('miR-29a', 'Gene', '407021', (159, 166))	('diabetic', 'Disease', 'MESH:D003920', (72, 80))	('miR-146a', 'Gene', '406938', (196, 204))	('diabetic', 'Disease', (72, 80))	('patients', 'Species', '9606', (105, 113))	('miR-34a', 'Gene', '407040', (177, 184))	('miR-375', 'Gene', '494324', (209, 216))	('miR-30d', 'Gene', '407033', (168, 175))	('miR-375', 'Gene', (209, 216))	('nT2D', 'Disease', (249, 253))	('elevated', 'PosReg', (223, 231))	('diabetes', 'Disease', 'MESH:D003920', (270, 278))	('pre', 'molecular_function', 'GO:0003904', ('266', '269'))	('miR-9', 'Var', (152, 157))
6323	23293934	Another improvement, which combined the use of LNA with tyramide signal amplification, resulted in rapid and efficient detection of miRNAs in frozen tissues.	('tyramide', 'Chemical', '-', (56, 64))	('detection', 'MPA', (119, 128))	('miRNAs', 'Var', (132, 138))
6334	23293934	Rluc has a bioluminescence emission peak near 480 nm, while QD705 has the characteristic fluorescent nanocrystal absorption spectrum with high absorption from 300-490 nm (Invitrogen, Life Technologies, Grand Island, NY).	('bioluminescence emission peak', 'MPA', (11, 40))	('nanocrystal absorption', 'Disease', 'MESH:C564600', (101, 123))	('nanocrystal absorption', 'Disease', (101, 123))	('bioluminescence', 'biological_process', 'GO:0008218', ('11', '26'))	('QD705', 'Var', (60, 65))
6452	25221363	HIK1083-reactive mucin was detected in all cases with focal expression observed in one (5.9%), multifocal expression observed in four cases (23.5%), and diffuse expression observed in 12 cases (70.6%).	('HIK1083-reactive', 'Var', (0, 16))	('mucin', 'Gene', (17, 22))	('mucin', 'Gene', '100508689', (17, 22))
6454	25221363	In flat lesions, MUC5AC expression was inversely related to the expression of MUC6 and HIK1083-reactive mucin (Fig.	('MUC5AC', 'Gene', (17, 23))	('MUC6', 'Gene', '4588', (78, 82))	('MUC5AC', 'Gene', '4586', (17, 23))	('expression', 'MPA', (24, 34))	('mucin', 'Gene', '100508689', (104, 109))	('MUC6', 'Gene', (78, 82))	('HIK1083-reactive', 'Var', (87, 103))	('mucin', 'Gene', (104, 109))
6490	25221363	The mechanisms responsible for the aberrant MUC5AC expression in IPMNs are unknown.	('MUC5AC', 'Gene', (44, 50))	('IPMNs', 'Disease', (65, 70))	('aberrant', 'Var', (35, 43))	('MUC5AC', 'Gene', '4586', (44, 50))
6496	25221363	This hypothesis was confirmed in our study, where gastric type was characterized by branch duct-type lesions often associated with pyloric gland-like structures, whereas the intestinal type was characterized by main duct-type lesions often associated with atrophy and fibrosis of the surrounding parenchyma.	('branch duct-type', 'Disease', (84, 100))	('pyloric gland-like structures', 'Disease', (131, 160))	('atrophy', 'Disease', 'MESH:D001284', (256, 263))	('associated', 'Reg', (240, 250))	('associated', 'Reg', (115, 125))	('fibrosis', 'Disease', (268, 276))	('atrophy', 'Disease', (256, 263))	('fibrosis', 'Disease', 'MESH:D005355', (268, 276))	('gastric', 'Disease', (50, 57))	('lesions', 'Var', (101, 108))
6497	25221363	In our immunohistochemical analyses, HIK1083-reactive mucin was observed in gastric and mixed phenotype, but not in intestinal type IPMN.	('mucin', 'Gene', (54, 59))	('mucin', 'Gene', '100508689', (54, 59))	('HIK1083-reactive', 'Var', (37, 53))	('gastric', 'Disease', (76, 83))
6510	23864756	The main agents were 5-FU (600 mg/m2, d 1, 8, and 15 for 1 cycle) and gemcitabine (1000 mg/m2, d 1, 8, and 15 for 1 cycle).	('gemcitabine', 'Chemical', 'MESH:C056507', (70, 81))	('600 mg/m2', 'Var', (27, 36))	('1000 mg/m2', 'Var', (83, 93))
6530	23545339	KRAS mutations are also found in PanIN lesions, with approximately 36% of PanIN-1A lesions and nearly 87% of PanIN-2 and -3 lesions harboring a KRAS mutation.	('PanIN-1A', 'Disease', (74, 82))	('KRAS', 'Gene', '16653', (144, 148))	('PanIN lesions', 'Disease', (33, 46))	('mutations', 'Var', (5, 14))	('harboring', 'Reg', (132, 141))	('mutation', 'Var', (149, 157))	('PanIN lesions', 'Disease', 'MESH:D051437', (33, 46))	('KRAS', 'Gene', (144, 148))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '16653', (0, 4))
6531	23545339	The near universal presence of KRAS mutations in PDAC and their high prevalence in PanIN lesions suggests activation of KRAS is both an initiating event and necessary for the development of PDAC, making this an attractive candidate for a targeted therapy.	('PDAC', 'Phenotype', 'HP:0006725', (190, 194))	('KRAS', 'Gene', (31, 35))	('PanIN lesions', 'Disease', 'MESH:D051437', (83, 96))	('KRAS', 'Gene', '16653', (31, 35))	('PDAC', 'Chemical', '-', (49, 53))	('mutations', 'Var', (36, 45))	('PDAC', 'Chemical', '-', (190, 194))	('KRAS', 'Gene', (120, 124))	('PDAC', 'Phenotype', 'HP:0006725', (49, 53))	('KRAS', 'Gene', '16653', (120, 124))	('PanIN lesions', 'Disease', (83, 96))
6539	23545339	Proof that mutations in KRAS are a critical event in PDAC development came from mouse models in which expression of oncogenic Kras (KrasG12D) at endogenous levels was targeted to pancreatic epithelium using the pancreatic-specific promoters Pdx-1 or p48/Ptf1a.	('mutations', 'Var', (11, 20))	('pancreatic', 'Disease', 'MESH:D010195', (211, 221))	('Ptf1', 'Species', '32651', (254, 258))	('mouse', 'Species', '10090', (80, 85))	('pancreatic', 'Disease', (179, 189))	('PDAC', 'Chemical', '-', (53, 57))	('PDAC', 'Phenotype', 'HP:0006725', (53, 57))	('pancreatic', 'Disease', (211, 221))	('p48', 'Gene', (250, 253))	('Kras', 'Gene', (126, 130))	('Pdx-1', 'Gene', '18609', (241, 246))	('Kras', 'Gene', (132, 136))	('Pdx-1', 'Gene', (241, 246))	('KRAS', 'Gene', (24, 28))	('p48', 'Gene', '16391', (250, 253))	('Kras', 'Gene', '16653', (126, 130))	('pancreatic', 'Disease', 'MESH:D010195', (179, 189))	('KRAS', 'Gene', '16653', (24, 28))	('Kras', 'Gene', '16653', (132, 136))
6557	23545339	In vitro, acinar cells can transdifferentiate to a ductal phenotype, and recent studies have shown that oncogenic Kras expression is sufficient to induce transdifferentiation in vitro even in the absence of exogenous growth factors.	('transdifferentiation', 'CPA', (154, 174))	('induce', 'Reg', (147, 153))	('Kras', 'Gene', (114, 118))	('transdifferentiation', 'biological_process', 'GO:0060290', ('154', '174'))	('oncogenic', 'Var', (104, 113))	('Kras', 'Gene', '16653', (114, 118))
6559	23545339	To this point, a mouse model relying on pancreatic-specific Pten deletion provides evidence that the expansion of centroacinar cells accounts for ductal metaplasia.	('ductal metaplasia', 'Disease', (146, 163))	('mouse', 'Species', '10090', (17, 22))	('Pten', 'Gene', (60, 64))	('Pten', 'Gene', '19211', (60, 64))	('pancreatic', 'Disease', 'MESH:D010195', (40, 50))	('pancreatic', 'Disease', (40, 50))	('metaplasia', 'biological_process', 'GO:0036074', ('153', '163'))	('deletion', 'Var', (65, 73))
6567	23545339	Second, pancreatitis provides a permissive environment for the development of PDAC and may be required in the absence of additional genetic lesions, such as mutations in tumor suppressor genes.	('pancreatitis', 'Phenotype', 'HP:0001733', (8, 20))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('pancreatitis', 'Disease', 'MESH:D010195', (8, 20))	('PDAC', 'Phenotype', 'HP:0006725', (78, 82))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('170', '186'))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('PDAC', 'Disease', (78, 82))	('mutations', 'Var', (157, 166))	('tumor', 'Disease', (170, 175))	('pancreatitis', 'Disease', (8, 20))	('PDAC', 'Chemical', '-', (78, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('170', '186'))
6580	23545339	Deletion of the genes encoding the Notch pathway ligand Dll1 or the DNA-binding protein RBJ-Jkappa leads to an accelerated differentiation of pancreatic progenitor cells into endocrine cells.	('pancreatic', 'Disease', 'MESH:D010195', (142, 152))	('rat', 'Species', '10116', (117, 120))	('accelerated', 'PosReg', (111, 122))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('pancreatic', 'Disease', (142, 152))	('Notch', 'Gene', '25496', (35, 40))	('ligand', 'molecular_function', 'GO:0005488', ('49', '55'))	('Notch', 'Gene', (35, 40))	('DNA-binding', 'molecular_function', 'GO:0003677', ('68', '79'))	('RBJ-Jkappa', 'Gene', (88, 98))	('Dll1', 'Gene', (56, 60))	('Dll1', 'Gene', '13388', (56, 60))	('differentiation', 'CPA', (123, 138))	('Deletion', 'Var', (0, 8))
6584	23545339	Deletion of Rbpj in pancreatic progenitors at embryonic day 10.5 causes a lack of acinar tissue and the appearance of large duct-like structures.	('Rbpj', 'Gene', '19664', (12, 16))	('Rbpj', 'Gene', (12, 16))	('lack', 'NegReg', (74, 78))	('pancreatic', 'Disease', 'MESH:D010195', (20, 30))	('large duct-like structures', 'CPA', (118, 144))	('pancreatic', 'Disease', (20, 30))	('acinar', 'MPA', (82, 88))	('Deletion', 'Var', (0, 8))
6586	23545339	Surprisingly, pancreatic-specific deletion of the Notch1 and Notch2 alleles does not lead to gross abnormalities in development, suggesting a Notch-independent function of Rbpj.	('Notch2', 'Gene', (61, 67))	('pancreatic', 'Disease', (14, 24))	('Notch', 'Gene', (50, 55))	('Notch', 'Gene', '25496', (142, 147))	('Notch2', 'Gene', '18129', (61, 67))	('Notch', 'Gene', (61, 66))	('Notch', 'Gene', (142, 147))	('Notch', 'Gene', '25496', (61, 66))	('deletion', 'Var', (34, 42))	('Notch', 'Gene', '25496', (50, 55))	('Rbpj', 'Gene', '19664', (172, 176))	('pancreatic', 'Disease', 'MESH:D010195', (14, 24))	('Rbpj', 'Gene', (172, 176))
6589	23545339	have demonstrated that ectopic Notch activation in explant cultures inhibits acinar differentiation.	('rat', 'Species', '10116', (12, 15))	('Notch', 'Gene', '25496', (31, 36))	('ectopic', 'Var', (23, 30))	('activation', 'PosReg', (37, 47))	('acinar differentiation', 'CPA', (77, 99))	('Notch', 'Gene', (31, 36))	('inhibits', 'NegReg', (68, 76))
6590	23545339	Furthermore, experiments in zebrafish demonstrate that the loss of Notch signaling accelerates acinar differentiation.	('zebrafish', 'Species', '7955', (28, 37))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('acinar differentiation', 'CPA', (95, 117))	('rat', 'Species', '10116', (45, 48))	('rat', 'Species', '10116', (89, 92))	('Notch', 'Gene', '25496', (67, 72))	('accelerates', 'PosReg', (83, 94))	('loss', 'Var', (59, 63))	('Notch', 'Gene', (67, 72))
6596	23545339	Upon deletion of Rbpj in Hes1+ cells, centroacinar cells rapidly transform to acinar cells.	('Rbpj', 'Gene', (17, 21))	('deletion', 'Var', (5, 13))	('Rbpj', 'Gene', '19664', (17, 21))	('transform', 'Reg', (65, 74))
6599	23545339	Deletion of Notch1 in the pancreatic epithelium impairs acinar regeneration following acute pancreatitis, indicating that Notch signaling plays a role in pancreatic homeostasis.	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('pancreatic epithelium impairs acinar regeneration', 'Disease', (26, 75))	('Notch', 'Gene', (122, 127))	('pancreatic homeostasis', 'Disease', (154, 176))	('regeneration', 'biological_process', 'GO:0031099', ('63', '75'))	('pancreatic epithelium impairs acinar regeneration', 'Disease', 'MESH:D010190', (26, 75))	('Notch', 'Gene', '25496', (12, 17))	('pancreatitis', 'Phenotype', 'HP:0001733', (92, 104))	('pancreatitis', 'Disease', 'MESH:D010195', (92, 104))	('homeostasis', 'biological_process', 'GO:0042592', ('165', '176'))	('pancreatic homeostasis', 'Disease', 'MESH:D010195', (154, 176))	('Notch', 'Gene', '25496', (122, 127))	('Notch', 'Gene', (12, 17))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (86, 104))	('pancreatitis', 'Disease', (92, 104))	('Deletion', 'Var', (0, 8))
6618	23545339	Antibodies that specifically antagonize Notch1 or Notch2 inhibit tumor growth in vivo by decreasing cell proliferation and increasing apoptosis.	('Notch2', 'Gene', (50, 56))	('cell proliferation', 'biological_process', 'GO:0008283', ('100', '118'))	('tumor', 'Disease', (65, 70))	('apoptosis', 'biological_process', 'GO:0006915', ('134', '143'))	('Notch2', 'Gene', '18129', (50, 56))	('apoptosis', 'CPA', (134, 143))	('inhibit', 'NegReg', (57, 64))	('increasing', 'PosReg', (123, 133))	('decreasing', 'NegReg', (89, 99))	('rat', 'Species', '10116', (112, 115))	('cell proliferation', 'CPA', (100, 118))	('Notch1', 'Gene', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('apoptosis', 'biological_process', 'GO:0097194', ('134', '143'))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('antagonize', 'Var', (29, 39))
6619	23545339	Furthermore, treatment with either the anti-Notch1 or anti-Notch2 antibody alone does not result in severe intestinal toxicity.	('antibody', 'cellular_component', 'GO:0042571', ('66', '74'))	('toxicity', 'Disease', 'MESH:D064420', (118, 126))	('antibody', 'cellular_component', 'GO:0019815', ('66', '74'))	('toxicity', 'Disease', (118, 126))	('Notch2', 'Gene', (59, 65))	('antibody', 'cellular_component', 'GO:0019814', ('66', '74'))	('anti-Notch1', 'Var', (39, 50))	('antibody', 'molecular_function', 'GO:0003823', ('66', '74'))	('Notch2', 'Gene', '18129', (59, 65))
6622	23545339	The first conclusive evidence showing Notch1 acts as a tumor suppressor came from studies in skin, where the loss of both Notch1 alleles leads to the development of spontaneous basal cell carcinomas in mice.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('mice', 'Species', '10090', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (177, 197))	('tumor suppressor', 'biological_process', 'GO:0051726', ('55', '71'))	('basal cell carcinomas', 'Disease', (177, 198))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (177, 198))	('tumor', 'Disease', (55, 60))	('loss', 'Var', (109, 113))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('55', '71'))	('Notch1', 'Gene', (122, 128))	('leads to', 'Reg', (137, 145))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (177, 198))
6628	23545339	In addition to non-melanoma skin cancers, Notch has been implicated as a tumor suppressor in prostate cancer, hepatocellular carcinoma, and small cell lung cancer, and loss-of-function mutations have been identified in human chronic myelomonocytic leukemia (CMML) and squamous cell carcinoma samples.	('prostate cancer', 'Disease', (93, 108))	('non-melanoma skin cancers', 'Disease', 'MESH:D012878', (15, 40))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (110, 134))	('squamous cell carcinoma', 'Disease', (268, 291))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('73', '89'))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('non-melanoma skin cancers', 'Disease', (15, 40))	('Notch', 'Gene', (42, 47))	('hepatocellular carcinoma', 'Disease', (110, 134))	('myelomonocytic leukemia', 'Disease', 'MESH:D054429', (233, 256))	('skin cancer', 'Phenotype', 'HP:0008069', (28, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('73', '89'))	('small cell lung cancer', 'Disease', 'MESH:D055752', (140, 162))	('small cell lung cancer', 'Disease', (140, 162))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (268, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('loss-of-function', 'NegReg', (168, 184))	('skin cancers', 'Phenotype', 'HP:0008069', (28, 40))	('tumor', 'Disease', (73, 78))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (225, 256))	('Notch', 'Gene', '25496', (42, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('human', 'Species', '9606', (219, 224))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (110, 134))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('myelomonocytic leukemia', 'Disease', (233, 256))	('prostate cancer', 'Disease', 'MESH:D011471', (93, 108))	('CMML', 'Phenotype', 'HP:0012325', (258, 262))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (268, 291))	('leukemia', 'Phenotype', 'HP:0001909', (248, 256))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (140, 162))	('mutations', 'Var', (185, 194))
6629	23545339	Somatic inactivating mutations in NICASTRIN and APH1, components of the gamma secretase complex, as well as mutations in NOTCH2 and MAML1 were identified in a panel of human CMML samples.	('human', 'Species', '9606', (168, 173))	('gamma secretase complex', 'cellular_component', 'GO:0070765', ('72', '95'))	('MAML1', 'Gene', (132, 137))	('mutations', 'Var', (108, 117))	('NOTCH2', 'Gene', (121, 127))	('CMML', 'Phenotype', 'HP:0012325', (174, 178))	('inactivating mutations', 'Var', (8, 30))	('MAML1', 'Gene', '9794', (132, 137))	('APH1', 'Gene', (48, 52))	('NOTCH2', 'Gene', '4853', (121, 127))	('APH1', 'Gene', '51107', (48, 52))	('NICASTRIN', 'Gene', (34, 43))
6630	23545339	Furthermore, mouse models of CMML show that loss of Notch signaling alters hematopoietic stem cell differentiation, resulting in the accumulation of monocyte progenitors and a CMML-like disease.	('mouse', 'Species', '10090', (13, 18))	('Notch', 'Gene', '25496', (52, 57))	('alters', 'Reg', (68, 74))	('monocyte progenitors', 'CPA', (149, 169))	('hematopoietic stem cell differentiation', 'biological_process', 'GO:0060218', ('75', '114'))	('Notch', 'Gene', (52, 57))	('hematopoietic stem cell differentiation', 'CPA', (75, 114))	('CMML', 'Phenotype', 'HP:0012325', (176, 180))	('loss', 'Var', (44, 48))	('CMML-like disease', 'Disease', (176, 193))	('CMML', 'Phenotype', 'HP:0012325', (29, 33))	('CMML-like disease', 'Disease', 'MESH:D054429', (176, 193))	('accumulation', 'PosReg', (133, 145))	('signaling', 'biological_process', 'GO:0023052', ('58', '67'))
6631	23545339	A similar study analyzing human head and neck squamous cell carcinoma (HNSCC) tumors identified inactivating mutations in NOTCH1 in 15% of patients, with the majority of the mutations occurring in the same region of the protein, N-terminal to the transmembrane domain.	('neck squamous cell carcinoma (HNSCC) tumors', 'Disease', 'MESH:D000077195', (41, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('transmembrane', 'cellular_component', 'GO:0044214', ('247', '260'))	('patients', 'Species', '9606', (139, 147))	('inactivating mutations', 'Var', (96, 118))	('NOTCH1', 'Gene', (122, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('transmembrane', 'cellular_component', 'GO:0016021', ('247', '260'))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('neck', 'cellular_component', 'GO:0044326', ('41', '45'))	('human', 'Species', '9606', (26, 31))
6632	23545339	Importantly, 9 of the 21 samples with NOTCH1 mutations in this study possess inactivating mutations in both alleles, supporting the notion that NOTCH1 acts as a classical tumor suppressor.	('mutations', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('NOTCH1', 'Gene', (38, 44))	('tumor suppressor', 'biological_process', 'GO:0051726', ('171', '187'))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('inactivating', 'MPA', (77, 89))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('171', '187'))
6633	23545339	Finally, loss-of-function mutations in NOTCH1 and NOTCH2 are also seen in human cutaneous squamous cell carcinoma and lung squamous cell carcinoma.	('NOTCH2', 'Gene', '4853', (50, 56))	('NOTCH1', 'Gene', (39, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cutaneous squamous cell carcinoma and lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 146))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (118, 146))	('mutations', 'Var', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (80, 113))	('NOTCH2', 'Gene', (50, 56))	('human', 'Species', '9606', (74, 79))	('loss-of-function', 'NegReg', (9, 25))
6634	23545339	Interestingly, the majority of these mutations are heterozygous, implying NOTCH may act as a haploinsufficient tumor suppressor.	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (93, 116))	('NOTCH', 'Gene', '25496', (74, 79))	('haploinsufficient tumor', 'Disease', (93, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('NOTCH', 'Gene', (74, 79))	('mutations', 'Var', (37, 46))	('tumor suppressor', 'biological_process', 'GO:0051726', ('111', '127'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('111', '127'))
6641	23545339	Recently, work from our group demonstrated that Notch1 suppresses PanIN formation in a mouse model of PDAC (Pdx1-Cre;LSL-KrasG12D;Notch1lox/lox), a result supported by findings showing that deletion of both Notch1 alleles in ptf1a+/Cre;LSL-KrasG12D mice caused a slight decrease in median survival.	('PDAC', 'Chemical', '-', (102, 106))	('mouse', 'Species', '10090', (87, 92))	('PDAC', 'Phenotype', 'HP:0006725', (102, 106))	('Kras', 'Gene', (240, 244))	('Kras', 'Gene', (121, 125))	('Notch1', 'Gene', (48, 54))	('PanIN formation', 'MPA', (66, 81))	('deletion', 'Var', (190, 198))	('Notch1', 'Gene', (207, 213))	('Kras', 'Gene', '16653', (240, 244))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))	('mice', 'Species', '10090', (249, 253))	('Kras', 'Gene', '16653', (121, 125))	('Pdx1', 'Gene', '18609', (108, 112))	('rat', 'Species', '10116', (37, 40))	('PDAC', 'Disease', (102, 106))	('ptf1', 'Species', '32651', (225, 229))	('suppresses', 'NegReg', (55, 65))	('decrease', 'NegReg', (270, 278))	('Pdx1', 'Gene', (108, 112))	('median survival', 'CPA', (282, 297))
6642	23545339	By contrast, other groups have identified an oncogenic role for Notch1:, coactivation of KrasG12D and Notch1-ICD in mature acinar cells led to significantly higher numbers of PanIN lesions compared to activation of KrasG12D alone.	('Kras', 'Gene', (215, 219))	('Kras', 'Gene', '16653', (215, 219))	('Notch1-ICD', 'Var', (102, 112))	('coactivation', 'Var', (73, 85))	('Kras', 'Gene', (89, 93))	('higher', 'PosReg', (157, 163))	('PanIN lesions', 'Disease', (175, 188))	('Kras', 'Gene', '16653', (89, 93))	('PanIN lesions', 'Disease', 'MESH:D051437', (175, 188))
6643	23545339	However, expression of Notch1-ICD, in the absence of oncogenic Kras, fails to alter acinar cell differentiation or induce PanIN lesions, suggesting that activation of Notch1 alone is not sufficient to drive tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('Notch1-ICD', 'Var', (23, 33))	('acinar cell differentiation', 'biological_process', 'GO:0090425', ('84', '111'))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('PanIN lesions', 'Disease', (122, 135))	('Kras', 'Gene', (63, 67))	('Kras', 'Gene', '16653', (63, 67))	('tumor', 'Disease', (207, 212))	('PanIN lesions', 'Disease', 'MESH:D051437', (122, 135))
6649	23545339	Whereas deletion of both Notch1 alleles in mice expressing oncogenic Kras accelerates PanIN progression and causes a slight decrease in median survival, deleting Notch2 prolongs survival and delays PDAC development, shifting the spectrum of lesions towards development of mucinous cystic-like neoplasms.	('accelerates', 'PosReg', (74, 85))	('deleting', 'Var', (153, 161))	('neoplasms', 'Phenotype', 'HP:0002664', (293, 302))	('PDAC', 'Phenotype', 'HP:0006725', (198, 202))	('decrease', 'NegReg', (124, 132))	('Kras', 'Gene', '16653', (69, 73))	('mucinous cystic-like neoplasms', 'Disease', (272, 302))	('prolongs', 'PosReg', (169, 177))	('Notch1', 'Gene', (25, 31))	('median survival', 'MPA', (136, 151))	('rat', 'Species', '10116', (80, 83))	('PDAC development', 'CPA', (198, 214))	('delays', 'NegReg', (191, 197))	('mice', 'Species', '10090', (43, 47))	('survival', 'CPA', (178, 186))	('Kras', 'Gene', (69, 73))	('Notch2', 'Gene', '18129', (162, 168))	('PanIN', 'MPA', (86, 91))	('PDAC', 'Chemical', '-', (198, 202))	('mucinous cystic-like neoplasms', 'Disease', 'MESH:D018297', (272, 302))	('Notch2', 'Gene', (162, 168))	('deletion', 'Var', (8, 16))
6650	23545339	The opposing outcomes observed upon Notch1 or Notch2 ablation may be explained by unique downstream targets or differential expression patterns of the receptors.	('ablation', 'Var', (53, 61))	('Notch1', 'Gene', (36, 42))	('Notch2', 'Gene', (46, 52))	('Notch2', 'Gene', '18129', (46, 52))
6658	23545339	Notch signaling has been implicated in ADM given that ectopic expression of NICD promotes transdifferentiation in explant culture models.	('Notch', 'Gene', (0, 5))	('NICD', 'Gene', (76, 80))	('transdifferentiation', 'biological_process', 'GO:0060290', ('90', '110'))	('promotes', 'PosReg', (81, 89))	('signaling', 'biological_process', 'GO:0023052', ('6', '15'))	('transdifferentiation', 'CPA', (90, 110))	('ectopic expression', 'Var', (54, 72))	('Notch', 'Gene', '25496', (0, 5))	('ADM', 'Disease', (39, 42))
6664	23545339	Finally, in a slightly different in vitro model of ADM using isolated rat acinar cells, inhibition of Notch signaling by a GSI increased the proliferation of metaplastic exocrine cells in a Hes1-independent manner.	('Notch', 'Gene', (102, 107))	('rat', 'Species', '10116', (70, 73))	('rat', 'Species', '10116', (148, 151))	('GSI', 'Chemical', '-', (123, 126))	('proliferation of metaplastic exocrine cells', 'CPA', (141, 184))	('signaling', 'biological_process', 'GO:0023052', ('108', '117'))	('Notch', 'Gene', '25496', (102, 107))	('increased', 'PosReg', (127, 136))	('inhibition', 'Var', (88, 98))
6669	23545339	In the skin, chimeric deletion of Notch1 leads to the spontaneous development of epidermal tumors, whereas deletion of either Notch2 or Notch3 has no phenotypic effect.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Notch3', 'Gene', (136, 142))	('chimeric deletion', 'Var', (13, 30))	('leads to', 'Reg', (41, 49))	('Notch2', 'Gene', (126, 132))	('epidermal tumors', 'Phenotype', 'HP:0010816', (81, 97))	('epidermal tumors', 'Disease', (81, 97))	('Notch2', 'Gene', '18129', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Notch1', 'Gene', (34, 40))	('epidermal tumors', 'Disease', 'MESH:D004814', (81, 97))	('Notch3', 'Gene', '18131', (136, 142))
6679	23545339	In contrast, Notch1 deletion is required for primary keratinocytes expressing oncogenic Hras to form tumors when injected into nude mice.	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('deletion', 'Var', (20, 28))	('nude mice', 'Species', '10090', (127, 136))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('rat', 'Species', '10116', (55, 58))	('tumors', 'Disease', (101, 107))	('Notch1', 'Gene', (13, 19))
6733	23340293	They were also stained with anti-cytokeratin (Ventana, Tucson, AZ, 760-2595) and anti-smooth muscle actin (Ventana, 760-2835) by immunohistochemistry and demonstrated to be tumorigenic in nude mice.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('Ventana', 'Var', (107, 114))	('rat', 'Species', '10116', (39, 42))	('tumor', 'Disease', (173, 178))	('nude mice', 'Species', '10090', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('rat', 'Species', '10116', (161, 164))	('anti-cytokeratin', 'Protein', (28, 44))
6778	23340293	The anthracycline, nogalamycin, was approximately 11x more effective against Panc502 compared to either Panc410 or the non-transformed pancreatic duct cell line, HPDE (data not shown).	('HPDE', 'CellLine', 'CVCL:4376', (162, 166))	('Panc502', 'CellLine', 'CVCL:E291', (77, 84))	('pancreatic duct', 'Disease', (135, 150))	('anthracycline', 'Chemical', 'MESH:D018943', (4, 17))	('pancreatic duct', 'Disease', 'MESH:D021441', (135, 150))	('Panc502', 'Var', (77, 84))	('nogalamycin', 'Chemical', 'MESH:D009621', (19, 30))	('effective', 'MPA', (59, 68))
6780	23340293	We also generated dose response curves using a panel of topoisomerase inhibitors, showing that topoisomerase I inhibitors were generally more effective than topoisomerase II inhibitors (Supplementary Fig.	('effective', 'MPA', (142, 151))	('rat', 'Species', '10116', (12, 15))	('topoisomerase', 'molecular_function', 'GO:0003917', ('95', '108'))	('topoisomerase', 'molecular_function', 'GO:0003918', ('95', '108'))	('topoisomerase', 'molecular_function', 'GO:0003917', ('56', '69'))	('topoisomerase I', 'Enzyme', (95, 110))	('topoisomerase', 'molecular_function', 'GO:0003918', ('56', '69'))	('inhibitors', 'Var', (111, 121))	('topoisomerase II', 'molecular_function', 'GO:0003918', ('157', '173'))
6783	23340293	Both nogalamycin and digitoxin demonstrated more activity against Panc502 than Panc410, supporting the notion that in vitro sensitivity does predict in vivo response, at least with these 2 drugs in these cell lines, as judged by tumor size (Fig.	('Panc502', 'Var', (66, 73))	('activity', 'MPA', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('digitoxin', 'Chemical', 'MESH:D004074', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('Panc502', 'CellLine', 'CVCL:E291', (66, 73))	('tumor', 'Disease', (229, 234))	('nogalamycin', 'Chemical', 'MESH:D009621', (5, 16))	('rat', 'Species', '10116', (38, 41))
6789	23340293	In each case, cell lines were documented to be tumorigenic in athymic mice, sequenced to document oncogenic mutations in the Kras2 gene, and DNA fingerprinted to confirm their patient origin (information available on request).	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('mutations', 'Var', (108, 117))	('Kras2', 'Gene', '16653', (125, 130))	('Kras2', 'Gene', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mice', 'Species', '10090', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('patient', 'Species', '9606', (176, 183))	('tumor', 'Disease', (47, 52))
6811	23340293	In the future, the combination of the patient's germline SNPs, somatic mutations, mRNA expression and epigenetic changes in the cancer, may play an increasing role in the choice of chemotherapy.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('epigenetic changes', 'Var', (102, 120))	('mRNA expression', 'MPA', (82, 97))	('patient', 'Species', '9606', (38, 45))	('mutations', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('play', 'Reg', (140, 144))	('cancer', 'Disease', (128, 134))
6814	23340293	Cell lines are useful for many other studies of cancer biology since they: i) can be expanded indefinitely, ii) contain all of the gene mutations present in the patient's primary cancer, iii) can be manipulated in vitro by adding or eliminating genes, iv) can be implanted in mice to test the effects of these manipulations on the ability to form tumors, and v) carry few if any additional genetic changes from the primary cancer.	('cancer', 'Disease', 'MESH:D009369', (423, 429))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('patient', 'Species', '9606', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (423, 429))	('tumors', 'Disease', (347, 353))	('tumors', 'Disease', 'MESH:D009369', (347, 353))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('mice', 'Species', '10090', (276, 280))	('cancer', 'Disease', (48, 54))	('mutations', 'Var', (136, 145))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('test', 'Reg', (284, 288))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('cancer', 'Disease', (179, 185))	('cancer', 'Disease', (423, 429))
6824	23340293	The replacement of stromal cells may be slightly less than 100% based on the extremely faint residual PCR product from DNA isolated from xenografts of cancers containing homozygous deletions.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('deletions', 'Var', (181, 190))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancers', 'Disease', (151, 158))
6837	20004512	Recent reports showed that deregulation of miRNA contribute to tumor development and progression and hence, have diagnostic and prognostic value in several human malignancies.	('tumor', 'Disease', (63, 68))	('deregulation', 'Var', (27, 39))	('progression', 'CPA', (85, 96))	('malignancies', 'Disease', 'MESH:D009369', (162, 174))	('miRNA', 'Protein', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('contribute', 'Reg', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('malignancies', 'Disease', (162, 174))	('human', 'Species', '9606', (156, 161))
6855	20004512	Several researchers reported that abnormal expression of miRNAs has been associated with cancers .	('miRNAs', 'Protein', (57, 63))	('abnormal', 'Var', (34, 42))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('associated', 'Reg', (73, 83))	('cancers', 'Disease', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
6856	20004512	Previous studies have shown that some miRNAs are associated with tumor promotion (oncogenes) and some inhibit the tumor by reducing cell proliferation, survival (tumor suppressors) and cellular differentiation (Figure 1) .	('reducing', 'NegReg', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cellular differentiation', 'CPA', (185, 209))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (114, 119))	('cell proliferation', 'CPA', (132, 150))	('inhibit', 'NegReg', (102, 109))	('miRNAs', 'Var', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cell proliferation', 'biological_process', 'GO:0008283', ('132', '150'))	('survival', 'CPA', (152, 160))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
6858	20004512	The association of miRNAs and cancers came from a study characterizing the chromosome 13q14 deletion in human chronic lymphocytic leukemia (CLL).	('CLL', 'Phenotype', 'HP:0005550', (140, 143))	('chromosome', 'cellular_component', 'GO:0005694', ('75', '85'))	('leukemia', 'Phenotype', 'HP:0001909', (130, 138))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (110, 138))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancers', 'Disease', (30, 37))	('deletion', 'Var', (92, 100))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (110, 138))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('human', 'Species', '9606', (104, 109))	('chronic lymphocytic leukemia', 'Disease', (110, 138))	('CLL', 'Disease', 'MESH:D015451', (140, 143))	('CLL', 'Disease', (140, 143))
6859	20004512	The chronic lymphocytic lymphoma and several solid tumors are associated with high incidence of chromosome 13q14 deletion.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('lymphocytic lymphoma', 'Disease', 'MESH:D015451', (12, 32))	('lymphocytic lymphoma', 'Disease', (12, 32))	('solid tumors', 'Disease', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('chronic lymphocytic lymphoma', 'Phenotype', 'HP:0005550', (4, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (24, 32))	('solid tumors', 'Disease', 'MESH:D009369', (45, 57))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('chromosome', 'Var', (96, 106))
6862	20004512	A increase in apoptosis was observed when there was an ectopic expression of miR-15a-16 in lymphoma cells that harbor the 13q14 deletion.	('lymphoma', 'Disease', 'MESH:D008223', (91, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (91, 99))	('ectopic expression', 'MPA', (55, 73))	('miR-15a', 'Gene', '406948', (77, 84))	('increase', 'PosReg', (2, 10))	('miR-15a', 'Gene', (77, 84))	('apoptosis', 'MPA', (14, 23))	('apoptosis', 'biological_process', 'GO:0097194', ('14', '23'))	('apoptosis', 'biological_process', 'GO:0006915', ('14', '23'))	('lymphoma', 'Disease', (91, 99))	('13q14 deletion', 'Var', (122, 136))
6867	20004512	For instance, the miR-375 and miR-376 were expressed at significantly higher levels in the mouse pancreas and pancreatic islet cells compared with mouse brain, heart, and liver tissue.	('miR-375', 'Gene', '723900', (18, 25))	('mouse', 'Species', '10090', (147, 152))	('pancreatic', 'Disease', (110, 120))	('miR-375', 'Gene', (18, 25))	('miR-376', 'Var', (30, 37))	('higher', 'PosReg', (70, 76))	('mouse', 'Species', '10090', (91, 96))	('pancreatic', 'Disease', 'MESH:D010195', (110, 120))
6872	20004512	Similarly, up-regulation of miR-142-3p, miR-142-5p, miR-155, and miR-146a expression was observed in human pancreatic neuroendocrine tumors (PNETs) as compared with normal human islets.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('miR-146a', 'Gene', '406938', (65, 73))	('up-regulation', 'PosReg', (11, 24))	('regulation', 'biological_process', 'GO:0065007', ('14', '24'))	('pancreatic neuroendocrine tumors', 'Disease', (107, 139))	('miR-155', 'Gene', '406947', (52, 59))	('human', 'Species', '9606', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('human', 'Species', '9606', (101, 106))	('miR-146a', 'Gene', (65, 73))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (107, 139))	('miR-155', 'Gene', (52, 59))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (118, 139))	('miR-142-5p', 'Var', (40, 50))	('miR-142-3p', 'Var', (28, 38))
6887	20004512	These experiments strengthen the hypothesis that the aberrant expression of miRNAs in solid tumors were crucial in regulating key cancer genes.	('solid tumors', 'Disease', 'MESH:D009369', (86, 98))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('solid tumors', 'Disease', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('miRNAs', 'Gene', (76, 82))	('aberrant', 'Var', (53, 61))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
6888	20004512	CpG methylation is one of the epigenetic mechanisms for miRNA deregulation in cancer tissue.	('miRNA', 'Protein', (56, 61))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('methylation', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('deregulation', 'MPA', (62, 74))
6894	20004512	Similarly, miR-34a expression was absent in several types of tumors due to the aberrant CpG methylation of its promoter.	('tumors', 'Disease', (61, 67))	('expression', 'MPA', (19, 29))	('miR-34a', 'Gene', (11, 18))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('aberrant', 'Var', (79, 87))	('methylation', 'biological_process', 'GO:0032259', ('92', '103'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('miR-34a', 'Gene', '407040', (11, 18))	('CpG methylation', 'Var', (88, 103))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
6895	20004512	Nineteen out of 24 primary prostate carcinomas displayed CpG methylation at the promoter sequence of the miR-34a gene, which resulted in the loss of its expression.	('methylation', 'Var', (61, 72))	('loss', 'NegReg', (141, 145))	('miR-34a', 'Gene', '407040', (105, 112))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('primary prostate carcinomas', 'Disease', (19, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('primary prostate carcinomas', 'Disease', 'MESH:D011471', (19, 46))	('miR-34a', 'Gene', (105, 112))	('expression', 'MPA', (153, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))
6896	20004512	The miR-34a promoter CpG methylation was also detected in breast, lung, colon, kidney, bladder, pancreatic carcinoma cell lines, melanoma cell lines and primary melanoma samples.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('breast', 'Disease', (58, 64))	('miR-34a', 'Gene', (4, 11))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (96, 116))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('detected', 'Reg', (46, 54))	('methylation', 'Var', (25, 36))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('colon', 'Disease', (72, 77))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('miR-34a', 'Gene', '407040', (4, 11))	('pancreatic carcinoma', 'Disease', (96, 116))
6910	20004512	Questions regarding the association of miRNAs and their role in cancer development remain unknown but it is suggested that a set of miRNAs might be associated with pancreatic tumorogenesis by acting as tumor suppressor or oncogene (Figure 1).	('miRNAs', 'Var', (132, 138))	('tumor', 'Disease', (175, 180))	('pancreatic tumorogenesis', 'Disease', (164, 188))	('tumor', 'Disease', (202, 207))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('202', '218'))	('pancreatic tumorogenesis', 'Disease', 'MESH:D010195', (164, 188))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('associated', 'Reg', (148, 158))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (164, 180))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor suppressor', 'biological_process', 'GO:0051726', ('202', '218'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
6914	20004512	Therefore, modulation of miRNA expression may be an important mechanism underlying the biological effects of curcumin.	('miRNA', 'Protein', (25, 30))	('curcumin', 'Chemical', 'MESH:D003474', (109, 117))	('modulation', 'Var', (11, 21))
6934	20004512	The over expression of miR-99, miR-100, miR-100-1/2, miR-125a, miR-125b-1, miR-199a-1, and miR-199a-2 was observed in cancers as well as in chronic pancreatitis but not in normal pancreatic tissue.	('miR-199a-1', 'Gene', (75, 85))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('miR-125a', 'Gene', (53, 61))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (140, 160))	('miR-125b-1', 'Gene', '406911', (63, 73))	('pancreatic', 'Disease', (179, 189))	('miR-199a-2', 'Gene', '406977', (91, 101))	('pancreatitis', 'Phenotype', 'HP:0001733', (148, 160))	('miR-199a-1', 'Gene', '406976', (75, 85))	('miR-100', 'Gene', (40, 47))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Disease', (118, 125))	('miR-100', 'Gene', (31, 38))	('miR-99', 'Var', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (140, 160))	('over expression', 'PosReg', (4, 19))	('miR-100', 'Gene', '406892', (40, 47))	('pancreatic', 'Disease', 'MESH:D010195', (179, 189))	('miR-199a-2', 'Gene', (91, 101))	('miR-100', 'Gene', '406892', (31, 38))	('miR-125b-1', 'Gene', (63, 73))	('miR-125a', 'Gene', '406910', (53, 61))	('chronic pancreatitis', 'Disease', (140, 160))
6935	20004512	Similarly, it has been reported that the over expression of miR-21, miR-221, miR-222, miR-181a, miR-181b, miR-181d, and miR-155 in tumor samples compared to benign pancreatic tissue.	('miR-181d', 'Gene', (106, 114))	('benign pancreatic', 'Disease', 'MESH:D010195', (157, 174))	('benign pancreatic', 'Disease', (157, 174))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('miR-181a', 'Var', (86, 94))	('miR-221', 'Gene', '407006', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('miR-222', 'Gene', (77, 84))	('over expression', 'PosReg', (41, 56))	('miR-155', 'Gene', (120, 127))	('miR-181b', 'Var', (96, 104))	('miR-222', 'Gene', '407007', (77, 84))	('tumor', 'Disease', (131, 136))	('miR-21', 'Gene', '406991', (60, 66))	('miR-221', 'Gene', (68, 75))	('miR-155', 'Gene', '406947', (120, 127))	('miR-21', 'Gene', (60, 66))	('miR-181d', 'Gene', '574457', (106, 114))
6942	20004512	Profiling of four miRNAs such as miR-21, miR-210, miR-155, and miR-196a in the plasma of pancreatic cancer patients revealed that elevated expression of miR-155 and miR196a was observed with the parallel progression of disease.	('miR-21', 'Gene', '406991', (33, 39))	('elevated', 'PosReg', (130, 138))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('miR-21', 'Gene', '406991', (41, 47))	('patients', 'Species', '9606', (107, 115))	('miR-210', 'Gene', '406992', (41, 48))	('miR-21', 'Gene', (33, 39))	('miR-155', 'Gene', (153, 160))	('miR-210', 'Gene', (41, 48))	('miR-155', 'Gene', (50, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('miR-155', 'Gene', '406947', (153, 160))	('miR-21', 'Gene', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('miR-196a', 'Var', (63, 71))	('miR-155', 'Gene', '406947', (50, 57))	('miR196a', 'Var', (165, 172))	('expression', 'MPA', (139, 149))	('pancreatic cancer', 'Disease', (89, 106))
6945	20004512	If the PDAC Progression is due to miRNA overexpression/down regulation, the targeting of the mature miRNAs or their precursors by synthetic, chemically-modified antisense oligonucleotides or overexpression of miRNAs ectopically might be considered for therapy.	('overexpression/down regulation', 'NegReg', (40, 70))	('PDAC', 'Chemical', '-', (7, 11))	('miRNA', 'MPA', (34, 39))	('regulation', 'biological_process', 'GO:0065007', ('60', '70'))	('oligonucleotides', 'Chemical', 'MESH:D009841', (171, 187))	('PDAC', 'Disease', (7, 11))	('antisense', 'Var', (161, 170))	('PDAC', 'Phenotype', 'HP:0006725', (7, 11))
6947	20004512	Transfection of the synthetic miRNAs (Gli-1-miRNA-3548) and its corresponding duplex (Duplex-3548), significantly inhibits Gli-1 leading to the inhibition of the proliferation, delayed cell division and activation of late apoptosis in MiaPACA-2 cancer cells .	('apoptosis', 'biological_process', 'GO:0006915', ('222', '231'))	('late apoptosis', 'CPA', (217, 231))	('Gli-1', 'Gene', (38, 43))	('Gli-1', 'Gene', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('Duplex-3548', 'Var', (86, 97))	('Gli-1', 'Gene', '2735', (38, 43))	('cancer', 'Disease', (245, 251))	('inhibits', 'NegReg', (114, 122))	('proliferation', 'CPA', (162, 175))	('Gli-1', 'Gene', '2735', (123, 128))	('apoptosis', 'biological_process', 'GO:0097194', ('222', '231'))	('cell division', 'biological_process', 'GO:0051301', ('185', '198'))	('delayed cell division', 'CPA', (177, 198))	('inhibition', 'NegReg', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('activation', 'PosReg', (203, 213))
6949	20004512	Restoring the expression of the let-7 level in pancreatic ductal adenocarcinoma derived cells with plasmid based synthetic let-7 or lentiviral transduction in vitro and in vivo strongly inhibits the cell proliferation, K-ras expression, and mitogen-activated protein kinase activation, but it fails to inhibit tumor growth progression after intratumoral gene transfer.	('protein', 'cellular_component', 'GO:0003675', ('259', '266'))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('protein kinase activation', 'biological_process', 'GO:0032147', ('259', '284'))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (47, 79))	('let-7', 'Var', (123, 128))	('K-ras', 'Gene', (219, 224))	('cell proliferation', 'CPA', (199, 217))	('cell proliferation', 'biological_process', 'GO:0008283', ('199', '217'))	('transduction', 'biological_process', 'GO:0009293', ('143', '155'))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('let-7', 'Gene', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('mitogen-activated', 'MPA', (241, 258))	('inhibits', 'NegReg', (186, 194))	('tumor', 'Disease', (310, 315))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (47, 79))	('K-ras', 'Gene', '3845', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('pancreatic ductal adenocarcinoma', 'Disease', (47, 79))	('tumor', 'Disease', (346, 351))
6952	20004512	Knock down of miR-21 and -221expression with their corresponding antisense oligonucleotides in HS766T cells results in cell cycle arrest (G1 phase) which is accompanied by an increased expression of PTEN, RECK, and p27 respectively.	('PTEN', 'Gene', '5728', (199, 203))	('miR-21', 'Gene', '406991', (14, 20))	('RECK', 'Gene', '8434', (205, 209))	('expression', 'MPA', (185, 195))	('miR-21', 'Gene', (14, 20))	('oligonucleotides', 'Chemical', 'MESH:D009841', (75, 91))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('119', '136'))	('increased', 'PosReg', (175, 184))	('p27', 'Gene', (215, 218))	('HS766T', 'CellLine', 'CVCL:0334', (95, 101))	('G1 phase', 'biological_process', 'GO:0051318', ('138', '146'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (119, 136))	('antisense', 'Var', (65, 74))	('p27', 'Gene', '3429', (215, 218))	('RECK', 'Gene', (205, 209))	('PTEN', 'Gene', (199, 203))
6953	20004512	Treatment of pancreatic cancer cells with the antisense oligonucleotides-gemcitabine combinations were synergistic.	('pancreatic cancer', 'Disease', (13, 30))	('oligonucleotides', 'Chemical', 'MESH:D009841', (56, 72))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (13, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (13, 30))	('antisense oligonucleotides-gemcitabine', 'Var', (46, 84))	('gemcitabine', 'Chemical', 'MESH:C056507', (73, 84))
6964	20004512	Silencing, or antisense blocking, and miRNA modifications of oncogenic miRNAs provide new avenues for treatment of pancreatic cancer as well as other type of cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('miRNA modifications', 'Var', (38, 57))	('pancreatic cancer', 'Disease', (115, 132))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('antisense blocking', 'Var', (14, 32))	('Silencing', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
7012	21430934	The laparoscopic biopsy revealed atypical ductal cells and this suggested pancreatic carcinoma.	('pancreatic carcinoma', 'Disease', (74, 94))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (74, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('atypical', 'Var', (33, 41))
7042	21430934	Therefore, the initial TNM staging was T4N1Mx (stage III or IV).	('TNM', 'Gene', '10178', (23, 26))	('TNM', 'Gene', (23, 26))	('T4N1Mx', 'Var', (39, 45))
7061	21430934	The use of a high HIFU energy (> 900 J/spot) was favored for approximately two months after initiating HIFU treatment at our center, yet it frequently caused severe abdominal pain.	('caused', 'Reg', (151, 157))	('abdominal pain', 'Phenotype', 'HP:0002027', (165, 179))	('abdominal pain', 'Disease', (165, 179))	('> 900 J/spot', 'Var', (31, 43))	('abdominal pain', 'Disease', 'MESH:D015746', (165, 179))	('pain', 'Phenotype', 'HP:0012531', (175, 179))
7082	21430934	In several animal studies, CCHT induced apoptosis and it inhibited tumor growth more than chemotherapy or HIFU alone.	('CCHT', 'Chemical', '-', (27, 31))	('apoptosis', 'CPA', (40, 49))	('inhibited', 'NegReg', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('CCHT', 'Var', (27, 31))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
7105	33912560	Non-coding RNAs (ncRNAs) enveloped in exosomes and released to the TME are shown to be involved in tumorigenesis and development, as well as act as important intracellular communication mediators.	('tumor', 'Disease', (99, 104))	('Non-coding', 'Var', (0, 10))	('involved', 'Reg', (87, 95))	('development', 'CPA', (117, 128))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('ncRNA', 'Gene', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('intracellular', 'cellular_component', 'GO:0005622', ('158', '171'))	('ncRNA', 'Gene', '220202', (17, 22))
7117	33912560	Studies suggest that plasma exosomal tsRNA (tRNA-ValTAC-3, tRNA-GlyTCC-5, tRNA-ValAAC-5, and tRNA-GluCTC-5) in hepatic carcinoma can serve as diagnostic biomarkers; piRNAs [piR-004800, piR-10506469, and piR-20548188 ] have exhibited crucial roles in tumorigenesis and progression of multiple myeloma.	('hepatic carcinoma', 'Phenotype', 'HP:0001402', (111, 128))	('tRNA', 'molecular_function', 'GO:0030533', ('93', '97'))	('[piR-004800', 'Var', (172, 183))	('hepatic carcinoma', 'Disease', 'MESH:D056486', (111, 128))	('tRNA', 'molecular_function', 'GO:0030533', ('74', '78'))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('piR-20548188 ]', 'Var', (203, 217))	('piR-10506469', 'Var', (185, 197))	('tRNA', 'molecular_function', 'GO:0030533', ('59', '63'))	('multiple myeloma', 'Disease', 'MESH:D009101', (283, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tRNA', 'molecular_function', 'GO:0030533', ('44', '48'))	('multiple myeloma', 'Phenotype', 'HP:0006775', (283, 299))	('tumor', 'Disease', (250, 255))	('hepatic carcinoma', 'Disease', (111, 128))	('multiple myeloma', 'Disease', (283, 299))
7161	33912560	In detail, miR-105 transferred to CAF can increase glycolysis and glutamine decomposition levels and release acetic acid and glutamate into the TME to provide energy or raw materials for tumor or protein synthesis.	('miR-105', 'Chemical', '-', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('acetic acid', 'Chemical', 'MESH:D019342', (109, 120))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))	('CAF', 'Gene', '8850', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('CAF', 'Gene', (34, 37))	('glycolysis', 'biological_process', 'GO:0006096', ('51', '61'))	('release acetic acid', 'MPA', (101, 120))	('tumor', 'Disease', (187, 192))	('glutamate', 'Chemical', 'MESH:D018698', (125, 134))	('protein synthesis', 'biological_process', 'GO:0006412', ('196', '213'))	('miR-105', 'Var', (11, 18))	('glutamine decomposition levels', 'MPA', (66, 96))	('glutamate', 'MPA', (125, 134))	('glycolysis', 'MPA', (51, 61))	('increase', 'PosReg', (42, 50))	('glutamine', 'Chemical', 'MESH:D005973', (66, 75))
7166	33912560	Tumor cells activate the beige-brown phenotype differentiation in adipocytes by encapsulating high levels of miRNA-144 and miRNA-126 via exosomes, enhance the catabolism of recipient adipocytes, and ultimately promote tumor progression through metabolic reprogramming.	('beige-brown phenotype differentiation', 'CPA', (25, 62))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('enhance', 'PosReg', (147, 154))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('catabolism', 'MPA', (159, 169))	('miRNA-126', 'Gene', '406913', (123, 132))	('miRNA-144', 'Var', (109, 118))	('miRNA-126', 'Gene', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('activate', 'PosReg', (12, 20))	('promote', 'PosReg', (210, 217))	('metabolic reprogramming', 'CPA', (244, 267))	('tumor', 'Disease', (218, 223))	('catabolism', 'biological_process', 'GO:0009056', ('159', '169'))
7167	33912560	Specifically, exosomal miRNA-144 promotes beige-brown adipocyte characteristics by down-regulating the MAP3K8/ERK1/2/PPARgamma pathway, while exosomal miRNA-126 activates the AMPK-related autophagy pathways and promotes the expression of HIF1alpha to achieve metabolic regulation by inhibiting IRS/Glut-4 signaling.	('AMPK', 'Gene', '5562', (175, 179))	('miRNA-126', 'Gene', (151, 160))	('autophagy', 'biological_process', 'GO:0006914', ('188', '197'))	('promotes', 'PosReg', (211, 219))	('exosomal', 'Var', (142, 150))	('down-regulating', 'NegReg', (83, 98))	('PPARgamma', 'Gene', '5468', (117, 126))	('MAP3K8', 'Gene', (103, 109))	('beige-brown adipocyte characteristics', 'CPA', (42, 79))	('AMPK', 'molecular_function', 'GO:0050405', ('175', '179'))	('expression', 'MPA', (224, 234))	('Glut-4', 'Gene', (298, 304))	('HIF1alpha', 'Gene', '3091', (238, 247))	('ERK1', 'molecular_function', 'GO:0004707', ('110', '114'))	('IRS', 'Gene', (294, 297))	('signaling', 'biological_process', 'GO:0023052', ('305', '314'))	('ERK1/2', 'Gene', (110, 116))	('MAP3K', 'molecular_function', 'GO:0004709', ('103', '108'))	('AMPK', 'Gene', (175, 179))	('ERK1/2', 'Gene', '5595;5594', (110, 116))	('activates', 'PosReg', (161, 170))	('miRNA-126', 'Gene', '406913', (151, 160))	('regulation', 'biological_process', 'GO:0065007', ('269', '279'))	('AMPK', 'molecular_function', 'GO:0004691', ('175', '179'))	('PPARgamma', 'Gene', (117, 126))	('IRS', 'Gene', '3376', (294, 297))	('HIF1alpha', 'Gene', (238, 247))	('MAP3K8', 'Gene', '1326', (103, 109))	('Glut-4', 'Gene', '6517', (298, 304))	('promotes', 'PosReg', (33, 41))	('autophagy', 'biological_process', 'GO:0016236', ('188', '197'))	('inhibiting', 'NegReg', (283, 293))	('AMPK', 'molecular_function', 'GO:0047322', ('175', '179'))
7171	33912560	For example, TAM releases miR-365-rich exosomes that are uptaken by pancreatic cancer cells and induce gemcitabine (cytidine analog) resistance through promoting pyrimidine metabolism, thereby increasing the nucleotide triphosphate pool that competes with gemcitabine to enter the DNA of cancer cells.	('pyrimidine metabolism', 'biological_process', 'GO:0006213', ('162', '183'))	('cancer', 'Disease', (288, 294))	('gemcitabine', 'MPA', (103, 114))	('pyrimidine', 'Chemical', 'MESH:C030986', (162, 172))	('TAM', 'Gene', '8205', (13, 16))	('resistance', 'MPA', (133, 143))	('pyrimidine metabolism', 'biological_process', 'GO:0006206', ('162', '183'))	('nucleotide triphosphate', 'Chemical', '-', (208, 231))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('gemcitabine', 'Chemical', 'MESH:C056507', (256, 267))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))	('pyrimidine metabolism', 'MPA', (162, 183))	('induce', 'PosReg', (96, 102))	('pancreatic cancer', 'Disease', (68, 85))	('cancer', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('DNA', 'cellular_component', 'GO:0005574', ('281', '284'))	('promoting', 'PosReg', (152, 161))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('nucleotide triphosphate pool', 'MPA', (208, 236))	('gemcitabine', 'Chemical', 'MESH:C056507', (103, 114))	('miR-365', 'Chemical', '-', (26, 33))	('increasing', 'PosReg', (193, 203))	('cytidine', 'Chemical', 'MESH:D003562', (116, 124))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('TAM', 'Gene', (13, 16))	('miR-365-rich', 'Var', (26, 38))	('pyrimidine metabolism', 'biological_process', 'GO:0006220', ('162', '183'))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
7172	33912560	In addition, miR-365 also upregulates the cytidine deaminase (CDA) level, which catabolizes gemcitabine.	('cytidine deaminase', 'Gene', '978', (42, 60))	('miR-365', 'Chemical', '-', (13, 20))	('upregulates', 'PosReg', (26, 37))	('CDA', 'Gene', '978', (62, 65))	('cytidine deaminase', 'Gene', (42, 60))	('miR-365', 'Var', (13, 20))	('gemcitabine', 'Chemical', 'MESH:C056507', (92, 103))	('CDA', 'Gene', (62, 65))
7174	33912560	For example, exosome-mediated transfer of miR-105 and miR-103 efficiently destroys the endothelial junctions and the integrity of these natural barriers against metastasis.	('miR-105', 'Chemical', '-', (42, 49))	('miR-105', 'Var', (42, 49))	('exosome', 'cellular_component', 'GO:0070062', ('13', '20'))	('endothelial', 'MPA', (87, 98))	('miR-103', 'Var', (54, 61))	('exosome-mediated', 'biological_process', 'GO:0099156', ('13', '29'))	('destroys', 'NegReg', (74, 82))	('miR-103', 'Chemical', '-', (54, 61))
7175	33912560	The overexpression of miR-105 in non-metastatic cancer cells induces metastasis and vascular permeability by targeting junction proteins, while miR-103 directly inhibits the expression of VE-cadherin (VE-Cad), p120-catenin (p120), and zonula occludens 1 (ZO-1).	('miR-103', 'Var', (144, 151))	('zonula occludens 1', 'Gene', '7082', (235, 253))	('p120', 'Gene', '1500', (224, 228))	('miR-105', 'Gene', (22, 29))	('ZO-1', 'Gene', (255, 259))	('cancer', 'Disease', (48, 54))	('p120', 'Gene', (210, 214))	('VE-Cad', 'Gene', '1003', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('miR-103', 'Chemical', '-', (144, 151))	('VE-cadherin', 'Gene', (188, 199))	('p120', 'Gene', (224, 228))	('overexpression', 'PosReg', (4, 18))	('targeting', 'MPA', (109, 118))	('metastasis', 'CPA', (69, 79))	('expression', 'MPA', (174, 184))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('inhibits', 'NegReg', (161, 169))	('induces', 'PosReg', (61, 68))	('vascular permeability', 'CPA', (84, 105))	('p120-catenin', 'Gene', '1500', (210, 222))	('miR-105', 'Chemical', '-', (22, 29))	('p120', 'Gene', '1500', (210, 214))	('cadherin', 'molecular_function', 'GO:0008014', ('191', '199'))	('zonula occludens', 'cellular_component', 'GO:0005923', ('235', '251'))	('p120-catenin', 'Gene', (210, 222))	('junction proteins', 'Protein', (119, 136))	('VE-Cad', 'Gene', (201, 207))	('ZO-1', 'Gene', '7082', (255, 259))	('VE-cadherin', 'Gene', '1003', (188, 199))	('zonula occludens 1', 'Gene', (235, 253))
7180	33912560	All these results suggest that exosomal miR-10b may activate the fibroblasts to facilitate CRC growth.	('miR-10b', 'Gene', (40, 47))	('activate', 'PosReg', (52, 60))	('facilitate', 'PosReg', (80, 90))	('fibroblasts', 'CPA', (65, 76))	('CRC growth', 'CPA', (91, 101))	('miR-10b', 'Gene', '406903', (40, 47))	('exosomal', 'Var', (31, 39))
7184	33912560	It is also worth noticing that miR-1247-3p secreted by HCC cells and carried via exosomes induces fibroblast activation to foster metastatic niche.	('fibroblast activation', 'biological_process', 'GO:0072537', ('98', '119'))	('HCC', 'Gene', (55, 58))	('induces', 'Reg', (90, 97))	('miR-1247-3p', 'Var', (31, 42))	('HCC', 'Gene', '619501', (55, 58))	('fibroblast activation to foster metastatic niche', 'CPA', (98, 146))
7186	33912560	Mechanically, miR-21 directly targets PTEN and activates the pyruvate dehydrogenase kinase isoenzyme 1 (PDK1)/AKT signaling pathway, whereas miR-1247-3p straightly targets B4GALT3, activating the beta1-integrin/NF-kappaB signaling in fibroblasts.	('miR-21', 'Gene', '406991', (14, 20))	('pyruvate dehydrogenase kinase isoenzyme 1', 'Gene', (61, 102))	('signaling', 'biological_process', 'GO:0023052', ('221', '230'))	('PDK1', 'molecular_function', 'GO:0004740', ('104', '108'))	('B4GALT3', 'Gene', '8703', (172, 179))	('AKT', 'Gene', (110, 113))	('beta1-integrin', 'Gene', (196, 210))	('activates', 'PosReg', (47, 56))	('PDK1', 'Gene', '5163', (104, 108))	('AKT signaling', 'biological_process', 'GO:0043491', ('110', '123'))	('PTEN', 'Gene', '5728', (38, 42))	('activating', 'PosReg', (181, 191))	('miR-21', 'Gene', (14, 20))	('pyruvate dehydrogenase kinase isoenzyme 1', 'Gene', '5163', (61, 102))	('miR-1247-3p', 'Var', (141, 152))	('AKT', 'Gene', '207', (110, 113))	('beta1-integrin', 'Gene', '3688', (196, 210))	('PDK1', 'Gene', (104, 108))	('signaling pathway', 'biological_process', 'GO:0007165', ('114', '131'))	('B4GALT3', 'Gene', (172, 179))	('PTEN', 'Gene', (38, 42))
7196	33912560	Circulating exosomal miR-221-3p from CSCC to human lymphatic endothelial cells (HLECs) results in the increased migration and tube formation of HLECs, and facilitates lymphangiogenesis through targeting VASH1 and activating the ERK/AKT signaling.	('AKT', 'Gene', '207', (232, 235))	('facilitates', 'PosReg', (155, 166))	('AKT signaling', 'biological_process', 'GO:0043491', ('232', '245'))	('miR-221-3p', 'Chemical', '-', (21, 31))	('lymphangiogenesis', 'CPA', (167, 184))	('ERK', 'molecular_function', 'GO:0004707', ('228', '231'))	('tube formation', 'biological_process', 'GO:0035148', ('126', '140'))	('miR-221-3p', 'Var', (21, 31))	('activating', 'PosReg', (213, 223))	('tube formation', 'CPA', (126, 140))	('targeting', 'Reg', (193, 202))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('167', '184'))	('ERK', 'Gene', '5594', (228, 231))	('AKT', 'Gene', (232, 235))	('VASH1', 'Gene', '22846', (203, 208))	('ERK', 'Gene', (228, 231))	('human', 'Species', '9606', (45, 50))	('migration', 'CPA', (112, 121))	('increased', 'PosReg', (102, 111))	('VASH1', 'Gene', (203, 208))
7228	33912560	The enhanced migration and invasion of HepG2 and 97L cells induced by co-culturing with LM3 exosomes can be reversed after knockdown of circPTGR1 expression.	('circPTGR1', 'Gene', (136, 145))	('enhanced', 'PosReg', (4, 12))	('HepG2', 'CellLine', 'CVCL:0027', (39, 44))	('invasion', 'CPA', (27, 35))	('knockdown', 'Var', (123, 132))	('LM3', 'CellLine', 'CVCL:5998', (88, 91))	('migration', 'CPA', (13, 22))
7238	33912560	Exosomes from oxaliplatin-resistant cells deliver circ_0005963 (termed ciRS-122) to sensitive cells, promoting glycolysis and drug resistance as a miR-122 sponge and enhancing the expression of PKM2.	('glycolysis', 'MPA', (111, 121))	('circ_0005963', 'Var', (50, 62))	('drug resistance', 'biological_process', 'GO:0042493', ('126', '141'))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (14, 25))	('drug resistance', 'Phenotype', 'HP:0020174', (126, 141))	('glycolysis', 'biological_process', 'GO:0006096', ('111', '121'))	('PKM2', 'Gene', (194, 198))	('expression', 'MPA', (180, 190))	('promoting', 'PosReg', (101, 110))	('drug resistance', 'biological_process', 'GO:0009315', ('126', '141'))	('enhancing', 'PosReg', (166, 175))	('drug resistance', 'MPA', (126, 141))	('miR-122', 'Gene', '406906', (147, 154))	('miR-122', 'Gene', (147, 154))	('PKM2', 'Gene', '5315', (194, 198))
7239	33912560	In addition, in vivo experiments reveal that decreasing si-ciRS-122 transportation could suppress glycolysis and increase sensitivity to oxaliplatin.	('oxaliplatin', 'Chemical', 'MESH:D000077150', (137, 148))	('glycolysis', 'MPA', (98, 108))	('si-ciRS-122 transportation', 'Var', (56, 82))	('increase', 'PosReg', (113, 121))	('decreasing', 'NegReg', (45, 55))	('glycolysis', 'biological_process', 'GO:0006096', ('98', '108'))	('suppress', 'NegReg', (89, 97))	('sensitivity to oxaliplatin', 'MPA', (122, 148))
7262	33912560	Of note is that, compared with normal fibroblasts, the expression of miR-21, miR-378e, miR-143, and miR-92a-3p in the CAF exosomes is significantly increased.	('miR-143', 'Gene', (87, 94))	('miR-378e', 'Gene', '100616498', (77, 85))	('miR-92a-3p', 'Var', (100, 110))	('CAF', 'Gene', '8850', (118, 121))	('increased', 'PosReg', (148, 157))	('miR-378e', 'Gene', (77, 85))	('expression', 'MPA', (55, 65))	('miR-21', 'Gene', (69, 75))	('miR-143', 'Gene', '406935', (87, 94))	('CAF', 'Gene', (118, 121))	('miR-21', 'Gene', '406991', (69, 75))
7268	33912560	In addition, CAF-derived exosomal miR-196a can be uptaken by head and neck cancer (HNC) cells and enhances cell growth and cisplatin resistance, which may be mediated by the translocation of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) and directly downregulate the expression of CDKN1B and ING5.	('expression', 'MPA', (274, 284))	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('cell growth', 'CPA', (107, 118))	('ING5', 'Gene', (299, 303))	('CAF', 'Gene', (13, 16))	('enhances', 'PosReg', (98, 106))	('uptaken', 'PosReg', (50, 57))	('head and neck cancer', 'Phenotype', 'HP:0012288', (61, 81))	('cell growth', 'biological_process', 'GO:0016049', ('107', '118'))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('downregulate', 'NegReg', (257, 269))	('heterogeneous nuclear ribonucleoprotein', 'molecular_function', 'GO:0008436', ('191', '230'))	('heterogeneous nuclear ribonucleoprotein A1', 'Gene', '3178', (191, 233))	('heterogeneous nuclear ribonucleoprotein', 'cellular_component', 'GO:0030530', ('191', '230'))	('CDKN1B', 'Gene', (288, 294))	('neck', 'cellular_component', 'GO:0044326', ('70', '74'))	('hnRNPA1', 'Gene', (235, 242))	('miR-196a', 'Var', (34, 42))	('heterogeneous nuclear ribonucleoprotein A1', 'Gene', (191, 233))	('cisplatin resistance', 'MPA', (123, 143))	('cancer', 'Disease', (75, 81))	('translocation', 'MPA', (174, 187))	('CDKN1B', 'Gene', '1027', (288, 294))	('CAF', 'Gene', '8850', (13, 16))	('hnRNPA1', 'Gene', '3178', (235, 242))	('ING5', 'Gene', '84289', (299, 303))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
7271	33912560	For example, exosomal PTENP1 suppresses the malignant phenotype of BC cells, which acts as a ceRNA sponge to promote the expression of PTEN by inhibiting the miR-17 levels, thereby inducing apoptosis and inhibiting BC cell invasion and migration.	('inducing', 'NegReg', (181, 189))	('PTENP1', 'Gene', (22, 28))	('expression', 'MPA', (121, 131))	('PTEN', 'Gene', '5728', (135, 139))	('PTENP1', 'Gene', '11191', (22, 28))	('PTEN', 'Gene', (22, 26))	('miR-17', 'Gene', '406952', (158, 164))	('exosomal', 'Var', (13, 21))	('PTEN', 'Gene', '5728', (22, 26))	('apoptosis', 'biological_process', 'GO:0097194', ('190', '199'))	('malignant phenotype of BC cells', 'CPA', (44, 75))	('apoptosis', 'biological_process', 'GO:0006915', ('190', '199'))	('promote', 'PosReg', (109, 116))	('miR-17', 'Gene', (158, 164))	('suppresses', 'NegReg', (29, 39))	('PTEN', 'Gene', (135, 139))	('inhibiting', 'NegReg', (143, 153))	('inhibiting', 'NegReg', (204, 214))	('apoptosis', 'CPA', (190, 199))
7281	33912560	Multiple studies have shown that exosomes from MSCs deliver miR-145-5p and miR-143, which inhibit cancer cell proliferation and metastasis, as well as induce cell apoptosis.	('inhibit', 'NegReg', (90, 97))	('miR-143', 'Gene', '406935', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('MSCs', 'molecular_function', 'GO:0043854', ('47', '51'))	('miR-143', 'Gene', (75, 82))	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('apoptosis', 'biological_process', 'GO:0006915', ('163', '172'))	('induce', 'PosReg', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('miR-145-5p', 'Chemical', '-', (60, 70))	('cell apoptosis', 'CPA', (158, 172))	('miR-145-5p', 'Var', (60, 70))	('cancer', 'Disease', (98, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('163', '172'))
7283	33912560	In addition, the exosomal miR-100 from MSCs to BC cells is associated with the decreased expression of vascular endothelial growth factor (VEGF) and the activation of the mTOR/HIF-1alpha signaling, which suppresses the angiogenesis of ECs.	('MSCs', 'molecular_function', 'GO:0043854', ('39', '43'))	('angiogenesis', 'CPA', (219, 231))	('vascular endothelial growth factor', 'Gene', (103, 137))	('miR-100', 'Gene', (26, 33))	('VEGF', 'Gene', '7422', (139, 143))	('HIF-1alpha', 'Gene', '3091', (176, 186))	('mTOR', 'Gene', '2475', (171, 175))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('103', '137'))	('expression', 'MPA', (89, 99))	('activation', 'PosReg', (153, 163))	('VEGF', 'Gene', (139, 143))	('decreased', 'NegReg', (79, 88))	('signaling', 'biological_process', 'GO:0023052', ('187', '196'))	('ECs', 'Disease', (235, 238))	('HIF-1alpha', 'Gene', (176, 186))	('miR-100', 'Gene', '406892', (26, 33))	('angiogenesis', 'biological_process', 'GO:0001525', ('219', '231'))	('suppresses', 'NegReg', (204, 214))	('exosomal', 'Var', (17, 25))	('vascular endothelial growth factor', 'Gene', '7422', (103, 137))	('mTOR', 'Gene', (171, 175))
7285	33912560	The transfer of miR-193a-3p, miR-210-3p, and miR-5100 from BMSCs to epithelial cancer cells via exosomes results in the activation of the STAT3 signaling and the upregulation of the mesenchymal-related molecules, thereby facilitating invasion and metastasis of lung cancer cells.	('epithelial cancer', 'Phenotype', 'HP:0031492', (68, 85))	('invasion', 'CPA', (234, 242))	('miR-21', 'Gene', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('miR-5100', 'Gene', '100847014', (45, 53))	('activation', 'PosReg', (120, 130))	('mesenchymal-related', 'Protein', (182, 201))	('cancer', 'Disease', (79, 85))	('STAT3', 'Gene', (138, 143))	('miR-193a-3p', 'Var', (16, 27))	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (247, 272))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (261, 272))	('STAT3', 'Gene', '6774', (138, 143))	('miR-5100', 'Gene', (45, 53))	('facilitating', 'PosReg', (221, 233))	('miR-21', 'Gene', '406991', (29, 35))	('upregulation', 'PosReg', (162, 174))	('cancer', 'Disease', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('metastasis of lung cancer', 'Disease', (247, 272))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
7296	33912560	Noticeably, MDSC miR-126a enhances the accumulation of MDSCs and tumor angiogenesis through regulation of S100A8/9.	('accumulation', 'MPA', (39, 51))	('S100A8/9', 'Gene', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('MDSCs', 'MPA', (55, 60))	('regulation', 'biological_process', 'GO:0065007', ('92', '102'))	('angiogenesis', 'biological_process', 'GO:0001525', ('71', '83'))	('miR-126a', 'Chemical', '-', (17, 25))	('enhances', 'PosReg', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('miR-126a', 'Var', (17, 25))	('S100A8/9', 'Gene', '6279;6280', (106, 114))
7299	33912560	For instance, it has been demonstrated that miR-501-3p is highly enriched in TAM-derived exosomes, which decreases the TGFBR3 levels through the activation of the TGF-beta signaling, thereby promoting PDAC cell migration and invasion.	('activation', 'PosReg', (145, 155))	('invasion', 'CPA', (225, 233))	('TAM', 'Gene', '8205', (77, 80))	('PDAC cell migration', 'CPA', (201, 220))	('signaling', 'biological_process', 'GO:0023052', ('172', '181'))	('cell migration', 'biological_process', 'GO:0016477', ('206', '220'))	('decreases', 'NegReg', (105, 114))	('TGF-beta', 'Gene', (163, 171))	('TGFBR3', 'Gene', '7049', (119, 125))	('TAM', 'Gene', (77, 80))	('promoting', 'PosReg', (191, 200))	('TGF-beta', 'Gene', '7039', (163, 171))	('miR-501-3p', 'Var', (44, 54))	('TGFBR3', 'Gene', (119, 125))
7300	33912560	In addition, the delivery of exosomal miR-223 to the co-cultured hypoxic EOC cells enhances drug resistance by activating the PTEN/PI3K/AKT pathway and is closely related to the recurrence of EOC.	('drug resistance', 'Phenotype', 'HP:0020174', (92, 107))	('PI3K', 'molecular_function', 'GO:0016303', ('131', '135'))	('EOC', 'Disease', (192, 195))	('exosomal', 'Var', (29, 37))	('miR-223', 'Gene', (38, 45))	('drug resistance', 'MPA', (92, 107))	('activating', 'PosReg', (111, 121))	('drug resistance', 'biological_process', 'GO:0009315', ('92', '107'))	('drug resistance', 'biological_process', 'GO:0042493', ('92', '107'))	('AKT', 'Gene', '207', (136, 139))	('PTEN', 'Gene', '5728', (126, 130))	('enhances', 'PosReg', (83, 91))	('miR-223', 'Gene', '407008', (38, 45))	('related', 'Reg', (163, 170))	('PTEN', 'Gene', (126, 130))	('AKT', 'Gene', (136, 139))
7301	33912560	TAM-derived exosomes also contain miR-365 that upregulates nucleotide triphosphates and induces cytidine deaminase, leading to gemcitabine resistance in PDAC cells.	('gemcitabine', 'Chemical', 'MESH:C056507', (127, 138))	('cytidine deaminase', 'Gene', '978', (96, 114))	('TAM', 'Gene', (0, 3))	('gemcitabine resistance', 'MPA', (127, 149))	('miR-365', 'Var', (34, 41))	('miR-365', 'Chemical', '-', (34, 41))	('cytidine deaminase', 'Gene', (96, 114))	('upregulates', 'PosReg', (47, 58))	('leading to', 'Reg', (116, 126))	('nucleotide triphosphates', 'MPA', (59, 83))	('TAM', 'Gene', '8205', (0, 3))	('induces', 'PosReg', (88, 95))	('nucleotide triphosphates', 'Chemical', '-', (59, 83))
7304	33912560	TAM-released miR-29a-3p and miR-21-5p are incorporated into CD4+ T cells via exosomes, which result in the imbalance of the Treg/Th17 ratio and formation of an immune-suppressive microenvironment, thereby facilitating EOC progression and metastasis.	('miR-21-5p', 'Gene', (28, 37))	('miR-21-5p', 'Gene', '406997', (28, 37))	('imbalance', 'Phenotype', 'HP:0002172', (107, 116))	('facilitating', 'PosReg', (205, 217))	('TAM', 'Gene', (0, 3))	('formation', 'biological_process', 'GO:0009058', ('144', '153'))	('metastasis', 'CPA', (238, 248))	('CD4', 'Gene', '920', (60, 63))	('TAM', 'Gene', '8205', (0, 3))	('EOC progression', 'CPA', (218, 233))	('miR-29a-3p', 'Var', (13, 23))	('CD4', 'Gene', (60, 63))	('imbalance', 'MPA', (107, 116))	('Treg', 'Chemical', '-', (124, 128))	('result in', 'Reg', (93, 102))
7311	33912560	Furthermore, exosomal lncRNA CCAL intrigues oxaliplatin resistance of CRC in vivo and in vitro, and exosomal miR-103 increases vascular permeability and tumor metastasis.	('tumor metastasis', 'Disease', (153, 169))	('ncRNA', 'Gene', (23, 28))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (44, 55))	('increases', 'PosReg', (117, 126))	('ncRNA', 'Gene', '220202', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('miR-103', 'Var', (109, 116))	('vascular permeability', 'MPA', (127, 148))	('oxaliplatin resistance', 'MPA', (44, 66))	('tumor metastasis', 'Disease', 'MESH:D009362', (153, 169))	('miR-103', 'Chemical', '-', (109, 116))
7345	33537239	We found that overexpression of HPDL in PDAC cells promotes tumorigenesis in vitro, whereas knockdown of HPDL inhibits cell proliferation and colony formation.	('PDAC', 'Phenotype', 'HP:0006725', (40, 44))	('cell proliferation', 'CPA', (119, 137))	('HPDL', 'Gene', '84842', (105, 109))	('HPDL', 'Gene', '84842', (32, 36))	('HPDL', 'Gene', (32, 36))	('HPDL', 'Gene', (105, 109))	('inhibits', 'NegReg', (110, 118))	('knockdown', 'Var', (92, 101))	('cell proliferation', 'biological_process', 'GO:0008283', ('119', '137'))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('promotes', 'PosReg', (51, 59))	('PDAC', 'Chemical', '-', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('formation', 'biological_process', 'GO:0009058', ('149', '158'))	('tumor', 'Disease', (60, 65))
7355	33537239	As PDAC progresses to malignancy, called acinar-to-ductal metaplasia (ADM), oncogenic mutations of KRAS essentially initiate precursor lesions called pancreatic intraepithelial neoplasias (PanINs).	('mutations', 'Var', (86, 95))	('PDAC', 'Chemical', '-', (3, 7))	('pancreatic intraepithelial neoplasias', 'Disease', 'MESH:D018290', (150, 187))	('metaplasia', 'biological_process', 'GO:0036074', ('58', '68'))	('KRAS', 'Gene', '3845', (99, 103))	('pancreatic intraepithelial neoplasias', 'Disease', (150, 187))	('malignancy', 'Disease', 'MESH:D009369', (22, 32))	('PDAC', 'Phenotype', 'HP:0006725', (3, 7))	('neoplasia', 'Phenotype', 'HP:0002664', (177, 186))	('neoplasias', 'Phenotype', 'HP:0002664', (177, 187))	('intraepithelial neoplasias', 'Phenotype', 'HP:0032187', (161, 187))	('KRAS', 'Gene', (99, 103))	('initiate', 'Reg', (116, 124))	('malignancy', 'Disease', (22, 32))	('acinar-to-ductal metaplasia', 'Disease', (41, 68))
7360	33537239	Moreover, oncogenic mutation of KRAS reprograms glutamine metabolism by upregulating aspartate transaminase (GOT1) and downregulating glutamate dehydrogenase (GLUD1) at the transcription level.	('glutamate', 'Chemical', 'MESH:D018698', (134, 143))	('glutamine metabolism', 'MPA', (48, 68))	('aspartate transaminase', 'MPA', (85, 107))	('GOT1', 'Gene', '2805', (109, 113))	('KRAS', 'Gene', (32, 36))	('mutation', 'Var', (20, 28))	('GOT1', 'Gene', (109, 113))	('aspartate', 'Chemical', 'MESH:D001224', (85, 94))	('KRAS', 'Gene', '3845', (32, 36))	('glutamine', 'Chemical', 'MESH:D005973', (48, 57))	('upregulating', 'PosReg', (72, 84))	('glutamate dehydrogenase', 'MPA', (134, 157))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('48', '68'))	('downregulating', 'NegReg', (119, 133))	('transcription', 'biological_process', 'GO:0006351', ('173', '186'))	('GLUD1', 'Gene', (159, 164))	('GLUD1', 'Gene', '2746', (159, 164))
7364	33537239	To account for this, a mitochondrion-localized protein SLC1A5 variant, functions as a glutamine transporter in the mitochondria, and mediates redox balancing in mitochondria.	('functions', 'Reg', (71, 80))	('glutamine', 'Chemical', 'MESH:D005973', (86, 95))	('redox balancing', 'MPA', (142, 157))	('mitochondria', 'cellular_component', 'GO:0005739', ('161', '173'))	('mitochondria', 'cellular_component', 'GO:0005739', ('115', '127'))	('SLC1A5', 'Gene', '6510', (55, 61))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('variant', 'Var', (62, 69))	('mitochondrion', 'cellular_component', 'GO:0005739', ('23', '36'))	('glutamine transporter', 'MPA', (86, 107))	('mediates', 'Reg', (133, 141))	('SLC1A5', 'Gene', (55, 61))
7427	33537239	Collectively, HPDL is upregulated in PDAC at both the mRNA and protein levels, in both tumor cell lines and tumor tissues, and high expression of HPDL is associated with poor prognosis in PDAC patients.	('HPDL', 'Gene', (146, 150))	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('upregulated', 'PosReg', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('PDAC', 'Phenotype', 'HP:0006725', (188, 192))	('tumor', 'Disease', (108, 113))	('PDAC', 'Chemical', '-', (37, 41))	('HPDL', 'Gene', '84842', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('PDAC', 'Phenotype', 'HP:0006725', (37, 41))	('patients', 'Species', '9606', (193, 201))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (87, 92))	('high expression', 'Var', (127, 142))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('HPDL', 'Gene', (14, 18))	('PDAC', 'Disease', (37, 41))	('HPDL', 'Gene', '84842', (14, 18))	('PDAC', 'Chemical', '-', (188, 192))
7451	33537239	As a result, overexpression of HPDL enhanced basal respiration and knockdown of HPDL diminished basal respiration and maximum uncoupled respiration.	('basal respiration', 'MPA', (45, 62))	('respiration', 'biological_process', 'GO:0007585', ('51', '62'))	('HPDL', 'Gene', (80, 84))	('respiration', 'biological_process', 'GO:0045333', ('102', '113'))	('basal respiration', 'MPA', (96, 113))	('knockdown', 'Var', (67, 76))	('diminished', 'NegReg', (85, 95))	('respiration', 'biological_process', 'GO:0007585', ('136', '147'))	('respiration', 'biological_process', 'GO:0045333', ('51', '62'))	('respiration', 'biological_process', 'GO:0045333', ('136', '147'))	('enhanced', 'PosReg', (36, 44))	('respiration', 'biological_process', 'GO:0007585', ('102', '113'))	('HPDL', 'Gene', '84842', (31, 35))	('HPDL', 'Gene', (31, 35))	('HPDL', 'Gene', '84842', (80, 84))
7501	33537239	According to bioinformatic analysis and IHC analysis, we found that HPDL was upregulated in PDAC, and high expression of HPDL was associated with poor prognosis.	('HPDL', 'Gene', (121, 125))	('PDAC', 'Disease', (92, 96))	('PDAC', 'Phenotype', 'HP:0006725', (92, 96))	('upregulated', 'PosReg', (77, 88))	('HPDL', 'Gene', '84842', (68, 72))	('high expression', 'Var', (102, 117))	('HPDL', 'Gene', (68, 72))	('PDAC', 'Chemical', '-', (92, 96))	('HPDL', 'Gene', '84842', (121, 125))
7538	32660466	Dysregulation of microRNAs (miRNAs) have been shown to play a significant role in progression of PDAC.	('Dysregulation', 'Var', (0, 13))	('microRNAs', 'Protein', (17, 26))	('PDAC', 'Disease', (97, 101))	('PDAC', 'Chemical', '-', (97, 101))
7542	32660466	Translational repression of eight key pro-tumorigenic and -fibrotic targets namely IGF-1, COL5A3, CLDN1, E2F7, MYBL2, ITGA6 and ADAMTS2 by miR-29a was observed in PSCs.	('CLDN1', 'Gene', (98, 103))	('miR-29a', 'Var', (139, 146))	('IGF-1', 'Gene', (83, 88))	('ADAMTS2', 'Gene', (128, 135))	('PSCs', 'Disease', (163, 167))	('ITGA6', 'Gene', (118, 123))	('tumor', 'Disease', (42, 47))	('MYBL2', 'Gene', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('CLDN1', 'Gene', '9076', (98, 103))	('IGF-1', 'Gene', '3479', (83, 88))	('E2F7', 'Gene', (105, 109))	('MYBL2', 'Gene', '4605', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('ITGA6', 'Gene', '3655', (118, 123))	('COL5A3', 'Gene', '50509', (90, 96))	('COL5A3', 'Gene', (90, 96))	('Translational', 'MPA', (0, 13))	('ADAMTS2', 'Gene', '9509', (128, 135))
7543	32660466	Using pathway analysis, we find that miR-29a modulates effectors of IGF-1-p53 signaling in PSCs that may hinder carcinogenesis.	('hinder', 'NegReg', (105, 111))	('carcinogenesis', 'Disease', 'MESH:D063646', (112, 126))	('miR-29a', 'Var', (37, 44))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('carcinogenesis', 'Disease', (112, 126))	('PSCs', 'Disease', (91, 95))	('modulates', 'Reg', (45, 54))	('effectors', 'MPA', (55, 64))	('p53', 'Gene', (74, 77))	('IGF-1', 'Gene', '3479', (68, 73))	('IGF-1', 'Gene', (68, 73))	('p53', 'Gene', '7157', (74, 77))
7553	32660466	Studies have further demonstrated the association of dysregulated miRNAs in stromal cells with progression of different types of cancer, including pancreatic cancer, indicating the potential of miRNAs in developing targeted therapies.	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('pancreatic cancer', 'Disease', (147, 164))	('association', 'Interaction', (38, 49))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', (158, 164))	('dysregulated', 'Var', (53, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('miRNAs', 'Gene', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
7554	32660466	In our previous work, we found microRNA-29a (miR-29a) to be pre-dominantly an anti-fibrotic molecule in PDAC, where miR-29a was significantly downregulated in activated PSCs and fibroblasts of murine and human PDAC as compared to normal pancreas, resulting in enhanced stromal extracellular matrix (ECM) deposition in PDAC microenvironment.	('extracellular matrix', 'cellular_component', 'GO:0031012', ('277', '297'))	('murine', 'Species', '10090', (193, 199))	('PDAC', 'Chemical', '-', (104, 108))	('miR-29a', 'Var', (116, 123))	('PDAC', 'Chemical', '-', (210, 214))	('enhanced', 'PosReg', (260, 268))	('downregulated', 'NegReg', (142, 155))	('human', 'Species', '9606', (204, 209))	('PDAC', 'Chemical', '-', (318, 322))	('pre', 'molecular_function', 'GO:0003904', ('60', '63'))	('stromal', 'MPA', (269, 276))	('microRNA-29a', 'Gene', (31, 43))	('microRNA-29a', 'Gene', '387222', (31, 43))
7560	32660466	To measure mature miR-29a expressions, TaqMan qRT-PCR reactions were set up using TaqMan Fast Advanced Mastermix (4444557, Applied Biosystems Foster City, CA) with TaqMan probe and primers for mature miR29a (002112, Applied Biosystems, Foster City, CA) or U6 snRNA (001973, Applied Biosystems, Foster City, CA).	('002112', 'Var', (208, 214))	('miR29a', 'Gene', '407021', (200, 206))	('miR29a', 'Gene', (200, 206))
7567	32660466	The primary antibodies used in this study were anti-IGF-1 (ab9572, Abcam, Cambridge, MA), anti-COL5A3 (PA5-77257, Thermo Fisher Scientific, Carlsbad, CA), anti-E2F7 (ab56022, Abcam, Cambridge, MA), anti-MYBL2 (PA546845, Thermo Fisher Scientific, Carlsbad, CA), anti-ITGA6 (3750, Cell Signaling Technology, Danvers, MA), anti-CLDN1 (4933S, Cell Signaling Technology, Danvers, MA), anti-ADAMTS2 (3485, Cell Signaling Technology, Danvers, MA), and anti-GAPDH (MA5-15738, Thermo Fisher Scientific, Carlsbad, CA).	('MYBL2', 'Gene', '4605', (203, 208))	('ITGA6', 'Gene', '3655', (266, 271))	('GAPDH', 'Gene', (450, 455))	('PA546845', 'Var', (210, 218))	('COL5A3', 'Gene', '50509', (95, 101))	('IGF-1', 'Gene', (52, 57))	('COL5A3', 'Gene', (95, 101))	('ADAMTS2', 'Gene', (385, 392))	('IGF-1', 'Gene', '3479', (52, 57))	('Signaling', 'biological_process', 'GO:0023052', ('284', '293'))	('Signaling', 'biological_process', 'GO:0023052', ('405', '414'))	('CLDN1', 'Gene', (325, 330))	('ITGA6', 'Gene', (266, 271))	('ADAMTS2', 'Gene', '9509', (385, 392))	('MYBL2', 'Gene', (203, 208))	('GAPDH', 'Gene', '2597', (450, 455))	('4933S', 'Var', (332, 337))	('Signaling', 'biological_process', 'GO:0023052', ('344', '353'))	('CLDN1', 'Gene', '9076', (325, 330))
7580	32660466	ADAMTS2, belonging to the ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS) family, is responsible for processing of collagen type I, II, III and V precursors (pro-collagens) into mature collagen by excision of amino-propeptide, which is essential for generation of collagen monomers and assembly of mature collagen fibrils.	('collagen', 'molecular_function', 'GO:0005202', ('321', '329'))	('collagen', 'molecular_function', 'GO:0005202', ('280', '288'))	('excision', 'Var', (213, 221))	('amino-propeptide', 'Chemical', '-', (225, 241))	('ADAMTS2', 'Gene', (0, 7))	('ADAMTS2', 'Gene', '9509', (0, 7))	('collagen', 'molecular_function', 'GO:0005202', ('201', '209'))	('collagen', 'molecular_function', 'GO:0005202', ('131', '139'))	('responsible', 'Reg', (101, 112))
7581	32660466	Inhibition of ADAMTS2 has been shown to reduce stromal deposition and modulate TGF-beta1 signaling.	('modulate', 'Reg', (70, 78))	('TGF-beta1', 'Gene', '7040', (79, 88))	('TGF-beta1', 'Gene', (79, 88))	('reduce', 'NegReg', (40, 46))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('ADAMTS2', 'Gene', (14, 21))	('Inhibition', 'Var', (0, 10))	('ADAMTS2', 'Gene', '9509', (14, 21))	('stromal deposition', 'CPA', (47, 65))
7589	32660466	Interestingly, one of the oncogenes PTPN1 in the pathway is also a predicted direct miR-29a target, however, our RNAseq data did not show differential expression for this gene with miR-29a overexpression, which could be an effect specific to the PSCs.	('miR-29a', 'Var', (181, 188))	('PTPN1', 'Gene', '5770', (36, 41))	('overexpression', 'PosReg', (189, 203))	('PTPN1', 'Gene', (36, 41))
7598	32660466	Nonetheless, it is apparent that miR-29a modulates extracellular IGF-1/IGF-1R signaling in PSCs, and intracellular NRAS expression in pancreatic cancer cells, which indicates a functional role of the molecule in tumor-stromal crosstalk via insulin/IRF -RAS/MAPK signaling mechanism in PDAC.	('insulin', 'molecular_function', 'GO:0016088', ('240', '247'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (134, 151))	('NRAS', 'Gene', (115, 119))	('MAPK', 'molecular_function', 'GO:0004707', ('257', '261'))	('IGF-1', 'Gene', '3479', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('modulates', 'Reg', (41, 50))	('tumor-stromal crosstalk via insulin', 'Disease', 'MESH:D036821', (212, 247))	('extracellular', 'cellular_component', 'GO:0005576', ('51', '64'))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('pancreatic cancer', 'Disease', (134, 151))	('IGF-1R', 'Gene', '3480', (71, 77))	('tumor-stromal crosstalk via insulin', 'Disease', (212, 247))	('IGF-1R', 'Gene', (71, 77))	('IGF-1', 'Gene', (65, 70))	('PDAC', 'Disease', (285, 289))	('miR-29a', 'Var', (33, 40))	('intracellular', 'cellular_component', 'GO:0005622', ('101', '114'))	('NRAS', 'Gene', '4893', (115, 119))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (134, 151))	('IGF-1', 'Gene', '3479', (65, 70))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('257', '271'))	('PDAC', 'Chemical', '-', (285, 289))	('IGF-1', 'Gene', (71, 76))
7609	32660466	Our western blot analysis indicated the highest repression of ITGA6, ADAMTS2 and IGF-1 protein levels with miR-29a overexpression in PSCs (Fig.	('repression', 'MPA', (48, 58))	('highest', 'Reg', (40, 47))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('IGF-1', 'Gene', '3479', (81, 86))	('PSCs', 'Disease', (133, 137))	('ITGA6', 'Gene', '3655', (62, 67))	('IGF-1', 'Gene', (81, 86))	('ITGA6', 'Gene', (62, 67))	('miR-29a', 'Var', (107, 114))	('ADAMTS2', 'Gene', (69, 76))	('protein levels', 'MPA', (87, 101))	('overexpression', 'PosReg', (115, 129))	('ADAMTS2', 'Gene', '9509', (69, 76))
7612	32660466	In addition, high IGF-1 with low IGFBP3 expressions associated with enhanced risks for PDAC.	('high IGF-', 'Phenotype', 'HP:0030269', (13, 22))	('low', 'NegReg', (29, 32))	('high', 'Var', (13, 17))	('PDAC', 'Chemical', '-', (87, 91))	('low IGFBP3 expressions', 'Phenotype', 'HP:0031037', (29, 51))	('IGFBP3', 'Gene', (33, 39))	('IGF-1', 'Gene', '3479', (18, 23))	('PDAC', 'Disease', (87, 91))	('IGF-1', 'Gene', (18, 23))	('IGFBP3', 'Gene', '3486', (33, 39))
7622	32660466	Evidently, miR-29a plays an anti-fibrotic role in PDAC by influencing ECM deposition via modulation of multiple targets in the collagen pathway.	('collagen', 'molecular_function', 'GO:0005202', ('127', '135'))	('PDAC', 'Disease', (50, 54))	('influencing', 'Reg', (58, 69))	('ECM', 'MPA', (70, 73))	('miR-29a', 'Var', (11, 18))	('modulation', 'Reg', (89, 99))	('collagen', 'Pathway', (127, 135))	('PDAC', 'Chemical', '-', (50, 54))	('anti-fibrotic', 'MPA', (28, 41))
7624	32660466	E2F7 associates with poor patient outcome in several types of cancer including PDAC and has been shown essential for mouse embryonic survival.	('patient', 'Species', '9606', (26, 33))	('PDAC', 'Chemical', '-', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mouse', 'Species', '10090', (117, 122))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('PDAC', 'Disease', (79, 83))	('E2F7', 'Var', (0, 4))
7625	32660466	Inhibition of E2F7 enhanced G1 phase percentage in prostate cancer reducing cellular proliferation.	('prostate cancer', 'Disease', 'MESH:D011471', (51, 66))	('prostate cancer', 'Disease', (51, 66))	('E2F7', 'Gene', (14, 18))	('prostate cancer', 'Phenotype', 'HP:0012125', (51, 66))	('G1 phase', 'biological_process', 'GO:0051318', ('28', '36'))	('Inhibition', 'Var', (0, 10))	('reducing', 'NegReg', (67, 75))	('cellular proliferation', 'CPA', (76, 98))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('G1 phase percentage', 'CPA', (28, 47))	('enhanced', 'PosReg', (19, 27))
7636	32660466	Depletion of p53 in stromal cells caused faster and more aggressive tumor development with enhanced invasion and metastasis of cancer cells, suggesting a paracrine mechanism of p53 in tumor progression.	('faster', 'PosReg', (41, 47))	('p53', 'Gene', (177, 180))	('Depletion', 'Var', (0, 9))	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('p53', 'Gene', '7157', (13, 16))	('cancer', 'Disease', (127, 133))	('aggressive tumor', 'Disease', 'MESH:D001523', (57, 73))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('p53', 'Gene', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('enhanced', 'PosReg', (91, 99))	('aggressive tumor', 'Disease', (57, 73))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('p53', 'Gene', '7157', (177, 180))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('more', 'PosReg', (52, 56))
7637	32660466	In addition, studies have reported the occurrence of inactivating p53 mutations in fibroblastic stromal cells and their association in promoting tumor progression and cancer cell metastasis in types of carcinogenesis, although the molecular mechanisms are still unclear.	('mutations', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('p53', 'Gene', '7157', (66, 69))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Disease', (167, 173))	('inactivating', 'Var', (53, 65))	('promoting', 'PosReg', (135, 144))	('carcinogenesis', 'Disease', 'MESH:D063646', (202, 216))	('tumor', 'Disease', (145, 150))	('carcinogenesis', 'Disease', (202, 216))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('p53', 'Gene', (66, 69))
7639	32660466	With p53 mutations, MYBL2 repression is uncoupled allowing enhanced binding of the molecule with MuvB and FOXM1 leading to activation of mitotic genes.	('MYBL2', 'Gene', (20, 25))	('binding', 'Interaction', (68, 75))	('MuvB', 'Gene', (97, 101))	('mutations', 'Var', (9, 18))	('enhanced', 'PosReg', (59, 67))	('FOXM1', 'Gene', (106, 111))	('p53', 'Gene', (5, 8))	('p53', 'Gene', '7157', (5, 8))	('FOXM1', 'Gene', '2305', (106, 111))	('activation', 'PosReg', (123, 133))	('binding', 'molecular_function', 'GO:0005488', ('68', '75'))	('mitotic genes', 'Gene', (137, 150))	('MYBL2', 'Gene', '4605', (20, 25))
7645	32660466	Although the exact mechanisms of MYBL2 and E2F7 in PSCs is still to be understood, our results suggest that dysregulation of miR-29a in PSCs derepresses genes such as IGF-1, MYBL2 and E2F7, which may in turn disrupt stromal p53 regulation, promoting PSC-mediated tumor proliferation.	('PSC-mediated', 'Disease', (250, 262))	('p53', 'Gene', '7157', (224, 227))	('stromal', 'Protein', (216, 223))	('derepresses', 'PosReg', (141, 152))	('MYBL2', 'Gene', (33, 38))	('dysregulation', 'Var', (108, 121))	('p53', 'Gene', (224, 227))	('MYBL2', 'Gene', '4605', (33, 38))	('tumor', 'Disease', (263, 268))	('promoting', 'PosReg', (240, 249))	('MYBL2', 'Gene', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('PSCs', 'Disease', (136, 140))	('IGF-1', 'Gene', (167, 172))	('regulation', 'biological_process', 'GO:0065007', ('228', '238'))	('E2F7', 'Gene', (184, 188))	('disrupt', 'NegReg', (208, 215))	('MYBL2', 'Gene', '4605', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('regulation', 'MPA', (228, 238))	('IGF-1', 'Gene', '3479', (167, 172))	('miR-29a', 'Gene', (125, 132))
7651	32660466	Given the functional relationship among the identified miR-29a targets in our PSCs dataset, it is likely that restoration of miR-29a in PSCs will dwindle or escalate the interconnected tumor-suppressive/pro-tumorigenic networks respectively in PDAC microenvironment, causing global regulation of the network functions to hinder the disease progression.	('tumor', 'Disease', (185, 190))	('dwindle', 'NegReg', (146, 153))	('escalate', 'PosReg', (157, 165))	('restoration', 'Var', (110, 121))	('PDAC', 'Chemical', '-', (244, 248))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('miR-29a', 'Gene', (125, 132))	('regulation', 'biological_process', 'GO:0065007', ('282', '292'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (207, 212))	('global regulation', 'MPA', (275, 292))
7660	32457840	This phenotype is supported by upregulated net acid extrusion and epithelial-to-mesenchymal transition (EMT), the latter typically induced by aberrant transforming growth factor-beta (TGFbeta) signaling.	('TGFbeta', 'Gene', (184, 191))	('epithelial-to-mesenchymal transition', 'CPA', (66, 102))	('transforming growth factor-beta', 'Gene', '7124', (151, 182))	('aberrant', 'Var', (142, 150))	('TGFbeta', 'Gene', '7039', (184, 191))	('upregulated', 'PosReg', (31, 42))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('66', '102'))	('transforming growth factor-beta', 'molecular_function', 'GO:0005160', ('151', '182'))	('net acid extrusion', 'MPA', (43, 61))	('signaling', 'biological_process', 'GO:0023052', ('193', '202'))	('net acid', 'Chemical', '-', (43, 51))	('EMT', 'biological_process', 'GO:0001837', ('104', '107'))	('transforming growth factor-beta', 'Gene', (151, 182))
7667	32457840	Proliferation was increased in Panc-1 cells and decreased in BxPC-3 cells, upon TGFbeta-1 treatment, and this, as well as EMT per se, was unaffected by NHE1- or NBCn1 inhibition.	('NBCn1', 'Gene', (161, 166))	('increased', 'PosReg', (18, 27))	('TGFbeta-1', 'Gene', (80, 89))	('NBCn1', 'Gene', '9497', (161, 166))	('Panc-1', 'CellLine', 'CVCL:0480', (31, 37))	('decreased', 'NegReg', (48, 57))	('BxPC-3', 'CellLine', 'CVCL:0186', (61, 67))	('EMT', 'biological_process', 'GO:0001837', ('122', '125'))	('NHE1', 'Gene', (152, 156))	('treatment', 'Var', (90, 99))	('NHE1', 'Gene', '6548', (152, 156))	('Proliferation', 'CPA', (0, 13))
7668	32457840	TGFbeta-1-induced EMT was associated with a 4-fold increase in Panc-1 cell invasiveness, which further increased ~10-fold upon knockdown of the tumor suppressor Merlin (Neurofibromatosis type 2).	('increase', 'PosReg', (51, 59))	('tumor', 'Disease', (144, 149))	('EMT', 'CPA', (18, 21))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (169, 186))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('144', '160'))	('Neurofibromatosis', 'Disease', (169, 186))	('Panc-1 cell invasiveness', 'Disease', (63, 87))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('Merlin', 'Gene', '4771', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('Merlin', 'Gene', (161, 167))	('EMT', 'biological_process', 'GO:0001837', ('18', '21'))	('TGFbeta-1-induced', 'Gene', (0, 17))	('knockdown', 'Var', (127, 136))	('Panc-1 cell invasiveness', 'Disease', 'MESH:D009362', (63, 87))	('tumor suppressor', 'biological_process', 'GO:0051726', ('144', '160'))	('Neurofibromatosis', 'Disease', 'MESH:C537392', (169, 186))
7672	32457840	NHE1 and NBCn1 are not required for EMT per se or EMT-associated proliferation changes, but are essential for the potentiation of invasiveness induced by Merlin knockdown.	('NBCn1', 'Gene', (9, 14))	('NHE1', 'Gene', (0, 4))	('EMT', 'biological_process', 'GO:0001837', ('50', '53'))	('Merlin', 'Gene', (154, 160))	('NHE1', 'Gene', '6548', (0, 4))	('Merlin', 'Gene', '4771', (154, 160))	('knockdown', 'Var', (161, 170))	('EMT', 'biological_process', 'GO:0001837', ('36', '39'))	('potentiation', 'PosReg', (114, 126))	('invasiveness', 'CPA', (130, 142))	('NBCn1', 'Gene', '9497', (9, 14))
7676	32457840	While PDAC genotypes are highly complex, the most widely characterized driver mutations are activating KRAS mutations, inactivating p53 tumor suppressor mutations, and inactivation or loss of the cyclin-dependent kinase inhibitor 2A (CDKN2A, P16INK4) and the transforming growth factor beta (TGF-beta) effector, SMAD4.	('transforming growth factor beta', 'Gene', (259, 290))	('TGF-beta', 'Gene', (292, 300))	('PDAC', 'Chemical', '-', (6, 10))	('inactivating', 'NegReg', (119, 131))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('259', '290'))	('CDKN2A', 'Gene', (234, 240))	('transforming growth factor beta', 'Gene', '7124', (259, 290))	('mutations', 'Var', (78, 87))	('tumor', 'Disease', (136, 141))	('activating', 'PosReg', (92, 102))	('CDKN2A', 'Gene', '1029', (234, 240))	('P16INK4', 'Gene', (242, 249))	('KRAS', 'Gene', '3845', (103, 107))	('SMAD4', 'Gene', (312, 317))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('196', '229'))	('p53', 'Gene', '7157', (132, 135))	('loss', 'NegReg', (184, 188))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('P16INK4', 'Gene', '1029', (242, 249))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('136', '152'))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (196, 232))	('KRAS', 'Gene', (103, 107))	('mutations', 'Var', (108, 117))	('p53', 'Gene', (132, 135))	('inactivation', 'Var', (168, 180))	('tumor suppressor', 'biological_process', 'GO:0051726', ('136', '152'))	('TGF-beta', 'Gene', '7039', (292, 300))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('213', '229'))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('SMAD4', 'Gene', '4089', (312, 317))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (196, 232))
7685	32457840	Illustrating the importance of TGFbeta signaling in this cancer, a recent study showed that almost 50% of PDAC patient tumors exhibited mutations in TGF-beta signaling components.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('TGFbeta', 'Gene', '7039', (31, 38))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (57, 63))	('signaling', 'biological_process', 'GO:0023052', ('158', '167'))	('PDAC', 'Disease', (106, 110))	('TGF-beta', 'Gene', (149, 157))	('PDAC', 'Chemical', '-', (106, 110))	('TGFbeta', 'Gene', (31, 38))	('mutations', 'Var', (136, 145))	('patient', 'Species', '9606', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('signaling', 'biological_process', 'GO:0023052', ('39', '48'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('TGF-beta', 'Gene', '7039', (149, 157))	('exhibited', 'Reg', (126, 135))
7686	32457840	While SMAD4 inactivating mutations are most common, mutations in SMAD3, TGFbeta receptor type I (TGFBR1) and-2 (TFGBR2) are also reported.	('mutations', 'Var', (52, 61))	('TGFbeta', 'Gene', '7039', (72, 79))	('SMAD4', 'Gene', '4089', (6, 11))	('TGFBR1', 'Gene', '7046', (97, 103))	('SMAD3', 'Gene', '4088', (65, 70))	('TGFBR1', 'Gene', (97, 103))	('SMAD3', 'Gene', (65, 70))	('SMAD4', 'Gene', (6, 11))	('inactivating mutations', 'Var', (12, 34))	('TGFbeta', 'Gene', (72, 79))	('TFGBR2', 'Gene', (112, 118))
7697	32457840	Furthermore, knockdown of the tumor suppressor Merlin potentiates TGFbeta-1-induced Panc-1 cell invasiveness in a manner dependent on both NHE1 and NBCn1.	('TGFbeta-1-induced', 'Gene', (66, 83))	('NBCn1', 'Gene', (148, 153))	('Merlin', 'Gene', '4771', (47, 53))	('NHE1', 'Gene', '6548', (139, 143))	('Merlin', 'Gene', (47, 53))	('Panc-1 cell invasiveness', 'Disease', 'MESH:D009362', (84, 108))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('potentiates', 'PosReg', (54, 65))	('NHE1', 'Gene', (139, 143))	('NBCn1', 'Gene', '9497', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('Panc-1 cell invasiveness', 'Disease', (84, 108))	('knockdown', 'Var', (13, 22))	('tumor', 'Disease', (30, 35))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))
7709	32457840	Cells were seeded to ~40% confluency in the relevant culture dishes and transfected with NHE1 siRNA (100 nM), NBCn1 siRNA (25 nM), Merlin siRNA (50 nM) or mock siRNA (50 nM), using Lipofectamine (Invitrogen) transfection reagent, according to the manufacturer's specifications.	('NHE1', 'Gene', (89, 93))	('50 nM', 'Var', (145, 150))	('NBCn1', 'Gene', (110, 115))	('25 nM', 'Var', (123, 128))	('100 nM', 'Var', (101, 107))	('NHE1', 'Gene', '6548', (89, 93))	('Lipofectamine', 'Chemical', 'MESH:C086724', (181, 194))	('Merlin', 'Gene', '4771', (131, 137))	('NBCn1', 'Gene', '9497', (110, 115))	('Merlin', 'Gene', (131, 137))
7750	32457840	To assess the role of SMAD4 in TGFbeta-1-induced EMT in Panc-1 cells, we knocked down SMAD4 by siRNA in Panc-1 cells, followed by TGFbeta-1 treatment for 48 h, and western blotting for E-cadherin and CTGF (Figures 2E-H).	('SMAD4', 'Gene', (22, 27))	('SMAD4', 'Gene', '4089', (86, 91))	('CTGF', 'Gene', '1490', (200, 204))	('Panc-1', 'CellLine', 'CVCL:0480', (56, 62))	('Panc-1', 'CellLine', 'CVCL:0480', (104, 110))	('CTGF', 'Gene', (200, 204))	('EMT', 'biological_process', 'GO:0001837', ('49', '52'))	('E-cadherin', 'Gene', (185, 195))	('E-cadherin', 'Gene', '999', (185, 195))	('cadherin', 'molecular_function', 'GO:0008014', ('187', '195'))	('SMAD4', 'Gene', '4089', (22, 27))	('SMAD4', 'Gene', (86, 91))	('knocked', 'Var', (73, 80))
7752	32457840	Confirming efficient knockdown, the SMAD4 protein level was reduced by more than 80% in SMAD4 siRNA-treated cells (Figures 2E,F).	('SMAD4', 'Gene', (88, 93))	('SMAD4', 'Gene', (36, 41))	('reduced', 'NegReg', (60, 67))	('knockdown', 'Var', (21, 30))	('SMAD4', 'Gene', '4089', (88, 93))	('SMAD4', 'Gene', '4089', (36, 41))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))
7753	32457840	Notably, the E-cadherin level was more than doubled by SMAD4 knockdown in the absence of TGFbeta-1, and this was only marginally reduced by TGFbeta-1-induced increase in CTGF expression was abolished in SMAD4-depleted cells (Figure 2G).	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('expression', 'MPA', (175, 185))	('CTGF', 'Gene', '1490', (170, 174))	('SMAD4', 'Gene', '4089', (203, 208))	('SMAD4', 'Gene', '4089', (55, 60))	('knockdown', 'Var', (61, 70))	('CTGF', 'Gene', (170, 174))	('E-cadherin', 'Gene', (13, 23))	('SMAD4', 'Gene', (203, 208))	('E-cadherin', 'Gene', '999', (13, 23))	('doubled', 'PosReg', (44, 51))	('SMAD4', 'Gene', (55, 60))
7754	32457840	Conversely, SMAD4 knockdown had no effect on the CTGF level under control conditions yet abolished the increase in CTGF induced by TGFbeta-1 treatment (Figure 2H).	('knockdown', 'Var', (18, 27))	('CTGF', 'Gene', (49, 53))	('SMAD4', 'Gene', (12, 17))	('CTGF', 'Gene', '1490', (115, 119))	('abolished', 'NegReg', (89, 98))	('CTGF', 'Gene', (115, 119))	('SMAD4', 'Gene', '4089', (12, 17))	('CTGF', 'Gene', '1490', (49, 53))	('TGFbeta-1', 'Gene', (131, 140))
7759	32457840	The TGFbeta-1-induced increase in NHE1 expression was strongly reduced by SMAD4 knockdown in Panc-1 cells (Figures 3E,F), whereas the modest increase in NBCn1 expression was not affected by SMAD4 knockdown (Figures 3E,G).	('NBCn1', 'Gene', '9497', (153, 158))	('knockdown', 'Var', (80, 89))	('SMAD4', 'Gene', (190, 195))	('SMAD4', 'Gene', (74, 79))	('reduced', 'NegReg', (63, 70))	('NHE1', 'Gene', (34, 38))	('NBCn1', 'Gene', (153, 158))	('increase', 'PosReg', (22, 30))	('SMAD4', 'Gene', '4089', (190, 195))	('NHE1', 'Gene', '6548', (34, 38))	('SMAD4', 'Gene', '4089', (74, 79))	('Panc-1', 'CellLine', 'CVCL:0480', (93, 99))	('expression', 'MPA', (39, 49))	('TGFbeta-1-induced', 'Gene', (4, 21))
7793	32457840	siRNA-mediated knockdown of NHE1 further increased TGFbeta-1-induced invasiveness, whereas knockdown of NBCn1 or both transporters in combination had no effect (Figures 6A,B).	('invasiveness', 'CPA', (69, 81))	('increased', 'PosReg', (41, 50))	('knockdown', 'Var', (15, 24))	('NBCn1', 'Gene', (104, 109))	('TGFbeta-1-induced', 'Gene', (51, 68))	('NHE1', 'Gene', (28, 32))	('increased TGFbeta-1', 'Phenotype', 'HP:0030269', (41, 60))	('NHE1', 'Gene', '6548', (28, 32))	('NBCn1', 'Gene', '9497', (104, 109))
7794	32457840	The unexpected exacerbation of invasiveness by NHE1 knockdown prompted us to ask whether the impact of NHE1 on PDAC cell invasiveness was genotype-dependent.	('NHE1', 'Gene', (47, 51))	('NHE1', 'Gene', '6548', (47, 51))	('exacerbation', 'PosReg', (15, 27))	('knockdown', 'Var', (52, 61))	('NHE1', 'Gene', (103, 107))	('PDAC', 'Chemical', '-', (111, 115))	('NHE1', 'Gene', '6548', (103, 107))	('invasiveness', 'MPA', (31, 43))
7796	32457840	siRNA-mediated knockdown of Merlin (Figure 6A) increased basal invasion 4-fold and almost doubled TGFbeta-1-induced invasiveness (Figure 6C).	('knockdown', 'Var', (15, 24))	('TGFbeta-1-induced', 'MPA', (98, 115))	('Merlin', 'Gene', (28, 34))	('increased', 'PosReg', (47, 56))	('Merlin', 'Gene', '4771', (28, 34))	('basal invasion', 'CPA', (57, 71))
7797	32457840	Notably, in Merlin-depleted cells, knockdown of either NHE1 or NBCn1 abolished the increase in invasion (Figure 6C).	('knockdown', 'Var', (35, 44))	('Merlin', 'Gene', '4771', (12, 18))	('invasion', 'MPA', (95, 103))	('Merlin', 'Gene', (12, 18))	('abolished', 'NegReg', (69, 78))	('NHE1', 'Gene', (55, 59))	('NBCn1', 'Gene', '9497', (63, 68))	('NHE1', 'Gene', '6548', (55, 59))	('NBCn1', 'Gene', (63, 68))
7798	32457840	These results show that Merlin depletion increases basal invasion and potentiated TGFbeta-1-induced invasiveness.	('increases', 'PosReg', (41, 50))	('Merlin', 'Gene', (24, 30))	('basal invasion', 'CPA', (51, 65))	('Merlin', 'Gene', '4771', (24, 30))	('TGFbeta-1-induced', 'Gene', (82, 99))	('depletion', 'Var', (31, 40))	('invasiveness', 'CPA', (100, 112))	('potentiated', 'PosReg', (70, 81))
7807	32457840	The great majority of patient PDAC tumors show activating KRAS mutations, and about 50% show mutations in TGFbeta pathway components, most commonly SMAD4 loss or inactivating mutations.	('mutations', 'Var', (63, 72))	('KRAS', 'Gene', (58, 62))	('PDAC', 'Chemical', '-', (30, 34))	('TGFbeta', 'Gene', '7039', (106, 113))	('KRAS', 'Gene', '3845', (58, 62))	('mutations', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('patient', 'Species', '9606', (22, 29))	('SMAD4', 'Gene', '4089', (148, 153))	('inactivating mutations', 'Var', (162, 184))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('TGFbeta', 'Gene', (106, 113))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('loss', 'NegReg', (154, 158))	('SMAD4', 'Gene', (148, 153))	('activating', 'PosReg', (47, 57))
7808	32457840	For further analysis we therefore selected Panc-1 cells, which harbor an activating KRAS mutation and express wild type SMAD4, and BxPC-3 cells, which are KRAS wild type and express a truncated, defective version of SMAD4.	('SMAD4', 'Gene', '4089', (216, 221))	('BxPC-3', 'CellLine', 'CVCL:0186', (131, 137))	('KRAS', 'Gene', (155, 159))	('KRAS', 'Gene', '3845', (155, 159))	('mutation', 'Var', (89, 97))	('SMAD4', 'Gene', (120, 125))	('KRAS', 'Gene', (84, 88))	('SMAD4', 'Gene', (216, 221))	('activating', 'PosReg', (73, 83))	('KRAS', 'Gene', '3845', (84, 88))	('Panc-1', 'CellLine', 'CVCL:0480', (43, 49))	('SMAD4', 'Gene', '4089', (120, 125))
7810	32457840	Accordingly, SMAD4 knockdown in Panc-1 cells largely abolished EMT.	('SMAD4', 'Gene', '4089', (13, 18))	('EMT', 'CPA', (63, 66))	('knockdown', 'Var', (19, 28))	('SMAD4', 'Gene', (13, 18))	('abolished', 'NegReg', (53, 62))	('Panc-1', 'CellLine', 'CVCL:0480', (32, 38))	('EMT', 'biological_process', 'GO:0001837', ('63', '66'))
7818	32457840	However, in congruence with the transporter upregulation, EMT induction was associated with an increase in steady state pHi and increased capacity for net acid extrusion in Panc-1 cells but not in BxPC-3 cells.	('net acid', 'Chemical', '-', (151, 159))	('pHi', 'Gene', '2821', (120, 123))	('capacity for net acid extrusion', 'MPA', (138, 169))	('induction', 'Var', (62, 71))	('increase', 'PosReg', (95, 103))	('increased', 'PosReg', (128, 137))	('BxPC-3', 'CellLine', 'CVCL:0186', (197, 203))	('pHi', 'Gene', (120, 123))	('EMT', 'biological_process', 'GO:0001837', ('58', '61'))	('Panc-1', 'CellLine', 'CVCL:0480', (173, 179))	('EMT', 'Gene', (58, 61))
7831	32457840	Forty-eight hours of TGFbeta-1 treatment robustly increased invasiveness of Panc-1 cells and this was not abolished by transporter knockdown; in fact, siRNA-mediated depletion of NHE1 modestly increased invasiveness, a finding reminiscent of our demonstration that counter to its general role in favoring motility and invasiveness, NHE1 inhibition actually increased motility of p95HER-overexpressing breast cancer cells, while inhibition of NBCs had no effect.	('increased', 'PosReg', (357, 366))	('invasiveness', 'CPA', (203, 215))	('NHE1', 'Gene', (179, 183))	('NHE1', 'Gene', (332, 336))	('breast cancer', 'Disease', (401, 414))	('cancer', 'Phenotype', 'HP:0002664', (408, 414))	('breast cancer', 'Phenotype', 'HP:0003002', (401, 414))	('NHE1', 'Gene', '6548', (179, 183))	('NHE1', 'Gene', '6548', (332, 336))	('Panc-1', 'CellLine', 'CVCL:0480', (76, 82))	('inhibition', 'Var', (337, 347))	('increased', 'PosReg', (193, 202))	('depletion', 'Var', (166, 175))	('breast cancer', 'Disease', 'MESH:D001943', (401, 414))	('motility', 'CPA', (367, 375))
7832	32457840	The lack of effect of NHE1 knockdown shown here contrasts the conclusion of a recent report using 10 muM cariporide to inhibit NHE1.	('NHE1', 'Gene', (22, 26))	('knockdown', 'Var', (27, 36))	('NHE1', 'Gene', '6548', (127, 131))	('NHE1', 'Gene', '6548', (22, 26))	('muM', 'Gene', '56925', (101, 104))	('inhibit', 'NegReg', (119, 126))	('cariporide', 'Chemical', 'MESH:C093373', (105, 115))	('muM', 'Gene', (101, 104))	('NHE1', 'Gene', (127, 131))
7833	32457840	Since NHE1 knockdown was highly efficient in our study, it seems possible that the effect of cariporide may reflect a contribution of NHE2, which, as noted above, would also have been inhibited at this concentration.	('cariporide', 'MPA', (93, 103))	('NHE1', 'Gene', (6, 10))	('NHE2', 'Gene', (134, 138))	('cariporide', 'Chemical', 'MESH:C093373', (93, 103))	('NHE1', 'Gene', '6548', (6, 10))	('NHE2', 'Gene', '6549', (134, 138))	('knockdown', 'Var', (11, 20))
7835	32457840	We therefore hypothesized that Merlin depletion would impact TGFbeta-1-induced invasiveness and its regulation by NHE1 and NBCn1.	('impact', 'Reg', (54, 60))	('depletion', 'Var', (38, 47))	('NBCn1', 'Gene', '9497', (123, 128))	('TGFbeta-1-induced', 'Gene', (61, 78))	('NHE1', 'Gene', (114, 118))	('Merlin', 'Gene', '4771', (31, 37))	('regulation', 'biological_process', 'GO:0065007', ('100', '110'))	('Merlin', 'Gene', (31, 37))	('NBCn1', 'Gene', (123, 128))	('NHE1', 'Gene', '6548', (114, 118))	('invasiveness', 'CPA', (79, 91))
7836	32457840	Indeed, Merlin knockdown in itself robustly increased invasiveness, and under these conditions, knockdown of either NHE1 or NBCn1 decreased invasiveness, a tendency seen under both basal and TGFbeta-stimulated conditions.	('knockdown', 'Var', (96, 105))	('Merlin', 'Gene', '4771', (8, 14))	('Merlin', 'Gene', (8, 14))	('knockdown', 'Var', (15, 24))	('NHE1', 'Gene', '6548', (116, 120))	('invasiveness', 'MPA', (54, 66))	('NBCn1', 'Gene', (124, 129))	('decreased invasiveness', 'Disease', (130, 152))	('TGFbeta', 'Gene', '7039', (191, 198))	('increased', 'PosReg', (44, 53))	('decreased invasiveness', 'Disease', 'MESH:D009361', (130, 152))	('TGFbeta', 'Gene', (191, 198))	('NBCn1', 'Gene', '9497', (124, 129))	('NHE1', 'Gene', (116, 120))
7847	32029455	Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('Amplifying', 'Var', (0, 10))
7850	32029455	PARP inhibitors act through synthetic lethality with mutations in DNA repair genes and were approved for the treatment of BRCA mutated ovarian and breast cancer.	('BRCA', 'Gene', (122, 126))	('DNA repair', 'biological_process', 'GO:0006281', ('66', '76'))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('PARP', 'Gene', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('mutations', 'Var', (53, 62))	('DNA repair genes', 'Gene', (66, 82))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (135, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('BRCA', 'Gene', '672', (122, 126))
7851	32029455	Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exploit and exacerbate replication deficiencies of cancer cells and may complement PARP inhibitors in targeting a broad range of cancer types with different sources of genomic instability.	('poly(ADP-ribose) glycohydrolase', 'Gene', '8505', (14, 45))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('deficiencies of cancer', 'Disease', (88, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('exacerbate', 'PosReg', (65, 75))	('deficiencies of cancer', 'Disease', 'MESH:D009369', (88, 110))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('PARG', 'Gene', (47, 51))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
7860	32029455	ROS induce DNA damage and mutations, resulting in genomic instability.	('genomic instability', 'MPA', (50, 69))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('ROS', 'Gene', (0, 3))	('mutations', 'Var', (26, 35))	('resulting in', 'Reg', (37, 49))	('DNA damage', 'MPA', (11, 21))
7866	32029455	In 2014, olaparib was approved as maintenance therapy for platinum-sensitive advanced ovarian cancer with germline mutations in DNA repair genes BRCA1/2 that are required for the homologous recombination (HR) pathway of double-strand break (DSB) repair.	('ovarian cancer', 'Disease', (86, 100))	('BRCA1/2', 'Gene', (145, 152))	('DNA repair', 'biological_process', 'GO:0006281', ('128', '138'))	('mutations', 'Var', (115, 124))	('BRCA1/2', 'Gene', '672;675', (145, 152))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('homologous recombination', 'biological_process', 'GO:0035825', ('179', '203'))	('platinum-sensitive', 'Disease', (58, 76))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (86, 100))	('olaparib', 'Chemical', 'MESH:C531550', (9, 17))	('platinum', 'Chemical', 'MESH:D010984', (58, 66))
7867	32029455	In 2016, rucaparib was approved for advanced ovarian cancer with both germline and somatic BRCA1/2 mutations.	('BRCA1/2', 'Gene', (91, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (45, 59))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('BRCA1/2', 'Gene', '672;675', (91, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (45, 59))	('ovarian cancer', 'Disease', (45, 59))	('rucaparib', 'Chemical', 'MESH:C531549', (9, 18))
7869	32029455	Last, in 2018, olaparib and talazoparib were approved for human epidermal growth factor receptor type 2 (HER2)-negative locally advanced or metastatic breast cancer with germline BRCA1/2 mutations.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('64', '87'))	('HER2', 'Gene', (105, 109))	('BRCA1/2', 'Gene', '672;675', (179, 186))	('human', 'Species', '9606', (58, 63))	('talazoparib', 'Chemical', 'MESH:C586365', (28, 39))	('HER2', 'Gene', '2064', (105, 109))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('mutations', 'Var', (187, 196))	('breast cancer', 'Disease', (151, 164))	('metastatic', 'CPA', (140, 150))	('olaparib', 'Chemical', 'MESH:C531550', (15, 23))	('locally advanced', 'Disease', (120, 136))	('BRCA1/2', 'Gene', (179, 186))
7870	32029455	Multiple clinical trials carried out since 2009 have demonstrated PARP inhibitor efficacy in BRCA mutated ovarian and breast cancer, but also prostate, pancreatic cancer, and small cell lung carcinoma (SCLC), irrespective of the BRCA status.	('BRCA', 'Gene', '672', (93, 97))	('BRCA', 'Gene', (229, 233))	('small cell lung carcinoma', 'Disease', (175, 200))	('SCLC', 'Disease', (202, 206))	('prostate', 'Disease', (142, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('SCLC', 'Phenotype', 'HP:0030357', (202, 206))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (152, 169))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (175, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('BRCA', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (152, 169))	('PARP', 'Gene', (66, 70))	('SCLC', 'Disease', 'MESH:D018288', (202, 206))	('mutated', 'Var', (98, 105))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (106, 131))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (175, 200))	('pancreatic cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('BRCA', 'Gene', '672', (229, 233))
7872	32029455	Rather than synergizing with deficiencies in DNA repair pathways, PARG inhibitors seem to exploit deficiencies in replication machinery and higher levels of replication stress in cancer cells.	('inhibitors', 'Var', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('PARG', 'Gene', (66, 70))	('higher', 'PosReg', (140, 146))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('DNA repair', 'biological_process', 'GO:0006281', ('45', '55'))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('replication', 'MPA', (114, 125))	('cancer', 'Disease', (179, 185))	('deficiencies', 'Var', (98, 110))
7873	32029455	In general, cancers with high levels of replication stress and genomic instability due to DNA repair deficiency and/or oncogene-induced increase in replication origin firing are particularly responsive to PARP and PARG inhibition.	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('cancers', 'Disease', (12, 19))	('replication origin firing', 'MPA', (148, 173))	('DNA repair', 'Gene', (90, 100))	('DNA repair', 'biological_process', 'GO:0006281', ('90', '100'))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('increase', 'PosReg', (136, 144))	('deficiency', 'Var', (101, 111))
7874	32029455	PARP and PARG inhibitors exploit and exacerbate these tumor vulnerabilities by inducing further DNA damage, preventing DNA repair and amassing unresolved replication intermediates that instigate replication and mitotic catastrophe.	('DNA repair', 'biological_process', 'GO:0006281', ('119', '129'))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('211', '230'))	('preventing', 'NegReg', (108, 118))	('inducing', 'Reg', (79, 87))	('PARP', 'Gene', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('DNA repair', 'MPA', (119, 129))	('amassing', 'Reg', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('PARG', 'Gene', (9, 13))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('exacerbate', 'PosReg', (37, 47))	('inhibitors', 'Var', (14, 24))	('tumor', 'Disease', (54, 59))	('DNA damage', 'MPA', (96, 106))	('unresolved replication intermediates', 'MPA', (143, 179))
7886	32029455	Their selectivity is based on formation of a PARP1/2-unique water-mediated hydrogen bond interaction with a regulatory subdomain residue (D766 in PARP1), which is conserved in PARP1/2 but not in other PARPs (Fig.	('water-mediated hydrogen bond interaction', 'MPA', (60, 100))	('PARP1/2', 'Gene', '64761;142;10038', (176, 183))	('PARP1/2', 'Gene', (45, 52))	('PARP1', 'Gene', (146, 151))	('hydrogen', 'Chemical', 'MESH:D006859', (75, 83))	('D766', 'Var', (138, 142))	('PARP1/2', 'Gene', (176, 183))	('formation', 'biological_process', 'GO:0009058', ('30', '39'))	('water', 'Chemical', 'MESH:D014867', (60, 65))	('PARP1/2', 'Gene', '64761;142;10038', (45, 52))
7889	32029455	Moreover, some PARP inhibitors such as rucaparib and niraparib also inhibit non-PARP targets, albeit with lower efficiency; rucaparib inhibits hexose-6-phosphate dehydrogenase (H6PD), while niraparib inhibits deoxycytidine kinase (DCK).	('inhibits', 'NegReg', (134, 142))	('rucaparib', 'Chemical', 'MESH:C531549', (124, 133))	('niraparib', 'Chemical', 'MESH:C545685', (190, 199))	('deoxycytidine kinase', 'Gene', '1633', (209, 229))	('rucaparib', 'Var', (124, 133))	('niraparib', 'Chemical', 'MESH:C545685', (53, 62))	('DCK', 'Gene', '1633', (231, 234))	('rucaparib', 'Chemical', 'MESH:C531549', (39, 48))	('inhibit', 'NegReg', (68, 75))	('hexose-6-phosphate dehydrogenase', 'Gene', '9563', (143, 175))	('DCK', 'Gene', (231, 234))	('H6PD', 'Gene', (177, 181))	('inhibits', 'NegReg', (200, 208))	('deoxycytidine kinase', 'Gene', (209, 229))	('H6PD', 'Gene', '9563', (177, 181))	('hexose-6-phosphate dehydrogenase', 'Gene', (143, 175))
7890	32029455	Such cross-inhibition may potentiate cancer cell death, as in the case of rucaparib and PARP/H6PD inhibition, but may also be detrimental for combination therapy with niraparib and nucleoside analogs such as gemcitabine due to cross-inhibition of DCK required for their activation.	('potentiate', 'PosReg', (26, 36))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('H6PD', 'Gene', (93, 97))	('rucaparib', 'Chemical', 'MESH:C531549', (74, 83))	('cancer', 'Disease', (37, 43))	('H6PD', 'Gene', '9563', (93, 97))	('gemcitabine', 'Chemical', 'MESH:C056507', (208, 219))	('nucleoside', 'Chemical', 'MESH:D009705', (181, 191))	('niraparib', 'Chemical', 'MESH:C545685', (167, 176))	('cross-inhibition', 'Var', (5, 21))	('cell death', 'biological_process', 'GO:0008219', ('44', '54'))	('detrimental', 'NegReg', (126, 137))	('DCK', 'Gene', '1633', (247, 250))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('DCK', 'Gene', (247, 250))
7892	32029455	PARP1 is the dominant target for DNA trapping by PARP inhibitors, as depletion of PARP1:but not PARP2:reduces sensitivity to PARP inhibitors.	('reduces', 'NegReg', (102, 109))	('sensitivity to PARP inhibitors', 'MPA', (110, 140))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('PARP1', 'Var', (82, 87))	('PARP2', 'Gene', '10038', (96, 101))	('PARP2', 'Gene', (96, 101))	('depletion', 'MPA', (69, 78))
7903	32029455	The quinazolinedione-type PARG inhibitor PDD00017273 inhibits PARG selectively and with high efficiency, is cell-permeable and cell-active, but has limited bioavailability, which makes it unsuitable for clinical application.	('PDD00017273', 'Chemical', '-', (41, 52))	('PDD00017273', 'Var', (41, 52))	('quinazolinedione', 'Chemical', 'MESH:D052999', (4, 20))	('PARG', 'Protein', (62, 66))	('inhibits', 'NegReg', (53, 61))
7905	32029455	Chemical library screening identified thioxanthine/methylxanthine derivatives JA2-4 and JA2131 as potent, specific, cell-permeable, and cell-active PARG inhibitors, which are also likely to show good bioavailability given their structural similarity with caffeine.	('methylxanthine', 'Chemical', 'MESH:C008514', (51, 65))	('JA2-4', 'Var', (78, 83))	('JA2131', 'Var', (88, 94))	('JA2131', 'Chemical', '-', (88, 94))	('thioxanthine', 'Chemical', 'MESH:C054700', (38, 50))	('caffeine', 'Chemical', 'MESH:D002110', (255, 263))
7909	32029455	RPA binds ssDNA and recruits the S/G2 checkpoint kinase ATR.	('S/G2', 'Var', (33, 37))	('RPA', 'cellular_component', 'GO:0005662', ('0', '3'))	('S/G2', 'SUBSTITUTION', 'None', (33, 37))	('recruits', 'PosReg', (20, 28))	('ATR', 'Gene', '545', (56, 59))	('ATR', 'Gene', (56, 59))	('binds', 'Interaction', (4, 9))
7911	32029455	In response to replication stress, PARP1 slows down replication forks to promote fork reversal by antagonizing the RECQ1 helicase, protects replication forks from degradation by the MRE11 nuclease, stabilizes RAD51 nucleofilaments at stalled forks together with PARP2, and activates the S-phase checkpoint kinase CHK1 (Fig.	('MRE11', 'Gene', (182, 187))	('RAD51', 'Gene', '5888', (209, 214))	('replication forks', 'MPA', (140, 157))	('S-phase checkpoint', 'biological_process', 'GO:0033314', ('287', '305'))	('S-phase checkpoint', 'biological_process', 'GO:0031573', ('287', '305'))	('RAD', 'biological_process', 'GO:1990116', ('209', '212'))	('replication forks', 'MPA', (52, 69))	('degradation', 'biological_process', 'GO:0009056', ('163', '174'))	('CHK1', 'Gene', '1111', (313, 317))	('promote', 'PosReg', (73, 80))	('MRE11', 'Gene', '4361', (182, 187))	('degradation', 'MPA', (163, 174))	('RECQ1', 'Gene', (115, 120))	('RECQ1', 'Gene', '5965', (115, 120))	('slows down', 'NegReg', (41, 51))	('PARP1', 'Var', (35, 40))	('fork', 'Disease', (81, 85))	('activates', 'PosReg', (273, 282))	('PARP2', 'Gene', '10038', (262, 267))	('stabilizes', 'MPA', (198, 208))	('PARP2', 'Gene', (262, 267))	('antagonizing', 'NegReg', (98, 110))	('CHK1', 'Gene', (313, 317))	('protects', 'NegReg', (131, 139))	('RAD51', 'Gene', (209, 214))	('S-phase', 'Enzyme', (287, 294))
7918	32029455	Genomic instability underlies the ability of cancer cells to acquire different tumorigenic properties.	('tumor', 'Disease', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Genomic instability', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cancer', 'Disease', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
7921	32029455	Many cancers have germline or somatic mutations in DNA repair genes.	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('DNA repair', 'biological_process', 'GO:0006281', ('51', '61'))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('cancers', 'Disease', (5, 12))	('DNA repair genes', 'Gene', (51, 67))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('germline', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
7922	32029455	Mutations in tumor suppressor genes such as the cell cycle checkpoint gene TP53 are common across different cancer types and allow cancer cells to escape senescence or apoptosis and continue proliferating in the presence of DNA damage.	('tumor', 'Disease', (13, 18))	('apoptosis', 'biological_process', 'GO:0097194', ('168', '177'))	('apoptosis', 'biological_process', 'GO:0006915', ('168', '177'))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('48', '69'))	('TP53', 'Gene', (75, 79))	('proliferating', 'CPA', (191, 204))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('13', '29'))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('senescence', 'biological_process', 'GO:0010149', ('154', '164'))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('DNA', 'cellular_component', 'GO:0005574', ('224', '227'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('13', '29'))	('TP53', 'Gene', '7157', (75, 79))
7927	32029455	For example, platinum drugs (carboplatin) improved response rate in BRCA mutated advanced triple-negative breast cancer (TNBC) patients and are more effective than taxanes.	('breast cancer', 'Disease', (106, 119))	('mutated', 'Var', (73, 80))	('improved', 'PosReg', (42, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('patients', 'Species', '9606', (127, 135))	('response rate', 'MPA', (51, 64))	('BRCA', 'Gene', '672', (68, 72))	('platinum', 'Chemical', 'MESH:D010984', (13, 21))	('taxanes', 'Chemical', 'MESH:D043823', (164, 171))	('BRCA', 'Gene', (68, 72))	('carboplatin', 'Chemical', 'MESH:D016190', (29, 40))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
7929	32029455	Two seminal studies showed how PARP inhibitors specifically kill HR-deficient cells mutated in BRCA1/2 (Fig.	('BRCA1/2', 'Gene', (95, 102))	('mutated', 'Var', (84, 91))	('PARP', 'Gene', (31, 35))	('HR-deficient', 'Disease', (65, 77))	('HR-deficient', 'Disease', 'MESH:D001919', (65, 77))	('BRCA1/2', 'Gene', '672;675', (95, 102))
7930	32029455	Carriers of heterozygous BRCA1/2 mutations are sensitive to PARP inhibitor treatment as they lose the wild-type allele during tumorigenesis and thereby become BRCA1/2-null.	('lose', 'NegReg', (93, 97))	('BRCA1/2', 'Gene', (159, 166))	('BRCA1/2', 'Gene', '672;675', (25, 32))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('BRCA1/2', 'Gene', '672;675', (159, 166))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('BRCA1/2', 'Gene', (25, 32))	('tumor', 'Disease', (126, 131))
7931	32029455	Since this first example of synthetic lethality between genetic defects and PARP inhibitors, it has become clear that oxidative stress and genomic instability, manifested not just through mutations in DNA repair proteins but also replication stress, sensitize cells to PARP and PARG inhibitors.	('genetic defects', 'Disease', 'MESH:D030342', (56, 71))	('DNA', 'cellular_component', 'GO:0005574', ('201', '204'))	('sensitize', 'Reg', (250, 259))	('oxidative stress', 'Phenotype', 'HP:0025464', (118, 134))	('DNA repair', 'biological_process', 'GO:0006281', ('201', '211'))	('mutations', 'Var', (188, 197))	('genetic defects', 'Disease', (56, 71))
7932	32029455	In addition to BRCA1/2, 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.	('RPA1', 'Gene', '6117', (88, 92))	('FEN1', 'Gene', '2237', (158, 162))	('RAD54', 'Gene', '8438', (112, 117))	('RAD51', 'Gene', (105, 110))	('ERCC1', 'Gene', '2067', (145, 150))	('RAD51', 'Gene', '5888', (105, 110))	('RPA1', 'Gene', (88, 92))	('mutations', 'Var', (24, 33))	('ATR', 'Gene', '545', (83, 86))	('CHEK1', 'Gene', '1111', (119, 124))	('NBN', 'Gene', '4683', (100, 103))	('ATM', 'Gene', (71, 74))	('FEN1', 'Gene', (158, 162))	('CDK12', 'Gene', '51755', (168, 173))	('ERCC1', 'Gene', (145, 150))	('POLB', 'Gene', '5423', (152, 156))	('CDK', 'molecular_function', 'GO:0004693', ('168', '171'))	('DNA damage response', 'biological_process', 'GO:0006974', ('37', '56'))	('FANC', 'Gene', '2175;675;12190;79728;5889;5888;672;12189', (133, 137))	('DSS1', 'Gene', (94, 98))	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('NBN', 'Gene', (100, 103))	('RAD', 'biological_process', 'GO:1990116', ('112', '115'))	('CHEK1', 'Gene', (119, 124))	('DSS1', 'Gene', '7979', (94, 98))	('RAD54', 'Gene', (112, 117))	('BRCA1/2', 'Gene', (15, 22))	('RPA', 'cellular_component', 'GO:0005662', ('88', '91'))	('ATR', 'Gene', (83, 86))	('FANC', 'Gene', (133, 137))	('RAD', 'biological_process', 'GO:1990116', ('105', '108'))	('CHEK2', 'Gene', (126, 131))	('PRKDC', 'Gene', '5591', (76, 81))	('ATM', 'Gene', '472', (71, 74))	('PRKDC', 'Gene', (76, 81))	('CDK12', 'Gene', (168, 173))	('BRCA1/2', 'Gene', '672;675', (15, 22))	('CHEK2', 'Gene', '11200', (126, 131))	('POLB', 'Gene', (152, 156))
7936	32029455	However, PARG depletion did not show synthetic lethality with BRCA1 mutations in different cancer cell lines, the PARG inhibitor JA2131 efficiently killed BRCA-proficient cancer cells, and only one out of six tested ovarian cancer cells with BRCA1/2 mutations showed sensitivity to PARG inhibition with PDD00017273.	('BRCA', 'Gene', '672', (62, 66))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('BRCA1/2', 'Gene', '672;675', (242, 249))	('cancer', 'Disease', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('BRCA', 'Gene', '672', (155, 159))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('BRCA', 'Gene', (62, 66))	('ovarian cancer', 'Disease', 'MESH:D010051', (216, 230))	('BRCA', 'Gene', '672', (242, 246))	('cancer', 'Disease', (171, 177))	('BRCA', 'Gene', (155, 159))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('BRCA', 'Gene', (242, 246))	('ovarian cancer', 'Disease', (216, 230))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('PDD00017273', 'Chemical', '-', (303, 314))	('BRCA1/2', 'Gene', (242, 249))	('JA2131', 'Chemical', '-', (129, 135))	('ovarian cancer', 'Phenotype', 'HP:0100615', (216, 230))	('cancer', 'Disease', (91, 97))	('mutations', 'Var', (250, 259))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (68, 77))
7939	32029455	PARG depletion or inhibition slows down replication forks, causes accumulation of reversed forks and ssDNA gaps, and prevents fork restart through suppression of the RECQ1 helicase (Fig.	('depletion', 'Var', (5, 14))	('slows down', 'NegReg', (29, 39))	('RECQ1', 'Gene', (166, 171))	('fork restart', 'MPA', (126, 138))	('prevents', 'NegReg', (117, 125))	('accumulation', 'PosReg', (66, 78))	('replication forks', 'CPA', (40, 57))	('RECQ1', 'Gene', '5965', (166, 171))	('inhibition', 'Var', (18, 28))	('suppression', 'NegReg', (147, 158))
7940	32029455	This causes cell cycle stalling in the S/G2 phase, accumulation of ssDNA as judged by RPA foci, and accumulation of DNA damage, as indicated by pan-nuclear gammaH2AX staining.	('ssDNA', 'Disease', (67, 72))	('G2 phase', 'biological_process', 'GO:0051319', ('41', '49'))	('cell cycle stalling', 'CPA', (12, 31))	('cell cycle', 'biological_process', 'GO:0007049', ('12', '22'))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('accumulation', 'PosReg', (100, 112))	('accumulation', 'PosReg', (51, 63))	('DNA damage', 'MPA', (116, 126))	('S/G2', 'Var', (39, 43))	('S/G2', 'SUBSTITUTION', 'None', (39, 43))	('RPA', 'cellular_component', 'GO:0005662', ('86', '89'))
7941	32029455	PARP1 or PARG depletion or inhibition sensitize cells to DNA-damaging agents and cause increased DNA damage levels due to decreased HR efficiency.	('increased', 'PosReg', (87, 96))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('DNA damage levels', 'MPA', (97, 114))	('depletion', 'Var', (14, 23))	('inhibition', 'Var', (27, 37))	('PARG', 'Gene', (9, 13))	('sensitize', 'Reg', (38, 47))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('decreased HR efficiency', 'Disease', (122, 145))	('PARP1', 'Gene', (0, 5))	('decreased HR efficiency', 'Disease', 'MESH:D007022', (122, 145))
7942	32029455	Collectively, loss or inhibition of PARP1 or PARG destabilize replication forks and cause fork breakage, particularly under conditions of HR deficiency, oxidative and replication stress, or exogenous DNA damage.	('destabilize', 'NegReg', (50, 61))	('loss', 'Var', (14, 18))	('replication forks', 'CPA', (62, 79))	('inhibition', 'NegReg', (22, 32))	('conditions of HR deficiency', 'Disease', (124, 151))	('PARP1', 'Gene', (36, 41))	('conditions of HR deficiency', 'Disease', 'MESH:D009135', (124, 151))	('fork breakage', 'CPA', (90, 103))	('DNA', 'cellular_component', 'GO:0005574', ('200', '203'))	('cause', 'Reg', (84, 89))	('PARG', 'Gene', (45, 49))
7943	32029455	For example, PARP inhibition increases fork rate and reduces fork reversal following camptothecin exposure more than PARP depletion.	('camptothecin', 'Chemical', 'MESH:D002166', (85, 97))	('fork reversal', 'MPA', (61, 74))	('fork rate', 'MPA', (39, 48))	('PARP', 'Protein', (13, 17))	('increases', 'PosReg', (29, 38))	('reduces', 'NegReg', (53, 60))	('inhibition', 'Var', (18, 28))
7949	32029455	PARP and PARG inhibitors activate the S/G2 checkpoint kinases ATR and CHK1, which generally halt the cell cycle to allow DNA repair and completion of DNA replication before mitotic entry.	('DNA repair', 'biological_process', 'GO:0006281', ('121', '131'))	('cell cycle', 'biological_process', 'GO:0007049', ('101', '111'))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('ATR', 'Gene', '545', (62, 65))	('ATR', 'Gene', (62, 65))	('DNA', 'cellular_component', 'GO:0005574', ('150', '153'))	('CHK1', 'Gene', (70, 74))	('mitotic entry', 'biological_process', 'GO:0051727', ('173', '186'))	('DNA replication', 'biological_process', 'GO:0006260', ('150', '165'))	('DNA repair', 'MPA', (121, 131))	('S/G2', 'Var', (38, 42))	('S/G2', 'SUBSTITUTION', 'None', (38, 42))	('CHK1', 'Gene', '1111', (70, 74))
7950	32029455	In accordance with the activation of the ATR checkpoint, PARG inhibitor PDD00017273-treated cells stall in the S/G2 phase without progressing into mitosis and assume a "fried egg" morphology.	('G2 phase', 'biological_process', 'GO:0051319', ('113', '121'))	('S/G2', 'Var', (111, 115))	('S/G2', 'SUBSTITUTION', 'None', (111, 115))	('PDD00017273', 'Chemical', '-', (72, 83))	('ATR', 'Gene', '545', (41, 44))	('assume', 'Reg', (159, 165))	('mitosis', 'Disease', '-', (147, 154))	('ATR', 'Gene', (41, 44))	('mitosis', 'Disease', (147, 154))	('mitosis', 'biological_process', 'GO:0000278', ('147', '154'))	('PDD00017273-treated', 'Var', (72, 91))
7951	32029455	Conversely, despite the activation of ATR and CHK1, cells treated with PARP inhibitors progress into mitosis and exhibit different mitotic defects, which arise from problems during S phase (Fig.	('CHK1', 'Gene', '1111', (46, 50))	('S phase', 'biological_process', 'GO:0051320', ('181', '188'))	('mitosis', 'Disease', (101, 108))	('mitosis', 'Disease', '-', (101, 108))	('mitotic defects', 'CPA', (131, 146))	('ATR', 'Gene', '545', (38, 41))	('ATR', 'Gene', (38, 41))	('progress', 'PosReg', (87, 95))	('inhibitors', 'Var', (76, 86))	('CHK1', 'Gene', (46, 50))	('mitosis', 'biological_process', 'GO:0000278', ('101', '108'))	('PARP', 'Gene', (71, 75))
7954	32029455	Moreover, PARP inhibition itself induces HR deficiency by reducing the expression of the E2F1 target genes involved in DNA replication and cell cycle regulation (e.g., PCNA, MCM7, and CCNA2) and HR factors such as BRCA1/2 and RAD51, as shown in prostate and small cell lung cancer.	('RAD', 'biological_process', 'GO:1990116', ('226', '229'))	('DNA replication', 'biological_process', 'GO:0006260', ('119', '134'))	('HR deficiency', 'Disease', (41, 54))	('reducing', 'NegReg', (58, 66))	('HR deficiency', 'Disease', 'MESH:D001919', (41, 54))	('E2F1', 'Gene', (89, 93))	('CCNA2', 'Gene', '890', (184, 189))	('prostate', 'Disease', (245, 253))	('MCM7', 'Gene', (174, 178))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('PCNA', 'Gene', (168, 172))	('E2F1', 'Gene', '1869', (89, 93))	('small cell lung cancer', 'Disease', 'MESH:D055752', (258, 280))	('MCM7', 'Gene', '4176', (174, 178))	('inhibition', 'Var', (15, 25))	('expression', 'MPA', (71, 81))	('small cell lung cancer', 'Disease', (258, 280))	('PARP', 'Gene', (10, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (269, 280))	('BRCA1/2', 'Gene', (214, 221))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('139', '160'))	('PCNA', 'Gene', '5111', (168, 172))	('RAD51', 'Gene', (226, 231))	('PCNA', 'molecular_function', 'GO:0003892', ('168', '172'))	('RAD51', 'Gene', '5888', (226, 231))	('CCNA2', 'Gene', (184, 189))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (258, 280))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('BRCA1/2', 'Gene', '672;675', (214, 221))
7959	32029455	Furthermore, PARP inhibition during S phase causes weakening of sister chromatid cohesion, resulting in premature loss of cohesion ("cohesion fatigue") and chromosome alignment problems in metaphase (Fig.	('weakening', 'NegReg', (51, 60))	('fatigue', 'Disease', 'MESH:D005221', (142, 149))	('cohesion', 'MPA', (122, 130))	('chromatid', 'cellular_component', 'GO:0005695', ('71', '80'))	('loss', 'NegReg', (114, 118))	('PARP', 'Protein', (13, 17))	('fatigue', 'Disease', (142, 149))	('S phase', 'biological_process', 'GO:0051320', ('36', '43'))	('chromatid', 'cellular_component', 'GO:0005694', ('71', '80'))	('chromosome alignment problems', 'CPA', (156, 185))	('fatigue', 'Phenotype', 'HP:0012378', (142, 149))	('inhibition', 'Var', (18, 28))	('sister chromatid', 'Protein', (64, 80))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('64', '89'))
7960	32029455	Mitotic catastrophe is a special type of cell death whereby cells die by apoptosis or slip out of mitosis through multinucleation or macronucleation due to chromosome missegregation, as well as micronucleation that results from lagging or acentric chromosomes.	('chromosome', 'cellular_component', 'GO:0005694', ('156', '166'))	('chromosome missegregation', 'CPA', (156, 181))	('Mitotic catastrophe', 'Disease', (0, 19))	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('micronucleation', 'Disease', (194, 209))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('cell death', 'biological_process', 'GO:0008219', ('41', '51'))	('lagging', 'Var', (228, 235))	('mitosis', 'Disease', (98, 105))	('mitosis', 'Disease', '-', (98, 105))	('mitosis', 'biological_process', 'GO:0000278', ('98', '105'))	('slip out', 'CPA', (86, 94))	('apoptosis', 'CPA', (73, 82))	('Mitotic catastrophe', 'biological_process', 'GO:0070270', ('0', '19'))
7961	32029455	While HR-deficient cancer cells were shown to respond better to PARP inhibitors, PARP inhibitors are also effective in HR-proficient cells that experience high levels of oxidative and replication stress.	('PARP', 'Gene', (64, 68))	('PARP', 'Gene', (81, 85))	('HR-deficient cancer', 'Disease', 'MESH:D009369', (6, 25))	('HR-deficient cancer', 'Disease', (6, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('inhibitors', 'Var', (69, 79))
7963	32029455	Unlike PARP inhibitors, the PARG inhibitor PDD00017273 exhibits cytostatic rather than cytotoxic effects by causing a replication catastrophe that is not transferred into mitosis but remains contained in interphase.	('mitosis', 'biological_process', 'GO:0000278', ('171', '178'))	('causing', 'Reg', (108, 115))	('interphase', 'biological_process', 'GO:0051325', ('204', '214'))	('PDD00017273', 'Chemical', '-', (43, 54))	('mitosis', 'Disease', (171, 178))	('replication catastrophe', 'CPA', (118, 141))	('mitosis', 'Disease', '-', (171, 178))	('PDD00017273', 'Var', (43, 54))	('inhibitor PDD00017273', 'Var', (33, 54))
7965	32029455	In sum, cytotoxicity of PARP inhibitors is a multistage process of the destabilization of replication forks through PARP entrapment and loss of PARP activity, the generation of unresolved replication intermediates and DSBs, their transmission into mitosis, and the induction of mitotic defects (premature loss of cohesion, misalignment, missegregation) that ultimately result in mitotic catastrophe.	('mitotic defects', 'CPA', (278, 293))	('destabilization', 'NegReg', (71, 86))	('cytotoxicity', 'Disease', (8, 20))	('misalignment', 'Var', (323, 335))	('result in', 'Reg', (369, 378))	('PARP', 'Gene', (116, 120))	('cytotoxicity', 'Disease', 'MESH:D064420', (8, 20))	('loss', 'NegReg', (305, 309))	('DSBs', 'Chemical', 'MESH:C007563', (218, 222))	('mitosis', 'Disease', '-', (248, 255))	('inhibitors', 'Var', (29, 39))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('379', '398'))	('mitosis', 'biological_process', 'GO:0000278', ('248', '255'))	('mitotic catastrophe', 'Disease', (379, 398))	('activity', 'MPA', (149, 157))	('loss', 'NegReg', (136, 140))	('mitosis', 'Disease', (248, 255))	('PARP', 'Gene', (24, 28))	('PARP', 'Gene', (144, 148))	('missegregation', 'Var', (337, 351))
7966	32029455	The cytostatic effects of PARG inhibitors involve fork stalling, which results in replication catastrophe and cell cycle arrest in S/G2.	('replication catastrophe', 'CPA', (82, 105))	('fork stalling', 'CPA', (50, 63))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (110, 127))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('110', '127'))	('S/G2', 'Var', (131, 135))	('results in', 'Reg', (71, 81))	('S/G2', 'SUBSTITUTION', 'None', (131, 135))	('cell cycle arrest', 'CPA', (110, 127))	('PARG', 'Gene', (26, 30))
7968	32029455	Hence, transcriptional deregulation may sensitize cancer cells to PARP inhibitors, as shown for DNA-repair proficient HER2-positive breast cancer cells whereby NF-kappaB overactivation is attenuated through PARP inhibition.	('cancer', 'Disease', (50, 56))	('HER2', 'Gene', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('transcriptional', 'MPA', (7, 22))	('deregulation', 'Var', (23, 35))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('DNA-repair', 'biological_process', 'GO:0006281', ('96', '106'))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('NF-kappaB', 'Protein', (160, 169))	('HER2', 'Gene', '2064', (118, 122))	('sensitize', 'Reg', (40, 49))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('overactivation', 'PosReg', (170, 184))	('breast cancer', 'Disease', (132, 145))	('cancer', 'Disease', (139, 145))	('attenuated', 'NegReg', (188, 198))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))
7970	32029455	Furthermore, PARP inhibitors reduce rDNA transcription and ribosome biogenesis in BRCA1/2-proficient cancer cells by preventing DDX21 ADP-ribosylation, and thereby reduce breast cancer growth.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('PARP', 'Gene', (13, 17))	('BRCA1/2', 'Gene', (82, 89))	('reduce', 'NegReg', (29, 35))	('inhibitors', 'Var', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('reduce', 'NegReg', (164, 170))	('DDX21', 'Gene', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('ribosome biogenesis', 'MPA', (59, 78))	('BRCA1/2', 'Gene', '672;675', (82, 89))	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('DDX21', 'Gene', '9188', (128, 133))	('transcription', 'biological_process', 'GO:0006351', ('41', '54'))	('breast cancer', 'Disease', (171, 184))	('rDNA transcription', 'MPA', (36, 54))	('ribosome', 'cellular_component', 'GO:0005840', ('59', '67'))	('ADP', 'Chemical', 'MESH:D000244', (134, 137))	('cancer', 'Disease', (101, 107))	('ribosome biogenesis', 'biological_process', 'GO:0042254', ('59', '78'))	('cancer', 'Disease', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ADP-ribosylation', 'MPA', (134, 150))	('preventing', 'NegReg', (117, 127))
7971	32029455	Since the first example of synthetic lethality between PARP inhibitors and BRCA1/2 mutations, it has become clear that any form of HR deficiency in tumors that phenocopies BRCA1/2 mutations, often referred to as BRCA-ness, may sensitize cells to PARP inhibitors.	('mutations', 'Var', (83, 92))	('BRCA-ness', 'Disease', 'MESH:C537443', (212, 221))	('BRCA1/2', 'Gene', '672;675', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mutations', 'Var', (180, 189))	('BRCA1/2', 'Gene', '672;675', (75, 82))	('BRCA1/2', 'Gene', (75, 82))	('HR deficiency in tumors', 'Disease', (131, 154))	('BRCA-ness', 'Disease', (212, 221))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('HR deficiency in tumors', 'Disease', 'MESH:D009369', (131, 154))	('PARP inhibitors', 'MPA', (246, 261))	('BRCA1/2', 'Gene', (172, 179))	('sensitize', 'Reg', (227, 236))
7972	32029455	Different patient biomarkers have been used to assess HR deficiency as a measure of sensitivity to PARP inhibitor treatment, such as mutations in DNA repair genes, their expression levels, as well as mutational and genomic signatures of HR deficiency.	('HR deficiency', 'Disease', 'MESH:D001919', (237, 250))	('HR deficiency', 'Disease', 'MESH:D001919', (54, 67))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('patient', 'Species', '9606', (10, 17))	('HR deficiency', 'Disease', (237, 250))	('expression levels', 'MPA', (170, 187))	('DNA repair genes', 'Gene', (146, 162))	('mutations', 'Var', (133, 142))	('DNA repair', 'biological_process', 'GO:0006281', ('146', '156'))	('HR deficiency', 'Disease', (54, 67))
7973	32029455	Ten percent to 15% of breast and ovarian cancer patients carry germline mutations in HR genes BRCA1 and BRCA2.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('BRCA2', 'Gene', (104, 109))	('BRCA2', 'Gene', '675', (104, 109))	('ovarian cancer', 'Phenotype', 'HP:0100615', (33, 47))	('BRCA1', 'Gene', (94, 99))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (22, 47))	('germline mutations', 'Var', (63, 81))	('patients', 'Species', '9606', (48, 56))
7974	32029455	Strikingly, 75% of germline mutations in metastatic cancers affect DNA repair genes such as MUTYH, BRCA2, CHEK2, and BRCA1.	('CHEK2', 'Gene', (106, 111))	('germline mutations', 'Var', (19, 37))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('MUTYH', 'Gene', (92, 97))	('MUTYH', 'Gene', '4595', (92, 97))	('DNA repair', 'biological_process', 'GO:0006281', ('67', '77'))	('BRCA1', 'Gene', (117, 122))	('BRCA2', 'Gene', (99, 104))	('affect', 'Reg', (60, 66))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('CHEK2', 'Gene', '11200', (106, 111))	('BRCA2', 'Gene', '675', (99, 104))	('DNA repair genes', 'Gene', (67, 83))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
7976	32029455	In addition to being directly inactivated by mutation, BRCA1 and RAD51C were also found to be down-regulated through promoter hypermethylation in breast and ovarian cancer.	('RAD51C', 'Gene', '5889', (65, 71))	('RAD', 'biological_process', 'GO:1990116', ('65', '68'))	('RAD51C', 'Gene', (65, 71))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (146, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('promoter', 'MPA', (117, 125))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	('mutation', 'Var', (45, 53))	('down-regulated', 'NegReg', (94, 108))	('BRCA1', 'Gene', (55, 60))
7984	32029455	In addition to microhomology-mediated indels as the main signature of BRCA1/2 deficiency, base substitutions and rearrangements also reflect an abrogation of DSB repair pathways.	('BRCA1/2 deficiency', 'Disease', (70, 88))	('BRCA1/2 deficiency', 'Disease', 'OMIM:612555', (70, 88))	('DSB repair pathways', 'Pathway', (158, 177))	('abrogation', 'NegReg', (144, 154))	('rearrangements', 'Var', (113, 127))	('base substitutions', 'Var', (90, 108))
7986	32029455	However, mutational signatures are not prognostic of PARP inhibitor sensitivity in the case of tumors with restored HR, which harbor mutational signatures but are resistant to PARP inhibitors due to restoration of the HR pathway (see "Mechanisms of Resistance to PARP Inhibitors").	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('restoration', 'PosReg', (199, 210))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('HR pathway', 'Pathway', (218, 228))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutational', 'Var', (133, 143))	('tumors', 'Disease', (95, 101))
7988	32029455	LOH, TAIs, and LSTs were shown to correlate well with mutations in HR genes BRCA1/2 in breast and ovarian cancer.	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (87, 112))	('BRCA1/2', 'Gene', (76, 83))	('mutations', 'Var', (54, 63))	('BRCA1/2', 'Gene', '672;675', (76, 83))	('ovarian cancer', 'Phenotype', 'HP:0100615', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
7996	32029455	Unlike RAD51, gammaH2AX foci are not a reliable predictor of sensitivity to PARP inhibition as gammaH2AX foci may correlate positively or negatively with HR deficiency and PARP inhibitor sensitivity.	('RAD51', 'Gene', (7, 12))	('negatively', 'NegReg', (138, 148))	('RAD', 'biological_process', 'GO:1990116', ('7', '10'))	('HR deficiency', 'Disease', (154, 167))	('RAD51', 'Gene', '5888', (7, 12))	('PARP inhibitor sensitivity', 'MPA', (172, 198))	('gammaH2AX', 'Var', (95, 104))	('HR deficiency', 'Disease', 'MESH:D001919', (154, 167))
7998	32029455	For example, loss of TP53 and RB1 coupled with amplification of MYC generate replication stress and sensitize small cell lung cancer cells (SCLC) to PARP inhibitors.	('sensitize', 'Reg', (100, 109))	('TP53', 'Gene', (21, 25))	('replication stress', 'MPA', (77, 95))	('SCLC', 'Disease', (140, 144))	('RB1', 'Gene', (30, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('loss', 'Var', (13, 17))	('SCLC', 'Phenotype', 'HP:0030357', (140, 144))	('small cell lung cancer', 'Disease', 'MESH:D055752', (110, 132))	('small cell lung cancer', 'Disease', (110, 132))	('MYC', 'Gene', (64, 67))	('RB1', 'Gene', '5925', (30, 33))	('TP53', 'Gene', '7157', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('amplification', 'MPA', (47, 60))	('SCLC', 'Disease', 'MESH:D018288', (140, 144))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (110, 132))	('MYC', 'Gene', '4609', (64, 67))	('generate', 'Reg', (68, 76))
8003	32029455	Mutations in genes required for Okazaki fragment processing such as FEN1 also sensitize cells to PARP inhibition, but FEN1 is rarely mutated in cancer.	('FEN1', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('sensitize', 'Reg', (78, 87))	('cancer', 'Disease', (144, 150))	('Mutations', 'Var', (0, 9))	('FEN1', 'Gene', '2237', (68, 72))	('FEN1', 'Gene', '2237', (118, 122))	('PARP inhibition', 'MPA', (97, 112))	('FEN1', 'Gene', (118, 122))
8006	32029455	RNASEH2B deletions are frequently found in chronic lymphocytic leukemia and metastatic prostate cancer, which renders them more sensitive to PARP inhibition.	('prostate cancer', 'Disease', (87, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('chronic lymphocytic leukemia', 'Disease', (43, 71))	('RNASEH2B', 'Gene', (0, 8))	('leukemia', 'Phenotype', 'HP:0001909', (63, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (87, 102))	('prostate cancer', 'Phenotype', 'HP:0012125', (87, 102))	('RNASEH2B', 'Gene', '79621', (0, 8))	('found', 'Reg', (34, 39))	('deletions', 'Var', (9, 18))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (43, 71))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (43, 71))
8009	32029455	PARP1 catalytic activity is enhanced by the receptor tyrosine kinase c-Met-mediated phosphorylation on Y907, which in turn reduces PARP inhibitor binding.	('c-Met', 'Gene', (69, 74))	('c-Met', 'Gene', '4233', (69, 74))	('binding', 'molecular_function', 'GO:0005488', ('146', '153'))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('enhanced', 'PosReg', (28, 36))	('catalytic activity', 'molecular_function', 'GO:0003824', ('6', '24'))	('catalytic activity', 'MPA', (6, 24))	('binding', 'Interaction', (146, 153))	('PARP inhibitor', 'Protein', (131, 145))	('Y907', 'Var', (103, 107))	('PARP1', 'Gene', (0, 5))	('reduces', 'NegReg', (123, 130))
8011	32029455	Endogenous inhibition of PARP activity through increased levels of NADP+ was shown to render ovarian cancer cells hypersensitive to PARP inhibitors irrespective of the BRCA status, suggesting that NADP+ levels could also be used as a biomarker of PARP inhibitor sensitivity.	('ovarian cancer', 'Disease', (93, 107))	('BRCA', 'Gene', (168, 172))	('BRCA', 'Gene', '672', (168, 172))	('hypersensitive', 'Disease', 'MESH:D004342', (114, 128))	('NADP+', 'Var', (67, 72))	('hypersensitive', 'Disease', (114, 128))	('increased', 'PosReg', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('PARP', 'Enzyme', (25, 29))	('ovarian cancer', 'Disease', 'MESH:D010051', (93, 107))	('inhibition', 'NegReg', (11, 21))	('NADP+', 'Chemical', 'MESH:D009249', (197, 202))	('NADP+', 'Chemical', 'MESH:D009249', (67, 72))	('activity', 'MPA', (30, 38))
8012	32029455	The very first clinical trials demonstrated the efficacy of the PARP inhibitor olaparib in breast and ovarian cancer patients carrying germline mutations in BRCA1/2, thus supporting the rationale for synthetic lethality.	('germline mutations', 'Var', (135, 153))	('BRCA1/2', 'Gene', '672;675', (157, 164))	('olaparib', 'Chemical', 'MESH:C531550', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (91, 116))	('BRCA1/2', 'Gene', (157, 164))	('patients', 'Species', '9606', (117, 125))	('efficacy', 'MPA', (48, 56))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))
8018	32029455	Olaparib treatment in advanced breast or ovarian cancer patients with BRCA1/2 germline mutations showed a 41% and a 33% objective response rate defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period (Table 2).	('patients', 'Species', '9606', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('patients', 'Species', '9606', (173, 181))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('BRCA1/2', 'Gene', '672;675', (70, 77))	('breast or ovarian cancer', 'Disease', (31, 55))	('Olaparib', 'Chemical', 'MESH:C531550', (0, 8))	('tumor', 'Disease', (187, 192))	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (31, 55))	('BRCA1/2', 'Gene', (70, 77))	('mutations', 'Var', (87, 96))
8019	32029455	Olaparib administered in high-grade serous and/or undifferentiated ovarian cancer patients showed a 41% and 24% objective response rate with or without BRCA1/2 mutations; however, there was no response in TNBC patients.	('ovarian cancer', 'Disease', 'MESH:D010051', (67, 81))	('BRCA1/2', 'Gene', (152, 159))	('mutations', 'Var', (160, 169))	('ovarian cancer', 'Disease', (67, 81))	('patients', 'Species', '9606', (82, 90))	('Olaparib', 'Chemical', 'MESH:C531550', (0, 8))	('BRCA1/2', 'Gene', '672;675', (152, 159))	('patients', 'Species', '9606', (210, 218))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (67, 81))
8020	32029455	A study comparing olaparib with placebo in platinum-sensitive, relapsed, high-grade serous ovarian cancer patients who had received two or more platinum-based regimens showed longer median progression-free survival from 4.3 to 11.2 mo for BRCA mutated cancer and from 5.5 to 7.4 mo for wild-type (WT) BRCA.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('progression-free survival', 'CPA', (189, 214))	('platinum', 'Chemical', 'MESH:D010984', (43, 51))	('olaparib', 'Chemical', 'MESH:C531550', (18, 26))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (84, 105))	('BRCA', 'Gene', (301, 305))	('mutated', 'Var', (244, 251))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('platinum', 'Chemical', 'MESH:D010984', (144, 152))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))	('longer', 'PosReg', (175, 181))	('cancer', 'Disease', (252, 258))	('serous ovarian cancer', 'Disease', (84, 105))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('BRCA', 'Gene', '672', (239, 243))	('to 7', 'Species', '1214577', (272, 276))	('cancer', 'Disease', (99, 105))	('BRCA', 'Gene', '672', (301, 305))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('BRCA', 'Gene', (239, 243))
8022	32029455	Long-term responders to olaparib with progression-free survival >2 yr had a prevalence of BRCA2 mutations and a high HRD score, confirming that mutations in HR genes such as BRCA2 and HRD score can be used as predictive biomarkers for PARP inhibitor response.	('HRD', 'Disease', (117, 120))	('BRCA2', 'Gene', '675', (174, 179))	('BRCA2', 'Gene', (90, 95))	('HRD', 'Disease', (184, 187))	('olaparib', 'Chemical', 'MESH:C531550', (24, 32))	('BRCA2', 'Gene', '675', (90, 95))	('HRD', 'Disease', '-', (117, 120))	('BRCA2', 'Gene', (174, 179))	('HRD', 'Disease', '-', (184, 187))	('mutations', 'Var', (96, 105))
8023	32029455	A study with platinum-resistant ovarian and breast cancer patients with three or more chemotherapy regimens for metastatic disease, all carrying BRCA1/2 mutations, showed a 31.1% and 12.9% tumor response rate to olaparib, indicating that olaparib may indeed be more effective in ovarian than breast cancer.	('olaparib', 'Chemical', 'MESH:C531550', (212, 220))	('BRCA1/2', 'Gene', (145, 152))	('tumor', 'Disease', (189, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('mutations', 'Var', (153, 162))	('BRCA1/2', 'Gene', '672;675', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('ovarian than breast cancer', 'Disease', 'MESH:D010051', (279, 305))	('ovarian than breast cancer', 'Disease', (279, 305))	('olaparib', 'Chemical', 'MESH:C531550', (238, 246))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('platinum', 'Chemical', 'MESH:D010984', (13, 21))	('patients', 'Species', '9606', (58, 66))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (32, 57))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
8025	32029455	In 2017, olaparib was approved by the FDA as maintenance therapy in platinum-sensitive high-grade ovarian cancer patients irrespective of the BRCA status, based on phase 3 clinical trials that showed longer median progression-free survival compared with placebo, from 5.5 mo to 19.1 mo or from 13.8 to 49.9 mo in patients with germline BRCA1/2 mutations (Table 2).	('BRCA1/2', 'Gene', '672;675', (336, 343))	('ovarian cancer', 'Disease', 'MESH:D010051', (98, 112))	('BRCA', 'Gene', (336, 340))	('BRCA', 'Gene', '672', (142, 146))	('ovarian cancer', 'Disease', (98, 112))	('patients', 'Species', '9606', (113, 121))	('BRCA', 'Gene', (142, 146))	('germline', 'Var', (327, 335))	('longer', 'PosReg', (200, 206))	('olaparib', 'Chemical', 'MESH:C531550', (9, 17))	('platinum', 'Chemical', 'MESH:D010984', (68, 76))	('BRCA1/2', 'Gene', (336, 343))	('ovarian cancer', 'Phenotype', 'HP:0100615', (98, 112))	('patients', 'Species', '9606', (313, 321))	('BRCA', 'Gene', '672', (336, 340))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
8026	32029455	In a phase-3 trial focusing on BRCA mutated and HER2-negative metastatic breast cancer patients, olaparib was compared with standard single-agent therapy (e.g., microtubule inhibitors, nucleoside, or fluoropyrimidine analogs) and showed a longer median progression-free survival and 59.9% objective response rate compared with 28.8% for patients receiving standard therapy.	('HER2', 'Gene', '2064', (48, 52))	('BRCA', 'Gene', '672', (31, 35))	('fluoropyrimidine', 'Chemical', '-', (200, 216))	('longer', 'PosReg', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('objective response', 'CPA', (289, 307))	('BRCA', 'Gene', (31, 35))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('nucleoside', 'Chemical', 'MESH:D009705', (185, 195))	('mutated', 'Var', (36, 43))	('microtubule', 'cellular_component', 'GO:0005874', ('161', '172'))	('breast cancer', 'Disease', (73, 86))	('olaparib', 'Chemical', 'MESH:C531550', (97, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('progression-free survival', 'CPA', (253, 278))	('patients', 'Species', '9606', (337, 345))	('patients', 'Species', '9606', (87, 95))	('HER2', 'Gene', (48, 52))
8027	32029455	As a result, olaparib was approved by the FDA for germline BRCA mutated metastatic breast cancer in 2018.	('BRCA', 'Gene', '672', (59, 63))	('BRCA', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('mutated', 'Var', (64, 71))	('olaparib', 'Chemical', 'MESH:C531550', (13, 21))
8028	32029455	It remains to be clarified whether olaparib also confers an advantage over standard chemotherapy in ovarian cancer, given that one clinical trial in advanced ovarian cancer patients with BRCA1/2 mutations whose disease had progressed or recurred after the use of platinum-based chemotherapy showed that the effect of olaparib was not superior to pegylated liposomal doxorubicin (PLD).	('ovarian cancer', 'Disease', (100, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (158, 172))	('patients', 'Species', '9606', (173, 181))	('BRCA1/2', 'Gene', (187, 194))	('olaparib', 'Chemical', 'MESH:C531550', (35, 43))	('doxorubicin', 'Chemical', 'MESH:D004317', (366, 377))	('ovarian cancer', 'Disease', 'MESH:D010051', (158, 172))	('platinum', 'Chemical', 'MESH:D010984', (263, 271))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('BRCA1/2', 'Gene', '672;675', (187, 194))	('ovarian cancer', 'Disease', (158, 172))	('ovarian cancer', 'Disease', 'MESH:D010051', (100, 114))	('mutations', 'Var', (195, 204))	('olaparib', 'Chemical', 'MESH:C531550', (317, 325))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))
8029	32029455	Rucaparib administered at 600 mg twice daily in platinum-sensitive, high-grade recurrent ovarian carcinoma patients showed longer median progression-free survival in BRCA mutated cancer compared with WT (12.8 mo vs. ~5 mo) and a 53.8% objective response rate in BRCA mutated patients (Table 2).	('platinum', 'Chemical', 'MESH:D010984', (48, 56))	('patients', 'Species', '9606', (107, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('BRCA', 'Gene', '672', (262, 266))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('longer', 'PosReg', (123, 129))	('BRCA', 'Gene', (262, 266))	('Rucaparib', 'Chemical', 'MESH:C531549', (0, 9))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (89, 106))	('BRCA', 'Gene', (166, 170))	('BRCA', 'Gene', '672', (166, 170))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (89, 106))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('patients', 'Species', '9606', (275, 283))	('mutated', 'Var', (171, 178))	('cancer', 'Disease', (179, 185))	('ovarian carcinoma', 'Disease', (89, 106))
8030	32029455	As a result, rucaparib was approved in 2016 for advanced ovarian cancer with germline and somatic BRCA1/2 mutations.	('ovarian cancer', 'Disease', 'MESH:D010051', (57, 71))	('ovarian cancer', 'Disease', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('rucaparib', 'Chemical', 'MESH:C531549', (13, 22))	('mutations', 'Var', (106, 115))	('BRCA1/2', 'Gene', (98, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (57, 71))	('BRCA1/2', 'Gene', '672;675', (98, 105))
8037	32029455	Compared with standard single-agent therapy in BRCA mutated advanced breast cancer patients, talazoparib showed longer median progression-free survival and a 62.6% objective response rate compared with 27.2% for patients receiving standard therapy.	('progression-free survival', 'CPA', (126, 151))	('longer', 'PosReg', (112, 118))	('objective response', 'CPA', (164, 182))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('talazoparib', 'Chemical', 'MESH:C586365', (93, 104))	('patients', 'Species', '9606', (83, 91))	('talazoparib', 'Var', (93, 104))	('patients', 'Species', '9606', (212, 220))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('BRCA', 'Gene', '672', (47, 51))	('BRCA', 'Gene', (47, 51))
8042	32029455	Germline BRCA2 mutations in prostate cancer patients are associated with worse clinical outcomes.	('BRCA2', 'Gene', (9, 14))	('prostate cancer', 'Disease', 'MESH:D011471', (28, 43))	('patients', 'Species', '9606', (44, 52))	('mutations', 'Var', (15, 24))	('BRCA2', 'Gene', '675', (9, 14))	('prostate cancer', 'Phenotype', 'HP:0012125', (28, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('prostate cancer', 'Disease', (28, 43))
8044	32029455	Another study showed a 33% response rate to olaparib in prostate cancer patients, where most of the responders had BRCA2 or ATM mutations.	('BRCA2', 'Gene', (115, 120))	('mutations', 'Var', (128, 137))	('ATM', 'Gene', '472', (124, 127))	('patients', 'Species', '9606', (72, 80))	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('BRCA2', 'Gene', '675', (115, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('olaparib', 'Chemical', 'MESH:C531550', (44, 52))	('ATM', 'Gene', (124, 127))	('prostate cancer', 'Disease', (56, 71))
8051	32029455	The first example of PARP inhibitor resistance was identified in Capan-1 cells derived from a pancreatic epithelial tumour, which had an intragenic deletion in BRCA2 of 458 bp resulting in removal of the inactivating frameshift mutation and expression of an almost full-length BRCA2 protein lacking 153 amino acids.	('deletion', 'Var', (148, 156))	('lacking', 'NegReg', (291, 298))	('pancreatic epithelial tumour', 'Disease', 'MESH:D010190', (94, 122))	('removal', 'NegReg', (189, 196))	('153 amino acids', 'MPA', (299, 314))	('epithelial tumour', 'Phenotype', 'HP:0031492', (105, 122))	('BRCA2', 'Gene', (160, 165))	('expression', 'MPA', (241, 251))	('inactivating frameshift mutation', 'Var', (204, 236))	('protein', 'cellular_component', 'GO:0003675', ('283', '290'))	('BRCA2', 'Gene', (277, 282))	('protein', 'Protein', (283, 290))	('pancreatic epithelial tumour', 'Disease', (94, 122))	('Capan-1', 'CellLine', 'CVCL:0237;0.013720403612204184', (65, 72))	('BRCA2', 'Gene', '675', (160, 165))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('BRCA2', 'Gene', '675', (277, 282))
8052	32029455	Since then, many examples of secondary mutations in BRCA1/2, as well as RAD51C, RAD51D, and PALB2, that genetically revert the mutation and restore functional full-length protein have been reported in breast, ovarian, pancreatic, and prostate carcinoma.	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('RAD51C', 'Gene', '5889', (72, 78))	('BRCA1/2', 'Gene', (52, 59))	('prostate carcinoma', 'Disease', 'MESH:D011472', (234, 252))	('pancreatic', 'Disease', 'MESH:D010195', (218, 228))	('ovarian', 'Disease', (209, 216))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (234, 252))	('RAD51C', 'Gene', (72, 78))	('PALB2', 'Gene', (92, 97))	('pancreatic', 'Disease', (218, 228))	('mutations', 'Var', (39, 48))	('RAD51D', 'Gene', '5892', (80, 86))	('BRCA1/2', 'Gene', '672;675', (52, 59))	('prostate carcinoma', 'Disease', (234, 252))	('PALB2', 'Gene', '79728', (92, 97))	('restore', 'PosReg', (140, 147))	('mutation', 'Var', (127, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('breast', 'Disease', (201, 207))	('RAD', 'biological_process', 'GO:1990116', ('72', '75'))	('full-length', 'MPA', (159, 170))	('RAD', 'biological_process', 'GO:1990116', ('80', '83'))	('protein', 'Protein', (171, 178))	('RAD51D', 'Gene', (80, 86))
8055	32029455	Such mutant BRCA1 protein may be stabilized by the heat shock chaperone HSP90 as shown in MDA-MB-436 breast cancer cells.	('protein', 'Protein', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('HSP90', 'Gene', (72, 77))	('HSP90', 'Gene', '3320', (72, 77))	('mutant', 'Var', (5, 11))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('MDA-MB-436', 'CellLine', 'CVCL:0623;0.0077137766618427805', (90, 100))	('breast cancer', 'Disease', (101, 114))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('shock', 'Phenotype', 'HP:0031273', (56, 61))	('BRCA1', 'Gene', (12, 17))
8058	32029455	Finally, inactivation of different NHEJ-promoting factors that inhibit DNA end resection, such as 53BP1, RIF1, PTIP, Artemis, REV7 (MAD2L2), the Shieldin complex (SHLD1-3 and REV7), and the CTC1-STN1-TEN1 (CST) complex, can also lead to a partial restoration of HR in BRCA1-deficient cells and mammary tumors.	('PTIP', 'Gene', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('RIF1', 'Gene', '55183', (105, 109))	('TEN1', 'Gene', (200, 204))	('BRCA1-deficient', 'Disease', (268, 283))	('tumors', 'Disease', (302, 308))	('inhibit', 'NegReg', (63, 70))	('53BP1', 'Gene', '7158', (98, 103))	('REV7', 'Gene', '10459', (175, 179))	('MAD', 'biological_process', 'GO:0072671', ('132', '135'))	('MAD2L2', 'Gene', (132, 138))	('REV7', 'Gene', (175, 179))	('tumors', 'Disease', 'MESH:D009369', (302, 308))	('BRCA1-deficient', 'Disease', 'OMIM:604370', (268, 283))	('CTC1', 'Gene', (190, 194))	('53BP1', 'Gene', (98, 103))	('REV7', 'Gene', '10459', (126, 130))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('MAD2L2', 'Gene', '10459', (132, 138))	('CST) complex', 'cellular_component', 'GO:1990879', ('206', '218'))	('NHEJ', 'biological_process', 'GO:0006303', ('35', '39'))	('REV7', 'Gene', (126, 130))	('inactivation', 'Var', (9, 21))	('TEN1', 'Gene', '100134934', (200, 204))	('STN1', 'Gene', '79991', (195, 199))	('RIF1', 'Gene', (105, 109))	('STN1', 'Gene', (195, 199))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('CTC1', 'Gene', '80169', (190, 194))	('PTIP', 'Gene', '22976', (111, 115))
8059	32029455	Furthermore, inactivation of dynein DYNLL1 and the HELB helicase can also promote end resection and restore the HR pathway independent of 53BP1, resulting in PARP inhibitor resistance in BRCA1-deficient cells.	('dynein', 'molecular_function', 'GO:0003777', ('29', '35'))	('inactivation', 'Var', (13, 25))	('PARP inhibitor resistance', 'MPA', (158, 183))	('promote', 'PosReg', (74, 81))	('restore', 'PosReg', (100, 107))	('HELB helicase', 'Protein', (51, 64))	('53BP1', 'Gene', (138, 143))	('BRCA1-deficient', 'Disease', (187, 202))	('DYNLL1', 'Gene', (36, 42))	('53BP1', 'Gene', '7158', (138, 143))	('HR pathway', 'Pathway', (112, 122))	('DYNLL1', 'Gene', '8655', (36, 42))	('BRCA1-deficient', 'Disease', 'OMIM:604370', (187, 202))	('end resection', 'CPA', (82, 95))
8060	32029455	Of note, while BRCA1 mutations are compatible with HR restoration upon inactivation of NHEJ-promoting factors, restoration of the HR pathway fully depends on functional BRCA2.	('NHEJ', 'biological_process', 'GO:0006303', ('87', '91'))	('BRCA2', 'Gene', (169, 174))	('BRCA2', 'Gene', '675', (169, 174))	('HR pathway', 'Pathway', (130, 140))	('BRCA1', 'Gene', (15, 20))	('mutations', 'Var', (21, 30))
8064	32029455	For example, loss or inhibition of PTIP, a downstream effector of 53BP1, protects forks from degradation in BRCA2-deficient cells by inhibiting the recruitment of the MRE11 nuclease to stalled forks, resulting in PARP inhibitor resistance.	('BRCA2', 'Gene', (108, 113))	('PTIP', 'Gene', (35, 39))	('inhibiting', 'NegReg', (133, 143))	('degradation', 'MPA', (93, 104))	('forks', 'MPA', (82, 87))	('recruitment', 'MPA', (148, 159))	('PARP inhibitor resistance', 'MPA', (213, 238))	('BRCA2', 'Gene', '675', (108, 113))	('53BP1', 'Gene', (66, 71))	('53BP1', 'Gene', '7158', (66, 71))	('MRE11', 'Gene', '4361', (167, 172))	('degradation', 'biological_process', 'GO:0009056', ('93', '104'))	('PTIP', 'Gene', '22976', (35, 39))	('MRE11', 'Gene', (167, 172))	('loss', 'Var', (13, 17))	('inhibition', 'NegReg', (21, 31))
8065	32029455	Furthermore, reduced expression of the Polycomb protein EZH2 in BRCA2 mutated cancer results in fork stabilization due to reduced H3K27 methylation and reduced recruitment of the MUS81 nuclease as a result.	('MUS81', 'Gene', '80198', (179, 184))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('fork stabilization', 'MPA', (96, 114))	('reduced', 'NegReg', (122, 129))	('reduced', 'NegReg', (152, 159))	('EZH2', 'Gene', '2146', (56, 60))	('BRCA2', 'Gene', (64, 69))	('EZH2', 'Gene', (56, 60))	('methylation', 'MPA', (136, 147))	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('MUS81', 'Gene', (179, 184))	('cancer', 'Disease', (78, 84))	('H3K27', 'Protein', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('reduced', 'NegReg', (13, 20))	('BRCA2', 'Gene', '675', (64, 69))	('recruitment', 'MPA', (160, 171))	('expression', 'MPA', (21, 31))	('methylation', 'biological_process', 'GO:0032259', ('136', '147'))	('mutated', 'Var', (70, 77))
8067	32029455	Increased expression of miR-493-5p was shown to induce resistance to PARP inhibitors in BRCA2 mutated carcinomas by down-regulating MRE11 and EXO1 and thereby stabilizing replication forks.	('carcinomas', 'Disease', 'MESH:D002277', (102, 112))	('EXO1', 'Gene', '9156', (142, 146))	('MRE11', 'Gene', '4361', (132, 137))	('induce', 'PosReg', (48, 54))	('BRCA2', 'Gene', (88, 93))	('resistance to', 'MPA', (55, 68))	('MRE11', 'Gene', (132, 137))	('EXO1', 'Gene', (142, 146))	('stabilizing', 'Reg', (159, 170))	('down-regulating', 'NegReg', (116, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('BRCA2', 'Gene', '675', (88, 93))	('replication forks', 'CPA', (171, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('miR-493-5p', 'Var', (24, 34))	('carcinomas', 'Disease', (102, 112))
8070	32029455	A clinically relevant PARP mutation found in an olaparib-resistant ovarian cancer patient occurs within the WGR domain (R591C).	('PARP', 'Gene', (22, 26))	('ovarian cancer', 'Disease', 'MESH:D010051', (67, 81))	('patient', 'Species', '9606', (82, 89))	('ovarian cancer', 'Disease', (67, 81))	('olaparib', 'Chemical', 'MESH:C531550', (48, 56))	('mutation', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (67, 81))	('R591C', 'Mutation', 'rs752905479', (120, 125))
8071	32029455	The mutated residue is critical for interdomain communication between the WGR and the DNA-binding domain; while being proficient in DNA binding, the PARP1 R591C mutant dissociates rapidly from DNA damage sites, indicating inefficient PARP DNA trapping.	('DNA', 'cellular_component', 'GO:0005574', ('239', '242'))	('dissociates', 'NegReg', (168, 179))	('DNA', 'cellular_component', 'GO:0005574', ('193', '196'))	('DNA binding', 'molecular_function', 'GO:0003677', ('132', '143'))	('PARP1', 'Gene', (149, 154))	('R591C', 'Mutation', 'rs752905479', (155, 160))	('DNA-binding', 'molecular_function', 'GO:0003677', ('86', '97'))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('R591C', 'Var', (155, 160))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))
8072	32029455	BRCA1 mutated breast cancer PDX models resistant to PARP inhibitors showed reduced PARP1 expression levels.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('BRCA1', 'Gene', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('reduced', 'NegReg', (75, 82))	('breast cancer', 'Disease', (14, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('PARP1', 'Protein', (83, 88))	('expression levels', 'MPA', (89, 106))	('mutated', 'Var', (6, 13))
8073	32029455	PARG mutations were identified in TNBC and high-grade serous ovarian cancers eligible for PARP inhibitor treatment.	('TNBC', 'Disease', (34, 38))	('PARG', 'Gene', (0, 4))	('ovarian cancers', 'Phenotype', 'HP:0100615', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('serous ovarian cancers', 'Disease', 'MESH:D010051', (54, 76))	('mutations', 'Var', (5, 14))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('serous ovarian cancers', 'Disease', (54, 76))	('ovarian cancer', 'Phenotype', 'HP:0100615', (61, 75))
8074	32029455	On the one hand, PARG depletion was shown to reduce sensitivity of HeLa cells to PARP inhibitors combined with DNA-damaging agents or mouse Brca2 mutated cells to PARP inhibitors alone.	('HeLa', 'CellLine', 'CVCL:0030;0.09616755933431861', (67, 71))	('PARP', 'Gene', (81, 85))	('depletion', 'Var', (22, 31))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('sensitivity', 'MPA', (52, 63))	('Brca2', 'Gene', (140, 145))	('reduce', 'NegReg', (45, 51))	('Brca2', 'Gene', '12190', (140, 145))	('mouse', 'Species', '10090', (134, 139))
8075	32029455	PARG deficiency may contribute to PARP inhibitor resistance by increasing PARP1 auto-PARylation that allows PARP1 dissociation from DNA (i.e., reduction in PARP trapping) and restoration of PARP signaling.	('PARG', 'Gene', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('195', '204'))	('contribute', 'Reg', (20, 30))	('PARP1', 'Gene', (108, 113))	('PAR', 'Chemical', 'MESH:D011064', (190, 193))	('PARP signaling', 'MPA', (190, 204))	('PARP1', 'Gene', (74, 79))	('increasing', 'PosReg', (63, 73))	('PAR', 'Chemical', 'MESH:D011064', (85, 88))	('auto-PARylation', 'MPA', (80, 95))	('PAR', 'Chemical', 'MESH:D011064', (108, 111))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('PAR', 'Chemical', 'MESH:D011064', (156, 159))	('deficiency', 'Var', (5, 15))	('PAR', 'Chemical', 'MESH:D011064', (74, 77))	('dissociation from DNA', 'MPA', (114, 135))	('PAR', 'Chemical', 'MESH:D011064', (34, 37))	('reduction', 'NegReg', (143, 152))	('PAR', 'Chemical', 'MESH:D011064', (0, 3))
8079	32029455	Overexpression of ATP-binding cassette (ABC) drug transporters is often associated with drug resistance.	('drug resistance', 'biological_process', 'GO:0009315', ('88', '103'))	('drug resistance', 'biological_process', 'GO:0042493', ('88', '103'))	('ATP-binding', 'molecular_function', 'GO:0005524', ('18', '29'))	('associated', 'Reg', (72, 82))	('drug', 'MPA', (88, 92))	('ATP', 'Chemical', 'MESH:D000255', (18, 21))	('Overexpression', 'Var', (0, 14))	('drug resistance', 'Phenotype', 'HP:0020174', (88, 103))
8083	32029455	Phase 1 clinical trials with PARP inhibitors in combination with chemotherapeutic agents such as temozolomide, cisplatin, carboplatin, paclitaxel, gemcitabine, or the topoisomerase inhibitor I topotecan showed severe myelosuppression in the form of neutropenia and thrombocytopenia as a side effect.	('thrombocytopenia', 'Disease', 'MESH:D013921', (265, 281))	('neutropenia', 'Phenotype', 'HP:0001875', (249, 260))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('carboplatin', 'Chemical', 'MESH:D016190', (122, 133))	('paclitaxel', 'Chemical', 'MESH:D017239', (135, 145))	('gemcitabine', 'Chemical', 'MESH:C056507', (147, 158))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (265, 281))	('inhibitors', 'Var', (34, 44))	('thrombocytopenia', 'Disease', (265, 281))	('neutropenia', 'Disease', (249, 260))	('myelosuppression', 'Disease', 'MESH:D001855', (217, 233))	('topoisomerase', 'molecular_function', 'GO:0003917', ('167', '180'))	('topotecan', 'Chemical', 'MESH:D019772', (193, 202))	('topoisomerase', 'molecular_function', 'GO:0003918', ('167', '180'))	('temozolomide', 'Chemical', 'MESH:D000077204', (97, 109))	('neutropenia', 'Disease', 'MESH:D009503', (249, 260))	('myelosuppression', 'Disease', (217, 233))	('PARP', 'Gene', (29, 33))
8085	32029455	Moreover, mutations that cause resistance to PARP inhibitors, such as loss of NHEJ factors, PARP1, or PARG, were shown to sensitize cells to different DNA-damaging agents such as radiotherapy, topoisomerase I inhibitors and temozolomide.	('loss', 'Gene', (70, 74))	('temozolomide', 'Chemical', 'MESH:D000077204', (224, 236))	('NHEJ', 'biological_process', 'GO:0006303', ('78', '82'))	('NHEJ factors', 'Gene', (78, 90))	('sensitize', 'Reg', (122, 131))	('DNA-damaging agents', 'MPA', (151, 170))	('PARP1', 'Gene', (92, 97))	('topoisomerase', 'molecular_function', 'GO:0003917', ('193', '206'))	('mutations', 'Var', (10, 19))	('topoisomerase', 'molecular_function', 'GO:0003918', ('193', '206'))	('PARG', 'Gene', (102, 106))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))
8086	32029455	The S/G2 checkpoint is essential to allow repair of DSBs induced by PARP inhibitors and to prevent premature mitotic entry and mitotic catastrophe.	('PARP', 'Gene', (68, 72))	('S/G2', 'Var', (4, 8))	('DSBs', 'Chemical', 'MESH:C007563', (52, 56))	('S/G2', 'SUBSTITUTION', 'None', (4, 8))	('mitotic catastrophe', 'CPA', (127, 146))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('127', '146'))	('mitotic entry', 'biological_process', 'GO:0051727', ('109', '122'))	('DSBs', 'Disease', (52, 56))	('inhibitors', 'Var', (73, 83))
8087	32029455	Inhibition of the S/G2 checkpoint kinases ATR and CHK1 results in unscheduled replication origin firing, exhausts nuclear RPA pools due to excess ssDNA, depletes dNTPs, and allows mitotic entry in the presence of underreplicated DNA and unrepaired DNA damage from interphase.	('S/G2', 'Var', (18, 22))	('S/G2', 'SUBSTITUTION', 'None', (18, 22))	('DNA', 'cellular_component', 'GO:0005574', ('229', '232'))	('DNA', 'cellular_component', 'GO:0005574', ('248', '251'))	('CHK1', 'Gene', '1111', (50, 54))	('unscheduled', 'MPA', (66, 77))	('depletes', 'NegReg', (153, 161))	('ATR', 'Gene', '545', (42, 45))	('exhausts', 'NegReg', (105, 113))	('interphase', 'biological_process', 'GO:0051325', ('264', '274'))	('nuclear RPA pools', 'MPA', (114, 131))	('mitotic entry', 'biological_process', 'GO:0051727', ('180', '193'))	('Inhibition', 'Var', (0, 10))	('allows', 'Reg', (173, 179))	('mitotic entry', 'CPA', (180, 193))	('dNTPs', 'MPA', (162, 167))	('dNTPs', 'Chemical', 'MESH:D010278', (162, 167))	('ATR', 'Gene', (42, 45))	('CHK1', 'Gene', (50, 54))	('RPA', 'cellular_component', 'GO:0005662', ('122', '125'))
8088	32029455	The combination of PARP inhibitors and ATR or CHK1 inhibitors in HR-deficient cells causes the release of the G2/M arrested cells, accumulation of chromosomal breaks, and aberrations in mitosis followed by cell death.	('inhibitors', 'Var', (24, 34))	('accumulation', 'PosReg', (131, 143))	('cell death', 'biological_process', 'GO:0008219', ('206', '216'))	('HR-deficient', 'Disease', 'MESH:D001919', (65, 77))	('ATR', 'Gene', (39, 42))	('CHK1', 'Gene', (46, 50))	('combination', 'Interaction', (4, 15))	('PARP', 'Gene', (19, 23))	('aberrations in mitosis', 'Disease', (171, 193))	('cell death', 'CPA', (206, 216))	('G2/M arrested cells', 'MPA', (110, 129))	('CHK1', 'Gene', '1111', (46, 50))	('ATR', 'Gene', '545', (39, 42))	('release', 'MPA', (95, 102))	('mitosis', 'biological_process', 'GO:0000278', ('186', '193'))	('aberrations in mitosis', 'Disease', 'MESH:D002869', (171, 193))	('chromosomal breaks', 'Phenotype', 'HP:0040012', (147, 165))	('HR-deficient', 'Disease', (65, 77))	('chromosomal', 'CPA', (147, 158))
8095	32029455	The combination of PARP and WEE1 inhibitors abrogates G2 arrest and induces mitotic catastrophe, yielding promising results in small cell lung cancer, KRAS mutated non-small cell lung cancers, gastric cancer, and TP53 mutated cancer.	('cancer', 'Disease', (184, 190))	('results', 'Reg', (116, 123))	('cancer', 'Disease', (201, 207))	('TP53', 'Gene', (213, 217))	('gastric cancer', 'Disease', 'MESH:D013274', (193, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('lung cancers', 'Phenotype', 'HP:0100526', (179, 191))	('non-small cell lung cancers', 'Disease', (164, 191))	('small cell lung cancer', 'Disease', 'MESH:D055752', (127, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('WEE1', 'Gene', (28, 32))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (164, 191))	('small cell lung cancer', 'Disease', (127, 149))	('mutated', 'Var', (156, 163))	('abrogates', 'NegReg', (44, 53))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Disease', (143, 149))	('gastric cancer', 'Phenotype', 'HP:0012126', (193, 207))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (168, 190))	('PARP', 'Gene', (19, 23))	('mitotic catastrophe', 'CPA', (76, 95))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('TP53', 'Gene', '7157', (213, 217))	('induces', 'Reg', (68, 75))	('KRAS', 'Gene', '3845', (151, 155))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (168, 191))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('76', '95'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (127, 149))	('KRAS', 'Gene', (151, 155))	('WEE1', 'Gene', '7465', (28, 32))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (164, 191))	('gastric cancer', 'Disease', (193, 207))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('small cell lung cancer', 'Disease', 'MESH:D055752', (168, 190))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
8098	32029455	Inhibition of BRD4 as the global transcription regulator is synthetic lethal with PARP inhibitors.	('transcription', 'biological_process', 'GO:0006351', ('33', '46'))	('BRD4', 'Gene', '23476', (14, 18))	('BRD4', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))
8099	32029455	BRD4 inhibition induces HR deficiency independent of the BRCA status by impairing CTIP, BRCA1, and RAD51 expression, inducing DNA damage and eventually resulting in mitotic catastrophe in various cancer cell lines and PDX models.	('inhibition', 'Var', (5, 15))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('resulting in', 'Reg', (152, 164))	('CTIP', 'Gene', (82, 86))	('CTIP', 'Gene', '5932', (82, 86))	('expression', 'MPA', (105, 115))	('impairing', 'NegReg', (72, 81))	('RAD', 'biological_process', 'GO:1990116', ('99', '102'))	('HR deficiency', 'Disease', (24, 37))	('mitotic catastrophe', 'CPA', (165, 184))	('BRD4', 'Gene', (0, 4))	('HR deficiency', 'Disease', 'MESH:D001919', (24, 37))	('inducing', 'Reg', (117, 125))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('165', '184'))	('DNA damage', 'MPA', (126, 136))	('cancer', 'Disease', (196, 202))	('BRCA', 'Gene', '672', (88, 92))	('BRCA', 'Gene', '672', (57, 61))	('BRD4', 'Gene', '23476', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('RAD51', 'Gene', (99, 104))	('BRCA', 'Gene', (57, 61))	('BRCA', 'Gene', (88, 92))	('RAD51', 'Gene', '5888', (99, 104))
8107	32029455	PARP inhibitors further synergize with inhibitors of the PI3K pathway, as shown in BRCA-proficient TNBC, BRCA1 mutated breast cancer mouse models, PIK3CA mutated ovarian cancer cells, and PTEN mutated endometrial cancer cells.	('mutated', 'Var', (111, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('mouse', 'Species', '10090', (133, 138))	('ovarian cancer', 'Disease', (162, 176))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('BRCA', 'Gene', '672', (83, 87))	('breast cancer', 'Disease', (119, 132))	('ovarian cancer', 'Phenotype', 'HP:0100615', (162, 176))	('PIK3CA', 'Gene', (147, 153))	('BRCA', 'Gene', '672', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('BRCA', 'Gene', (83, 87))	('endometrial cancer', 'Phenotype', 'HP:0012114', (201, 219))	('BRCA', 'Gene', (105, 109))	('PI3K', 'molecular_function', 'GO:0016303', ('57', '61'))	('PIK3CA', 'Gene', '18706', (147, 153))	('endometrial cancer', 'Disease', (201, 219))	('PI3K pathway', 'Pathway', (57, 69))	('ovarian cancer', 'Disease', 'MESH:D010051', (162, 176))	('endometrial cancer', 'Disease', 'MESH:D016889', (201, 219))
8112	32029455	PARP inhibition also reduces E2F1 genomic binding and expression of the E2F1 target genes and may thereby synergize with hypoxic effects induced by antiangiogenic agents.	('expression', 'MPA', (54, 64))	('E2F1', 'Gene', '1869', (72, 76))	('E2F1', 'Gene', (72, 76))	('inhibition', 'Var', (5, 15))	('E2F1', 'Gene', '1869', (29, 33))	('E2F1', 'Gene', (29, 33))	('PARP', 'Protein', (0, 4))	('hypoxic', 'Disease', (121, 128))	('hypoxic', 'Disease', 'MESH:D000860', (121, 128))	('binding', 'molecular_function', 'GO:0005488', ('42', '49'))	('genomic', 'Protein', (34, 41))	('reduces', 'NegReg', (21, 28))
8115	32029455	DNA damage or DNA repair defects caused by BRCA or ERCC1 mutations can also activate this pathway and thereby potentiate PARP inhibitor effects in ERCC1-deficient nonsmall cell lung cancer, BRCA1-deficient TNBC, and ovarian cancer.	('ERCC1', 'Gene', '2067', (147, 152))	('DNA repair', 'biological_process', 'GO:0006281', ('14', '24'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('ERCC1-deficient nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (147, 188))	('ERCC1', 'Gene', '2067', (51, 56))	('mutations', 'Var', (57, 66))	('BRCA', 'Gene', (190, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('defects', 'Var', (25, 32))	('ERCC1', 'Gene', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('ERCC1', 'Gene', (51, 56))	('activate', 'PosReg', (76, 84))	('BRCA', 'Gene', '672', (43, 47))	('ERCC1-deficient nonsmall cell lung cancer', 'Disease', (147, 188))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (166, 188))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('PARP inhibitor effects', 'MPA', (121, 143))	('potentiate', 'PosReg', (110, 120))	('BRCA1-deficient TNBC, and ovarian cancer', 'Disease', 'MESH:D010051', (190, 230))	('BRCA', 'Gene', (43, 47))	('ovarian cancer', 'Phenotype', 'HP:0100615', (216, 230))	('BRCA', 'Gene', '672', (190, 194))
8120	32029455	Phase II trials of the PD-L1 antibody durvalumab or pembrolizumab in combination with olaparib or niraparib showed clinical response in patients with advanced SCLC, germline BRCA1/2 mutated breast and platinum-sensitive ovarian cancer, but also in prostate cancer and platinum-resistant ovarian cancer patients irrespective of BRCA mutations.	('mutated', 'Var', (182, 189))	('BRCA', 'Gene', '672', (174, 178))	('platinum', 'Chemical', 'MESH:D010984', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('antibody', 'cellular_component', 'GO:0019815', ('29', '37'))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('ovarian cancer', 'Disease', (220, 234))	('ovarian cancer', 'Disease', 'MESH:D010051', (287, 301))	('BRCA', 'Gene', (174, 178))	('SCLC', 'Disease', 'MESH:D018288', (159, 163))	('niraparib', 'Chemical', 'MESH:C545685', (98, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (248, 263))	('ovarian cancer', 'Phenotype', 'HP:0100615', (220, 234))	('antibody', 'cellular_component', 'GO:0019814', ('29', '37'))	('prostate cancer', 'Phenotype', 'HP:0012125', (248, 263))	('prostate cancer', 'Disease', (248, 263))	('BRCA1/2', 'Gene', (174, 181))	('BRCA', 'Gene', '672', (327, 331))	('ovarian cancer', 'Disease', (287, 301))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('olaparib', 'Chemical', 'MESH:C531550', (86, 94))	('antibody', 'molecular_function', 'GO:0003823', ('29', '37'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (287, 301))	('platinum', 'Chemical', 'MESH:D010984', (268, 276))	('BRCA1/2', 'Gene', '672;675', (174, 181))	('antibody', 'cellular_component', 'GO:0042571', ('29', '37'))	('SCLC', 'Disease', (159, 163))	('pembrolizumab', 'Chemical', 'MESH:C582435', (52, 65))	('BRCA', 'Gene', (327, 331))	('durvalumab', 'Chemical', 'MESH:C000613593', (38, 48))	('breast', 'Disease', (190, 196))	('patients', 'Species', '9606', (136, 144))	('SCLC', 'Phenotype', 'HP:0030357', (159, 163))	('ovarian cancer', 'Disease', 'MESH:D010051', (220, 234))	('patients', 'Species', '9606', (302, 310))
8121	32029455	Cancer cells experience high levels of replication stress and often harbor germline or somatic mutations in DNA damage response genes.	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('germline', 'Var', (75, 83))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('harbor', 'Reg', (68, 74))	('DNA damage response genes', 'Gene', (108, 133))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('DNA damage response', 'biological_process', 'GO:0006974', ('108', '127'))
8123	32029455	The original concept of synthetic lethality between PARP inhibitors and breast and ovarian cancer mutations in BRCA1/2 has now expanded to include a range of cancer types exhibiting homologous recombination deficiency and replication stress.	('homologous recombination', 'biological_process', 'GO:0035825', ('182', '206'))	('BRCA1/2', 'Gene', (111, 118))	('cancer', 'Disease', (91, 97))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (72, 97))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('mutations', 'Var', (98, 107))	('cancer', 'Disease', (158, 164))	('BRCA1/2', 'Gene', '672;675', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
8141	31788038	Alternate splicing of PKM pre-mRNA by heterogeneous nuclear ribonucleoprotein A1/2 and polypyrimidine-tract binding protein (PTBP1), results in PKM2 generation.	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('PTBP1', 'Gene', '5725', (125, 130))	('PKM2', 'Gene', (144, 148))	('pre', 'molecular_function', 'GO:0003904', ('26', '29'))	('PKM', 'Gene', (144, 147))	('splicing', 'biological_process', 'GO:0045292', ('10', '18'))	('PKM', 'Gene', '5315', (144, 147))	('PKM2', 'Gene', '5315', (144, 148))	('results in', 'Reg', (133, 143))	('PTBP1', 'Gene', (125, 130))	('A1/2 and polypyrimidine-tract binding protein', 'Gene', '28887;597;23545', (78, 123))	('Alternate splicing', 'Var', (0, 18))	('PKM', 'Gene', '5315', (22, 25))	('heterogeneous nuclear ribonucleoprotein', 'molecular_function', 'GO:0008436', ('38', '77'))	('PKM', 'Gene', (22, 25))	('heterogeneous nuclear ribonucleoprotein', 'cellular_component', 'GO:0030530', ('38', '77'))	('binding', 'molecular_function', 'GO:0005488', ('108', '115'))
8145	31788038	High expression levels of PKM2 have been shown to be associated with increased chemosensitivity to 5-fluorouracil (5-FU) and epirubicin in breast and cervical cancer.	('PKM2', 'Gene', '5315', (26, 30))	('increased', 'PosReg', (69, 78))	('epirubicin', 'Chemical', 'MESH:D015251', (125, 135))	('epirubicin', 'MPA', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (99, 113))	('chemosensitivity to 5-fluorouracil', 'MPA', (79, 113))	('5-FU', 'Chemical', 'MESH:D005472', (115, 119))	('breast and cervical cancer', 'Disease', 'MESH:D001943', (139, 165))	('High expression levels', 'Var', (0, 22))	('PKM2', 'Gene', (26, 30))
8152	31788038	It has been demonstrated that the inhibition of PKM2 slows tumor growth or causes tumor cell death.	('tumor cell death', 'Disease', 'MESH:D003643', (82, 98))	('cell death', 'biological_process', 'GO:0008219', ('88', '98'))	('tumor', 'Disease', (59, 64))	('causes', 'Reg', (75, 81))	('inhibition', 'Var', (34, 44))	('PKM2', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor cell death', 'Disease', (82, 98))	('slows', 'NegReg', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('PKM2', 'Gene', '5315', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
8154	31788038	RNA interference and peptide aptamers that ablate PKM2 have been reported to elicit anticancer effects, such as the impairment of tumor growth, the induction of apoptotic cell death and increasing sensitivity to chemotherapy.	('apoptotic cell death', 'biological_process', 'GO:0006915', ('161', '181'))	('elicit', 'Reg', (77, 83))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('RNA interference', 'biological_process', 'GO:0016246', ('0', '16'))	('sensitivity to chemotherapy', 'CPA', (197, 224))	('RNA interference', 'MPA', (0, 16))	('ablate', 'Var', (43, 49))	('apoptotic cell death', 'CPA', (161, 181))	('impairment of tumor', 'Disease', (116, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('PKM2', 'Gene', (50, 54))	('impairment of tumor', 'Disease', 'MESH:D009369', (116, 135))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PKM2', 'Gene', '5315', (50, 54))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('increasing', 'PosReg', (186, 196))
8176	31788038	Data gathered from multiple xenograft cancer models suggest that metformin may inhibit the progression and recrudescence of cancer.	('inhibit', 'NegReg', (79, 86))	('cancer', 'Disease', (38, 44))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('metformin', 'Var', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('metformin', 'Chemical', 'MESH:D008687', (65, 74))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
8177	31788038	Moreover, metformin induces tumor cell death and increases sensitivity to chemotherapeutic drugs via the inhibition of PKM2.	('PKM2', 'Gene', (119, 123))	('PKM2', 'Gene', '5315', (119, 123))	('metformin', 'Var', (10, 19))	('inhibition', 'NegReg', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor cell death', 'Disease', 'MESH:D003643', (28, 44))	('increases', 'PosReg', (49, 58))	('metformin', 'Chemical', 'MESH:D008687', (10, 19))	('sensitivity to chemotherapeutic drugs', 'MPA', (59, 96))	('cell death', 'biological_process', 'GO:0008219', ('34', '44'))	('tumor cell death', 'Disease', (28, 44))
8178	31788038	For instance, Shang et al demonstrated that metformin enhanced the sensitivity of osteosarcoma stem cells to cisplatin, by reducing the expression level of PKM2.	('metformin', 'Var', (44, 53))	('reducing', 'NegReg', (123, 131))	('osteosarcoma', 'Phenotype', 'HP:0002669', (82, 94))	('metformin', 'Chemical', 'MESH:D008687', (44, 53))	('sensitivity', 'MPA', (67, 78))	('expression level', 'MPA', (136, 152))	('PKM2', 'Gene', (156, 160))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))	('enhanced', 'PosReg', (54, 62))	('PKM2', 'Gene', '5315', (156, 160))	('osteosarcoma', 'Disease', (82, 94))	('osteosarcoma', 'Disease', 'MESH:D012516', (82, 94))
8183	31788038	Cheng et al discovered that metformin inhibits transforming growth factor beta1 (TGF-beta1)-induced EMT in cervical cancer cells, and also investigated the mechanisms involved in tumorigenesis (which reduced PKM2 expression levels).	('metformin', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('EMT', 'biological_process', 'GO:0001837', ('100', '103'))	('metformin', 'Chemical', 'MESH:D008687', (28, 37))	('EMT', 'CPA', (100, 103))	('TGF-beta1', 'Gene', (81, 90))	('inhibits', 'NegReg', (38, 46))	('reduced', 'NegReg', (200, 207))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('47', '78'))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('TGF-beta1', 'Gene', '7040', (81, 90))	('tumor', 'Disease', (179, 184))	('transforming growth factor beta1', 'Gene', '7040', (47, 79))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cervical cancer', 'Disease', 'MESH:D002583', (107, 122))	('cervical cancer', 'Disease', (107, 122))	('transforming growth factor beta1', 'Gene', (47, 79))	('PKM2', 'Gene', (208, 212))	('PKM2', 'Gene', '5315', (208, 212))
8188	31788038	VK3 also improves the efficacy of anticancer drugs such as doxorubicin (DOX).	('doxorubicin', 'MPA', (59, 70))	('improves', 'PosReg', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('efficacy', 'MPA', (22, 30))	('DOX', 'Chemical', 'MESH:D004317', (72, 75))	('doxorubicin', 'Chemical', 'MESH:D004317', (59, 70))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('VK3', 'Var', (0, 3))
8189	31788038	Moreover, a clinical trial suggested that VK3 improves cell sensitivity to Inopera: Chen et al discovered that VK3 and 5 inhibit PKM2 significantly more than PKM1 and pyruvate kinase isoenzyme L, while other isoforms of PK are predominantly expressed in most adult tissues and the liver.	('inhibit', 'NegReg', (121, 128))	('PKM2', 'Gene', '5315', (129, 133))	('VK3', 'Var', (111, 114))	('pyruvate', 'Chemical', 'MESH:D011773', (167, 175))	('PKM2', 'Gene', (129, 133))	('PKM', 'Gene', (129, 132))	('PKM', 'Gene', '5315', (129, 132))	('PKM', 'Gene', (158, 161))	('PKM', 'Gene', '5315', (158, 161))
8242	31788038	He et al discovered that aerobic glycolysis was significantly upregulated in 5-FU-resistant cells.	('5-FU', 'Chemical', 'MESH:D005472', (77, 81))	('upregulated', 'PosReg', (62, 73))	('glycolysis', 'biological_process', 'GO:0006096', ('33', '43'))	('aerobic glycolysis', 'MPA', (25, 43))	('5-FU-resistant', 'Var', (77, 91))
8253	31788038	Shi et al determined that combining plasmid short hairpin (sh)RNA-PKM2 with standard docetaxel treatment significantly improved its efficacy.	('efficacy', 'MPA', (132, 140))	('docetaxel', 'Chemical', 'MESH:C067311', (85, 94))	('plasmid', 'Var', (36, 43))	('PKM2', 'Gene', (66, 70))	('PKM2', 'Gene', '5315', (66, 70))	('improved', 'PosReg', (119, 127))	('RNA', 'cellular_component', 'GO:0005562', ('62', '65'))
8257	31788038	These results further suggest that targeting PKM2 has the potential to improve the treatment outcomes of patients with NSCLC, by increasing the chemotherapeutic efficacy of docetaxel.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('patients', 'Species', '9606', (105, 113))	('increasing', 'PosReg', (129, 139))	('PKM2', 'Gene', (45, 49))	('PKM2', 'Gene', '5315', (45, 49))	('treatment', 'MPA', (83, 92))	('targeting', 'Var', (35, 44))	('NSCLC', 'Disease', (119, 124))	('docetaxel', 'Chemical', 'MESH:C067311', (173, 182))	('improve', 'PosReg', (71, 78))
8269	31788038	Numerous studies have confirmed that the inhibition of PKM2 increased tumor cell sensitivity to chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('PKM2', 'Gene', (55, 59))	('increased', 'PosReg', (60, 69))	('inhibition', 'Var', (41, 51))	('PKM2', 'Gene', '5315', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
8287	31814735	UBE2S could enhance EMT by the VHL/HIF-1alpha/STAT3 pathway via the ubiquitin-proteasome system.	('VHL', 'Gene', '7428', (31, 34))	('EMT', 'CPA', (20, 23))	('STAT3', 'Gene', '6774', (46, 51))	('HIF-1alpha', 'Gene', (35, 45))	('UBE2S', 'Var', (0, 5))	('STAT3', 'Gene', (46, 51))	('ubiquitin-proteasome system', 'MPA', (68, 95))	('proteasome', 'cellular_component', 'GO:0000502', ('78', '88'))	('HIF-1alpha', 'Gene', '3091', (35, 45))	('proteasome', 'molecular_function', 'GO:0004299', ('78', '88'))	('enhance', 'PosReg', (12, 19))	('VHL', 'Gene', (31, 34))	('ubiquitin', 'molecular_function', 'GO:0031386', ('68', '77'))	('EMT', 'biological_process', 'GO:0001837', ('20', '23'))
8288	31814735	Co-expression of CDC20 may represent a novel and promising therapeutic target for the patients with PDAC.	('PDAC', 'Disease', 'MESH:D021441', (100, 104))	('Co-expression', 'Var', (0, 13))	('PDAC', 'Disease', (100, 104))	('PDAC', 'Phenotype', 'HP:0006725', (100, 104))	('CDC20', 'Gene', (17, 22))	('CDC20', 'Gene', '991', (17, 22))	('patients', 'Species', '9606', (86, 94))
8308	31814735	In normoxic condition, knockout of HIF-1alpha was shown to deteriorate the growth of tumor in vitro.	('tumor', 'Disease', (85, 90))	('deteriorate', 'NegReg', (59, 70))	('HIF-1alpha', 'Gene', (35, 45))	('knockout', 'Var', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('HIF-1alpha', 'Gene', '3091', (35, 45))
8311	31814735	For instance, high UBE2C expression is thought to be associated with poor survivals in breast cancer and ovarian carcinoma.	('expression', 'MPA', (25, 35))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (105, 122))	('ovarian carcinoma', 'Disease', (105, 122))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('high', 'Var', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('UBE2C', 'Gene', '11065', (19, 24))	('UBE2C', 'Gene', (19, 24))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (105, 122))
8313	31814735	Here we provide the first evidence that the expression of UBE2S promoted pancreatic cancer cell EMT and the interaction between UBE2S and VHL via the ubiquitin-proteasome system, suggesting that UBE2S significantly enhanced the VHL/HIF-1alpha/STAT3-induced EMT and metastasis in vitro and in vivo by attenuating the activity of the promoter.	('UBE2S', 'Gene', (58, 63))	('promoted', 'PosReg', (64, 72))	('VHL', 'Gene', (228, 231))	('EMT', 'biological_process', 'GO:0001837', ('96', '99'))	('promoter', 'MPA', (332, 340))	('enhanced', 'PosReg', (215, 223))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))	('EMT', 'biological_process', 'GO:0001837', ('257', '260'))	('attenuating', 'NegReg', (300, 311))	('HIF-1alpha', 'Gene', '3091', (232, 242))	('VHL', 'Gene', '7428', (228, 231))	('expression', 'Var', (44, 54))	('interaction', 'Interaction', (108, 119))	('proteasome', 'molecular_function', 'GO:0004299', ('160', '170'))	('VHL', 'Gene', (138, 141))	('activity', 'MPA', (316, 324))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('HIF-1alpha', 'Gene', (232, 242))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('proteasome', 'cellular_component', 'GO:0000502', ('160', '170'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('150', '159'))	('STAT3', 'Gene', (243, 248))	('VHL', 'Gene', '7428', (138, 141))	('UBE2S', 'Var', (195, 200))	('pancreatic cancer', 'Disease', (73, 90))	('STAT3', 'Gene', '6774', (243, 248))
8319	31814735	RNA-sequencing dataset of PDAC cohort which was downloaded from TCGA (https://tcga-data.nci.nih.gov/tcga/) and GSE16515 were divided into two groups according to median UBE2S expression.	('PDAC', 'Disease', 'MESH:D021441', (26, 30))	('PDAC', 'Disease', (26, 30))	('PDAC', 'Phenotype', 'HP:0006725', (26, 30))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('GSE16515', 'Var', (111, 119))
8334	31814735	The primary antibodies used for Western blot analyses were anti-UBE2S (Cell Signaling Technology) and anti-beta-Actin (Cell Signaling Technology).	('beta-Actin', 'Gene', (107, 117))	('beta-Actin', 'Gene', '728378', (107, 117))	('Signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('anti-UBE2S', 'Var', (59, 69))	('Signaling', 'biological_process', 'GO:0023052', ('124', '133'))
8350	31814735	To identify the candidate genes in the carcinogenesis and progression of PDAC, three microarray datasets GSE15471, GSE16515 and GSE28735 were downloaded from GEO database.	('carcinogenesis', 'Disease', 'MESH:D063646', (39, 53))	('carcinogenesis', 'Disease', (39, 53))	('PDAC', 'Phenotype', 'HP:0006725', (73, 77))	('PDAC', 'Disease', 'MESH:D021441', (73, 77))	('PDAC', 'Disease', (73, 77))	('GSE15471', 'Var', (105, 113))
8358	31814735	Furthermore, Kaplan-Meier survival analysis showed that patients with high UBE2S expression had a shorter overall survival (Figure 1L).	('patients', 'Species', '9606', (56, 64))	('overall survival', 'MPA', (106, 122))	('high', 'Var', (70, 74))	('UBE2S', 'Gene', (75, 80))	('shorter', 'NegReg', (98, 105))
8362	31814735	To investigate the role of UBE2S in pancreatic cancer cell proliferation, UBE2S in PANC-1 and CFPAC-1 cell lines were expressed and knocked down using RNAi.	('PANC-1', 'CellLine', 'CVCL:0480', (83, 89))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (36, 53))	('CFPAC-1', 'CellLine', 'CVCL:1119', (94, 101))	('UBE2S', 'Gene', (74, 79))	('RNAi', 'biological_process', 'GO:0016246', ('151', '155'))	('cell proliferation', 'biological_process', 'GO:0008283', ('54', '72'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('pancreatic cancer', 'Disease', 'MESH:D010190', (36, 53))	('pancreatic cancer', 'Disease', (36, 53))	('knocked', 'Var', (132, 139))
8363	31814735	Besides, SW1990 cells which expressed lower levels of UBE2S were infected with pLVX-Puro-UBE2S lentivirus or pretty blank pLVX-Puro lentivirus (vector), and the expression was significantly up-regulated in transfected SW1990 cells compared to the controls (Figure 2D).	('expression', 'MPA', (161, 171))	('pLVX-Puro-UBE2S', 'Var', (79, 94))	('up-regulated', 'PosReg', (190, 202))	('SW1990', 'CellLine', 'CVCL:1723', (9, 15))	('SW1990', 'CellLine', 'CVCL:1723', (218, 224))
8365	31814735	Figure 2I and J demonstrated that the volume and size of the tumors from PANC1-siUBE2S cells were smaller than those of the tumors originating from the control group, suggesting that the knockdown of UBE2S expression rendered a lower ability of proliferation in vivo.	('smaller', 'NegReg', (98, 105))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('knockdown', 'Var', (187, 196))	('UBE2S', 'Gene', (200, 205))	('PANC1', 'Gene', '104066', (73, 78))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('PANC1', 'Gene', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('lower', 'NegReg', (228, 233))
8370	31814735	Besides, over-expressing UBE2S reduced the expression level of the same EMT-inducing transcription factors, especially Twist1, as compared to the control group (Figure 3E and F), indicating that UBE2S enhanced EMT stimulated by those factors through a VHL-independent mechanism.	('VHL', 'Gene', (252, 255))	('EMT', 'CPA', (210, 213))	('reduced', 'NegReg', (31, 38))	('UBE2S', 'Var', (195, 200))	('EMT', 'biological_process', 'GO:0001837', ('210', '213'))	('VHL', 'Gene', '7428', (252, 255))	('EMT', 'biological_process', 'GO:0001837', ('72', '75'))	('UBE2S', 'Var', (25, 30))	('Twist1', 'Gene', '7291', (119, 125))	('enhanced', 'PosReg', (201, 209))	('expression level', 'MPA', (43, 59))	('transcription', 'biological_process', 'GO:0006351', ('85', '98'))	('Twist1', 'Gene', (119, 125))
8372	31814735	Furthermore, MG132 treatment largely abolished the inhibitory effect of UBE2S on snail, Twist1 and HIF-1alpha protein levels in cells (Figure 4A).	('snail', 'Gene', '6615', (81, 86))	('Twist1', 'Gene', '7291', (88, 94))	('MG132', 'Var', (13, 18))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('Twist1', 'Gene', (88, 94))	('HIF-1alpha', 'Gene', '3091', (99, 109))	('snail', 'Gene', (81, 86))	('HIF-1alpha', 'Gene', (99, 109))	('abolished', 'NegReg', (37, 46))	('inhibitory', 'MPA', (51, 61))
8373	31814735	The Western blotting results indicated that UBE2S inhibited the expression of related EMT factors such as Snail and Twist1 via the ubiquitin-proteasome system (Figure 4B).	('expression', 'MPA', (64, 74))	('Snail', 'Gene', '6615', (106, 111))	('Snail', 'Gene', (106, 111))	('Twist1', 'Gene', '7291', (116, 122))	('Twist1', 'Gene', (116, 122))	('proteasome', 'cellular_component', 'GO:0000502', ('141', '151'))	('EMT', 'biological_process', 'GO:0001837', ('86', '89'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('131', '140'))	('proteasome', 'molecular_function', 'GO:0004299', ('141', '151'))	('ubiquitin-proteasome', 'MPA', (131, 151))	('UBE2S', 'Var', (44, 49))	('inhibited', 'NegReg', (50, 59))
8374	31814735	These data, therefore, suggested that UBE2S promoted PDAC cell metastasis and invasion by up-regulating EMT process via standard ubiquitination reactions.	('promoted', 'PosReg', (44, 52))	('PDAC', 'Phenotype', 'HP:0006725', (53, 57))	('PDAC', 'Disease', 'MESH:D021441', (53, 57))	('UBE2S', 'Var', (38, 43))	('invasion', 'CPA', (78, 86))	('PDAC', 'Disease', (53, 57))	('EMT', 'biological_process', 'GO:0001837', ('104', '107'))	('EMT process', 'CPA', (104, 115))	('up-regulating', 'PosReg', (90, 103))
8377	31814735	Moreover, UBE2S over-expression also prohibited the protein level and ubiquitination of VHL, causing the change of downstream proteins.	('prohibited', 'NegReg', (37, 47))	('over-expression', 'Var', (16, 31))	('UBE2S', 'Gene', (10, 15))	('protein level', 'MPA', (52, 65))	('VHL', 'Gene', (88, 91))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))	('ubiquitination', 'MPA', (70, 84))	('VHL', 'Gene', '7428', (88, 91))	('downstream proteins', 'MPA', (115, 134))	('change', 'Reg', (105, 111))
8379	31814735	UBE2S silencing also significantly reduced the expression level and activity of p-STAT3, while the protein STAT3 did not display a difference (Figure 4D).	('STAT3', 'Gene', (107, 112))	('reduced', 'NegReg', (35, 42))	('STAT3', 'Gene', '6774', (82, 87))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('activity', 'MPA', (68, 76))	('expression level', 'MPA', (47, 63))	('STAT3', 'Gene', (82, 87))	('STAT3', 'Gene', '6774', (107, 112))	('silencing', 'Var', (6, 15))	('UBE2S', 'Gene', (0, 5))
8382	31814735	Moreover, the GSEA results also demonstrated that UBE2S could affect the downstream proteins through the IL6-JAK-STAT3 pathway.	('affect', 'Reg', (62, 68))	('STAT3', 'Gene', '6774', (113, 118))	('JAK', 'molecular_function', 'GO:0004713', ('109', '112'))	('proteins', 'Protein', (84, 92))	('IL6', 'molecular_function', 'GO:0005138', ('105', '108'))	('STAT3', 'Gene', (113, 118))	('UBE2S', 'Var', (50, 55))
8397	31814735	This study examined the gene expression profiles of GSE15471, GSE16515 and GSE28735 in several tumor and normal tissue samples to identify the molecular mechanism of PDAC and to seek some biomarkers beneficial to treatment.	('PDAC', 'Disease', (166, 170))	('PDAC', 'Phenotype', 'HP:0006725', (166, 170))	('gene expression', 'biological_process', 'GO:0010467', ('24', '39'))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('GSE15471', 'Var', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('GSE28735', 'Var', (75, 83))	('GSE16515', 'Var', (62, 70))	('PDAC', 'Disease', 'MESH:D021441', (166, 170))	('tumor', 'Disease', (95, 100))
8401	31814735	Chen et al found that UBE2S can promote the invasion and metastasis of esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('metastasis of esophageal squamous cell carcinoma', 'Disease', (57, 105))	('UBE2S', 'Var', (22, 27))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('promote', 'PosReg', (32, 39))	('metastasis of esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (57, 105))
8407	31814735	Besides, GSEA analysis indicated that EMT signaling and IL6-JAK-STAT3 pathway were facilitated in PDAC with high expression of UBE2S.	('JAK', 'molecular_function', 'GO:0004713', ('60', '63'))	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('UBE2S', 'Gene', (127, 132))	('PDAC', 'Disease', 'MESH:D021441', (98, 102))	('PDAC', 'Disease', (98, 102))	('PDAC', 'Phenotype', 'HP:0006725', (98, 102))	('IL6', 'molecular_function', 'GO:0005138', ('56', '59'))	('STAT3', 'Gene', '6774', (64, 69))	('EMT', 'biological_process', 'GO:0001837', ('38', '41'))	('STAT3', 'Gene', (64, 69))	('high expression', 'Var', (108, 123))	('EMT signaling', 'CPA', (38, 51))	('facilitated', 'PosReg', (83, 94))
8412	31814735	It is generally accepted that the deletion and mutation of VHL lead to the development of many types of tumors.	('VHL', 'Gene', '7428', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('mutation', 'Var', (47, 55))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('deletion', 'Var', (34, 42))	('lead to', 'Reg', (63, 70))	('VHL', 'Gene', (59, 62))
8414	31814735	VHL deletion causes the activation of HIF-1alpha, thereby controlling biological behaviors such as cell proliferation and EMT progressions, which explains the reason why VHL promotes tumors' development.	('cell proliferation', 'CPA', (99, 117))	('VHL', 'Gene', (170, 173))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('VHL', 'Gene', '7428', (170, 173))	('HIF-1alpha', 'Gene', '3091', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('EMT', 'biological_process', 'GO:0001837', ('122', '125'))	('cell proliferation', 'biological_process', 'GO:0008283', ('99', '117'))	('VHL', 'Gene', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('deletion', 'Var', (4, 12))	('activation', 'PosReg', (24, 34))	('VHL', 'Gene', '7428', (0, 3))	('tumors', 'Disease', (183, 189))	('HIF-1alpha', 'Gene', (38, 48))	('EMT', 'CPA', (122, 125))
8416	31814735	Solid evidence has indicated that under normoxic conditions, UBE2S can reduce the level of VHL protein and activate HIF-1alpha, hence promoting the proliferation and EMT progressions of renal cell carcinoma and melanoma cells.	('renal cell carcinoma', 'Disease', 'MESH:D002292', (186, 206))	('reduce', 'NegReg', (71, 77))	('EMT', 'biological_process', 'GO:0001837', ('166', '169'))	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('HIF-1alpha', 'Gene', (116, 126))	('level of', 'MPA', (82, 90))	('renal cell carcinoma', 'Disease', (186, 206))	('proliferation', 'CPA', (148, 161))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (186, 206))	('VHL', 'Gene', (91, 94))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('activate', 'PosReg', (107, 115))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('VHL', 'Gene', '7428', (91, 94))	('UBE2S', 'Var', (61, 66))	('HIF-1alpha', 'Gene', '3091', (116, 126))	('EMT progressions', 'CPA', (166, 182))	('promoting', 'PosReg', (134, 143))
8425	31814735	To investigate the molecular mechanism of UBE2S on EMT-related factors' expression and HIF-1alpha, we treated PANC-1 and SW1990 cells, which had been transduced with the siRNA and pLVX-Puro-UBE2S lentivirus; MG132 treatment largely abolished the inhibitory effect of UBE2S on snail, Twist1 and HIF-1alpha in cells.	('snail', 'Gene', (276, 281))	('HIF-1alpha', 'Gene', (87, 97))	('PANC-1', 'CellLine', 'CVCL:0480', (110, 116))	('EMT', 'biological_process', 'GO:0001837', ('51', '54'))	('HIF-1alpha', 'Gene', '3091', (294, 304))	('inhibitory effect', 'MPA', (246, 263))	('SW1990', 'CellLine', 'CVCL:1723', (121, 127))	('Twist1', 'Gene', (283, 289))	('snail', 'Gene', '6615', (276, 281))	('MG132', 'Var', (208, 213))	('abolished', 'NegReg', (232, 241))	('HIF-1alpha', 'Gene', (294, 304))	('HIF-1alpha', 'Gene', '3091', (87, 97))	('Twist1', 'Gene', '7291', (283, 289))
8437	31814735	Kidokoro discovered that inactivation of p53 observed in various cancer tissues is perhaps the cause of the CDC20 up-regulation.	('p53', 'Gene', '7157', (41, 44))	('inactivation', 'Var', (25, 37))	('CDC20', 'Gene', (108, 113))	('up-regulation', 'PosReg', (114, 127))	('CDC20', 'Gene', '991', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('regulation', 'biological_process', 'GO:0065007', ('117', '127'))	('p53', 'Gene', (41, 44))
8440	31814735	Craney reported that the phosphorylation of a specific serine residue in the APC/C coactivator CDC20 prevents delivery of UBE2S to the APC/C, allowing UBE2S to bind to the APC/C and catalyze ubiquitin chain elongation.	('APC', 'Gene', '324', (135, 138))	('APC', 'Gene', '324', (77, 80))	('APC', 'Gene', '324', (172, 175))	('APC', 'cellular_component', 'GO:0005680', ('172', '175'))	('prevents', 'NegReg', (101, 109))	('bind', 'Interaction', (160, 164))	('APC', 'Gene', (135, 138))	('APC', 'Gene', (77, 80))	('phosphorylation', 'Var', (25, 40))	('serine', 'Chemical', 'MESH:C047902', (55, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('25', '40'))	('APC', 'Gene', (172, 175))	('catalyze', 'MPA', (182, 190))	('ubiquitin', 'molecular_function', 'GO:0031386', ('191', '200'))	('CDC20', 'Gene', '991', (95, 100))	('delivery', 'MPA', (110, 118))	('ubiquitin chain elongation', 'MPA', (191, 217))	('CDC20', 'Gene', (95, 100))	('APC', 'cellular_component', 'GO:0005680', ('77', '80'))	('APC', 'cellular_component', 'GO:0005680', ('135', '138'))
8441	31814735	More importantly, previous results of bioinformatic analysis indicated that the co-expression of UBE2S and CDC20 perhaps offers new possibility of early diagnosis, dynamic monitoring of curative effect and new drug target of pancreatic cancer.	('CDC20', 'Gene', '991', (107, 112))	('pancreatic cancer', 'Disease', (225, 242))	('UBE2S', 'Gene', (97, 102))	('pancreatic cancer', 'Disease', 'MESH:D010190', (225, 242))	('co-expression', 'Var', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (225, 242))	('CDC20', 'Gene', (107, 112))
8450	31814735	In vitro experiments, it was demonstrated that UBE2S overexpression promoted but UBE2S knockdown suppressed cell proliferation and migration via modulation of VHL/HIF-1alpha/STAT3 signaling pathway.	('HIF-1alpha', 'Gene', '3091', (163, 173))	('VHL', 'Gene', '7428', (159, 162))	('signaling pathway', 'biological_process', 'GO:0007165', ('180', '197'))	('HIF-1alpha', 'Gene', (163, 173))	('cell proliferation', 'biological_process', 'GO:0008283', ('108', '126'))	('UBE2S', 'Gene', (81, 86))	('STAT3', 'Gene', '6774', (174, 179))	('cell proliferation', 'CPA', (108, 126))	('VHL', 'Gene', (159, 162))	('suppressed', 'NegReg', (97, 107))	('STAT3', 'Gene', (174, 179))	('modulation', 'Reg', (145, 155))	('knockdown', 'Var', (87, 96))
8528	28941651	Mutations in TP53, PIK3CA, and PTEN have been associated with advanced neoplasia (high-grade dysplasia or invasive cancer) in mucinous cysts, with a sensitivity of 91% and specificity of 97%.	('PTEN', 'Gene', (31, 35))	('TP53', 'Gene', (13, 17))	('mucinous cysts', 'Disease', (126, 140))	('PIK3CA', 'Gene', '5290', (19, 25))	('neoplasia', 'Disease', 'MESH:D009369', (71, 80))	('PTEN', 'Gene', '5728', (31, 35))	('neoplasia', 'Disease', (71, 80))	('invasive cancer', 'Disease', (106, 121))	('Mutations', 'Var', (0, 9))	('invasive cancer', 'Disease', 'MESH:D009362', (106, 121))	('TP53', 'Gene', '7157', (13, 17))	('PIK3CA', 'Gene', (19, 25))	('neoplasia', 'Phenotype', 'HP:0002664', (71, 80))	('associated with', 'Reg', (46, 61))	('dysplasia', 'Disease', (93, 102))	('mucinous cysts', 'Disease', 'MESH:D002288', (126, 140))	('mucinous cyst', 'Phenotype', 'HP:0200040', (126, 139))	('dysplasia', 'Disease', 'MESH:D004476', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('mucinous cysts', 'Phenotype', 'HP:0200040', (126, 140))
8575	28941651	Hyperenhancement or iso-enhancement has strong negative predictive value for pancreatic cancer.	('negative', 'NegReg', (47, 55))	('Hyperenhancement', 'Var', (0, 16))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('iso-enhancement', 'Var', (20, 35))	('pancreatic cancer', 'Disease', (77, 94))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
8600	28941651	Further, these CTCs contained the same mutations as seen in regional lymph nodes of patients who later underwent surgery.	('contained', 'Reg', (20, 29))	('patients', 'Species', '9606', (84, 92))	('mutations', 'Var', (39, 48))
8610	30972876	Three novel genetic variants in NRF2 signaling pathway genes are associated with pancreatic cancer risk Pancreatic cancer (PanC) is one of the most lethal solid malignancies, and metastatic PanC is often present at the time of diagnosis.	('signaling pathway', 'biological_process', 'GO:0007165', ('37', '54'))	('NRF2', 'Gene', '4780', (32, 36))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('malignancies', 'Disease', (161, 173))	('Pancreatic cancer', 'Disease', (104, 121))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('associated', 'Reg', (65, 75))	('NRF2', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('genetic variants', 'Var', (12, 28))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('pancreatic cancer', 'Disease', (81, 98))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))
8612	30972876	Because the nuclear factor erythroid2-related factor2 (NRF2) signaling pathway is involved in human cancers, we hypothesize that genetic variants in NRF2 pathway genes are associated with PanC risk.	('genetic variants', 'Var', (129, 145))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('NRF2', 'Gene', (55, 59))	('NRF2', 'Gene', '4780', (149, 153))	('nuclear factor erythroid2-related factor2', 'Gene', '4780', (12, 53))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('associated', 'Reg', (172, 182))	('signaling pathway', 'biological_process', 'GO:0007165', ('61', '78'))	('nuclear factor erythroid2-related factor2', 'Gene', (12, 53))	('NRF2', 'Gene', (149, 153))	('human', 'Species', '9606', (94, 99))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('NRF2', 'Gene', '4780', (55, 59))	('PanC', 'Disease', (188, 192))	('cancers', 'Disease', (100, 107))
8613	30972876	To test this hypothesis, we assessed associations between 31 583 common single nucleotide polymorphisms (SNP) in 164 NRF2-related genes and PanC risk using three published genome-wide association study (GWAS) datasets, which included 8474 cases and 6944 controls of European descent.	('PanC', 'Disease', (140, 144))	('single nucleotide polymorphisms', 'Var', (72, 103))	('NRF2', 'Gene', (117, 121))	('associations', 'Interaction', (37, 49))	('NRF2', 'Gene', '4780', (117, 121))
8614	30972876	We found that three novel SNP (ie, rs3124761, rs17458086 and rs1630747) were significantly associated with PanC risk (P = 5.17 x 10-7, 5.61 x 10-4 and 5.52 x 10-4, respectively).	('rs17458086', 'Mutation', 'rs17458086', (46, 56))	('rs3124761', 'Var', (35, 44))	('rs3124761', 'Mutation', 'rs3124761', (35, 44))	('PanC', 'Disease', (107, 111))	('rs1630747', 'Mutation', 'rs1630747', (61, 70))	('rs17458086', 'Var', (46, 56))	('rs1630747', 'Var', (61, 70))	('associated', 'Reg', (91, 101))
8615	30972876	Furthermore, eQTL analysis showed that both rs3124761 T and rs17458086 C alleles were associated with increased mRNA expression levels of SLC2A6 and SLC2A13, respectively (P < 0.05).	('SLC2A6', 'Gene', (138, 144))	('rs3124761', 'Mutation', 'rs3124761', (44, 53))	('rs17458086', 'Mutation', 'rs17458086', (60, 70))	('mRNA expression levels', 'MPA', (112, 134))	('rs17458086 C', 'Var', (60, 72))	('SLC2A13', 'Gene', (149, 156))	('rs3124761 T', 'Var', (44, 55))	('increased', 'PosReg', (102, 111))	('SLC2A6', 'Gene', '11182', (138, 144))	('SLC2A13', 'Gene', '114134', (149, 156))
8616	30972876	In conclusion, genetic variants in NRF2 pathway genes could play a role in susceptibility to PanC, and further functional exploration of the underlying molecular mechanisms is warranted.	('genetic variants', 'Var', (15, 31))	('NRF2', 'Gene', '4780', (35, 39))	('play', 'Reg', (60, 64))	('NRF2', 'Gene', (35, 39))	('role', 'Reg', (67, 71))	('PanC', 'Disease', (93, 97))	('susceptibility', 'Reg', (75, 89))
8632	30972876	In the subsequent meta-analysis of the three populations, 1073 SNP remained associated with PanC risk at P < 0.05 in an additive genetic model, of which 13 SNP on SLC2A6, PDGFB, SLC5A3, SLC2A13 and MAPK8 passed multiple testing corrections with an FDR <0.15 (Figure 2A; Table 1).	('SLC2A6', 'Gene', (163, 169))	('MAPK', 'molecular_function', 'GO:0004707', ('198', '202'))	('SLC2A13', 'Gene', '114134', (186, 193))	('PDGFB', 'Gene', '5155', (171, 176))	('MAPK8', 'Gene', '5599', (198, 203))	('associated', 'Reg', (76, 86))	('SLC5A3', 'Gene', '6526', (178, 184))	('SLC2A13', 'Gene', (186, 193))	('SNP', 'Var', (156, 159))	('PDGFB', 'Gene', (171, 176))	('MAPK8', 'Gene', (198, 203))	('SLC5A3', 'Gene', (178, 184))	('PanC', 'Disease', (92, 96))	('SLC2A6', 'Gene', '11182', (163, 169))
8633	30972876	Although some SNP in some chromosome regions (ie, 22q13.1-PGDFB and 10q11.22-MAPK8) have been reported by GWAS or pathway-based analyses,8, 35 three SNP (ie, SLC2A6 rs3124761 at 9q34, SLC2A13 rs17458086 at 12q12, and SLC5A3 rs1630747 at 21q22.11) are novel findings (Figure 2B-D), for which we carried out additional in silico analysis for their functional relevance.	('SLC2A13', 'Gene', '114134', (184, 191))	('rs1630747', 'Var', (224, 233))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('rs17458086', 'Mutation', 'rs17458086', (192, 202))	('SLC2A6', 'Gene', '11182', (158, 164))	('rs17458086', 'Var', (192, 202))	('MAPK8', 'Gene', '5599', (77, 82))	('SLC2A6', 'Gene', (158, 164))	('SLC5A3', 'Gene', (217, 223))	('SLC5A3', 'Gene', '6526', (217, 223))	('SLC2A13', 'Gene', (184, 191))	('MAPK', 'molecular_function', 'GO:0004707', ('77', '81'))	('MAPK8', 'Gene', (77, 82))	('rs1630747', 'Mutation', 'rs1630747', (224, 233))	('rs3124761', 'Var', (165, 174))	('rs3124761', 'Mutation', 'rs3124761', (165, 174))
8634	30972876	Specifically, the genotypes of SLC2A6 rs3124761 C/T, SLC2A13 rs17458086 T/C, and SLC5A3 rs1630747 A/C were significantly associated with PanC risk in the additive models (P < 0.0001, P = 0.004, and P = 0.002, respectively, Table 2).	('rs3124761', 'Mutation', 'rs3124761', (38, 47))	('rs17458086 T/C', 'Var', (61, 75))	('rs17458086', 'Mutation', 'rs17458086', (61, 71))	('SLC2A13', 'Gene', '114134', (53, 60))	('rs1630747 A/C', 'Var', (88, 101))	('associated with', 'Reg', (121, 136))	('rs1630747', 'Mutation', 'rs1630747', (88, 97))	('SLC5A3', 'Gene', '6526', (81, 87))	('rs3124761 C/T', 'Var', (38, 51))	('SLC5A3', 'Gene', (81, 87))	('SLC2A6', 'Gene', '11182', (31, 37))	('SLC2A13', 'Gene', (53, 60))	('SLC2A6', 'Gene', (31, 37))	('PanC', 'Disease', (137, 141))
8635	30972876	In dominant models, both the rs3124761 T allele and rs17458086 C allele carriers were at increased risk of PanC (OR = 1.19, 95% CI = 1.11-1.27, and P < 0.0001; OR = 1.36, 95% CI = 1.14-1.64, and P < 0.001), whereas the rs1630747 C allele was associated with reduced risk (OR = 0.89, 95% CI = 0.84-0.96, P = 0.001), compared with their corresponding wild-type alleles (Table 2).	('rs1630747', 'Mutation', 'rs1630747', (219, 228))	('rs3124761 T', 'Var', (29, 40))	('PanC', 'Disease', (107, 111))	('rs1630747 C', 'Var', (219, 230))	('rs3124761', 'Mutation', 'rs3124761', (29, 38))	('rs17458086', 'Mutation', 'rs17458086', (52, 62))	('rs17458086 C', 'Var', (52, 64))
8636	30972876	In recessive models, the rs3124761 TT genotype carriers were at increased risk of PanC (OR = 1.28, 95% CI = 1.04-1.57, and P = 0.0191), whereas the rs1630747 CC genotype was associated with reduced risk (OR = 0.88, 95% CI = 0.77-0.99, P = 0.0433) compared with their corresponding wild-type genotypes (Table 2).	('rs1630747', 'Mutation', 'rs1630747', (148, 157))	('rs1630747 CC', 'Var', (148, 160))	('rs3124761', 'Var', (25, 34))	('rs3124761', 'Mutation', 'rs3124761', (25, 34))	('PanC', 'Disease', (82, 86))
8637	30972876	We then combined the risk genotypes of rs3124761 CT+TT, rs17458086 TC+CC, and rs1630747 AA into a single genetic score NUG.	('rs1630747', 'Mutation', 'rs1630747', (78, 87))	('rs1630747 AA', 'Var', (78, 90))	('rs17458086', 'Mutation', 'rs17458086', (56, 66))	('rs17458086', 'Var', (56, 66))	('rs3124761', 'Var', (39, 48))	('rs3124761', 'Mutation', 'rs3124761', (39, 48))
8638	30972876	It is notable that the three SNP are predicted to alter the ability to bind with some motifs, among which are rs3124761 T, rs17458086 C and rs1630747 C alleles that are predicted to disrupt the TF-binding motifs for the RARG, BCL2, and ZN784 proteins, respectively (Figure 3B,G, Figure S4B).	('disrupt', 'NegReg', (182, 189))	('BCL2', 'Gene', (226, 230))	('RARG', 'Gene', (220, 224))	('TF-binding motifs', 'MPA', (194, 211))	('rs1630747 C', 'Var', (140, 151))	('alter', 'Reg', (50, 55))	('rs17458086', 'Mutation', 'rs17458086', (123, 133))	('rs17458086 C', 'Var', (123, 135))	('rs3124761', 'Mutation', 'rs3124761', (110, 119))	('TF-binding', 'molecular_function', 'GO:0008134', ('194', '204'))	('BCL2', 'molecular_function', 'GO:0015283', ('226', '230'))	('bind', 'Interaction', (71, 75))	('rs1630747', 'Mutation', 'rs1630747', (140, 149))	('RARG', 'Gene', '5916', (220, 224))	('ZN784', 'Chemical', '-', (236, 241))	('BCL2', 'Gene', '596', (226, 230))	('rs3124761 T', 'Var', (110, 121))
8639	30972876	This suggests that RARG, BCL2, and ZN784 binding motifs can be altered by rs3124761, rs17458086, and rs1630747, respectively, and thus change SLC2A6, SLC2A13, and SLC5A3 mRNA expression levels.	('rs1630747', 'Mutation', 'rs1630747', (101, 110))	('SLC5A3', 'Gene', (163, 169))	('RARG', 'Gene', (19, 23))	('BCL2', 'Gene', '596', (25, 29))	('binding', 'molecular_function', 'GO:0005488', ('41', '48'))	('altered', 'Reg', (63, 70))	('rs1630747', 'Var', (101, 110))	('SLC2A13', 'Gene', (150, 157))	('SLC2A13', 'Gene', '114134', (150, 157))	('rs17458086', 'Mutation', 'rs17458086', (85, 95))	('RARG', 'Gene', '5916', (19, 23))	('binding', 'Interaction', (41, 48))	('BCL2', 'Gene', (25, 29))	('rs3124761', 'Var', (74, 83))	('SLC5A3', 'Gene', '6526', (163, 169))	('rs3124761', 'Mutation', 'rs3124761', (74, 83))	('SLC2A6', 'Gene', '11182', (142, 148))	('SLC2A6', 'Gene', (142, 148))	('ZN784', 'Chemical', '-', (35, 40))	('rs17458086', 'Var', (85, 95))	('BCL2', 'molecular_function', 'GO:0015283', ('25', '29'))	('change', 'Reg', (135, 141))
8640	30972876	By using Student's t test or linear regression analysis of the logarithm transformed expression values (log2), we showed that the rs3124761 T allele (risk) was correlated with increased mRNA expression levels of SLC2A6 in either additive or dominant models (P = 0.0357 and 0.0129, respectively, Figure 3C,D).	('increased', 'PosReg', (176, 185))	('SLC2A6', 'Gene', (212, 218))	('SLC2A6', 'Gene', '11182', (212, 218))	('mRNA expression levels', 'MPA', (186, 208))	('rs3124761', 'Var', (130, 139))	('rs3124761', 'Mutation', 'rs3124761', (130, 139))
8641	30972876	We also found that the rs17458086 C (risk) allele was significantly correlated with higher mRNA expression levels of SLC2A13 compared with the T (protective) allele (P = 0.026 in both the additive model and the dominant model due to lack of CC homozygote (Figure 3H,I).	('mRNA expression levels', 'MPA', (91, 113))	('rs17458086', 'Mutation', 'rs17458086', (23, 33))	('SLC2A13', 'Gene', (117, 124))	('rs17458086 C', 'Var', (23, 35))	('SLC2A13', 'Gene', '114134', (117, 124))	('higher', 'PosReg', (84, 90))
8645	30972876	In the present study of the NRF2-pathway-based approach analysis of published GWAS datasets, we identified 13 loci to be associated with PanC risk, including three novel loci (ie, SLC5A3 rs1630747, SLC2A13 rs17458086 and SLC2A6 rs3124761), which merit additional follow-up investigations for their functional mechanisms underlying the observed associations.	('SLC2A6', 'Gene', '11182', (221, 227))	('SLC2A13', 'Gene', '114134', (198, 205))	('SLC2A6', 'Gene', (221, 227))	('associated', 'Reg', (121, 131))	('NRF2', 'Gene', (28, 32))	('rs1630747', 'Mutation', 'rs1630747', (187, 196))	('rs17458086', 'Mutation', 'rs17458086', (206, 216))	('rs17458086', 'Var', (206, 216))	('SLC2A13', 'Gene', (198, 205))	('rs3124761', 'Var', (228, 237))	('rs3124761', 'Mutation', 'rs3124761', (228, 237))	('SLC5A3', 'Gene', '6526', (180, 186))	('PanC', 'Disease', (137, 141))	('SLC5A3', 'Gene', (180, 186))	('rs1630747', 'Var', (187, 196))	('NRF2', 'Gene', '4780', (28, 32))
8646	30972876	The first genetic variant rs3124761 to be addressed is located in the intron of SLC2A6 on Chr9q34.	('rs3124761', 'Mutation', 'rs3124761', (26, 35))	('rs3124761', 'Var', (26, 35))	('SLC2A6', 'Gene', (80, 86))	('SLC2A6', 'Gene', '11182', (80, 86))
8647	30972876	The rs3124761 T allele was identified to be associated with an increased PanC risk compared with the corresponding wild-type C allele.	('PanC', 'Disease', (73, 77))	('rs3124761', 'Mutation', 'rs3124761', (4, 13))	('rs3124761 T', 'Var', (4, 15))
8648	30972876	The base change from C to T is predicted to reduce the DNA-binding ability with the RARG motif.	('DNA-binding', 'Interaction', (55, 66))	('reduce', 'NegReg', (44, 50))	('DNA-binding', 'molecular_function', 'GO:0003677', ('55', '66'))	('RARG', 'Gene', '5916', (84, 88))	('base change', 'Var', (4, 15))	('RARG', 'Gene', (84, 88))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))
8650	30972876	eQTL data from 373 lymphocyte cells further highlighted that the substitution of rs3124761 C to T significantly enhanced mRNA expression of SLC2A6.	('enhanced', 'PosReg', (112, 120))	('rs3124761 C', 'Var', (81, 92))	('SLC2A6', 'Gene', (140, 146))	('SLC2A6', 'Gene', '11182', (140, 146))	('mRNA expression', 'MPA', (121, 136))	('rs3124761', 'Mutation', 'rs3124761', (81, 90))
8651	30972876	The 9q34 region is one of the most frequently altered regions in human cancers.10, 20 A series of SNP located in the ABO gene tagged by rs505922 and rs630014 in this region have been reported by a GWAS to be related to PanC susceptibility.20 Another recently published associated SNP located in the ABO gene was rs687289, which was identified by GTEx functional prediction.21 However, our linkage disequilibrium (LD) analysis showed that SLC2A6 rs3124761 was in low LD with any of the three ABO SNP previously reported.	('SLC2A6', 'Gene', (438, 444))	('SLC2A6', 'Gene', '11182', (438, 444))	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('rs687289', 'Mutation', 'rs687289', (312, 320))	('ABO', 'Gene', (299, 302))	('ABO', 'Gene', (491, 494))	('ABO', 'Gene', '28', (491, 494))	('ABO', 'Gene', '28', (299, 302))	('ABO', 'Gene', (117, 120))	('ABO', 'Gene', '28', (117, 120))	('rs505922', 'Mutation', 'rs505922', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('rs630014', 'Mutation', 'rs630014', (149, 157))	('rs3124761', 'Var', (445, 454))	('rs3124761', 'Mutation', 'rs3124761', (445, 454))
8652	30972876	The second genetic variant rs17458086 is located in the intron of SLC2A13 on Chr12q12.	('SLC2A13', 'Gene', '114134', (66, 73))	('rs17458086', 'Var', (27, 37))	('SLC2A13', 'Gene', (66, 73))	('rs17458086', 'Mutation', 'rs17458086', (27, 37))
8653	30972876	We found, for the first time, that carriers of the SLC2A13 rs17458086 C allele had a 1.38-fold increased PanC risk compared with TT carriers.	('SLC2A13', 'Gene', (51, 58))	('rs17458086', 'Mutation', 'rs17458086', (59, 69))	('rs17458086 C', 'Var', (59, 71))	('SLC2A13', 'Gene', '114134', (51, 58))	('PanC', 'Disease', (105, 109))
8654	30972876	The change from T allele to C allele is predicted to reduce the DNA-binding ability with the BCL2 motif.	('reduce', 'NegReg', (53, 59))	('BCL2', 'Gene', '596', (93, 97))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('change', 'Var', (4, 10))	('BCL2', 'molecular_function', 'GO:0015283', ('93', '97'))	('DNA-binding', 'Interaction', (64, 75))	('BCL2', 'Gene', (93, 97))	('DNA-binding', 'molecular_function', 'GO:0003677', ('64', '75'))
8655	30972876	Therefore, SLC2A13 expression should be increased when the BCL2 motif, which is predicted to suppress expression of the gene, binds to SLC2A13 rs17458086 C instead of the T allele.	('BCL2', 'Gene', '596', (59, 63))	('expression', 'MPA', (19, 29))	('SLC2A13', 'Gene', '114134', (135, 142))	('BCL2', 'molecular_function', 'GO:0015283', ('59', '63'))	('SLC2A13', 'Gene', (11, 18))	('expression', 'MPA', (102, 112))	('rs17458086', 'Mutation', 'rs17458086', (143, 153))	('BCL2', 'Gene', (59, 63))	('rs17458086 C', 'Var', (143, 155))	('SLC2A13', 'Gene', (135, 142))	('SLC2A13', 'Gene', '114134', (11, 18))	('increased', 'PosReg', (40, 49))	('binds', 'Interaction', (126, 131))
8656	30972876	eQTL data further demonstrated that the substitution of rs17458086 T to C significantly enhanced the mRNA expression of SLC2A13.	('SLC2A13', 'Gene', (120, 127))	('SLC2A13', 'Gene', '114134', (120, 127))	('rs17458086 T', 'Var', (56, 68))	('rs17458086', 'Mutation', 'rs17458086', (56, 66))	('enhanced', 'PosReg', (88, 96))	('mRNA expression', 'MPA', (101, 116))
8660	30972876	More than 80 SLC transporters have been implicated in monogenic disorders, and many genetic variants in the SLC transporter genes associated with common diseases have been identified through genotype analysis of candidate genes, or from GWAS.38 The 14 human GLUT proteins, encoded by the SLC2 gene, have various substrate specificities and are involved in the transport of several hexoses in addition to myoinositol.39 GLUT proteins in the digestive system serve as important mediators in maintaining normal functions, including the absorption of nutrients and ions, excretion of bile acids, and metabolism of toxins.40, 41, 42 Dysregulation of the SLC2 gene is likely to be associated with carcinogenesis, tumor progression, metastasis, and chemoresistance.	('tumor', 'Phenotype', 'HP:0002664', (707, 712))	('GLUT', 'Gene', '6513', (258, 262))	('Dysregulation', 'Var', (628, 641))	('SLC', 'Gene', '6366', (288, 291))	('myoinositol', 'Chemical', 'MESH:D007294', (404, 415))	('associated', 'Reg', (675, 685))	('SLC', 'Gene', (13, 16))	('GLUT', 'Gene', (258, 262))	('SLC', 'Gene', (649, 652))	('SLC', 'Gene', (108, 111))	('excretion', 'biological_process', 'GO:0007588', ('567', '576'))	('transport', 'biological_process', 'GO:0006810', ('360', '369'))	('toxins.40', 'Var', (610, 619))	('chemoresistance', 'CPA', (742, 757))	('tumor', 'Disease', (707, 712))	('metabolism', 'biological_process', 'GO:0008152', ('596', '606'))	('metastasis', 'CPA', (726, 736))	('SLC', 'Gene', '6366', (13, 16))	('SLC', 'Gene', (288, 291))	('hexose', 'Chemical', 'MESH:D006601', (381, 387))	('tumor', 'Disease', 'MESH:D009369', (707, 712))	('carcinogenesis', 'Disease', (691, 705))	('SLC', 'Gene', '6366', (649, 652))	('human', 'Species', '9606', (252, 257))	('SLC', 'Gene', '6366', (108, 111))	('GLUT', 'Gene', '6513', (419, 423))	('carcinogenesis', 'Disease', 'MESH:D063646', (691, 705))	('GLUT', 'Gene', (419, 423))
8663	30972876	There are neither reported data about glucose transport activity for GLUT13/HMIT, nor any available information about the expression of the facilitative glucose transporter family in cancer.37 Genetic alterations of SLC2A13 were observed to be prevalent in the early stage of lung cancer in Serbians, suggesting that structural changes of SLC2A13 could play a role in the development of non-small cell lung cancer.45  Additionally, several SNP in SLC2A13 were found to be closely related to Parkinson's disease independently or dependently at a genome-wide significance level.46, 47 SLC5A3 encodes a sodium myoinositol transporter involved in the response to hyperosmotic stress, and the sequence of SLC5A3 lies completely within that of MRPS6 that encodes a subunit of the mitochondrial ribosome.48 SLC5A3/MRPS6 rs9982601 was previously identified to have a genome-wide association with early-onset myocardial infarction.49 This SNP was also found to be associated with mRNA expression of MRPS6 in blood, with the risk C allele correlated with an increased mRNA expression.48 We observed, for the first time, that the SLC5A3 rs1630747 C allele was associated with a reduced PanC risk compared with the corresponding wild-type allele.	('rs1630747', 'Mutation', 'rs1630747', (1126, 1135))	('glucose transport', 'biological_process', 'GO:1904659', ('38', '55'))	('cancer', 'Disease', (407, 413))	('hyperosmotic stress', 'Disease', (659, 678))	('myocardial infarction', 'Disease', (900, 921))	('MRPS6', 'Gene', '64968', (990, 995))	('SLC5A3', 'Gene', '6526', (1119, 1125))	('MRPS6', 'Gene', (807, 812))	('SLC2A13', 'Gene', '114134', (447, 454))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('SLC5A3', 'Gene', (583, 589))	('rs1630747 C', 'Var', (1126, 1137))	('SLC5A3', 'Gene', '6526', (700, 706))	('lung cancer', 'Disease', (276, 287))	('MRPS6', 'Gene', '64968', (807, 812))	('glucose', 'Chemical', 'MESH:D005947', (38, 45))	("Parkinson's disease", 'Disease', 'MESH:D010300', (491, 510))	('cancer', 'Disease', (183, 189))	('SLC2A13', 'Gene', (216, 223))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (387, 413))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('MRPS6', 'Gene', '64968', (738, 743))	('rs9982601', 'Mutation', 'rs9982601', (813, 822))	('HMIT', 'Gene', (76, 80))	('myocardial infarction', 'Disease', 'MESH:D009203', (900, 921))	('sodium myoinositol', 'Chemical', '-', (600, 618))	('SLC2A13', 'Gene', '114134', (216, 223))	('SLC5A3', 'Gene', (1119, 1125))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('SLC5A3', 'Gene', (700, 706))	('reduced', 'NegReg', (1167, 1174))	('HMIT', 'Gene', '114134', (76, 80))	('cancer', 'Disease', 'MESH:D009369', (407, 413))	('glucose', 'Chemical', 'MESH:D005947', (153, 160))	('mitochondrial ribosome', 'cellular_component', 'GO:0005761', ('774', '796'))	('lung cancer', 'Disease', 'MESH:D008175', (276, 287))	('non-small cell lung cancer', 'Disease', (387, 413))	('SLC5A3', 'Gene', '6526', (800, 806))	('PanC', 'Disease', (1175, 1179))	('lung cancer', 'Disease', 'MESH:D008175', (402, 413))	('lung cancer', 'Phenotype', 'HP:0100526', (276, 287))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('SLC2A13', 'Gene', (339, 346))	('GLUT', 'Gene', '6513', (69, 73))	('MRPS6', 'Gene', (738, 743))	('cancer', 'Disease', (281, 287))	('SLC5A3', 'Gene', '6526', (583, 589))	('lung cancer', 'Phenotype', 'HP:0100526', (402, 413))	('SLC2A13', 'Gene', '114134', (339, 346))	('hyperosmotic stress', 'Disease', 'MESH:D004194', (659, 678))	('MRPS6', 'Gene', (990, 995))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	("Parkinson's disease", 'Disease', (491, 510))	('SLC5A3', 'Gene', (800, 806))	('GLUT', 'Gene', (69, 73))	('SLC2A13', 'Gene', (447, 454))
8664	30972876	However, we failed to identify any variants in the NRF2 gene to be associated with PanC risk.	('NRF2', 'Gene', (51, 55))	('PanC', 'Disease', (83, 87))	('variants', 'Var', (35, 43))	('associated', 'Reg', (67, 77))	('NRF2', 'Gene', '4780', (51, 55))
8666	30972876	All three identified variants are located in the intron regions of these genes instead of in the promoter sites coupled with antioxidant response element for NRF2 binding.	('variants', 'Var', (21, 29))	('NRF2', 'Gene', (158, 162))	('binding', 'molecular_function', 'GO:0005488', ('163', '170'))	('binding', 'Interaction', (163, 170))	('NRF2', 'Gene', '4780', (158, 162))
8681	30424804	These PD-1 + CD137 + CD8+ T-cells expressed high levels of interferon-gamma (median 80-90%) in response to stimulation with CD3/CD28 activation beads, and this expression was higher than that of PD-1 + CD137-CD8+ T-cells (p < 0.001).	('CD8', 'Gene', (208, 211))	('CD8', 'Gene', '925', (208, 211))	('interferon-gamma', 'Gene', '396991', (59, 75))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('59', '75'))	('higher', 'PosReg', (175, 181))	('CD8', 'Gene', (21, 24))	('CD137', 'Gene', '21942', (13, 18))	('PD-1', 'Var', (6, 10))	('CD8', 'Gene', '925', (21, 24))	('CD137', 'Gene', '21942', (202, 207))	('CD137', 'Gene', (13, 18))	('interferon-gamma', 'Gene', (59, 75))	('CD137', 'Gene', (202, 207))
8700	30424804	High CSF-1R expression in PDAC has also been associated with worse prognosis compared to low CSF-1R expression.	('CSF-1R', 'Gene', (5, 11))	('High', 'Var', (0, 4))	('CSF-1', 'molecular_function', 'GO:0005011', ('5', '10'))	('PDAC', 'Phenotype', 'HP:0006725', (26, 30))	('CSF-1', 'molecular_function', 'GO:0005011', ('93', '98'))	('expression', 'MPA', (12, 22))	('PDAC', 'Chemical', '-', (26, 30))
8701	30424804	Inhibition of CSF-1R can lead to preferential TAM depletion and modulate the remaining myeloid cells toward a more anti-tumor phenotype and away from pro-tumor properties.	('TAM', 'Chemical', '-', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CSF-1', 'molecular_function', 'GO:0005011', ('14', '19'))	('modulate', 'Reg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('Inhibition', 'Var', (0, 10))	('preferential', 'PosReg', (33, 45))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('TAM depletion', 'MPA', (46, 59))	('CSF-1R', 'Gene', (14, 20))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', (154, 159))
8702	30424804	The combination of anti-CSF-1R and anti-PD-1 antibodies promotes anti-tumor activity in pre-clinical models, and this combination is actively investigated in several clinical trials for many types of tumors, including pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (218, 235))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('CSF-1', 'molecular_function', 'GO:0005011', ('24', '29'))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('anti-PD-1', 'Gene', (35, 44))	('tumor', 'Disease', (200, 205))	('pancreatic cancer', 'Disease', 'MESH:D010190', (218, 235))	('anti-CSF-1R', 'Var', (19, 30))	('combination', 'Interaction', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('pancreatic cancer', 'Disease', (218, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('pre', 'molecular_function', 'GO:0003904', ('88', '91'))	('tumor', 'Disease', (70, 75))	('tumors', 'Disease', (200, 206))	('promotes', 'PosReg', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
8711	30424804	Lymphoid cells were CD45+ and CD3+ or CD20+ or CD56+, and myeloid markers were CD45+ and CD3-CD20-CD56-.	('CD4', 'Gene', (20, 23))	('CD56+', 'Var', (47, 52))	('CD4', 'Gene', (79, 82))	('CD4', 'Gene', '404704', (20, 23))	('CD4', 'Gene', '404704', (79, 82))	('CD3-CD20-CD56-', 'Var', (89, 103))	('CD20+', 'Var', (38, 43))
8714	30424804	KPC is a previously established PDAC tumor cell line that was derived from transgenic mice in a C57Bl6 background with tissue-specific Kras and p53 knock-in mutations.	('PDAC', 'Phenotype', 'HP:0006725', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('p53', 'Gene', '22059', (144, 147))	('transgenic mice', 'Species', '10090', (75, 90))	('mutations', 'Var', (157, 166))	('tumor', 'Disease', (37, 42))	('PDAC', 'Chemical', '-', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('p53', 'Gene', (144, 147))
8777	30424804	This analysis demonstrated that the addition of alphaCSF-1R both before and after the GVAX vaccination not only induced greater numbers of PD-1+ CD4+ or CD8+ tumor infiltrating T-cells in the "GVAX + alphaPD-1 + Pre/Post-alphaCSF-1R" group (Additional file 1: Figure S1A-D), but also increased the number and percentage of PD-1 + CD137+ T-cells (Fig.	('GVAX', 'Chemical', '-', (86, 90))	('tumor', 'Disease', (158, 163))	('greater', 'PosReg', (120, 127))	('CD8', 'Gene', (153, 156))	('CD137', 'Gene', (330, 335))	('CD4', 'Gene', (145, 148))	('GVAX', 'Chemical', '-', (193, 197))	('CD8', 'Gene', '925', (153, 156))	('rat', 'Species', '10116', (170, 173))	('CD4', 'Gene', '404704', (145, 148))	('increased', 'PosReg', (284, 293))	('rat', 'Species', '10116', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('PD-1+', 'Var', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('CD137', 'Gene', '21942', (330, 335))
8785	30424804	The addition of alphaCSF-1R both before and after GVAX vaccination in the "GVAX + alphaPD-1 + Pre/Post-alphaCSF-1R" group also increased the number and percentage of PD-1 + OX40+ co-expressing CD4+ T-cells compared to the control groups, non-treatment and GVAX + alphaPD-1 treatment (Fig.	('GVAX', 'Chemical', '-', (50, 54))	('GVAX', 'Chemical', '-', (256, 260))	('CD4', 'Gene', (193, 196))	('GVAX', 'Chemical', '-', (75, 79))	('PD-1 + OX40+', 'Var', (166, 178))	('CD4', 'Gene', '404704', (193, 196))	('increased', 'PosReg', (127, 136))
8786	30424804	Up to 40% of PD-1+ CD4+ T-cells expressed OX40+ in the "GVAX + alphaPD-1 + Pre/Post-alphaCSF-1R" group, which is about 2 times higher than the non-alphaCSF-1R containing groups (Fig.	('CD4', 'Gene', (19, 22))	('GVAX', 'Chemical', '-', (56, 60))	('CD4', 'Gene', '404704', (19, 22))	('OX40+', 'Var', (42, 47))
8788	30424804	Nonetheless, the percentage of PD-1 + OX40+ T-cells amongst CD8+ T-cells was a higher in the "GVAX + alphaPD-1 + Pre/Post-alphaCSF-1R" group compared to control treatments, non-treatment and GVAX + alphaPD-1 groups, whereas there was no statistically significant difference between the "GVAX + alphaPD-1 + Pre-alphaCSF-1R" and "GVAX + alphaPD-1 + Post-alphaCSF-1R" and the control groups.	('GVAX', 'Chemical', '-', (94, 98))	('GVAX', 'Chemical', '-', (191, 195))	('CD8', 'Gene', '925', (60, 63))	('PD-1 + OX40+', 'Var', (31, 43))	('GVAX', 'Chemical', '-', (287, 291))	('GVAX', 'Chemical', '-', (328, 332))	('CD8', 'Gene', (60, 63))
8790	30424804	These result suggest that alphaCSF-1R may convert the PD-1+ exhausted T-cells into activated effector T-cells that express CD137.	('PD-1+', 'Var', (54, 59))	('CD137', 'Gene', (123, 128))	('CD137', 'Gene', '21942', (123, 128))	('convert', 'Reg', (42, 49))
8799	30424804	This study subsequently demonstrated in a preclinical model that anti-CSF-1R antibody therapy enhanced the antitumor activity of the combination of GVAX and anti-PD-1 antibody.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('GVAX', 'Chemical', '-', (148, 152))	('antibody', 'cellular_component', 'GO:0019815', ('167', '175'))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('antibody', 'cellular_component', 'GO:0042571', ('77', '85'))	('antibody', 'cellular_component', 'GO:0042571', ('167', '175'))	('antibody', 'cellular_component', 'GO:0019814', ('167', '175'))	('antibody', 'molecular_function', 'GO:0003823', ('167', '175'))	('anti-CSF-1R', 'Var', (65, 76))	('tumor', 'Disease', (111, 116))	('antibody', 'cellular_component', 'GO:0019815', ('77', '85'))	('enhanced', 'PosReg', (94, 102))	('CSF-1', 'molecular_function', 'GO:0005011', ('70', '75'))	('antibody', 'cellular_component', 'GO:0019814', ('77', '85'))	('antibody', 'molecular_function', 'GO:0003823', ('77', '85'))	('rat', 'Species', '10116', (31, 34))
8804	30424804	Furthermore, combination immunotherapy including anti-CSF-1R also increased OX40 expression amongst PD-1+ CD4+ T-cells, though there was minimal expression of OX40 on PD-1+ CD8+ T-cells.	('CD4', 'Gene', (106, 109))	('CD8', 'Gene', '925', (173, 176))	('increased', 'PosReg', (66, 75))	('anti-CSF-1R', 'Var', (49, 60))	('CD4', 'Gene', '404704', (106, 109))	('OX40 expression', 'MPA', (76, 91))	('CD8', 'Gene', (173, 176))	('CSF-1', 'molecular_function', 'GO:0005011', ('54', '59'))
8805	30424804	CD137 and OX40 are members of the tumor necrosis factor receptor (TNFR) superfamily, and are involved in T-cell expansion and prevention of antigen-induced cell death.	('T-cell', 'CPA', (105, 111))	('necrosis', 'biological_process', 'GO:0070265', ('40', '48'))	('necrosis', 'biological_process', 'GO:0019835', ('40', '48'))	('OX40', 'Var', (10, 14))	('necrosis', 'biological_process', 'GO:0008220', ('40', '48'))	('tumor necrosis', 'Disease', (34, 48))	('necrosis', 'biological_process', 'GO:0001906', ('40', '48'))	('involved', 'Reg', (93, 101))	('CD137', 'Gene', '21942', (0, 5))	('cell death', 'biological_process', 'GO:0008219', ('156', '166'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('34', '55'))	('tumor necrosis', 'Disease', 'MESH:D009336', (34, 48))	('CD137', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('necrosis', 'biological_process', 'GO:0008219', ('40', '48'))	('cell expansion', 'biological_process', 'GO:0016049', ('107', '121'))
8806	30424804	It was previously thought that there was a dichotomy in roles between these two members of the TNFR superfamily, such that OX40 played a more central function for CD4+ T-cell expansion and survival, and 41BB played a similar function for CD8+ T-cells, and to some extent, our findings may reflect this.	('OX40', 'Var', (123, 127))	('cell expansion', 'biological_process', 'GO:0016049', ('170', '184'))	('CD4', 'Gene', (163, 166))	('CD4', 'Gene', '404704', (163, 166))	('CD8', 'Gene', (238, 241))	('CD8', 'Gene', '925', (238, 241))
8812	30424804	More importantly, as the majority of the PD-1 + CD137+ T-cells have the capacity of expressing IFN-gamma, even if this subpopulation of T-cells is small, they may still possess a strong anti-tumor effector T-cell function.	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('PD-1 +', 'Var', (41, 47))	('CD137', 'Gene', '21942', (48, 53))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('IFN-gamma', 'Gene', (95, 104))	('CD137', 'Gene', (48, 53))	('IFN-gamma', 'Gene', '396991', (95, 104))
8814	30424804	It remains to be explored how anti-CSF-1R antibody leads to the significant increase in the percentage and number of intratumoral PD-1+ CD4+ and PD-1+ CD8+ T-cells that express CD137 and PD-1+ CD4+ T-cells that express OX40.	('anti-CSF-1R', 'Var', (30, 41))	('CD8', 'Gene', '925', (151, 154))	('rat', 'Species', '10116', (120, 123))	('tumor', 'Disease', (122, 127))	('antibody', 'cellular_component', 'GO:0019814', ('42', '50'))	('CD137', 'Gene', '21942', (177, 182))	('CD4', 'Gene', '404704', (136, 139))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('CSF-1', 'molecular_function', 'GO:0005011', ('35', '40'))	('antibody', 'molecular_function', 'GO:0003823', ('42', '50'))	('increase', 'PosReg', (76, 84))	('CD8', 'Gene', (151, 154))	('CD4', 'Gene', (193, 196))	('antibody', 'cellular_component', 'GO:0042571', ('42', '50'))	('CD137', 'Gene', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('CD4', 'Gene', '404704', (193, 196))	('antibody', 'cellular_component', 'GO:0019815', ('42', '50'))	('CD4', 'Gene', (136, 139))
8818	30424804	Having anti-CSF1R antibody both before and after the GVAX treatment yields the largest survival benefit and the largest increase in PD-1 + CD137+ T-cells and PD-1 + OX40+ CD4+ T-cells.	('antibody', 'cellular_component', 'GO:0019814', ('18', '26'))	('survival benefit', 'CPA', (87, 103))	('CD137', 'Gene', '21942', (139, 144))	('CD4', 'Gene', '404704', (171, 174))	('antibody', 'molecular_function', 'GO:0003823', ('18', '26'))	('PD-1', 'Var', (132, 136))	('PD-1', 'Var', (158, 162))	('CD137', 'Gene', (139, 144))	('GVAX', 'Chemical', '-', (53, 57))	('CSF1', 'molecular_function', 'GO:0005011', ('12', '16'))	('antibody', 'cellular_component', 'GO:0042571', ('18', '26'))	('increase', 'PosReg', (120, 128))	('antibody', 'cellular_component', 'GO:0019815', ('18', '26'))	('CD4', 'Gene', (171, 174))
8821	30424804	Nevertheless, anti-tumor efficacy of the combination of anti-PD-1 antibody, GVAX and anti-CSF1R antibody warrants further investigation in human studies for PDAC.	('GVAX', 'Chemical', '-', (76, 80))	('antibody', 'cellular_component', 'GO:0042571', ('66', '74'))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('antibody', 'cellular_component', 'GO:0019815', ('96', '104'))	('CSF1', 'molecular_function', 'GO:0005011', ('90', '94'))	('anti-PD-1', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('PDAC', 'Phenotype', 'HP:0006725', (157, 161))	('antibody', 'cellular_component', 'GO:0019814', ('96', '104'))	('antibody', 'cellular_component', 'GO:0019815', ('66', '74'))	('human', 'Species', '9606', (139, 144))	('antibody', 'molecular_function', 'GO:0003823', ('96', '104'))	('tumor', 'Disease', (19, 24))	('antibody', 'cellular_component', 'GO:0019814', ('66', '74'))	('antibody', 'molecular_function', 'GO:0003823', ('66', '74'))	('antibody', 'cellular_component', 'GO:0042571', ('96', '104'))	('PDAC', 'Chemical', '-', (157, 161))
8891	27995795	The search parameters were set as follows: cysteine alkylation defined as static modification (+57.021464), and methionine oxidation (+15.9949) and asparagine-deamidation (+0.9840) as dynamic modifications.	('+57.021464', 'Var', (95, 105))	('methionine', 'Chemical', 'MESH:D008715', (112, 122))	('asparagine-deamidation', 'MPA', (148, 170))	('+0.9840', 'Var', (172, 179))	('+15.9949', 'Var', (134, 142))	('asparagine', 'Chemical', 'MESH:D001216', (148, 158))	('methionine oxidation', 'MPA', (112, 132))	('cysteine alkylation', 'MPA', (43, 62))	('cysteine', 'Chemical', 'MESH:D003545', (43, 51))
8921	27995795	Majority of the double-charged peptides shows Xcorr values greater than 2.45.	('peptides', 'Chemical', 'MESH:D010455', (31, 39))	('double-charged', 'Var', (16, 30))	('Xcorr values', 'MPA', (46, 58))
8932	27995795	Hence, confinement of quantification to the peptides with m/z between 410 and 900 results in augmented quality of quantification for a large set of peptides and proteins.	('m/z', 'Var', (58, 61))	('quality', 'MPA', (103, 110))	('augmented', 'PosReg', (93, 102))	('peptides', 'Chemical', 'MESH:D010455', (148, 156))	('peptides', 'Chemical', 'MESH:D010455', (44, 52))
8941	27995795	Evidently, peptides containing labile residues, in particular methionine and those containing miss-cleavages show higher variation.	('variation', 'MPA', (121, 130))	('methionine', 'Var', (62, 72))	('peptides', 'Chemical', 'MESH:D010455', (11, 19))	('methionine', 'Chemical', 'MESH:D008715', (62, 72))	('miss-cleavages', 'Var', (94, 108))
8958	27995795	These peptides may include peptides with reactive or variant amino acid residues or PTMs, peptides with low abundance, or peptides with poor chromatographic characteristics or low mass spectrometric sensitivity.	('peptides', 'Chemical', 'MESH:D010455', (122, 130))	('peptides', 'Chemical', 'MESH:D010455', (6, 14))	('peptides', 'Chemical', 'MESH:D010455', (27, 35))	('variant', 'Var', (53, 60))	('peptides', 'Chemical', 'MESH:D010455', (90, 98))	('amino', 'Protein', (61, 66))
8998	29245924	Here, we show that RUNX1 is highly expressed in pancreatic adenocarcinoma tissues and knocking down of RUNX1 attenuated aggressiveness in pancreatic cell lines.	('attenuated aggressiveness', 'Disease', (109, 134))	('attenuated aggressiveness', 'Disease', 'MESH:C538265', (109, 134))	('pancreatic', 'Disease', (138, 148))	('knocking down', 'Var', (86, 99))	('pancreatic adenocarcinoma tissues', 'Disease', (48, 81))	('aggressiveness', 'Phenotype', 'HP:0000718', (120, 134))	('pancreatic', 'Disease', 'MESH:D010195', (48, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (48, 73))	('RUNX1', 'Gene', (103, 108))	('pancreatic', 'Disease', 'MESH:D010195', (138, 148))	('pancreatic', 'Disease', (48, 58))	('pancreatic adenocarcinoma tissues', 'Disease', 'MESH:D010190', (48, 81))
9011	29245924	Recently, mutations of transcription factor CBFB and deletions of RUNX1 causing Runx1/Cbfb complex loss of function in breast cancer has been identified by whole-genome sequencing.	('RUNX1', 'Gene', (66, 71))	('Cbfb', 'Gene', (86, 90))	('Runx1', 'Gene', '861', (80, 85))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('deletions', 'Var', (53, 62))	('transcription', 'biological_process', 'GO:0006351', ('23', '36'))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('transcription factor', 'molecular_function', 'GO:0000981', ('23', '43'))	('CBFB', 'Gene', '865', (44, 48))	('Cbfb', 'Gene', '865', (86, 90))	('mutations', 'Var', (10, 19))	('CBFB', 'Gene', (44, 48))	('loss of function', 'NegReg', (99, 115))	('Runx1', 'Gene', (80, 85))
9012	29245924	RUNX1 mutation in breast cancer can predict poor outcome, all indicating that defective RUNX1 function might also act as an important factor in epithelial tumors, not only in acute myeloid leukemia.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (175, 197))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('RUNX1', 'Gene', (88, 93))	('mutation', 'Var', (6, 14))	('breast cancer', 'Disease', (18, 31))	('acute myeloid leukemia', 'Disease', (175, 197))	('leukemia', 'Phenotype', 'HP:0001909', (189, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (181, 197))	('epithelial tumors', 'Disease', (144, 161))	('RUNX1', 'Gene', (0, 5))	('function', 'MPA', (94, 102))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (175, 197))	('defective', 'Var', (78, 87))	('epithelial tumors', 'Disease', 'MESH:D002277', (144, 161))
9018	29245924	Further, we showed that overexpression of miR-93 or knocking down of HMGA2 both can decrease the invasive ability of pancreatic cancer.	('decrease', 'NegReg', (84, 92))	('invasive ability of', 'CPA', (97, 116))	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('miR-93', 'Var', (42, 48))	('knocking down', 'Var', (52, 65))	('pancreatic cancer', 'Disease', (117, 134))	('overexpression', 'PosReg', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('HMGA2', 'Gene', (69, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))
9020	29245924	To screen pancreatic cancer gene expression profiles, we selected two qualified gene expression microarray datasets (GSE71989 and GSE28735), and identified genes that were differentially expressed in pancreatic tumors and non-tumor tissues (P<0.01) in both independent cohorts (Figure 1A).	('gene expression', 'biological_process', 'GO:0010467', ('28', '43'))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (200, 216))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('GSE71989', 'Var', (117, 125))	('pancreatic cancer', 'Disease', 'MESH:D010190', (10, 27))	('pancreatic cancer', 'Disease', (10, 27))	('pancreatic tumors', 'Disease', 'MESH:D010190', (200, 217))	('gene expression', 'biological_process', 'GO:0010467', ('80', '95'))	('pancreatic tumors', 'Disease', (200, 217))	('non-tumor', 'Disease', (222, 231))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (10, 27))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('GSE28735', 'Var', (130, 138))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (200, 217))	('non-tumor', 'Disease', 'MESH:D009369', (222, 231))
9036	29245924	High RUNX1 level has a shorter overall survival time for patients (Figure 1F).	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (57, 65))	('RUNX1', 'Gene', (5, 10))	('overall survival', 'MPA', (31, 47))	('shorter', 'NegReg', (23, 30))
9044	29245924	We first overexpressed and knock down RUNX1 in pancreatic cell lines (PANC-1, MIA PaCa -2) to see whether the miR-93 level can be altered.	('pancreatic', 'Disease', 'MESH:D010195', (47, 57))	('pancreatic', 'Disease', (47, 57))	('MIA PaCa -2', 'CellLine', 'CVCL:0428', (78, 89))	('RUNX1', 'Gene', (38, 43))	('PANC-1', 'CellLine', 'CVCL:0480', (70, 76))	('knock down', 'Var', (27, 37))
9054	29245924	Epithelial-mesenchymal transition (EMT) is an early event migration of cancer, also indicating an invasive potential of tumor cells, here, we found that in PANC-1 cell lines, epithelial marker E-cadherin was greatly increased and mesenchymal markers vimentin, N-cadherin were drasticlly decreased after MIR-93 transfection on both protein and mRNA level (Figure 4E-4F), suggesting an EMT suppression status.	('N-cadherin', 'Gene', (260, 270))	('cadherin', 'molecular_function', 'GO:0008014', ('195', '203'))	('N-cadherin', 'Gene', '1000', (260, 270))	('PANC-1', 'CellLine', 'CVCL:0480', (156, 162))	('vimentin', 'Gene', '7431', (250, 258))	('vimentin', 'Gene', (250, 258))	('decreased', 'NegReg', (287, 296))	('transfection', 'Var', (310, 322))	('cancer', 'Disease', (71, 77))	('Epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('0', '33'))	('vimentin', 'cellular_component', 'GO:0045099', ('250', '258'))	('protein', 'cellular_component', 'GO:0003675', ('331', '338'))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cadherin', 'molecular_function', 'GO:0008014', ('262', '270'))	('EMT', 'biological_process', 'GO:0001837', ('35', '38'))	('MIR-93', 'Gene', '407051', (303, 309))	('increased', 'PosReg', (216, 225))	('tumor', 'Disease', (120, 125))	('MIR-93', 'Gene', (303, 309))	('E-cadherin', 'Gene', (193, 203))	('E-cadherin', 'Gene', '999', (193, 203))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('EMT', 'biological_process', 'GO:0001837', ('384', '387'))	('Epithelial-mesenchymal transition', 'CPA', (0, 33))	('vimentin', 'cellular_component', 'GO:0045098', ('250', '258'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
9112	29245924	ab35962, polyclonal, dilution: 1:500, Abcam), and anti-HMGA2 (Cat.	('anti-HMGA2', 'Var', (50, 60))	('Cat', 'Gene', '847', (62, 65))	('Cat', 'Gene', (62, 65))	('Cat', 'molecular_function', 'GO:0004096', ('62', '65'))
9126	29245924	Equal amounts of protein (15 mug) were loaded on 8-12% SDS-PAGE gel and then transferred to PVDF membranes (Bio-Rad), which were incubated overnight at 4 C with primary antibodies against RUNX1 (1:1000), E-cadherin (1:400), Vimentin (1:1000), Snail (1:1000), Slug (1:2000), beta-actin or GAPDH (1:1000), ZEB1 (1:400), K-ras (1:1000) or beta-catenin (1:1000) respectively.	('E-cadherin', 'Gene', (204, 214))	('E-cadherin', 'Gene', '999', (204, 214))	('1:400', 'Var', (310, 315))	('1:1000', 'Var', (234, 240))	('beta-catenin', 'Gene', '1499', (336, 348))	('ZEB1', 'Gene', '6935', (304, 308))	('Vimentin', 'cellular_component', 'GO:0045099', ('224', '232'))	('K-ras', 'Gene', '3845', (318, 323))	('Rad', 'biological_process', 'GO:1990116', ('112', '115'))	('RUNX1', 'Gene', (188, 193))	('1:1000', 'Var', (295, 301))	('Snail', 'Gene', (243, 248))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('Rad', 'Gene', '6236', (112, 115))	('1:1000', 'Var', (325, 331))	('beta-actin or GAPDH', 'Gene', '728378;2597', (274, 293))	('Rad', 'Gene', (112, 115))	('mug', 'molecular_function', 'GO:0043739', ('29', '32'))	('Slug', 'Gene', (259, 263))	('beta-actin or GAPDH', 'Gene', (274, 293))	('Vimentin', 'cellular_component', 'GO:0045098', ('224', '232'))	('ZEB1', 'Gene', (304, 308))	('K-ras', 'Gene', (318, 323))	('1:400', 'Var', (216, 221))	('1:2000', 'Var', (265, 271))	('1:1000', 'Var', (195, 201))	('Vimentin', 'Gene', '7431', (224, 232))	('cadherin', 'molecular_function', 'GO:0008014', ('206', '214'))	('Snail', 'Gene', '6615', (243, 248))	('Slug', 'Gene', '6591', (259, 263))	('1:1000', 'Var', (250, 256))	('beta-catenin', 'Gene', (336, 348))	('Vimentin', 'Gene', (224, 232))
9181	27344157	In the univariate analyses of survival, the low CRP/Alb ratio group had a longer median overall survival than the high CRP/Alb ratio group (5.0 vs 2.9 months, P < 0.001).	('CRP/Alb', 'Gene', (119, 126))	('CRP/Alb', 'Gene', '1401;213', (119, 126))	('longer', 'PosReg', (74, 80))	('low', 'Var', (44, 47))	('overall survival', 'MPA', (88, 104))	('CRP/Alb', 'Gene', '1401;213', (48, 55))	('CRP/Alb', 'Gene', (48, 55))
9186	27344157	To identify the interaction between the CRP/Alb ratio and mGPS for OS, we categorized patients into four groups based on two indexes, including mGPS score of 1 and CRP/Alb ratio < 0.54; mGPS score of 1 and CRP/Alb ratio >= 0.54; mGPS score of 2 and CRP/Alb ratio < 0.54; and mGPS score of 2 and CRP/Alb ratio >= 0.54.	('CRP/Alb', 'Gene', '1401;213', (40, 47))	('CRP/Alb', 'Gene', '1401;213', (249, 256))	('CRP/Alb', 'Gene', (295, 302))	('CRP/Alb', 'Gene', (164, 171))	('CRP/Alb', 'Gene', '1401;213', (206, 213))	('CRP/Alb', 'Gene', (206, 213))	('CRP/Alb', 'Gene', (249, 256))	('CRP/Alb', 'Gene', '1401;213', (295, 302))	('mGPS', 'Var', (144, 148))	('CRP/Alb', 'Gene', '1401;213', (164, 171))	('CRP/Alb', 'Gene', (40, 47))	('patients', 'Species', '9606', (86, 94))
9193	27344157	For the intrinsic pathway, inflammation and tumor growth are driven by genetic mutations that cause the activation of transcription factors, release of inflammatory mediators (chemokines, cytokines, and prostaglandins), and subsequent infiltration of inflammatory cells and angiogenesis.	('inflammation', 'biological_process', 'GO:0006954', ('27', '39'))	('driven by', 'Reg', (61, 70))	('activation', 'PosReg', (104, 114))	('intrinsic pathway', 'Pathway', (8, 25))	('angiogenesis', 'CPA', (274, 286))	('transcription', 'biological_process', 'GO:0006351', ('118', '131'))	('prostaglandins', 'Chemical', 'MESH:D011453', (203, 217))	('infiltration', 'CPA', (235, 247))	('transcription', 'Protein', (118, 131))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('angiogenesis', 'biological_process', 'GO:0001525', ('274', '286'))	('inflammatory mediators', 'MPA', (152, 174))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('inflammation', 'Disease', 'MESH:D007249', (27, 39))	('inflammation', 'Disease', (27, 39))	('release', 'MPA', (141, 148))	('tumor', 'Disease', (44, 49))	('mutations', 'Var', (79, 88))
9224	25897428	Recent work now indicates that acquisition of an activating Kras mutation in acinar cells initiates signaling that leads to chemoattraction of M1-poliarized macrophages.	('Kras', 'Gene', (60, 64))	('chemoattraction', 'biological_process', 'GO:0050918', ('124', '139'))	('Kras', 'Gene', '16653', (60, 64))	('activating', 'PosReg', (49, 59))	('mutation', 'Var', (65, 73))	('leads to', 'Reg', (115, 123))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('chemoattraction of M1-poliarized macrophages', 'MPA', (124, 168))
9231	25897428	These ADM progenitor cells in context of oncogenic signaling (Kras mutation or augmented EGF-R) initiate the formation of pancreatic lesions and eventually development of PDA.	('Kras', 'Gene', '16653', (62, 66))	('formation', 'biological_process', 'GO:0009058', ('109', '118'))	('mutation', 'Var', (67, 75))	('PDA', 'Phenotype', 'HP:0006725', (171, 174))	('EGF', 'molecular_function', 'GO:0005154', ('89', '92'))	('PDA', 'Disease', (171, 174))	('Kras', 'Gene', (62, 66))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('PDA', 'Chemical', '-', (171, 174))	('pancreatic lesions', 'Disease', (122, 140))	('pancreatic lesions', 'Disease', 'MESH:D010182', (122, 140))	('initiate', 'PosReg', (96, 104))	('EGF-R', 'Gene', (89, 94))
9241	25897428	an activating Kras mutation) can progress to a pre-neoplastic cell type such as the one forming pancreatic intraepithelial neoplasia (PanIN).	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (107, 132))	('pre', 'molecular_function', 'GO:0003904', ('47', '50'))	('mutation', 'Var', (19, 27))	('pancreatic intraepithelial neoplasia', 'Disease', (96, 132))	('activating', 'PosReg', (3, 13))	('pancreatic intraepithelial neoplasia', 'Disease', 'MESH:D018290', (96, 132))	('Kras', 'Gene', (14, 18))	('Kras', 'Gene', '16653', (14, 18))	('progress', 'PosReg', (33, 41))	('neoplasia', 'Phenotype', 'HP:0002664', (123, 132))
9243	25897428	In order to drive the development of pancreatic cancer, oncogenic Kras needs additional inflammatory stimuli to reach pathological activity levels.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (37, 54))	('pancreatic cancer', 'Disease', (37, 54))	('oncogenic', 'Var', (56, 65))	('Kras', 'Gene', '16653', (66, 70))	('Kras', 'Gene', (66, 70))	('pancreatic cancer', 'Disease', 'MESH:D010190', (37, 54))
9244	25897428	Even more intriguing is that the acquisition of an oncogenic Kras mutation in acinar cells can initiate microinflammation and chemoattraction of M1-polarized macrophages.	('chemoattraction', 'CPA', (126, 141))	('Kras', 'Gene', (61, 65))	('Kras', 'Gene', '16653', (61, 65))	('inflammation', 'Disease', 'MESH:D007249', (109, 121))	('initiate', 'Reg', (95, 103))	('inflammation', 'Disease', (109, 121))	('mutation', 'Var', (66, 74))	('chemoattraction', 'biological_process', 'GO:0050918', ('126', '141'))
9249	25897428	The requirement of such crosstalk between acinar cells with Kras mutations and M1-polarized macrophages as a necessary event for the initiation of pancreatic precancerous lesions was demonstrated by depletion of macrophages in animals which attenuated the progression of Kras-caused lesions.	('Kras', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('initiation of pancreatic precancerous lesions', 'Disease', (133, 178))	('Kras', 'Gene', '16653', (60, 64))	('Kras', 'Gene', (271, 275))	('Kras', 'Gene', '16653', (271, 275))	('initiation of pancreatic precancerous lesions', 'Disease', 'MESH:D011230', (133, 178))	('mutations', 'Var', (65, 74))
9251	25897428	Understanding the crosstalk between the pancreatic microenvironment and acinar cells expressing oncogenic mutations is important for several reasons.	('pancreatic', 'Disease', 'MESH:D010195', (40, 50))	('pancreatic', 'Disease', (40, 50))	('mutations', 'Var', (106, 115))
9257	25897428	Macrophages induce cell death of target cells via reactive oxygen species (ROS), and mutant Kras has been shown to upregulate Nrf2, a transcription factor that upregulates a multitude of antioxidant genes.	('Nrf2', 'Gene', '18024', (126, 130))	('cell death', 'biological_process', 'GO:0008219', ('19', '29'))	('cell death', 'CPA', (19, 29))	('Kras', 'Gene', (92, 96))	('Kras', 'Gene', '16653', (92, 96))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (50, 73))	('Nrf2', 'Gene', (126, 130))	('ROS', 'Chemical', 'MESH:D017382', (75, 78))	('transcription factor', 'molecular_function', 'GO:0000981', ('134', '154'))	('transcription', 'biological_process', 'GO:0006351', ('134', '147'))	('mutant', 'Var', (85, 91))	('reactive oxygen species', 'MPA', (50, 73))	('upregulate', 'PosReg', (115, 125))
9266	25897428	In the developing cancer, ablation of macrophages using gadolinium chloride also has been demonstrated to prevent KrasG12D-mediated microinflammation and formation of precancerous lesions.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('formation', 'biological_process', 'GO:0009058', ('154', '163'))	('Kras', 'Gene', '16653', (114, 118))	('prevent', 'NegReg', (106, 113))	('gadolinium chloride', 'Chemical', 'MESH:C038958', (56, 75))	('inflammation', 'Disease', 'MESH:D007249', (137, 149))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('precancerous lesions', 'Disease', 'MESH:D011230', (167, 187))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ablation', 'Var', (26, 34))	('inflammation', 'Disease', (137, 149))	('precancerous lesions', 'Disease', (167, 187))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('Kras', 'Gene', (114, 118))
9268	25897428	In addition, CD40 agonists destruct the tumor stroma by targeting macrophages and also reestablish the tumor immune surveillance in PDA.	('agonists', 'Var', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor stroma', 'Disease', (40, 52))	('PDA', 'Chemical', '-', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (40, 45))	('PDA', 'Phenotype', 'HP:0006725', (132, 135))	('CD40', 'Gene', '21939', (13, 17))	('tumor stroma', 'Disease', 'MESH:D009369', (40, 52))	('reestablish', 'PosReg', (87, 98))	('targeting', 'Reg', (56, 65))	('CD40', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('destruct', 'NegReg', (27, 35))
9269	25897428	For example preventing a M1 to M2 subtype switch in pancreata with KrasG12D-caused lesions, although it may increase ADM events, may also prevent progression to PanINs and pancreatic cancer.	('increase', 'PosReg', (108, 116))	('Kras', 'Gene', (67, 71))	('Kras', 'Gene', '16653', (67, 71))	('ADM events', 'MPA', (117, 127))	('pancreatic cancer', 'Disease', (172, 189))	('pancreatic cancer', 'Disease', 'MESH:D010190', (172, 189))	('preventing', 'NegReg', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('prevent', 'NegReg', (138, 145))	('PanINs', 'Disease', (161, 167))	('lesions', 'Var', (83, 90))	('M1 to M2 subtype switch', 'MPA', (25, 48))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (172, 189))
9282	25135483	In another group of 26 patients treated according to a similar protocol (RTOG 97-04), high pp38 expression was an independent predictor of improved patient survival.	('p38', 'Gene', '5594', (92, 95))	('patients', 'Species', '9606', (23, 31))	('patient survival', 'CPA', (148, 164))	('improved', 'PosReg', (139, 147))	('p38', 'Gene', (92, 95))	('patient', 'Species', '9606', (148, 155))	('high', 'Var', (86, 90))	('patient', 'Species', '9606', (23, 30))
9285	25135483	These include the overexpression of growth factors and their respective high-affinity receptors, excessive production of cytokines, a desmoplastic microenvironment with areas of hypoxia and attenuated/leaky vascular perfusion, a plethora of molecular alterations that include mutated Kras in 95% of PDAC patients, aberrant non-coding RNA expression, and suppression of cancer-directed immune mechanisms.	('plethora', 'Phenotype', 'HP:0001050', (229, 237))	('cancer', 'Disease', (369, 375))	('Kras', 'Gene', (284, 288))	('suppression', 'NegReg', (354, 365))	('patients', 'Species', '9606', (304, 312))	('aberrant non-coding', 'Var', (314, 333))	('hypoxia', 'Disease', (178, 185))	('production', 'MPA', (107, 117))	('hypoxia', 'Disease', 'MESH:D000860', (178, 185))	('Kras', 'Gene', '3845', (284, 288))	('mutated', 'Var', (276, 283))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('RNA', 'cellular_component', 'GO:0005562', ('334', '337'))	('PDAC', 'Disease', (299, 303))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('overexpression', 'PosReg', (18, 32))
9294	25135483	Three of these cell lines (Panc5.04, A10.7 and A38.44) expressed pp38 and its downstream target phospho-ATF2 (pATF2), suggesting that pp38 was active in these cells.	('A38.44', 'CellLine', 'CVCL:E276', (47, 53))	('p38', 'Gene', (135, 138))	('p38', 'Gene', '5594', (66, 69))	('A38.44', 'Var', (47, 53))	('Panc5.04', 'CellLine', 'CVCL:1637', (27, 35))	('A10.7', 'CellLine', 'CVCL:E301', (37, 42))	('p38', 'Gene', '5594', (135, 138))	('p38', 'Gene', (66, 69))
9295	25135483	They next used three distinct p38 inhibitors (SB202190, SB203580 and SB239063) and determined that all three pyridinyl imidazoles enhanced cell proliferation and decreased pATF2 levels, confirming the presence of active pp38 in these cells.	('p38', 'Gene', '5594', (30, 33))	('enhanced', 'PosReg', (130, 138))	('pyridinyl imidazoles', 'Chemical', '-', (109, 129))	('SB239063', 'Chemical', 'MESH:C406525', (69, 77))	('pATF2 levels', 'MPA', (172, 184))	('p38', 'Gene', (221, 224))	('decreased', 'NegReg', (162, 171))	('SB239063', 'Var', (69, 77))	('cell proliferation', 'CPA', (139, 157))	('p38', 'Gene', (30, 33))	('SB202190', 'Chemical', 'MESH:C090942', (46, 54))	('SB203580', 'Chemical', 'MESH:C093642', (56, 64))	('SB203580', 'Var', (56, 64))	('SB202190', 'Var', (46, 54))	('p38', 'Gene', '5594', (221, 224))	('cell proliferation', 'biological_process', 'GO:0008283', ('139', '157'))
9297	25135483	SB202190 also increased pJNK levels in Panc5.04, A10.7 and A38.44 cells, whereas pJNK inhibition by SP600125 blocked the growth-stimulatory effects of p38 inhibition.	('increased', 'PosReg', (14, 23))	('SB202190', 'Chemical', 'MESH:C090942', (0, 8))	('JNK', 'Gene', '5599', (25, 28))	('JNK', 'Gene', '5599', (82, 85))	('SB202190', 'Var', (0, 8))	('p38', 'Gene', '5594', (151, 154))	('JNK', 'Gene', (82, 85))	('Panc5.04', 'CellLine', 'CVCL:1637', (39, 47))	('A10.7', 'CellLine', 'CVCL:E301', (49, 54))	('A38.44', 'CellLine', 'CVCL:E276', (59, 65))	('SP600125', 'Var', (100, 108))	('SP600125', 'Chemical', 'MESH:C432165', (100, 108))	('JNK', 'Gene', (25, 28))	('p38', 'Gene', (151, 154))
9302	25135483	Thus, both SP600125-mediated JNK inhibition and si-RNA-mediated knockdown of MKK7 prevented SB202190-induced proliferation, confirming that pp38-mediated growth-inhibitory effects in PDAC are due to its ability to suppress pJNK proliferative actions.	('JNK', 'Gene', '5599', (224, 227))	('p38', 'Gene', '5594', (141, 144))	('RNA', 'cellular_component', 'GO:0005562', ('51', '54'))	('SP600125-mediated', 'Var', (11, 28))	('MKK7', 'Gene', (77, 81))	('proliferation', 'CPA', (109, 122))	('suppress', 'NegReg', (214, 222))	('JNK', 'Gene', (29, 32))	('JNK', 'Gene', '5599', (29, 32))	('SB202190', 'Chemical', 'MESH:C090942', (92, 100))	('growth-inhibitory effects', 'MPA', (154, 179))	('prevented', 'NegReg', (82, 91))	('MKK7', 'Gene', '5609', (77, 81))	('p38', 'Gene', (141, 144))	('SB202190-induced', 'Gene', (92, 108))	('JNK', 'Gene', (224, 227))	('JNK', 'molecular_function', 'GO:0004705', ('29', '32'))	('SP600125', 'Chemical', 'MESH:C432165', (11, 19))	('MKK7', 'molecular_function', 'GO:0004708', ('77', '81'))
9303	25135483	Zhong and colleagues next tested the effects of SB202190 and SP600125 in a subcutaneous xenograft model, using Panc5.04 and A10.7 cells expressing pp38, and A2.1 and A6L cells that express very low levels of either pp38 or pJNK.	('Panc5.04', 'CellLine', 'CVCL:1637', (111, 119))	('SB202190', 'Chemical', 'MESH:C090942', (48, 56))	('JNK', 'Gene', '5599', (224, 227))	('p38', 'Gene', (148, 151))	('tested', 'Reg', (26, 32))	('p38', 'Gene', '5594', (216, 219))	('SP600125', 'Chemical', 'MESH:C432165', (61, 69))	('SB202190', 'Var', (48, 56))	('p38', 'Gene', '5594', (148, 151))	('A6L', 'CellLine', 'CVCL:E302', (166, 169))	('SP600125', 'Var', (61, 69))	('A10.7', 'CellLine', 'CVCL:E301', (124, 129))	('JNK', 'Gene', (224, 227))	('p38', 'Gene', (216, 219))
9304	25135483	In tumors derived from Panc5.04 and A10.7 cells, inhibition of pp38 resulted in enhanced growth, whereas pJNK inhibition with SP600125 attenuated growth.	('A10.7', 'CellLine', 'CVCL:E301', (36, 41))	('growth', 'MPA', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('p38', 'Gene', '5594', (64, 67))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('growth', 'MPA', (89, 95))	('attenuated', 'NegReg', (135, 145))	('Panc5.04', 'CellLine', 'CVCL:1637', (23, 31))	('SP600125', 'Chemical', 'MESH:C432165', (126, 134))	('JNK', 'Gene', (106, 109))	('p38', 'Gene', (64, 67))	('enhanced', 'PosReg', (80, 88))	('inhibition', 'Var', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('JNK', 'Gene', '5599', (106, 109))
9315	23148552	Both sequence multi-site variations (MSV) and copy-number variants (CNV) of the defensin-encoding genes are associated with increased risk for various diseases, including cancer and inflammatory conditions such as psoriasis and acute pancreatitis.	('acute pancreatitis', 'Phenotype', 'HP:0001735', (228, 246))	('psoriasis', 'Disease', 'MESH:D011565', (214, 223))	('psoriasis', 'Disease', (214, 223))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('acute pancreatitis', 'Disease', (228, 246))	('acute pancreatitis', 'Disease', 'MESH:D010195', (228, 246))	('psoriasis', 'Phenotype', 'HP:0003765', (214, 223))	('copy-number variants', 'Var', (46, 66))	('cancer', 'Disease', (171, 177))	('associated', 'Reg', (108, 118))	('defensin-encoding genes', 'Gene', (80, 103))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('pancreatitis', 'Phenotype', 'HP:0001733', (234, 246))
9316	23148552	In a case-control study, we investigated the association between MSV in DEFB104 as well as defensin gene (DEF) cluster copy number (CN), and pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP).	('CP', 'Phenotype', 'HP:0006280', (207, 209))	('PDAC', 'Chemical', '-', (175, 179))	('pancreatitis', 'Phenotype', 'HP:0001733', (193, 205))	('DEFB104', 'Gene', '140596', (72, 79))	('pancreatitis', 'Disease', 'MESH:D010195', (193, 205))	('DEFB104', 'Gene', (72, 79))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (141, 173))	('PDAC', 'Phenotype', 'HP:0006725', (175, 179))	('DEF', 'Gene', (106, 109))	('pancreatic ductal adenocarcinoma', 'Disease', (141, 173))	('pancreatitis', 'Disease', (193, 205))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (185, 205))	('MSV', 'Var', (65, 68))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (141, 173))
9338	23148552	The corresponding haplotypes comprise four MSV (rs17843871, rs2680507, rs17843872 and rs4259430) around exon 1 of DEFB104.	('rs2680507', 'Mutation', 'rs2680507', (60, 69))	('rs17843872', 'Var', (71, 81))	('rs17843872', 'Mutation', 'rs17843872', (71, 81))	('rs17843871', 'Var', (48, 58))	('DEFB104', 'Gene', '140596', (114, 121))	('rs2680507', 'Var', (60, 69))	('DEFB104', 'Gene', (114, 121))	('rs4259430', 'Mutation', 'rs4259430', (86, 95))	('rs4259430', 'Var', (86, 95))	('rs17843871', 'Mutation', 'rs17843871', (48, 58))
9339	23148552	While haplotypes GGGC and CAAT were significantly under-represented among patients, GAAT and GAAC were significantly over-represented.	('GAAT', 'Disease', 'None', (84, 88))	('over-represented', 'PosReg', (117, 133))	('under-represented', 'NegReg', (50, 67))	('CAAT', 'Disease', (26, 30))	('patients', 'Species', '9606', (74, 82))	('GAAT', 'Disease', (84, 88))	('GGGC', 'Gene', (17, 21))	('haplotypes', 'Var', (6, 16))
9341	23148552	The aim of the present study was to search for associations between MSV-based DEFB104 haplotypes and DEF cluster b CNs on the one hand, and pancreatic ductal adenocarcinoma and chronic pancreatitis on the other.	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (177, 197))	('pancreatitis', 'Disease', (185, 197))	('pancreatic ductal adenocarcinoma', 'Disease', (140, 172))	('pancreatitis', 'Disease', 'MESH:D010195', (185, 197))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (140, 172))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (140, 172))	('pancreatitis', 'Phenotype', 'HP:0001733', (185, 197))	('DEFB104', 'Gene', '140596', (78, 85))	('haplotypes', 'Var', (86, 96))	('associations', 'Interaction', (47, 59))	('DEFB104', 'Gene', (78, 85))
9356	23148552	In the present study, both sequence variants in a ss-defensin gene and CN variants of the cluster containing this gene were investigated for a putative association with PDAC and CP.	('PDAC', 'Disease', (169, 173))	('PDAC', 'Phenotype', 'HP:0006725', (169, 173))	('CP', 'Phenotype', 'HP:0006280', (178, 180))	('ss-defensin gene', 'Gene', (50, 66))	('PDAC', 'Chemical', '-', (169, 173))	('association', 'Interaction', (152, 163))	('variants', 'Var', (36, 44))
9359	23148552	Earlier, we have demonstrated association between DEFB104 haplotypes and sporadic prostate cancer as well as under-representation of high diploid DEF cluster CN in patients with this disease.	('sporadic prostate cancer', 'Disease', 'MESH:D011471', (73, 97))	('sporadic prostate cancer', 'Disease', (73, 97))	('DEFB104', 'Gene', '140596', (50, 57))	('haplotypes', 'Var', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('prostate cancer', 'Phenotype', 'HP:0012125', (82, 97))	('DEFB104', 'Gene', (50, 57))	('patients', 'Species', '9606', (164, 172))	('association', 'Interaction', (30, 41))
9374	23148552	Amplification from individual genomic DNAs was carried out using primers 5'-TTCTGTAGCCCCAACACCTC-3' and 5'-GGTGCCAAGGACATCTAGGA-3', resulting in a 500 bp PCR product spanning four MSV (rs17843871, rs2680507, rs17843872, rs4259430) around exon 1 of DEFB104 (GenBank Refseq NM_080389.2).	('rs17843871', 'Var', (185, 195))	('rs2680507', 'Var', (197, 206))	('DEFB104', 'Gene', '140596', (248, 255))	('rs4259430', 'Var', (220, 229))	('DEFB104', 'Gene', (248, 255))	('rs4259430', 'Mutation', 'rs4259430', (220, 229))	('rs17843872', 'Mutation', 'rs17843872', (208, 218))	('rs17843871', 'Mutation', 'rs17843871', (185, 195))	('rs2680507', 'Mutation', 'rs2680507', (197, 206))	('rs17843872', 'Var', (208, 218))
9396	22091389	We recently conducted a three-step proteome analysis involving removal of 12 abundant proteins and subsequent reversed-phase high-performance liquid chromatography fractionation and one-dimensional electrophoresis: we successfully identified three proteins including YKL-50 as a promising biomarker of sepsis.	('YKL-50', 'Var', (267, 273))	('sepsis', 'Disease', 'MESH:D018805', (302, 308))	('sepsis', 'Phenotype', 'HP:0100806', (302, 308))	('sepsis', 'Disease', (302, 308))
9563	19667060	These data demonstrate that MPs activate and aggregate platelets via a TF-dependent pathway in vitro.	('rat', 'Species', '10116', (18, 21))	('platelets', 'CPA', (55, 64))	('TF-dependent pathway', 'Pathway', (71, 91))	('MPs', 'Var', (28, 31))	('activate', 'PosReg', (32, 40))	('aggregate', 'MPA', (45, 54))
9584	19667060	The presence of PSGL-1 targets MPs to sites of thrombosis, whereas active TF actively participates in the formation of the thrombus by generating thrombin and fibrin.	('fibrin', 'MPA', (159, 165))	('thrombin', 'Gene', '14061', (146, 154))	('thrombin', 'Gene', (146, 154))	('rat', 'Species', '10116', (139, 142))	('thrombus', 'Disease', (123, 131))	('thrombosis', 'Disease', (47, 57))	('formation', 'biological_process', 'GO:0009058', ('106', '115'))	('presence', 'Var', (4, 12))	('PSGL-1', 'Gene', (16, 22))	('thrombus', 'Disease', 'MESH:D013927', (123, 131))	('thrombosis', 'Disease', 'MESH:D013927', (47, 57))
9603	19667060	Different hypotheses may explain why MPs and not their parental cells bind to a growing thrombus.	('thrombus', 'Disease', 'MESH:D013927', (88, 96))	('MPs', 'Var', (37, 40))	('bind', 'Interaction', (70, 74))	('thrombus', 'Disease', (88, 96))
9606	19667060	In our conditions, Panc02-derived MPs have a more dramatic effect on thrombosis in arterioles compared with venules, whereas LLC1-derived MPs have the opposite effect.	('Panc02', 'CellLine', 'CVCL:D627', (19, 25))	('thrombosis', 'Disease', (69, 79))	('MPs', 'Var', (34, 37))	('thrombosis', 'Disease', 'MESH:D013927', (69, 79))	('Panc02-derived', 'Var', (19, 33))	('LLC', 'cellular_component', 'GO:0038045', ('125', '128'))
9618	19667060	Second, MPs affect thrombus formation, likely via the expression of active TF on their surface.	('affect', 'Reg', (12, 18))	('thrombus', 'Disease', (19, 27))	('MPs', 'Var', (8, 11))	('formation', 'biological_process', 'GO:0009058', ('28', '37'))	('thrombus', 'Disease', 'MESH:D013927', (19, 27))
9650	19667060	For MP labeling, 30 microl of freshly thawed PFP or of the MP suspension was incubated for 30 min with 10 microl FITC-annexin V or PE-anti-mouse monoclonal antibodies (30 microg/ml anti-CD41, 40 microg/ml anti-TER-119, 40 microg/ml anti-CD45, 40 microg/ml anti-CD31, or 50 microg/ml anti-PSGL-1).	('TER-119', 'Gene', (210, 217))	('CD41', 'Gene', (186, 190))	('annexin V', 'Gene', '11747', (118, 127))	('TER-119', 'Gene', '104231', (210, 217))	('FITC', 'Chemical', 'MESH:D016650', (113, 117))	('anti-CD45', 'Var', (232, 241))	('PE', 'Chemical', '-', (131, 133))	('TER', 'cellular_component', 'GO:0097047', ('210', '213'))	('mouse', 'Species', '10090', (139, 144))	('annexin V', 'Gene', (118, 127))	('anti-CD31', 'Var', (256, 265))	('CD41', 'Gene', '16399', (186, 190))
9681	19667060	S1 shows the box plot distribution of CD31+CD41- MPs and TER119+ MPs in healthy and tumor-bearing mice (data are from Table I).	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('TER', 'cellular_component', 'GO:0097047', ('57', '60'))	('TER119+ MPs', 'Var', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('CD41', 'Gene', (43, 47))	('CD41', 'Gene', '16399', (43, 47))	('mice', 'Species', '10090', (98, 102))
9686	18790753	In vitro treatment of pancreatic cancer cell lines with IPI-269609 resembled effects observed using cyclopamine (i.e., Gli-responsive reporter knock-down, down-regulation of the Hedgehog target genes Gli1 and Ptch, as well as abrogation of cell migration and colony formation in soft agar).	('Ptch', 'Gene', (209, 213))	('agar', 'Chemical', 'MESH:D000362', (284, 288))	('IPI-269609', 'Chemical', 'MESH:C532361', (56, 66))	('abrogation', 'NegReg', (226, 236))	('regulation', 'biological_process', 'GO:0065007', ('160', '170'))	('Gli1', 'Gene', (200, 204))	('cell migration', 'CPA', (240, 254))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (22, 39))	('Ptch', 'Gene', '19206', (209, 213))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cell migration', 'biological_process', 'GO:0016477', ('240', '254'))	('pancreatic cancer', 'Disease', (22, 39))	('cyclopamine', 'Chemical', 'MESH:C000541', (100, 111))	('formation', 'biological_process', 'GO:0009058', ('266', '275'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (22, 39))	('Gli1', 'Gene', '14632', (200, 204))	('down-regulation', 'NegReg', (155, 170))	('IPI-269609', 'Var', (56, 66))
9687	18790753	Single-agent IPI-269609 profoundly inhibited systemic metastases in orthotopic xenografts established from human pancreatic cancer cell lines, although Hedgehog blockade had minimal effect on primary tumor volume.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('human', 'Species', '9606', (107, 112))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('IPI-269609', 'Chemical', 'MESH:C532361', (13, 23))	('tumor', 'Disease', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('metastases', 'Disease', (54, 64))	('pancreatic cancer', 'Disease', (113, 130))	('IPI-269609', 'Var', (13, 23))	('inhibited', 'NegReg', (35, 44))	('metastases', 'Disease', 'MESH:D009362', (54, 64))	('pancreatic cancer', 'Disease', 'MESH:D010190', (113, 130))	('ade', 'Chemical', '-', (166, 169))
9689	18790753	Selective ex vivo depletion of aldehyde dehydrogenase-bright cells with IPI-269609 was accompanied by significant reduction in tumor engraftment rates in athymic mice.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('reduction', 'NegReg', (114, 123))	('tumor', 'Disease', (127, 132))	('depletion', 'NegReg', (18, 27))	('mice', 'Species', '10090', (162, 166))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('IPI-269609', 'Var', (72, 82))	('IPI-269609', 'Chemical', 'MESH:C532361', (72, 82))
9690	18790753	Pharmacologic blockade of aberrant Hedgehog signaling might prove to be an effective therapeutic strategy for inhibition of systemic metastases in pancreatic cancer, likely through targeting subsets of cancer cells with tumor-initiating ("cancer stem cell") properties.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('inhibition', 'NegReg', (110, 120))	('aberrant', 'Var', (26, 34))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', (239, 245))	('pancreatic cancer', 'Disease', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('ade', 'Chemical', '-', (19, 22))	('Hedgehog signaling', 'Gene', (35, 53))	('signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('metastases', 'Disease', 'MESH:D009362', (133, 143))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('metastases', 'Disease', (133, 143))	('cancer', 'Disease', (202, 208))
9698	18790753	Recently, aberrant reactivation of the Hedgehog signaling pathway has been described in several gastrointestinal tract cancers including pancreatic cancer.	('gastrointestinal tract cancers', 'Disease', (96, 126))	('Hedgehog signaling pathway', 'Pathway', (39, 65))	('gastrointestinal tract cancers', 'Disease', 'MESH:D004067', (96, 126))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (137, 154))	('described', 'Reg', (75, 84))	('pancreatic cancer', 'Disease', (137, 154))	('aberrant reactivation', 'Var', (10, 31))	('pancreatic cancer', 'Disease', 'MESH:D010190', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
9729	18790753	Determination of in vitro ALDH activity after treatment with IPI-269609 (6 micromol/L) or solvent only in low-serum conditions (0.5% FBS) was carried out as previously described.	('IPI-269609', 'Var', (61, 71))	('IPI-269609', 'Chemical', 'MESH:C532361', (61, 71))	('ALDH', 'Gene', (26, 30))	('ALDH', 'Gene', '11670', (26, 30))
9736	18790753	every 4th day, and (d) combination of gemcitabine and IPI-269609.	('gemcitabine', 'Chemical', 'MESH:C056507', (38, 49))	('IPI-269609', 'Var', (54, 64))	('combination', 'Interaction', (23, 34))	('IPI-269609', 'Chemical', 'MESH:C532361', (54, 64))
9747	18790753	Three weeks after surgical implantation of E3LZ10.7 xenograft tumor chunks, the presence of intrapancreatic tumors was confirmed by ultrasound scan (Vevo660, Visual Sonics) and measured in three orthogonal axes, a, b, and c; tumor volumes were determined as V = (abc) / 2.	('V = (abc) / 2', 'Gene', (258, 271))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('intrapancreatic tumors', 'Disease', (92, 114))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('xenograft tumor', 'Disease', 'MESH:D009369', (52, 67))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('V = (abc) / 2', 'Gene', '11305', (258, 271))	('tumor', 'Disease', (62, 67))	('intrapancreatic tumors', 'Disease', 'MESH:D009369', (92, 114))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('E3LZ10.7', 'Var', (43, 51))	('xenograft tumor', 'Disease', (52, 67))
9748	18790753	Mice were distributed into two groups with similar average tumor volumes and randomly assigned to receive either IPI-269609 (20 mg/d p.o.)	('IPI-269609', 'Chemical', 'MESH:C532361', (113, 123))	('tumor', 'Disease', (59, 64))	('IPI-269609', 'Var', (113, 123))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
9749	18790753	or mock treatment with solvent only for 30 d. In the case of Capan-1, based on the idea to asses maximum effect on primary tumor growth by continuous pathway knockdown and longer treatment period, drug application was initiated by s.c. implantation of two 14D Alzet osmotic pumps (Alzet) 2 wk after orthotopic tumor implantation, and treatment was continued for 6 wk with exchange of pumps every 14 d. For application with Alzet pumps, IPI-269609 was dissolved in 30% (2-hydroxy-propyl)-beta-cyclodextrin (Sigma-Aldrich) in sterile water at 40 g/L; control animals received pumps with 30% cyclodextrin in water only.	('cyclodextrin', 'Chemical', 'MESH:D003505', (589, 601))	('Alzet', 'Chemical', '-', (281, 286))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('Alzet', 'Chemical', '-', (260, 265))	('IPI-269609', 'Var', (436, 446))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('Alzet', 'Chemical', '-', (423, 428))	('water', 'Chemical', 'MESH:D014867', (532, 537))	('peri', 'Gene', '103968', (189, 193))	('(2-hydroxy-propyl)-beta-cyclodextrin', 'Chemical', 'MESH:D000073738', (468, 504))	('tumor', 'Disease', (310, 315))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('peri', 'Gene', (189, 193))	('cyclodextrin', 'Chemical', 'MESH:D003505', (492, 504))	('IPI-269609', 'Chemical', 'MESH:C532361', (436, 446))	('water', 'Chemical', 'MESH:D014867', (605, 610))
9758	18790753	Relative quantification of cells with high ALDH expression was done using Frida analysis software.7 To further dissect the contribution of Hedgehog signaling to tumor initiation, the Hedgehog pathway was blocked with IPI-269609 only at a 7-d interval shortly before and after s.c. injection of pancreatic cancer cells into nude mice.	('tumor initiation', 'Disease', (161, 177))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('blocked', 'NegReg', (204, 211))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (294, 311))	('pancreatic cancer', 'Disease', 'MESH:D010190', (294, 311))	('ALDH', 'Gene', (43, 47))	('Hedgehog pathway', 'Pathway', (183, 199))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('IPI-269609', 'Var', (217, 227))	('tumor initiation', 'Disease', 'MESH:D009369', (161, 177))	('IPI-269609', 'Chemical', 'MESH:C532361', (217, 227))	('pancreatic cancer', 'Disease', (294, 311))	('nude mice', 'Species', '10090', (323, 332))	('ALDH', 'Gene', '11670', (43, 47))
9759	18790753	In particular, pancreatic cancer cell line E3LZ10.7 or Capan-1 was treated with 6 micromol/L IPI-269609 or an equivalent amount of solvent in vitro for 3d.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (15, 32))	('IPI-269609', 'Var', (93, 103))	('IPI-269609', 'Chemical', 'MESH:C532361', (93, 103))	('pancreatic cancer', 'Disease', 'MESH:D010190', (15, 32))	('pancreatic cancer', 'Disease', (15, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
9765	18790753	Treatment with 6 micromol/L IPI-269609 significantly inhibited the Gli-responsive reporter activity of LightII cells as compared with solvent-treated controls.	('IPI-269609', 'Chemical', 'MESH:C532361', (28, 38))	('Gli-responsive reporter activity', 'MPA', (67, 99))	('inhibited', 'NegReg', (53, 62))	('IPI-269609', 'Var', (28, 38))
9766	18790753	1B, IPI-269609 impeded the reporter activity of ShhN-stimulated LightII cells in a dose-dependent manner.	('Shh', 'Gene', '20423', (48, 51))	('impeded', 'NegReg', (15, 22))	('IPI-269609', 'Var', (4, 14))	('IPI-269609', 'Chemical', 'MESH:C532361', (4, 14))	('Shh', 'Gene', (48, 51))	('reporter activity', 'MPA', (27, 44))
9768	18790753	Using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assays on a panel of 21 pancreatic cancer cell lines, including several low-passage cell lines generated at our institution, we found a wide range of growth inhibition (0% to almost 100%) on treatment with 6 micromol/L IPI-269609 in low-serum conditions for 96 hours (Fig.	('IPI-269609', 'Chemical', 'MESH:C532361', (285, 295))	('3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (6, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('pancreatic cancer', 'Disease', (90, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('growth', 'MPA', (216, 222))	('IPI-269609', 'Var', (285, 295))
9772	18790753	Incubation with IPI-269609 (6 micromol/L) for 48 hours resulted in down-regulation of the Hedgehog target gene Gli1 at the mRNA level in vitro (Fig.	('down-regulation', 'NegReg', (67, 82))	('IPI-269609', 'Var', (16, 26))	('IPI-269609', 'Chemical', 'MESH:C532361', (16, 26))	('Gli1', 'Gene', (111, 115))	('Gli1', 'Gene', '14632', (111, 115))	('regulation', 'biological_process', 'GO:0065007', ('72', '82'))
9774	18790753	Namely, cell migration, as observed in wound healing assays, and colony formation in soft agar were both dramatically reduced on IPI-269609-mediated Hedgehog inhibition (Fig.	('colony formation in soft agar', 'CPA', (65, 94))	('wound healing', 'biological_process', 'GO:0042060', ('39', '52'))	('IPI-269609-mediated', 'Var', (129, 148))	('reduced', 'NegReg', (118, 125))	('Hedgehog', 'CPA', (149, 157))	('cell migration', 'biological_process', 'GO:0016477', ('8', '22'))	('IPI-269609', 'Chemical', 'MESH:C532361', (129, 139))	('cell migration', 'CPA', (8, 22))	('inhibition', 'NegReg', (158, 168))	('agar', 'Chemical', 'MESH:D000362', (90, 94))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))
9775	18790753	Inhibition of Hedgehog signaling in pancreatic cancer cell lines had previously been shown to reduce a subpopulation of SSC-low/ALDH-bright cells with tumor initiating (clonogenic) properties.	('pancreatic cancer', 'Disease', 'MESH:D010190', (36, 53))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('signaling', 'biological_process', 'GO:0023052', ('23', '32'))	('tumor', 'Disease', (151, 156))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (36, 53))	('ALDH', 'Gene', '11670', (128, 132))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('ALDH', 'molecular_function', 'GO:0004030', ('128', '132'))	('reduce', 'NegReg', (94, 100))	('Hedgehog', 'Protein', (14, 22))	('ALDH', 'Gene', (128, 132))	('pancreatic cancer', 'Disease', (36, 53))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
9776	18790753	In line with these previous results, we found that incubation of E3LZ10.7 with IPI-269609 (6 micromol/L) at low-serum conditions significantly reduced this fraction of SSC-low/ALDH-bright cells ~4-fold (Fig.	('E3LZ10.7', 'Var', (65, 73))	('reduced', 'NegReg', (143, 150))	('ALDH', 'molecular_function', 'GO:0004030', ('176', '180'))	('ALDH', 'Gene', '11670', (176, 180))	('IPI-269609', 'Chemical', 'MESH:C532361', (79, 89))	('ALDH', 'Gene', (176, 180))	('IPI-269609', 'Gene', (79, 89))
9779	18790753	every 4th day, or (d) combination treatment with IPI-269609 and gemcitabine at the given doses.	('IPI-269609', 'Var', (49, 59))	('combination', 'Interaction', (22, 33))	('IPI-269609', 'Chemical', 'MESH:C532361', (49, 59))	('gemcitabine', 'Chemical', 'MESH:C056507', (64, 75))
9781	18790753	3, s.c. tumor growth was slightly inhibited in IPI-269609-treated animals as compared with controls with an ~40% smaller average tumor volume at the end of treatment; however, these differences did not reach statistical significance, possibly due to the small number of animals per treatment arm and considerable interindividual variation in xenograft tumor sizes.	('smaller', 'NegReg', (113, 120))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('xenograft tumor', 'Disease', (342, 357))	('inhibited', 'NegReg', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (352, 357))	('xenograft tumor', 'Disease', 'MESH:D009369', (342, 357))	('IPI-269609', 'Chemical', 'MESH:C532361', (47, 57))	('tumor', 'Disease', (8, 13))	('IPI-269609-treated', 'Var', (47, 65))	('tumor', 'Disease', (129, 134))
9782	18790753	Treatment with gemcitabine or the combination of IPI-269609 plus gemcitabine, on the other hand, led to marked inhibition of s.c. tumor growth as compared with mock-treated controls [all P < 0.01 beginning after 15 days of drug treatment (D15)].	('IPI-269609', 'Var', (49, 59))	('IPI-269609', 'Chemical', 'MESH:C532361', (49, 59))	('gemcitabine', 'Chemical', 'MESH:C056507', (65, 76))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('gemcitabine', 'Chemical', 'MESH:C056507', (15, 26))	('tumor', 'Disease', (130, 135))	('inhibition', 'NegReg', (111, 121))
9785	18790753	Previous studies have shown that cyclopamine has minimal effects on s.c. tumor growth while profoundly inhibiting systemic metastases.	('cyclopamine', 'Chemical', 'MESH:C000541', (33, 44))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('inhibiting', 'NegReg', (103, 113))	('tumor', 'Disease', (73, 78))	('metastases', 'Disease', (123, 133))	('metastases', 'Disease', 'MESH:D009362', (123, 133))	('cyclopamine', 'Var', (33, 44))
9786	18790753	Therefore, we wanted to examine whether IPI-269609 was capable of suppressing the development of distant organ metastases of pancreatic cancer xenografts in vivo.	('metastases of pancreatic cancer', 'Disease', 'MESH:D009362', (111, 142))	('suppressing', 'NegReg', (66, 77))	('IPI-269609', 'Chemical', 'MESH:C532361', (40, 50))	('IPI-269609', 'Var', (40, 50))	('metastases of pancreatic cancer', 'Disease', (111, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))
9789	18790753	The tumor take rate for E3LZ10.7 was 100% with our surgical implantation method.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('E3LZ10.7', 'Var', (24, 32))
9790	18790753	Whereas Hedgehog blockade with IPI-269609 had no effect on intrapancreatic "primary" tumor growth (Fig.	('tumor', 'Disease', (85, 90))	('IPI-269609', 'Chemical', 'MESH:C532361', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ade', 'Chemical', '-', (22, 25))	('IPI-269609', 'Var', (31, 41))
9791	18790753	4A), we observed complete abrogation of distant metastases in IPI-269609-treated animals, whereas metastases in at least one distant organ site were observed in 5 of 5 (100%) of mock-treated animals (Table 1).	('IPI-269609', 'Chemical', 'MESH:C532361', (62, 72))	('metastases', 'Disease', 'MESH:D009362', (48, 58))	('IPI-269609-treated', 'Var', (62, 80))	('metastases', 'Disease', (98, 108))	('metastases', 'Disease', 'MESH:D009362', (98, 108))	('abrogation', 'NegReg', (26, 36))	('metastases', 'Disease', (48, 58))
9796	18790753	At the end of treatment, Capan-1 tumor volumes tended to be smaller in IPI-269609-treated mice, but again this difference did not reach statistical significance (P = 0.095) due to considerable interindividual variation in tumor size (data not shown).	('Capan-1', 'Gene', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('IPI-269609', 'Chemical', 'MESH:C532361', (71, 81))	('mice', 'Species', '10090', (90, 94))	('IPI-269609-treated', 'Var', (71, 89))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', (33, 38))	('smaller', 'NegReg', (60, 67))
9799	18790753	Previous studies by others have shown that a subpopulation of cells with high ALDH activity shows increased clonogenic potential in a variety of malignancies, and we have recently shown that Hedgehog inhibition reduces this population in pancreatic cancer cell lines in vitro.	('malignancies', 'Disease', (145, 157))	('activity', 'MPA', (83, 91))	('ALDH', 'Gene', (78, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (238, 255))	('ALDH', 'molecular_function', 'GO:0004030', ('78', '82'))	('pancreatic cancer', 'Disease', (238, 255))	('increased', 'PosReg', (98, 107))	('clonogenic potential', 'CPA', (108, 128))	('malignancies', 'Disease', 'MESH:D009369', (145, 157))	('pancreatic cancer', 'Disease', 'MESH:D010190', (238, 255))	('high', 'Var', (73, 77))	('ALDH', 'Gene', '11670', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
9802	18790753	Of note, Hedgehog pathway inhibition with IPI-269609 was accompanied by a significant reduction of cells with high ALDH activity in vivo in these tumors as observed using immunohistochemistry (Fig.	('tumors', 'Disease', (146, 152))	('reduction', 'NegReg', (86, 95))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('ALDH', 'molecular_function', 'GO:0004030', ('115', '119'))	('cells', 'MPA', (99, 104))	('inhibition', 'NegReg', (26, 36))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('ALDH', 'Gene', '11670', (115, 119))	('IPI-269609', 'Var', (42, 52))	('Hedgehog pathway', 'Pathway', (9, 25))	('activity', 'MPA', (120, 128))	('IPI-269609', 'Chemical', 'MESH:C532361', (42, 52))	('ALDH', 'Gene', (115, 119))
9804	18790753	Because metastasis is functionally equivalent to tumor initiation at a distant site, we hypothesized that ex vivo pretreatment of cells with IPI-269609 could preferentially eliminate the tumorigenic subpopulation and block xenograft engraftment.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('IPI-269609', 'Var', (141, 151))	('block', 'NegReg', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor initiation', 'Disease', 'MESH:D009369', (49, 65))	('IPI-269609', 'Chemical', 'MESH:C532361', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('eliminate', 'NegReg', (173, 182))	('tumor', 'Disease', (49, 54))	('tumor initiation', 'Disease', (49, 65))	('tumor', 'Disease', (187, 192))	('xenograft engraftment', 'CPA', (223, 244))
9805	18790753	To further corroborate this hypothesis, we speculated whether blockade of Hedgehog signaling solely during the time of tumor initiation was sufficient to affect the growth of pancreatic cancer xenografts.	('pancreatic cancer', 'Disease', 'MESH:D010190', (175, 192))	('tumor initiation', 'Disease', (119, 135))	('pancreatic cancer', 'Disease', (175, 192))	('Hedgehog signaling', 'Gene', (74, 92))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('blockade', 'Var', (62, 70))	('growth', 'MPA', (165, 171))	('affect', 'Reg', (154, 160))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (175, 192))	('tumor initiation', 'Disease', 'MESH:D009369', (119, 135))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('ade', 'Chemical', '-', (67, 70))
9806	18790753	For this purpose, pancreatic cancer cell line E3LZ10.7 or Capan-1 was incubated with IPI-269609 (6 micromol/L) or solvent for 3 days preceding s.c. injection into nude mice.	('nude mice', 'Species', '10090', (163, 172))	('pancreatic cancer', 'Disease', (18, 35))	('pancreatic cancer', 'Disease', 'MESH:D010190', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('IPI-269609', 'Var', (85, 95))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (18, 35))	('IPI-269609', 'Chemical', 'MESH:C532361', (85, 95))
9807	18790753	At the same time, Hedgehog signaling was blocked with IPI-269609 in nude mice using s.c. Alzet pumps.	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('Alzet', 'Chemical', '-', (89, 94))	('IPI-269609', 'Var', (54, 64))	('IPI-269609', 'Chemical', 'MESH:C532361', (54, 64))	('nude mice', 'Species', '10090', (68, 77))	('blocked', 'NegReg', (41, 48))	('Hedgehog', 'Protein', (18, 26))
9812	18790753	Surprisingly, this peri-implantational Hedgehog block-ade was sufficient to cause significant growth retardation in xenografts of both Capan-1 (data not shown) and E3LZ10.7 (Fig.	('ade', 'Chemical', '-', (54, 57))	('growth retardation', 'Disease', (94, 112))	('peri', 'Gene', (19, 23))	('E3LZ10.7', 'Var', (164, 172))	('growth retardation', 'Phenotype', 'HP:0001510', (94, 112))	('growth retardation', 'Disease', 'MESH:D006130', (94, 112))	('peri', 'Gene', '103968', (19, 23))
9814	18790753	Aberrant reactivation of Hedgehog signaling in pancreatic cancer was first described in 2003 by two groups, including our own.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (47, 64))	('Aberrant reactivation', 'Var', (0, 21))	('pancreatic cancer', 'Disease', 'MESH:D010190', (47, 64))	('pancreatic cancer', 'Disease', (47, 64))	('Hedgehog signaling', 'Pathway', (25, 43))
9815	18790753	Hedgehog activation seems to mainly be mediated through aberrant ligand overexpression by pancreatic cancer cells, but more recently, alternative mechanisms have been proposed that might contribute to increased Hedgehog pathway activity in pancreatic cancer as well (e.g., through silencing of the pathway inhibitor human Hedgehog interacting protein due to promoter hypermethylation; ref.).	('promoter hypermethylation', 'Var', (358, 383))	('Hedgehog interacting protein', 'Gene', '64399', (322, 350))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('pancreatic cancer', 'Disease', (240, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('increased', 'PosReg', (201, 210))	('ligand', 'molecular_function', 'GO:0005488', ('65', '71'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (240, 257))	('human', 'Species', '9606', (316, 321))	('pancreatic cancer', 'Disease', (90, 107))	('silencing', 'NegReg', (281, 290))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('protein', 'cellular_component', 'GO:0003675', ('343', '350'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Hedgehog pathway', 'Pathway', (211, 227))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (240, 257))	('activity', 'MPA', (228, 236))	('Hedgehog interacting protein', 'Gene', (322, 350))
9818	18790753	Indeed, a recent report by our own group showed that Hedgehog blockade with cyclopamine led to a marked inhibition of colony formation in vitro and prevented the development of metastases in vivo using orthotopic xenografts, and that treatment of pancreatic cancer cell lines led to reduction of a SSC-low/ALDH-bright subpopulation that show tumor-initiating properties in vitro.	('inhibition', 'NegReg', (104, 114))	('colony formation', 'CPA', (118, 134))	('pancreatic cancer', 'Disease', (247, 264))	('reduction', 'NegReg', (283, 292))	('metastases', 'Disease', 'MESH:D009362', (177, 187))	('ade', 'Chemical', '-', (67, 70))	('metastases', 'Disease', (177, 187))	('prevented', 'NegReg', (148, 157))	('ALDH', 'Gene', '11670', (306, 310))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (247, 264))	('tumor', 'Disease', (342, 347))	('Hedgehog', 'Gene', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('cyclopamine', 'Var', (76, 87))	('formation', 'biological_process', 'GO:0009058', ('125', '134'))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('pancreatic cancer', 'Disease', 'MESH:D010190', (247, 264))	('blockade', 'Var', (62, 70))	('ALDH', 'molecular_function', 'GO:0004030', ('306', '310'))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('cyclopamine', 'Chemical', 'MESH:C000541', (76, 87))	('ALDH', 'Gene', (306, 310))
9819	18790753	In the present study, we show that the novel small-molecule Hedgehog inhibitor IPI-269609 fully resembles the properties of cyclopamine to block Hedgehog signaling in pancreatic cancer cells in vitro and in vivo.	('pancreatic cancer', 'Disease', 'MESH:D010190', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('Hedgehog signaling', 'MPA', (145, 163))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (167, 184))	('block', 'NegReg', (139, 144))	('IPI-269609', 'Var', (79, 89))	('cyclopamine', 'Chemical', 'MESH:C000541', (124, 135))	('IPI-269609', 'Chemical', 'MESH:C532361', (79, 89))	('pancreatic cancer', 'Disease', (167, 184))
9823	18790753	In the present study, we found that similar to cyclopamine, treatment with IPI-269609 reduces this subpopulation in pancreatic cancer cell lines in vitro.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('reduces', 'NegReg', (86, 93))	('cyclopamine', 'Chemical', 'MESH:C000541', (47, 58))	('IPI-269609', 'Chemical', 'MESH:C532361', (75, 85))	('IPI-269609', 'Var', (75, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('pancreatic cancer', 'Disease', (116, 133))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))
9826	18790753	The findings presented here support a recent report by Bar et al., who describe that cyclopamine treatment reduced the fraction of ALDH-bright glioblastoma cells and abrogated its ability to form neurospheres in vitro as well as its potential to grow tumors in athymic mice.	('ALDH', 'Gene', (131, 135))	('cyclopamine', 'Var', (85, 96))	('glioblastoma', 'Disease', (143, 155))	('abrogated', 'NegReg', (166, 175))	('cyclopamine', 'Chemical', 'MESH:C000541', (85, 96))	('tumors', 'Disease', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('reduced', 'NegReg', (107, 114))	('ALDH', 'molecular_function', 'GO:0004030', ('131', '135'))	('glioblastoma', 'Disease', 'MESH:D005909', (143, 155))	('mice', 'Species', '10090', (269, 273))	('ALDH', 'Gene', '11670', (131, 135))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
9844	18790753	Taken together, the results presented here support the concept that pharmacologically targeting aberrant Hedge-hog signaling is a valid approach for the development of novel therapeutic regimens for pancreatic cancer.	('pancreatic cancer', 'Disease', (199, 216))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('aberrant', 'Var', (96, 104))	('Hedge-hog', 'Protein', (105, 114))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))
9893	33680969	N6-Methyladenosine (m6A) was highly enriched within LINC00857 and enhanced its RNA stability.	('N6-Methyladenosine', 'Var', (0, 18))	('m6A', 'Gene', '56339', (20, 23))	('N6-Methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('LINC00857', 'Gene', '439990', (52, 61))	('enhanced', 'PosReg', (66, 74))	('LINC00857', 'Gene', (52, 61))	('RNA', 'cellular_component', 'GO:0005562', ('79', '82'))	('RNA stability', 'CPA', (79, 92))	('m6A', 'Gene', (20, 23))
9911	33680969	GEPIA database analysis was used to assess the expression levels of LINC00857 or E2F3 and find the association between the survival rate and LINC00857 or E2F3 expression in PC patients.	('LINC00857', 'Gene', '439990', (68, 77))	('patients', 'Species', '9606', (176, 184))	('PC', 'Phenotype', 'HP:0002894', (173, 175))	('LINC00857', 'Gene', (141, 150))	('LINC00857', 'Gene', (68, 77))	('LINC00857', 'Gene', '439990', (141, 150))	('E2F3', 'Var', (154, 158))	('association', 'Interaction', (99, 110))
9935	33680969	The pMIR-REPORT  (RiboBio), covering wild type (WT), or mutant (MT) LINC00857/E2F3 3'-UTR sequences was employed for carrying out the dual-luciferase reporter assay.	('LINC00857', 'Gene', '439990', (68, 77))	('mutant', 'Var', (56, 62))	('LINC00857', 'Gene', (68, 77))
9936	33680969	Accompanied by WT or MT LINC00857/E2F3 3'-UTR vector, cells (1x105) saw transient co-transfection with the miR-150-5p mimic or the negative control.	('LINC00857', 'Gene', '439990', (24, 33))	('miR-150-5p mimic', 'Var', (107, 123))	('LINC00857', 'Gene', (24, 33))	('miR-150-5p', 'Chemical', '-', (107, 117))
9943	33680969	The results showed that the overall survival rate (HR=1.6, p=0.034) and disease-free survival rate (HR=1.9, p=0.0046) of PC patients with high expression of LINC00857 were remarkably lower than those of low expression group ( Figures 1A, B ).	('LINC00857', 'Gene', '439990', (157, 166))	('disease-free survival rate', 'CPA', (72, 98))	('LINC00857', 'Gene', (157, 166))	('high expression', 'Var', (138, 153))	('lower', 'NegReg', (183, 188))	('PC', 'Phenotype', 'HP:0002894', (121, 123))	('patients', 'Species', '9606', (124, 132))
9952	33680969	Based on the online bioinformatics database m6Avar , we found four RRACU m6A sequence motifs in the exon region (at chr10:81978357, 81977798, 81977927, and 81978636).	('m6A', 'Gene', (73, 76))	('chr10:81978357', 'Var', (116, 130))	('81977798', 'Var', (132, 140))	('m6A', 'Gene', '56339', (73, 76))	('m6A', 'Gene', (44, 47))	('81977927', 'Var', (142, 150))	('m6A', 'Gene', '56339', (44, 47))	('81978636', 'Var', (156, 164))
9956	33680969	We then performed shRNA-mediated silencing of METTL3 ( Figure 2B ) and found that downregulation of METTL3 resulted in the decreased m6A level of both total RNA and LINC00857 in SW1990 cells ( Figures 2C, D ).	('RNA', 'cellular_component', 'GO:0005562', ('157', '160'))	('decreased', 'NegReg', (123, 132))	('METTL3', 'Gene', '56339', (100, 106))	('silencing', 'Var', (33, 42))	('downregulation', 'NegReg', (82, 96))	('SW1990', 'CellLine', 'CVCL:1723', (178, 184))	('METTL3', 'Gene', (100, 106))	('m6A', 'Gene', (133, 136))	('LINC00857', 'Gene', (165, 174))	('METTL3', 'Gene', '56339', (46, 52))	('METTL3', 'Gene', (46, 52))	('m6A', 'Gene', '56339', (133, 136))	('LINC00857', 'Gene', '439990', (165, 174))
9957	33680969	Then we explored whether m6A modification could affect LINC00857 RNA metabolism and found that knockdown of METTL3 led to lower expression of LINC00857 in SW1990 cells ( Figure 2E ).	('lower', 'NegReg', (122, 127))	('affect', 'Reg', (48, 54))	('RNA', 'cellular_component', 'GO:0005562', ('65', '68'))	('m6A', 'Gene', '56339', (25, 28))	('LINC00857', 'Gene', '439990', (142, 151))	('METTL3', 'Gene', '56339', (108, 114))	('LINC00857', 'Gene', '439990', (55, 64))	('knockdown', 'Var', (95, 104))	('RNA metabolism', 'biological_process', 'GO:0016070', ('65', '79'))	('SW1990', 'CellLine', 'CVCL:1723', (155, 161))	('METTL3', 'Gene', (108, 114))	('expression', 'MPA', (128, 138))	('LINC00857', 'Gene', (142, 151))	('m6A', 'Gene', (25, 28))	('LINC00857', 'Gene', (55, 64))
9959	33680969	The results indicated that LINC00857 showed lower RNA stability after silencing of METTL3 in SW1990 cells ( Figure 2F ).	('lower', 'NegReg', (44, 49))	('RNA stability', 'CPA', (50, 63))	('silencing', 'Var', (70, 79))	('METTL3', 'Gene', '56339', (83, 89))	('LINC00857', 'Gene', '439990', (27, 36))	('METTL3', 'Gene', (83, 89))	('SW1990', 'CellLine', 'CVCL:1723', (93, 99))	('RNA', 'cellular_component', 'GO:0005562', ('50', '53'))	('LINC00857', 'Gene', (27, 36))
9960	33680969	It was suggested that the m6A level of LINC00857 was higher in PC cells, and its modification in LINC00857 improved transcripts stability.	('higher', 'PosReg', (53, 59))	('improved', 'PosReg', (107, 115))	('modification', 'Var', (81, 93))	('LINC00857', 'Gene', (39, 48))	('LINC00857', 'Gene', '439990', (97, 106))	('m6A', 'Gene', (26, 29))	('transcripts stability', 'MPA', (116, 137))	('LINC00857', 'Gene', '439990', (39, 48))	('m6A', 'Gene', '56339', (26, 29))	('PC', 'Phenotype', 'HP:0002894', (63, 65))	('LINC00857', 'Gene', (97, 106))
9971	33680969	According to RIP assays, relative to the negative control (NC) group, miR-150-5p was the most increased miRNA in the group with LINC00857-overexpression ( Figure 4E ).	('miR-150-5p', 'Var', (70, 80))	('LINC00857', 'Gene', (128, 137))	('miR-150-5p', 'Chemical', '-', (70, 80))	('increased', 'PosReg', (94, 103))	('LINC00857', 'Gene', '439990', (128, 137))
9973	33680969	In comparison with the miR-NC group, LINC00857 enrichment was much higher in the miR-150-5p mimic group ( Figure 4G ).	('higher', 'PosReg', (67, 73))	('enrichment', 'MPA', (47, 57))	('LINC00857', 'Gene', (37, 46))	('miR-150-5p', 'Chemical', '-', (81, 91))	('LINC00857', 'Gene', '439990', (37, 46))	('miR-150-5p mimic', 'Var', (81, 97))
9974	33680969	It was indicated that LINC00857 and miR-150-5p were present in the same RNA-induced silencing complex.	('LINC00857', 'Gene', (22, 31))	('miR-150-5p', 'Var', (36, 46))	('miR-150-5p', 'Chemical', '-', (36, 46))	('LINC00857', 'Gene', '439990', (22, 31))	('RNA-induced silencing complex', 'cellular_component', 'GO:0016442', ('72', '101'))
9976	33680969	According to  Figure 4I , miR-150-5p mimic remarkably decreased the luciferase activity in the PC cells transfected with the wild-type (WT) LINC00857 sequence, while the luciferase activity showed no obvious alteration in cells transfected with the mutant (Mut) LINC00857.	('luciferase activity', 'molecular_function', 'GO:0050248', ('170', '189'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('170', '189'))	('LINC00857', 'Gene', (140, 149))	('activity', 'MPA', (79, 87))	('LINC00857', 'Gene', '439990', (140, 149))	('luciferase activity', 'molecular_function', 'GO:0047077', ('68', '87'))	('PC', 'Phenotype', 'HP:0002894', (95, 97))	('luciferase activity', 'molecular_function', 'GO:0045289', ('68', '87'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('68', '87'))	('decreased', 'NegReg', (54, 63))	('miR-150-5p mimic', 'Var', (26, 42))	('luciferase', 'Enzyme', (68, 78))	('miR-150-5p', 'Chemical', '-', (26, 36))	('luciferase activity', 'molecular_function', 'GO:0050397', ('68', '87'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('170', '189'))	('LINC00857', 'Gene', (262, 271))	('luciferase activity', 'molecular_function', 'GO:0050248', ('68', '87'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('170', '189'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('170', '189'))	('LINC00857', 'Gene', '439990', (262, 271))
9979	33680969	MiR-150-5p was down-expressed in PC tissues and cells ( Figures 5A, C ).	('PC', 'Phenotype', 'HP:0002894', (33, 35))	('down-expressed', 'NegReg', (15, 29))	('MiR-150-5p', 'Var', (0, 10))	('MiR-150-5p', 'Chemical', '-', (0, 10))
9980	33680969	Furthermore, Pearson correlation analysis revealed that miR-150-5p was moderately negative correlation with LINC00857 in PC tissues ( Figure 5B ).	('miR-150-5p', 'Var', (56, 66))	('miR-150-5p', 'Chemical', '-', (56, 66))	('LINC00857', 'Gene', '439990', (108, 117))	('PC', 'Phenotype', 'HP:0002894', (121, 123))	('LINC00857', 'Gene', (108, 117))	('negative', 'NegReg', (82, 90))
9981	33680969	As revealed from the results of CCK-8 and colony formation assays, miR-150-5p overexpression restricted PC cells proliferation ( Figures 5D, E ).	('restricted', 'NegReg', (93, 103))	('miR-150-5p', 'Var', (67, 77))	('CCK-8', 'Chemical', 'MESH:D012844', (32, 37))	('overexpression', 'PosReg', (78, 92))	('miR-150-5p', 'Chemical', '-', (67, 77))	('formation', 'biological_process', 'GO:0009058', ('49', '58'))	('PC', 'Phenotype', 'HP:0002894', (104, 106))
9982	33680969	In addition, the apoptotic rate of PC cells transfected with miR-150-5p mimic was increased ( Figure 5F ).	('apoptotic rate', 'CPA', (17, 31))	('miR-150-5p mimic', 'Var', (61, 77))	('PC', 'Phenotype', 'HP:0002894', (35, 37))	('increased', 'PosReg', (82, 91))	('miR-150-5p', 'Chemical', '-', (61, 71))
9983	33680969	Given the mentioned data, miR-150-5p was down-expressed in PC and inhibited the progression of PC cells.	('PC', 'Phenotype', 'HP:0002894', (95, 97))	('down-expressed', 'NegReg', (41, 55))	('miR-150-5p', 'Chemical', '-', (26, 36))	('inhibited', 'NegReg', (66, 75))	('miR-150-5p', 'Var', (26, 36))	('PC', 'Phenotype', 'HP:0002894', (59, 61))	('progression of', 'CPA', (80, 94))
9991	33680969	miR-150-5p mimic suppressed the luciferase activity of E2F3-WT, but not for the activity of E2F3-MUT ( Figure 7B ).	('luciferase activity', 'molecular_function', 'GO:0045289', ('32', '51'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('32', '51'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('32', '51'))	('miR-150-5p', 'Chemical', '-', (0, 10))	('luciferase activity', 'molecular_function', 'GO:0050248', ('32', '51'))	('luciferase', 'Enzyme', (32, 42))	('suppressed', 'NegReg', (17, 27))	('activity', 'MPA', (43, 51))	('luciferase activity', 'molecular_function', 'GO:0047077', ('32', '51'))	('miR-150-5p mimic', 'Var', (0, 16))	('E2F3-WT', 'Var', (55, 62))
9992	33680969	By detecting the mRNA and protein expression, it was discovered that the E2F3 expression in PC cells was inhibited by overexpressed miR-150-5p ( Figures 7C, D ).	('E2F3', 'Gene', (73, 77))	('expression', 'MPA', (78, 88))	('miR-150-5p', 'Var', (132, 142))	('inhibited', 'NegReg', (105, 114))	('PC', 'Phenotype', 'HP:0002894', (92, 94))	('miR-150-5p', 'Chemical', '-', (132, 142))	('overexpressed', 'PosReg', (118, 131))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))
9993	33680969	Thus, it was judged that miR-150-5p targeted E2F3.	('miR-150-5p', 'Var', (25, 35))	('targeted', 'Reg', (36, 44))	('E2F3', 'Gene', (45, 49))	('miR-150-5p', 'Chemical', '-', (25, 35))
9994	33680969	To identify E2F3 involved in PC progression, the prognostic role of E2F3 was analyzed via the GEPIA database, which showed that the overall survival rate (HR=1.5, p=0.063) and disease-free survival rate (HR=1.6, p=0.043) of PC patients with high expression of E2F3 were remarkably lower than those of low expression group ( Figures 8A, B ).	('lower', 'NegReg', (281, 286))	('PC', 'Phenotype', 'HP:0002894', (29, 31))	('disease-free survival rate', 'CPA', (176, 202))	('high expression', 'Var', (241, 256))	('PC', 'Phenotype', 'HP:0002894', (224, 226))	('patients', 'Species', '9606', (227, 235))	('E2F3', 'Gene', (260, 264))
9997	33680969	It was demonstrated that si-LINC00857-2 inhibited the expression of E2F3, while pc-E2F3 could improve the expression ( Figure 8H ).	('expression', 'MPA', (54, 64))	('si-LINC00857-2', 'Gene', '439990', (25, 39))	('inhibited', 'NegReg', (40, 49))	('expression', 'MPA', (106, 116))	('E2F3', 'Gene', (68, 72))	('improve', 'PosReg', (94, 101))	('pc-E2F3', 'Var', (80, 87))	('si-LINC00857-2', 'Gene', (25, 39))
10000	33680969	The mentioned results suggested that E2F3 is responsible for LINC00857-mediated progression of PC cells.	('E2F3', 'Var', (37, 41))	('LINC00857', 'Gene', (61, 70))	('PC', 'Phenotype', 'HP:0002894', (95, 97))	('responsible', 'Reg', (45, 56))	('LINC00857', 'Gene', '439990', (61, 70))
10003	33680969	Searching from GEPIA database, we found that high expression of LINC00857 was associated with poor prognosis in PC.	('LINC00857', 'Gene', (64, 73))	('LINC00857', 'Gene', '439990', (64, 73))	('high expression', 'Var', (45, 60))	('PC', 'Phenotype', 'HP:0002894', (112, 114))
10010	33680969	It was demonstrated that m6A alteration may have an impact on the targeted mRNA or miRNA and is related to the progression of various cancers.	('targeted mRNA or miRNA', 'MPA', (66, 88))	('m6A', 'Gene', '56339', (25, 28))	('related to', 'Reg', (96, 106))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('impact', 'Reg', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('m6A', 'Gene', (25, 28))	('alteration', 'Var', (29, 39))
10018	33680969	MiR-150-5p is reported to be downregulated in different cancers and acts as a tumor suppressor miRNA.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('MiR-150-5p', 'Var', (0, 10))	('MiR-150-5p', 'Chemical', '-', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('78', '94'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('tumor', 'Disease', (78, 83))	('downregulated', 'NegReg', (29, 42))
10020	33680969	In addition, miR-150-5p is reported to inhibit hepatoma cell migration and invasion by regulating MMP14.	('MMP', 'molecular_function', 'GO:0004235', ('98', '101'))	('MMP14', 'Gene', '4323', (98, 103))	('MMP14', 'Gene', (98, 103))	('invasion', 'CPA', (75, 83))	('inhibit', 'NegReg', (39, 46))	('hepatoma', 'Disease', (47, 55))	('miR-150-5p', 'Var', (13, 23))	('cell migration', 'biological_process', 'GO:0016477', ('56', '70'))	('hepatoma', 'Disease', 'MESH:D006528', (47, 55))	('regulating', 'Reg', (87, 97))	('miR-150-5p', 'Chemical', '-', (13, 23))
10021	33680969	Our findings revealed the importance of the association between LINC00857 and miR-150-5p in tumorigenesis.	('LINC00857', 'Gene', '439990', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('LINC00857', 'Gene', (64, 73))	('tumor', 'Disease', (92, 97))	('miR-150-5p', 'Chemical', '-', (78, 88))	('miR-150-5p', 'Var', (78, 88))	('association', 'Interaction', (44, 55))
10023	33680969	Using an online database, we predicted E2F3 as a potential target of miR-150-5p, which was affirmed by luciferase reporter assay.	('miR-150-5p', 'Chemical', '-', (69, 79))	('E2F3', 'Gene', (39, 43))	('miR-150-5p', 'Var', (69, 79))
10024	33680969	Furthermore, overexpression of miR-150-5p inhibited E2F3 mRNA and protein expression.	('miR-150-5p', 'Var', (31, 41))	('E2F3', 'Gene', (52, 56))	('miR-150-5p', 'Chemical', '-', (31, 41))	('overexpression', 'PosReg', (13, 27))	('inhibited', 'NegReg', (42, 51))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
10026	33680969	Previous studies have shown that E2F3 contributed to proliferation through regulating the cell cycle in NSCLC.	('regulating', 'Reg', (75, 85))	('E2F3', 'Var', (33, 37))	('NSCLC', 'Disease', (104, 109))	('cell cycle', 'CPA', (90, 100))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('cell cycle', 'biological_process', 'GO:0007049', ('90', '100'))
10029	33680969	Herein, it was indicated that E2F3 was a target of miR-150-5p, promoting PC cell proliferation.	('PC', 'Phenotype', 'HP:0002894', (73, 75))	('miR-150-5p', 'Var', (51, 61))	('promoting', 'PosReg', (63, 72))	('miR-150-5p', 'Chemical', '-', (51, 61))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('E2F3', 'Var', (30, 34))
10054	33193628	It has been reported that about 90% of the later stage pancreatic cancers have point mutations of KRAS, indicating that KRAS may be used as a diagnostic marker of PDAC.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (55, 73))	('point mutations', 'Var', (79, 94))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('PDAC', 'Chemical', '-', (163, 167))	('KRAS', 'Gene', (120, 124))	('KRAS', 'Gene', (98, 102))	('KRAS', 'Gene', '3845', (120, 124))	('KRAS', 'Gene', '3845', (98, 102))	('pancreatic cancers', 'Disease', 'MESH:D010190', (55, 73))	('pancreatic cancers', 'Disease', (55, 73))
10100	33193628	For instance, cellular adhesion molecules LICAM mediates the homologous interaction between the tumor and nerves and increases PNI to promote the development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('promote', 'PosReg', (134, 141))	('homologous interaction', 'MPA', (61, 83))	('tumor', 'Disease', (96, 101))	('PNI', 'MPA', (127, 130))	('LICAM', 'Var', (42, 47))	('cellular adhesion molecules', 'Protein', (14, 41))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
10105	33193628	This evidence supports our findings that there is a close relationship between GO:0006996 (organelle organization), hsa04060 (Cytokine-cytokine receptor interaction), and PDAC PNI.	('GO:0006996', 'Var', (79, 89))	('organelle organization', 'biological_process', 'GO:0006996', ('91', '113'))	('organelle', 'cellular_component', 'GO:0043226', ('91', '100'))	('hsa04060', 'Var', (116, 124))	('PDAC', 'Chemical', '-', (171, 175))
10106	33193628	In addition, some studies have shown that the activation of the NF- kappaB signaling pathway affects a wide range of biological processes, including immunity, inflammation, stress response, B cell development, and lymphoid organogenesis, while PNI in PDAC is associated with lymph node metastasis.	('associated with', 'Reg', (259, 274))	('PDAC', 'Chemical', '-', (251, 255))	('NF- kappaB', 'Gene', '4790', (64, 74))	('affects', 'Reg', (93, 100))	('organogenesis', 'biological_process', 'GO:0048513', ('223', '236'))	('biological processes', 'CPA', (117, 137))	('lymphoid organogenesis', 'CPA', (214, 236))	('B cell development', 'CPA', (190, 208))	('inflammation', 'Disease', 'MESH:D007249', (159, 171))	('signaling pathway', 'biological_process', 'GO:0007165', ('75', '92'))	('B cell development', 'biological_process', 'GO:0030183', ('190', '208'))	('inflammation', 'Disease', (159, 171))	('PDAC', 'Gene', (251, 255))	('activation', 'PosReg', (46, 56))	('inflammation', 'biological_process', 'GO:0006954', ('159', '171'))	('PNI', 'Var', (244, 247))	('lymph node', 'Disease', (275, 285))	('immunity', 'CPA', (149, 157))	('stress response', 'CPA', (173, 188))	('NF- kappaB', 'Gene', (64, 74))
10119	33193628	suggested that XPO1 inhibition can down-regulate the expression of miR-145 target pathways via up-regulating the expression of tumor suppressive miR-145, therefore leading to the inhibition of migration and proliferation of PDAC.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('expression', 'MPA', (113, 123))	('miR-145', 'Gene', '406937', (145, 152))	('miR-145', 'Gene', (67, 74))	('PDAC', 'Chemical', '-', (224, 228))	('tumor', 'Disease', (127, 132))	('inhibition', 'Var', (20, 30))	('migration', 'CPA', (193, 202))	('up-regulating', 'PosReg', (95, 108))	('miR-145', 'Gene', '406937', (67, 74))	('inhibition', 'NegReg', (179, 189))	('expression', 'MPA', (53, 63))	('down-regulate', 'NegReg', (35, 48))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('XPO1', 'Gene', '7514', (15, 19))	('XPO1', 'Gene', (15, 19))	('miR-145', 'Gene', (145, 152))
10121	33193628	developed some newly specific inhibitors of nuclear export targeting XPO1, which have been proven to inhibit the proliferation of pancreatic cancer cells and tumor invasion effectively.	('tumor', 'Disease', (158, 163))	('inhibit', 'NegReg', (101, 108))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('inhibitors', 'Var', (30, 40))	('XPO1', 'Gene', '7514', (69, 73))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (130, 147))	('XPO1', 'Gene', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('nuclear export', 'MPA', (44, 58))	('pancreatic cancer', 'Disease', (130, 147))	('proliferation', 'CPA', (113, 126))	('nuclear export', 'biological_process', 'GO:0051168', ('44', '58'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (130, 147))
10141	32767982	m6A RNA modification occurs by methylation of the sixth N atom of adenine (A) in mRNAs or ncRNAs.	('methylation', 'MPA', (31, 42))	('RNA modification', 'biological_process', 'GO:0009451', ('4', '20'))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('m6A', 'Var', (0, 3))	('adenine', 'Chemical', 'MESH:D000225', (66, 73))
10144	32767982	Recent studies have shown that m6A modification acts a vital role in the diagnosis, treatment and prognosis of cancer patients as well as in carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('carcinogenesis', 'Disease', 'MESH:D063646', (141, 155))	('modification', 'Var', (35, 47))	('m6A', 'Protein', (31, 34))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('patients', 'Species', '9606', (118, 126))	('carcinogenesis', 'Disease', (141, 155))
10147	32767982	m6A modification can affect ncRNA splicing and maturation involved in carcinogenesis (Table 1).	('m6A modification', 'Var', (0, 16))	('maturation', 'MPA', (47, 57))	('modification', 'Var', (4, 16))	('carcinogenesis', 'Disease', 'MESH:D063646', (70, 84))	('ncRNA splicing', 'MPA', (28, 42))	('carcinogenesis', 'Disease', (70, 84))	('affect', 'Reg', (21, 27))	('splicing', 'biological_process', 'GO:0045292', ('34', '42'))
10151	32767982	METTL3/14 depletion promotes myeloid differentiation and suppresses the progression of acute myeloid leukemia (AML).	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (87, 109))	('AML', 'Disease', 'MESH:D015470', (111, 114))	('myeloid differentiation', 'CPA', (29, 52))	('suppresses', 'NegReg', (57, 67))	('AML', 'Disease', (111, 114))	('promotes', 'PosReg', (20, 28))	('METTL3/14', 'Gene', (0, 9))	('METTL3/14', 'Gene', '56339;57721', (0, 9))	('depletion', 'Var', (10, 19))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (87, 109))	('AML', 'Phenotype', 'HP:0004808', (111, 114))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('acute myeloid leukemia', 'Disease', (87, 109))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (93, 109))
10155	32767982	FTO shares the motifs with Fe (II)- and 2-oxoglutarate-dependent oxygenase and is related to increased fat mass.	('oxygenase', 'molecular_function', 'GO:0016701', ('65', '74'))	('increased', 'PosReg', (93, 102))	('FTO', 'Var', (0, 3))	('fat', 'Gene', (103, 106))	('Fe (II)', 'Chemical', '-', (27, 34))	('fat', 'Gene', '2195', (103, 106))	('2-oxoglutarate', 'Chemical', 'MESH:D007656', (40, 54))
10159	32767982	YTHDF1 controls pre-crossing axon guidance in the spinal cord by regulating m6A-modified Robo3.1.	('pre', 'molecular_function', 'GO:0003904', ('16', '19'))	('axon guidance', 'biological_process', 'GO:0007411', ('29', '42'))	('Robo3.1', 'MPA', (89, 96))	('YTHDF1', 'Gene', '54915', (0, 6))	('m6A-modified', 'Var', (76, 88))	('axon', 'cellular_component', 'GO:0030424', ('29', '33'))	('YTHDF1', 'Gene', (0, 6))
10161	32767982	As is known to us, the dysregulation of miRNAs is involved in various bio-behaviors, such as mouse prenatal development, immune response, inflammatory response and carcinogenesis.	('dysregulation', 'Var', (23, 36))	('mouse', 'Species', '10090', (93, 98))	('miRNAs', 'Protein', (40, 46))	('carcinogenesis', 'Disease', 'MESH:D063646', (164, 178))	('carcinogenesis', 'Disease', (164, 178))	('immune response', 'biological_process', 'GO:0006955', ('121', '136'))	('inflammatory response', 'biological_process', 'GO:0006954', ('138', '159'))	('involved', 'Reg', (50, 58))
10163	32767982	METTL3 suppresses osteogenic processes by promoting the maturation of miR-7212-5p and downregulating its target fibroblast growth factor receptor 3 (FGFR3).	('miR-7212-5p', 'Chemical', '-', (70, 81))	('promoting', 'PosReg', (42, 51))	('downregulating', 'NegReg', (86, 100))	('FGFR', 'molecular_function', 'GO:0005007', ('149', '153'))	('fibroblast growth factor receptor 3', 'Gene', '2261', (112, 147))	('osteogenic processes', 'CPA', (18, 38))	('FGFR3', 'Gene', '2261', (149, 154))	('METTL3', 'Gene', (0, 6))	('suppresses', 'NegReg', (7, 17))	('miR-7212-5p', 'Var', (70, 81))	('FGFR3', 'Gene', (149, 154))	('fibroblast growth factor receptor 3', 'Gene', (112, 147))	('maturation', 'CPA', (56, 66))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('112', '136'))
10164	32767982	m6A methylation can modify the maturation of miRNAs involved in cell proliferation and tumorigenesis (Fig.	('miRNAs', 'MPA', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cell proliferation', 'CPA', (64, 82))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('tumor', 'Disease', (87, 92))	('methylation', 'Var', (4, 15))	('modify', 'Reg', (20, 26))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('m6A', 'Var', (0, 3))	('maturation', 'MPA', (31, 41))
10165	32767982	miR-25-3p acts as a pivotal role in pancreatic ductal adenocarcinoma (PDAC).	('PDAC', 'Phenotype', 'HP:0006725', (70, 74))	('miR-25-3p', 'Var', (0, 9))	('pancreatic ductal adenocarcinoma', 'Disease', (36, 68))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (36, 68))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (36, 68))	('PDAC', 'Chemical', '-', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('miR-25-3p', 'Chemical', '-', (0, 9))
10167	32767982	METTL3 also enhances the binding of pri-miR-221/222 with DGCR8 involved in the proliferation of bladder cancer.	('miR-221', 'Gene', '407006', (40, 47))	('binding', 'Interaction', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('DGCR8', 'Gene', (57, 62))	('miR-221', 'Gene', (40, 47))	('bladder cancer', 'Phenotype', 'HP:0009725', (96, 110))	('binding', 'molecular_function', 'GO:0005488', ('25', '32'))	('METTL3', 'Var', (0, 6))	('DGCR8', 'Gene', '54487', (57, 62))	('bladder cancer', 'Disease', 'MESH:D001749', (96, 110))	('bladder cancer', 'Disease', (96, 110))	('enhances', 'PosReg', (12, 20))
10168	32767982	m6A modification affects arsenite-induced carcinogenesis via modifying multiple miRNAs (miR-106b, miR-18a/b, miR-3607, miR-423, miR-30a, miR-320b/d/e).	('miR-18a/b', 'Gene', (98, 107))	('miR-106b', 'Gene', '406900', (88, 96))	('miR-3607', 'Gene', '100500805', (109, 117))	('miR-320b/d/e', 'Var', (137, 149))	('miR-30a', 'Gene', '407029', (128, 135))	('miR-423', 'Gene', (119, 126))	('carcinogenesis', 'Disease', 'MESH:D063646', (42, 56))	('arsenite-induced', 'MPA', (25, 41))	('arsenite', 'Chemical', 'MESH:C015001', (25, 33))	('affects', 'Reg', (17, 24))	('modification', 'Var', (4, 16))	('modifying', 'Reg', (61, 70))	('carcinogenesis', 'Disease', (42, 56))	('miR-106b', 'Gene', (88, 96))	('miR-423', 'Gene', '494335', (119, 126))	('miR-18a/b', 'Gene', '406953', (98, 107))	('miR-30a', 'Gene', (128, 135))	('miR-3607', 'Gene', (109, 117))
10172	32767982	LncRNAs, a subgroup of non-coding RNAs over 200 nucleotides in length can be modified by m6A methylation in cancer (Fig.	('m6A methylation', 'Var', (89, 104))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('modified', 'Reg', (77, 85))	('methylation', 'Var', (93, 104))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
10173	32767982	m6A methylation facilitates lncRNA X-inactive specific transcript (XIST)-mediated transcriptional repression.	('XIST', 'Gene', '7503', (67, 71))	('XIST', 'Gene', (67, 71))	('X-inactive specific transcript', 'Gene', (35, 65))	('X-inactive specific transcript', 'Gene', '7503', (35, 65))	('methylation', 'Var', (4, 15))	('facilitates', 'PosReg', (16, 27))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('m6A methylation', 'Var', (0, 15))
10174	32767982	YTHDC1 preferentially recognizes the m6A residues of XIST and RBM15/15B and participates in XIST-mediated gene silencing.	('XIST', 'Gene', '7503', (53, 57))	('XIST', 'Gene', '7503', (92, 96))	('YTHDC1', 'Gene', (0, 6))	('YTHDC1', 'Gene', '91746', (0, 6))	('participates', 'Reg', (76, 88))	('XIST', 'Gene', (53, 57))	('XIST', 'Gene', (92, 96))	('RBM15', 'Gene', '64783', (62, 67))	('m6A', 'Var', (37, 40))	('gene silencing', 'biological_process', 'GO:0016458', ('106', '120'))	('RBM15', 'Gene', (62, 67))	('preferentially', 'PosReg', (7, 21))
10189	32767982	ALKBH5 favors the invasion and metastasis of gastric cancer (GC) by demethylating lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1).	('ALKBH5', 'Gene', (0, 6))	('metastasis of gastric cancer', 'Disease', 'MESH:D013274', (31, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (45, 59))	('demethylating', 'Var', (68, 81))	('ALKBH5', 'Gene', '54890', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('GC', 'Phenotype', 'HP:0012126', (61, 63))	('metastasis of gastric cancer', 'Disease', (31, 59))	('favors', 'PosReg', (7, 13))	('NEAT1', 'Gene', '283131', (132, 137))	('invasion', 'CPA', (18, 26))	('lncRNA', 'MPA', (82, 88))	('NEAT1', 'Gene', (132, 137))
10192	32767982	Minigenes of ribosomes-circRNAs (Ribo-circRNAs) can facilitate protein translation in drosophila heads and circ-ZNF609 boosts protein translation and myoblasts cell proliferation.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('ZNF609', 'Gene', (112, 118))	('protein translation', 'biological_process', 'GO:0006412', ('63', '82'))	('drosophila', 'Species', '7227', (86, 96))	('boosts', 'PosReg', (119, 125))	('facilitate', 'PosReg', (52, 62))	('Minigenes', 'Var', (0, 9))	('ZNF609', 'Gene', '23060', (112, 118))	('protein translation', 'MPA', (126, 145))	('protein translation', 'MPA', (63, 82))	('cell proliferation', 'biological_process', 'GO:0008283', ('160', '178'))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('myoblasts cell proliferation', 'CPA', (150, 178))	('protein translation', 'biological_process', 'GO:0006412', ('126', '145'))
10194	32767982	Mammalian cells can recognize the m6A modification on circRNAs to inhibit innate immunity by abrogating immune gene activation and adjuvant activity.	('abrogating', 'NegReg', (93, 103))	('Mammalian', 'Species', '9606', (0, 9))	('adjuvant activity', 'CPA', (131, 148))	('immune gene activation', 'CPA', (104, 126))	('inhibit', 'NegReg', (66, 73))	('innate immunity', 'biological_process', 'GO:0045087', ('74', '89'))	('innate immunity', 'CPA', (74, 89))	('m6A', 'Var', (34, 37))
10195	32767982	In addition, the dysregulation of circRNAs is associated with the progression of multiple cancers, such as breast cancer, gastric cancer (GC), gallbladder cancer and cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('bladder cancer', 'Phenotype', 'HP:0009725', (147, 161))	('cancer', 'Disease', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('gallbladder cancer', 'Disease', 'MESH:D005706', (143, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('multiple cancers', 'Disease', 'MESH:D009369', (81, 97))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('associated', 'Reg', (46, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('dysregulation', 'Var', (17, 30))	('gastric cancer', 'Disease', (122, 136))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('multiple cancers', 'Disease', (81, 97))	('breast cancer', 'Disease', (107, 120))	('gallbladder cancer', 'Disease', (143, 161))	('cancer', 'Disease', (155, 161))	('circRNAs', 'Gene', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (130, 136))	('GC', 'Phenotype', 'HP:0012126', (138, 140))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', (114, 120))
10197	32767982	m6A modification can be involved in the progression of GC by regulating circRNA poliovirus receptor-related 3 (circPVRL3).	('regulating', 'Reg', (61, 71))	('involved', 'Reg', (24, 32))	('circRNA', 'MPA', (72, 79))	('GC', 'Phenotype', 'HP:0012126', (55, 57))	('poliovirus', 'Species', '138950', (80, 90))	('m6A', 'Var', (0, 3))
10199	32767982	miR-149-3p inhibits adipogenesis lineage differentiation and potentiates osteogenic lineage differentiation by targeting FTO.	('adipogenesis', 'biological_process', 'GO:0060612', ('20', '32'))	('inhibits', 'NegReg', (11, 19))	('potentiates', 'PosReg', (61, 72))	('miR-149-3p', 'Var', (0, 10))	('osteogenic lineage differentiation', 'CPA', (73, 107))	('miR-149-3p', 'Chemical', '-', (0, 10))	('adipogenesis', 'biological_process', 'GO:0045444', ('20', '32'))	('FTO', 'Gene', (121, 124))	('adipogenesis', 'MPA', (20, 32))
10204	32767982	miR-141 suppresses the proliferation of pancreatic cancer by forming the miR-141/IGF2BP2/P13K/Akt axis.	('P13K', 'Var', (89, 93))	('suppresses', 'NegReg', (8, 18))	('IGF2BP2', 'Gene', '10644', (81, 88))	('Akt', 'Gene', (94, 97))	('miR-141', 'Gene', '406933', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('IGF2BP2', 'Gene', (81, 88))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('proliferation', 'CPA', (23, 36))	('P13K', 'SUBSTITUTION', 'None', (89, 93))	('miR-141', 'Gene', (0, 7))	('Akt', 'Gene', '207', (94, 97))	('pancreatic cancer', 'Disease', (40, 57))	('miR-141', 'Gene', '406933', (0, 7))	('pancreatic cancer', 'Disease', 'MESH:D010190', (40, 57))	('miR-141', 'Gene', (73, 80))
10217	32767982	m6A methylation serves as new biomarkers for diagnosis and prognosis in cancer.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('methylation', 'Var', (4, 15))	('m6A', 'Protein', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('cancer', 'Disease', (72, 78))
10223	32767982	m6A methylation also participates in drug resistance and cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('methylation', 'Var', (4, 15))	('participates', 'Reg', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('drug resistance', 'CPA', (37, 52))	('drug resistance', 'Phenotype', 'HP:0020174', (37, 52))	('drug resistance', 'biological_process', 'GO:0009315', ('37', '52'))	('drug resistance', 'biological_process', 'GO:0042493', ('37', '52'))	('m6A methylation', 'Var', (0, 15))
10233	32767982	The interaction between m6A methylation and ncRNAs can impact the different life activities including cancer cell proliferation, invasion and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('interaction', 'Interaction', (4, 15))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cell proliferation', 'biological_process', 'GO:0008283', ('109', '127'))	('impact', 'Reg', (55, 61))	('methylation', 'Var', (28, 39))	('m6A', 'Protein', (24, 27))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))
10254	32266066	Inhibition of glycolysis but not mitochondrial metabolism leads to attenuation of PMCA function, cytotoxic calcium overload and cell death in PDAC cells.	('attenuation', 'NegReg', (67, 78))	('calcium', 'Chemical', 'MESH:D002118', (107, 114))	('PDAC', 'Chemical', '-', (142, 146))	('Inhibition of glycolysis', 'biological_process', 'GO:0045820', ('0', '24'))	('PDAC', 'Phenotype', 'HP:0006725', (142, 146))	('cell death', 'CPA', (128, 138))	('metabolism', 'biological_process', 'GO:0008152', ('47', '57'))	('cytotoxic', 'MPA', (97, 106))	('Inhibition', 'Var', (0, 10))	('PMCA', 'Protein', (82, 86))	('cell death', 'biological_process', 'GO:0008219', ('128', '138'))	('glycolysis', 'MPA', (14, 24))
10255	32266066	Moreover, reversal of the Warburg effect protects PMCA function in PDAC cells treated with glycolytic inhibitors.	('reversal', 'Var', (10, 18))	('PMCA function', 'MPA', (50, 63))	('PDAC', 'Phenotype', 'HP:0006725', (67, 71))	('PDAC', 'Chemical', '-', (67, 71))
10265	32266066	F16BP, the product of PFK1 activity also activates pyruvate kinase M2 (PKM2), responsible for the production of pyruvate, the final step of glycolysis, thus acting to drive glycolysis further.	('activates', 'PosReg', (41, 50))	('pyruvate kinase M2', 'Gene', (51, 69))	('glycolysis', 'MPA', (173, 183))	('pyruvate', 'Chemical', 'MESH:D019289', (112, 120))	('PKM2', 'Gene', '5315', (71, 75))	('pyruvate kinase M2', 'Gene', '5315', (51, 69))	('F16BP', 'Var', (0, 5))	('F16BP', 'Chemical', 'MESH:C029063', (0, 5))	('PFK', 'molecular_function', 'GO:0003872', ('22', '25'))	('glycolysis', 'biological_process', 'GO:0006096', ('140', '150'))	('pyruvate', 'Chemical', 'MESH:D019289', (51, 59))	('PFK1', 'Gene', '5214', (22, 26))	('glycolysis', 'biological_process', 'GO:0006096', ('173', '183'))	('PFK1', 'Gene', (22, 26))	('PKM2', 'Gene', (71, 75))
10267	32266066	F26BP is produced by phosphofructokinase-fructose-bisphosphatases (PFKFBs), which phosphorylate F6P to produce F26BP.	('F26BP', 'Var', (111, 116))	('F6P', 'Chemical', 'MESH:C027618', (96, 99))	('F26BP', 'Var', (0, 5))
10268	32266066	PFKFBs are bifunctional enzymes that also possess phosphatase activity and can, therefore, remove phosphate from F26BP to regenerate F6P.	('phosphatase', 'Enzyme', (50, 61))	('F6P', 'Chemical', 'MESH:C027618', (133, 136))	('phosphate', 'Chemical', 'MESH:D010710', (98, 107))	('PFKFBs', 'Gene', (0, 6))	('phosphatase activity', 'molecular_function', 'GO:0016791', ('50', '70'))	('remove phosphate', 'MPA', (91, 107))	('F26BP', 'Var', (113, 118))	('regenerate F6P', 'MPA', (122, 136))
10270	32266066	PFKFB3 is able to produce F26BP at a high rate and thus drives the Warburg effect.	('Warburg effect', 'CPA', (67, 81))	('PFKFB3', 'Gene', (0, 6))	('drives', 'PosReg', (56, 62))	('F26BP', 'Var', (26, 31))	('PFKFB3', 'Gene', '5209', (0, 6))
10271	32266066	Under hypoxic conditions, this kinase:phosphatase activity can be increased up to 3000-fold following phosphorylation at Ser460 by PKA or AMPK.	('Ser460', 'Chemical', '-', (121, 127))	('Ser460', 'Var', (121, 127))	('AMPK', 'molecular_function', 'GO:0050405', ('138', '142'))	('increased', 'PosReg', (66, 75))	('AMPK', 'molecular_function', 'GO:0004691', ('138', '142'))	('PKA', 'molecular_function', 'GO:0004691', ('131', '134'))	('phosphatase activity', 'MPA', (38, 58))	('AMPK', 'molecular_function', 'GO:0047322', ('138', '142'))	('Ser', 'cellular_component', 'GO:0005790', ('121', '124'))	('PKA', 'cellular_component', 'GO:0005952', ('131', '134'))	('AMPK', 'Gene', '5562', (138, 142))	('AMPK', 'Gene', (138, 142))	('phosphorylation', 'biological_process', 'GO:0016310', ('102', '117'))	('phosphatase activity', 'molecular_function', 'GO:0016791', ('38', '58'))
10316	32266066	Glycolytic ATP is required for PMCA function; inhibition of glycolysis using iodoacetate (IAA) and bromopyruvate (BrPy) causes cytotoxic calcium overload and cell death in PDAC cells.	('inhibition', 'Var', (46, 56))	('inhibition of glycolysis', 'biological_process', 'GO:0045820', ('46', '70'))	('PDAC', 'Chemical', '-', (172, 176))	('cytotoxic calcium overload', 'MPA', (127, 153))	('BrPy', 'Chemical', 'MESH:C017092', (114, 118))	('cell death', 'CPA', (158, 168))	('glycolysis', 'MPA', (60, 70))	('ATP', 'Chemical', 'MESH:D000255', (11, 14))	('bromopyruvate', 'Chemical', 'MESH:C017092', (99, 112))	('iodoacetate', 'Chemical', 'MESH:D007461', (77, 88))	('calcium', 'Chemical', 'MESH:D002118', (137, 144))	('cell death', 'biological_process', 'GO:0008219', ('158', '168'))	('PDAC', 'Phenotype', 'HP:0006725', (172, 176))	('IAA', 'Chemical', 'MESH:D007461', (90, 93))
10328	32266066	MIA PaCa-2 cells were selected going forward, these cells have high PFKFB3 expression, high growth rate and have been identified as highly glycolytic in comparison to other PDAC cell lines; they also express mutant p53 and mutant K-RAS, the most common mutations in PDAC.	('PDAC', 'Phenotype', 'HP:0006725', (266, 270))	('K-RAS', 'Gene', (230, 235))	('mutant', 'Var', (223, 229))	('PDAC', 'Phenotype', 'HP:0006725', (173, 177))	('PFKFB3', 'Gene', (68, 74))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (0, 10))	('mutant', 'Var', (208, 214))	('p53', 'Gene', (215, 218))	('p53', 'Gene', '7157', (215, 218))	('PFKFB3', 'Gene', '5209', (68, 74))	('PDAC', 'Chemical', '-', (266, 270))	('PDAC', 'Chemical', '-', (173, 177))	('express', 'Reg', (200, 207))	('high', 'PosReg', (63, 67))	('K-RAS', 'Gene', '3845', (230, 235))	('expression', 'MPA', (75, 85))
10339	32266066	When 10 muM PFK15 was added for 30 min between clearance phases, a significant reduction of clearance rate was observed in MIA PaCa-2 but not HPSCs when compared with time-matched controls (R2/R1 = 0.52 +- 0.04 (n = 5) and 0.76 +- 0.06 (n = 4) respectively, Fig.	('MIA', 'Var', (123, 126))	('PFK1', 'Gene', '5214', (12, 16))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (123, 133))	('muM', 'Gene', '56925', (8, 11))	('PFK1', 'Gene', (12, 16))	('PFK', 'molecular_function', 'GO:0003872', ('12', '15'))	('muM', 'Gene', (8, 11))	('clearance rate', 'MPA', (92, 106))	('reduction', 'NegReg', (79, 88))
10359	32266066	Previous work leading to this study demonstrated that glycolytic inhibitors, but not mitochondrial inhibitors cause significant global ATP depletion and the consequent inhibition of PMCA activity and calcium overload.	('global ATP depletion', 'MPA', (128, 148))	('calcium', 'Chemical', 'MESH:D002118', (200, 207))	('activity', 'MPA', (187, 195))	('PMCA', 'Enzyme', (182, 186))	('inhibition', 'NegReg', (168, 178))	('glycolytic inhibitors', 'Var', (54, 75))	('ATP', 'Chemical', 'MESH:D000255', (135, 138))	('calcium overload', 'MPA', (200, 216))
10383	32266066	Increasing the ATP demand of Na+/K+ ATPases causes an increase in glycolysis but not OXPHOS, whilst inhibition of Na+/K+ ATPases has the opposite effect on glycolysis.	('glycolysis', 'biological_process', 'GO:0006096', ('66', '76'))	('Na+/K+', 'Var', (29, 35))	('increase', 'PosReg', (54, 62))	('OXPHOS', 'biological_process', 'GO:0002082', ('85', '91'))	('glycolysis', 'biological_process', 'GO:0006096', ('156', '166'))	('ATP demand', 'MPA', (15, 25))	('ATP', 'Chemical', 'MESH:D000255', (121, 124))	('glycolysis', 'MPA', (66, 76))	('ATP', 'Chemical', 'MESH:D000255', (15, 18))	('ATP', 'Chemical', 'MESH:D000255', (36, 39))
10395	32266066	Inhibition of PFKFB3 in the PDAC cell line MIA PaCa-2 causes inhibition of PMCA function, which leads to cytotoxic calcium overload and cell death.	('cell death', 'CPA', (136, 146))	('cell death', 'biological_process', 'GO:0008219', ('136', '146'))	('calcium', 'Chemical', 'MESH:D002118', (115, 122))	('PDAC', 'Chemical', '-', (28, 32))	('inhibition', 'NegReg', (61, 71))	('leads to', 'Reg', (96, 104))	('PDAC', 'Phenotype', 'HP:0006725', (28, 32))	('PFKFB3', 'Gene', (14, 20))	('PMCA', 'Protein', (75, 79))	('Inhibition', 'Var', (0, 10))	('function', 'MPA', (80, 88))	('PFKFB3', 'Gene', '5209', (14, 20))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (43, 53))	('cytotoxic calcium overload', 'MPA', (105, 131))
10413	31533487	Second, there are no therapies targeting the most prevalent mutations in the disease, such as KRAS, CDKN2A, TP53, and SMAD4 mutations.	('SMAD4', 'Gene', (118, 123))	('mutations', 'Var', (124, 133))	('KRAS', 'Gene', (94, 98))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('KRAS', 'Gene', '3845', (94, 98))	('SMAD4', 'Gene', '4089', (118, 123))	('CDKN2A', 'Gene', (100, 106))	('CDKN2A', 'Gene', '1029', (100, 106))
10434	31533487	later performed PCR to detect KRAS mutations in the cfDNA of plasma from 3 pancreatic ductal adenocarcinoma (PDAC) patients.	('patients', 'Species', '9606', (115, 123))	('PDAC', 'Phenotype', 'HP:0006725', (109, 113))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (75, 107))	('pancreatic ductal adenocarcinoma', 'Disease', (75, 107))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (75, 107))	('KRAS', 'Gene', (30, 34))	('KRAS', 'Gene', '3845', (30, 34))	('mutations', 'Var', (35, 44))
10435	31533487	More recently, several groups have attempted to validate the clinical utility of mutation detection in the cfDNA of PDAC patients.	('PDAC', 'Phenotype', 'HP:0006725', (116, 120))	('mutation', 'Var', (81, 89))	('cfDNA', 'Disease', (107, 112))	('PDAC', 'Disease', (116, 120))	('patients', 'Species', '9606', (121, 129))
10436	31533487	For instance, Kinugasa et al., using ddPCR, observed KRAS mutations in 62.5% of serum samples from 75 pancreatic cancer patients in all stages of disease and found that these mutations were correlated with worse overall survival (OS).	('mutations', 'Var', (58, 67))	('observed', 'Reg', (44, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('mutations', 'Var', (175, 184))	('KRAS', 'Gene', (53, 57))	('patients', 'Species', '9606', (120, 128))	('overall survival', 'MPA', (212, 228))	('KRAS', 'Gene', '3845', (53, 57))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
10443	31533487	combined KRAS mutation detection in ctDNA and a library of cancer-associated protein biomarkers (including CA19-9, CEA, HGF, OPN) in assessing 221 patients with resectable PDAC and 182 healthy donors.	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('CA19-9', 'Chemical', 'MESH:C086528', (107, 113))	('HGF', 'Gene', (120, 123))	('KRAS', 'Gene', (9, 13))	('CEA', 'Gene', (115, 118))	('OPN', 'Gene', '6696', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('CEA', 'Gene', '1084', (115, 118))	('HGF', 'Gene', '3082', (120, 123))	('mutation', 'Var', (14, 22))	('OPN', 'Gene', (125, 128))	('KRAS', 'Gene', '3845', (9, 13))	('patients', 'Species', '9606', (147, 155))	('PDAC', 'Phenotype', 'HP:0006725', (172, 176))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
10445	31533487	in the same group used PCR based Safe Sequencing System assays to detect KRAS mutations from 42 patients using matched plasma samples prior and after operations from pancreatic cancer patients (in early stages).	('KRAS', 'Gene', (73, 77))	('KRAS', 'Gene', '3845', (73, 77))	('patients', 'Species', '9606', (184, 192))	('pancreatic cancer', 'Disease', (166, 183))	('mutations', 'Var', (78, 87))	('pancreatic cancer', 'Disease', 'MESH:D010190', (166, 183))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (166, 183))
10446	31533487	They found KRAS mutation in 38 patients (90.5%), with detected KRAS (i.e.	('KRAS', 'Gene', (11, 15))	('mutation', 'Var', (16, 24))	('KRAS', 'Gene', '3845', (63, 67))	('found', 'Reg', (5, 10))	('KRAS', 'Gene', '3845', (11, 15))	('patients', 'Species', '9606', (31, 39))	('KRAS', 'Gene', (63, 67))
10464	31533487	found that ultrasensitive droplet digital PCR (ddPCR) of exoDNA had higher rates of KRAS mutation detection (67%, 80%, and 85%) than did ddPCR of paired ctDNA (46%, 31%, and 58%) in patients with localized, locally advanced, and metastatic PDAC, respectively.	('mutation', 'Var', (89, 97))	('metastatic PDAC', 'Disease', (229, 244))	('locally advanced', 'Disease', (207, 223))	('KRAS', 'Gene', (84, 88))	('localized', 'Disease', (196, 205))	('KRAS', 'Gene', '3845', (84, 88))	('PDAC', 'Phenotype', 'HP:0006725', (240, 244))	('patients', 'Species', '9606', (182, 190))
10466	31533487	used ddPCR to detect KRAS and TP53 mutations in patients with PDAC (40% and 4%, respectively), chronic pancreatitis (5/9 KRAS and no TP53), and intraductal papillary mucinous neoplasias (2/7 KRAS and 1/7 both).	('pancreatitis', 'Phenotype', 'HP:0001733', (103, 115))	('mucinous neoplasias', 'Phenotype', 'HP:0031495', (166, 185))	('PDAC', 'Phenotype', 'HP:0006725', (62, 66))	('pancreatitis', 'Disease', 'MESH:D010195', (103, 115))	('TP53', 'Gene', (30, 34))	('KRAS', 'Gene', '3845', (121, 125))	('pancreatitis', 'Disease', (103, 115))	('KRAS', 'Gene', '3845', (191, 195))	('papillary mucinous neoplasias', 'Disease', (156, 185))	('TP53', 'Gene', '7157', (133, 137))	('neoplasias', 'Phenotype', 'HP:0002664', (175, 185))	('KRAS', 'Gene', (121, 125))	('KRAS', 'Gene', (191, 195))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (95, 115))	('PDAC', 'Disease', (62, 66))	('TP53', 'Gene', '7157', (30, 34))	('papillary mucinous neoplasias', 'Disease', 'MESH:C565310', (156, 185))	('KRAS', 'Gene', '3845', (21, 25))	('KRAS', 'Gene', (21, 25))	('patients', 'Species', '9606', (48, 56))	('TP53', 'Gene', (133, 137))	('mutations', 'Var', (35, 44))
10467	31533487	Both of these studies found circulating mutant molecules in the apparently healthy population, which suggests that there is a "baseline" rate of circulating mutant molecules that is present in the aging population, either from clonal hematopoiesis or possibly, an occult neoplasm (Table 1).	('mutant molecules', 'Var', (157, 173))	('hematopoiesis', 'biological_process', 'GO:0030097', ('232', '245'))	('hematopoiesis', 'Disease', (234, 247))	('aging', 'biological_process', 'GO:0007568', ('195', '200'))	('neoplasm', 'Disease', 'MESH:D009369', (271, 279))	('neoplasm', 'Phenotype', 'HP:0002664', (271, 279))	('hematopoiesis', 'Disease', 'MESH:C536227', (234, 247))	('neoplasm', 'Disease', (271, 279))
10470	31533487	Subjecting 173 samples from 103 PDAC patients to ddPCR, the authors detected KRAS mutations in the exosomes of 44% of patients using ultracentrifugation (UC) versus in 73% of cases using a pull-down method with antibodies against these surface proteins as "bait" for exosome separation.	('PDAC', 'Phenotype', 'HP:0006725', (32, 36))	('exosome', 'cellular_component', 'GO:0070062', ('265', '272'))	('patients', 'Species', '9606', (37, 45))	('mutations', 'Var', (82, 91))	('KRAS', 'Gene', (77, 81))	('detected', 'Reg', (68, 76))	('KRAS', 'Gene', '3845', (77, 81))	('patients', 'Species', '9606', (118, 126))
10472	31533487	The authors demonstrated both the prognostic and predictive utility of measuring mutant nucleic acid in pancreatic cancer liquid biopsies.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('mutant nucleic acid', 'Var', (81, 100))	('pancreatic cancer', 'Disease', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('nucleic acid', 'cellular_component', 'GO:0005561', ('88', '100'))
10502	31533487	used ScreenCell filtration to isolate CTCs from 58 PDAC patients and used ddPCR to detect KRAS mutations in CTCs of 42/58 patients.	('patients', 'Species', '9606', (56, 64))	('KRAS', 'Gene', (90, 94))	('KRAS', 'Gene', '3845', (90, 94))	('patients', 'Species', '9606', (122, 130))	('PDAC', 'Phenotype', 'HP:0006725', (51, 55))	('mutations', 'Var', (95, 104))
10504	31533487	They reported that 42% (11 of 26 patients) of the solid tissues and matched CTCs had a discordant KRAS mutation status.	('mutation', 'Var', (103, 111))	('KRAS', 'Gene', '3845', (98, 102))	('patients', 'Species', '9606', (33, 41))	('KRAS', 'Gene', (98, 102))
10530	31428515	Mice deficient in Padi4 demonstrate decreased pancreatic tumor growth, associated with a reduction in circulating extracellular DNA levels, diminished pancreatic stromal activation and improved survival in murine orthotopic pancreatic adenocarcinoma.	('Padi4', 'Gene', (18, 23))	('improved', 'PosReg', (185, 193))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (224, 249))	('pancreatic adenocarcinoma', 'Disease', (224, 249))	('pancreatic', 'Disease', (46, 56))	('Mice', 'Species', '10090', (0, 4))	('murine', 'Species', '10090', (206, 212))	('Padi4', 'Gene', '18602', (18, 23))	('deficient', 'Var', (5, 14))	('extracellular', 'cellular_component', 'GO:0005576', ('114', '127'))	('pancreatic tumor', 'Disease', (46, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('pancreatic tumor', 'Disease', 'MESH:D010190', (46, 62))	('pancreatic', 'Disease', 'MESH:D010195', (224, 234))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (46, 62))	('reduction', 'NegReg', (89, 98))	('pancreatic', 'Disease', 'MESH:D010195', (151, 161))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (224, 249))	('survival', 'CPA', (194, 202))	('pancreatic', 'Disease', 'MESH:D010195', (46, 56))	('pancreatic', 'Disease', (224, 234))	('diminished', 'NegReg', (140, 150))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('circulating extracellular DNA levels', 'MPA', (102, 138))	('pancreatic', 'Disease', (151, 161))	('decreased', 'NegReg', (36, 45))
10534	31428515	Furthermore, deletion of the receptor for advanced glycation end products (RAGE) in pancreatic stellate cells abrogates the effects of DNA in promoting stellate cell proliferation and decreases tumor growth.	('stellate cell proliferation', 'CPA', (152, 179))	('decreases tumor', 'Disease', (184, 199))	('abrogates', 'NegReg', (110, 119))	('promoting', 'PosReg', (142, 151))	('RAGE', 'Gene', '11596', (75, 79))	('receptor for advanced glycation end products', 'Gene', '11596', (29, 73))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('RAGE', 'Gene', (75, 79))	('cell proliferation', 'biological_process', 'GO:0008283', ('161', '179'))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('deletion', 'Var', (13, 21))	('receptor for advanced glycation end products', 'Gene', (29, 73))	('pancreatic stellate', 'Disease', 'MESH:D010195', (84, 103))	('pancreatic stellate', 'Disease', (84, 103))	('decreases tumor', 'Disease', 'MESH:D009369', (184, 199))
10555	31428515	To confirm that genetic knockdown of Padi4 resulted in decreased NETs, we performed immunofluorescence staining of tumor specimens for citrullinated histone H3 (Cit H3), which is formed during the release of NETs when PADI4 citrullinates histones to allow for unwinding and subsequent expulsion from the neutrophil.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Padi4', 'Gene', '18602', (37, 42))	('tumor', 'Disease', (115, 120))	('decreased', 'NegReg', (55, 64))	('Cit', 'biological_process', 'GO:0106106', ('161', '164'))	('citrullinated histone H3', 'Chemical', '-', (135, 159))	('unwinding', 'MPA', (260, 269))	('NETs', 'MPA', (65, 69))	('Padi4', 'Gene', (37, 42))	('knockdown', 'Var', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
10579	31428515	On day 14 post-tumor inoculation, tumor volume in Panc02 plus PSC group was 75.4 +- 17.0 compared to 20.4 +- 4.86 in tumor cell alone group, p = .002.	('Panc02', 'CellLine', 'CVCL:D627', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Panc02', 'Var', (50, 56))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
10599	31428515	There are several inhibitors of PADI4 that have been shown to inhibit mouse and human PADI4 and NET formation that warrant further exploration.	('PADI4', 'Gene', (86, 91))	('mouse', 'Species', '10090', (70, 75))	('NET formation', 'CPA', (96, 109))	('PADI4', 'Gene', (32, 37))	('human', 'Species', '9606', (80, 85))	('formation', 'biological_process', 'GO:0009058', ('100', '109'))	('inhibit', 'NegReg', (62, 69))	('inhibitors', 'Var', (18, 28))
10606	31428515	We have also previously shown that neutrophil depletion results in decreased DNA in tumor-bearing mice.	('DNA', 'MPA', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('neutrophil depletion', 'Var', (35, 55))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('decreased', 'NegReg', (67, 76))	('mice', 'Species', '10090', (98, 102))
10623	31428515	PADI4 inhibition and DNase administration may be novel therapeutic interventions in pancreatic cancer patients.	('PADI4', 'Protein', (0, 5))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (84, 101))	('patients', 'Species', '9606', (102, 110))	('pancreatic cancer', 'Disease', (84, 101))	('inhibition', 'Var', (6, 16))	('pancreatic cancer', 'Disease', 'MESH:D010190', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
10691	30144430	Post-translational and epigenetics changes are widely involved in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Post-translational', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('epigenetics changes', 'Var', (23, 42))	('cancer', 'Disease', (66, 72))
10695	30144430	The EMT transcription factor Zeb1 expression is associated with the mesenchymal phenotype in PDAC cells and inhibition of GSK3B induces EMT.	('EMT', 'biological_process', 'GO:0001837', ('136', '139'))	('inhibition of GSK', 'biological_process', 'GO:1902948', ('108', '125'))	('EMT', 'biological_process', 'GO:0001837', ('4', '7'))	('associated', 'Reg', (48, 58))	('transcription', 'biological_process', 'GO:0006351', ('8', '21'))	('GSK3B', 'Gene', (122, 127))	('induces', 'PosReg', (128, 135))	('Zeb1', 'Gene', '21417', (29, 33))	('GSK', 'molecular_function', 'GO:0050321', ('122', '125'))	('Zeb1', 'Gene', (29, 33))	('transcription factor', 'molecular_function', 'GO:0000981', ('8', '28'))	('inhibition', 'Var', (108, 118))	('PD', 'Disease', 'MESH:D010300', (93, 95))	('EMT', 'CPA', (136, 139))
10699	30144430	With this background, we hypothesized that co-targeting GSK3B and HDAC would not only increase killing of the cancer and prevent their resistance to apoptosis, but would also inhibit pro-EMT/metastasis and drug resistance.	('inhibit', 'NegReg', (175, 182))	('increase', 'PosReg', (86, 94))	('HDAC', 'Gene', (66, 70))	('drug resistance', 'CPA', (206, 221))	('apoptosis', 'biological_process', 'GO:0097194', ('149', '158'))	('apoptosis', 'biological_process', 'GO:0006915', ('149', '158'))	('pro-EMT/metastasis', 'CPA', (183, 201))	('cancer', 'Disease', (110, 116))	('co-targeting', 'Var', (43, 55))	('resistance to apoptosis', 'MPA', (135, 158))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('drug resistance', 'biological_process', 'GO:0009315', ('206', '221'))	('drug resistance', 'biological_process', 'GO:0042493', ('206', '221'))	('drug resistance', 'Phenotype', 'HP:0020174', (206, 221))	('killing', 'CPA', (95, 102))	('EMT', 'biological_process', 'GO:0001837', ('187', '190'))	('prevent', 'NegReg', (121, 128))	('GSK3B', 'Gene', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('GSK', 'molecular_function', 'GO:0050321', ('56', '59'))
10702	30144430	Our studies show that metavert increased the survival of mice in both models and prevented metastasis by affecting both tumor cells' proliferation, metabolic profiles, and different markers of advanced cancer without affecting healthy organs.	('prevented', 'NegReg', (81, 90))	('mice', 'Species', '10090', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('increased', 'PosReg', (31, 40))	('affecting', 'Reg', (105, 114))	('metabolic profiles', 'MPA', (148, 166))	('metastasis', 'CPA', (91, 101))	('survival', 'CPA', (45, 53))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('metavert', 'Var', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Disease', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
10739	30144430	At least two HDACs including HDAC4 and HDAC7 as well as the phosphorylated form of HDAC7 are highly present in pancreatic tumor tissues of KPC mice compared to pancreatic normal tissues from mice of the same background (Fig.	('KPC', 'Var', (139, 142))	('HDAC4', 'Gene', (29, 34))	('HDAC7', 'Gene', '56233', (83, 88))	('HDAC7', 'Gene', (83, 88))	('pancreatic tumor', 'Disease', 'MESH:D010190', (111, 127))	('HDAC4', 'Gene', '208727', (29, 34))	('mice', 'Species', '10090', (191, 195))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (111, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('HDAC7', 'Gene', '56233', (39, 44))	('pancreatic tumor', 'Disease', (111, 127))	('HDAC7', 'Gene', (39, 44))	('mice', 'Species', '10090', (143, 147))
10765	30144430	3D) suggesting that metavert will not only increase the cancer cell killing effect of chemotherapies as shown earlier, but will also prevent resistance that develops with other chemotherapeutic agents.	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('prevent', 'NegReg', (133, 140))	('cell killing', 'biological_process', 'GO:0001906', ('63', '75'))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('resistance', 'CPA', (141, 151))	('increase', 'PosReg', (43, 51))	('cancer', 'Disease', (56, 62))	('metavert', 'Var', (20, 28))
10769	30144430	Quantitative results of cell-by cell high-content analysis prove that metavert induced a 62% greater abundance of H3K9Ac, and in conjunction, an increase in H3K9Ac/DAPI co-localization (indicated by the angle of the co-localization slope: delta=4.2  versus delta=22.7 ) on average across exposed cells (Fig.	('H3K9Ac/DAPI', 'Protein', (157, 168))	('metavert', 'Var', (70, 78))	('increase', 'PosReg', (145, 153))	('greater', 'PosReg', (93, 100))	('localization', 'biological_process', 'GO:0051179', ('172', '184'))	('H3K9Ac', 'Protein', (114, 120))	('H3K9Ac', 'Chemical', 'MESH:C024755', (157, 163))	('co-localization', 'MPA', (169, 184))	('localization', 'biological_process', 'GO:0051179', ('219', '231'))	('H3K9Ac', 'Chemical', 'MESH:C024755', (114, 120))
10770	30144430	Representative scatter plots of individual cells indicate that H3K9Ac/DAPI co-localization slope was significantly increased by metavert (Fig.	('metavert', 'Var', (128, 136))	('increased', 'PosReg', (115, 124))	('H3K9Ac/DAPI', 'Protein', (63, 74))	('H3K9Ac', 'Chemical', 'MESH:C024755', (63, 69))	('co-localization slope', 'MPA', (75, 96))
10779	30144430	Metavert significantly improved the survival of KPC mice compared to control-treated KPC mice.	('mice', 'Species', '10090', (89, 93))	('mice', 'Species', '10090', (52, 56))	('improved', 'PosReg', (23, 31))	('KPC', 'Var', (48, 51))	('survival', 'CPA', (36, 44))
10782	30144430	The average tumor weight at the time of death was decreased by metavert by 50% (Fig.	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('decreased', 'NegReg', (50, 59))	('tumor', 'Disease', (12, 17))	('metavert', 'Var', (63, 71))
10813	30144430	To confirm the in vivo data in KPC mice we used a syngeneic model of PDAC by injecting the B6.129 mixed background mouse with mouse pancreatic cancer cells UN-KPC961-Luc expressing luciferase in the pancreas.	('mouse', 'Species', '10090', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('UN-KPC961-Luc', 'CellLine', 'CVCL:1U13', (156, 169))	('pancreatic cancer', 'Disease', (132, 149))	('mouse', 'Species', '10090', (115, 120))	('pancreatic cancer', 'Disease', 'MESH:D010190', (132, 149))	('UN-KPC961-Luc', 'Var', (156, 169))	('mice', 'Species', '10090', (35, 39))	('PD', 'Disease', 'MESH:D010300', (69, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 149))
10815	30144430	Imaging of the tumors after 3 weeks of treatment showed a decrease in tumor size in mice treated with metavert compared to control-treated mice (Fig.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('mice', 'Species', '10090', (84, 88))	('tumor', 'Disease', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('decrease', 'NegReg', (58, 66))	('tumor', 'Disease', (15, 20))	('mice', 'Species', '10090', (139, 143))	('metavert', 'Var', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumors', 'Disease', (15, 21))
10818	30144430	Pancreatic size showed significant decrease in metavert-treated mice compared to control group (60% decrease) (Fig.	('decrease', 'NegReg', (35, 43))	('metavert-treated', 'Var', (47, 63))	('Pancreatic size', 'CPA', (0, 15))	('mice', 'Species', '10090', (64, 68))
10831	30144430	The in vitro data showed an additive effect when combining HDAC-I/II and GSK3B inhibitors on preventing cancer cell survival.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('inhibitors', 'Var', (79, 89))	('GSK', 'molecular_function', 'GO:0050321', ('73', '76'))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('GSK3B', 'Gene', (73, 78))
10837	30144430	Metavert decreased complete glucose oxidation in the TCA cycle suggesting that it promotes alternate fatty acid substrate oxidation in mitochondria.	('TCA', 'Enzyme', (53, 56))	('promotes', 'PosReg', (82, 90))	('fatty acid', 'Chemical', 'MESH:D005227', (101, 111))	('mitochondria', 'cellular_component', 'GO:0005739', ('135', '147'))	('decreased', 'NegReg', (9, 18))	('complete glucose oxidation', 'MPA', (19, 45))	('Metavert', 'Var', (0, 8))	('TCA', 'Chemical', 'MESH:C000589078', (53, 56))	('glucose', 'Chemical', 'MESH:D005947', (28, 35))	('TCA cycle', 'biological_process', 'GO:0006099', ('53', '62'))
10838	30144430	In fact, glucose uptake was increased by metavert; however, the glucose metabolism was decreased most likely because of the use of glucose for glycogen synthesis instead of producing substrates for building blocks for proliferation and use in the TCA cycle.	('increased', 'PosReg', (28, 37))	('glucose uptake', 'MPA', (9, 23))	('decreased', 'NegReg', (87, 96))	('TCA', 'Chemical', 'MESH:C000589078', (247, 250))	('glucose uptake', 'biological_process', 'GO:0046323', ('9', '23'))	('glucose', 'Chemical', 'MESH:D005947', (131, 138))	('glucose', 'Chemical', 'MESH:D005947', (9, 16))	('glycogen synthesis', 'biological_process', 'GO:0005978', ('143', '161'))	('glucose metabolism', 'Disease', (64, 82))	('glucose', 'Chemical', 'MESH:D005947', (64, 71))	('TCA cycle', 'biological_process', 'GO:0006099', ('247', '256'))	('metavert', 'Var', (41, 49))	('glucose metabolism', 'biological_process', 'GO:0006006', ('64', '82'))	('glucose metabolism', 'Disease', 'MESH:D044882', (64, 82))
10848	30144430	Metavert altered not only tumor cell features, but also its microenvironment.	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('altered', 'Reg', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('Metavert', 'Var', (0, 8))
10859	30144430	Metavert shifts the phenotype of the cancer cells towards a more normal-like phenotype and promotes anti-tumor effects synergistically with current modes of therapy.	('promotes', 'PosReg', (91, 99))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('Metavert', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', (105, 110))
10991	28734735	Deregulated proliferation and growth factor release further influences blood vessel development, which is characterized by leaky vessels that inefficiently deliver nutrients and remove waste products of cellular metabolism, like lactate.	('influences', 'Reg', (60, 70))	('blood vessel development', 'biological_process', 'GO:0001568', ('71', '95'))	('blood vessel development', 'CPA', (71, 95))	('Deregulated', 'Var', (0, 11))	('cellular metabolism', 'biological_process', 'GO:0044237', ('203', '222'))	('lactate', 'Chemical', 'MESH:D019344', (229, 236))	('proliferation', 'CPA', (12, 25))	('lactate', 'MPA', (229, 236))
11018	28734735	Perhaps most importantly, co-targeting this pathway with anti-angiogenesis agents and mTOR inhibitors revealed new, unique vulnerabilities in cancer metabolism, which occurred in part by activating glucose uptake in normoxic cancer cells.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('co-targeting', 'Var', (26, 38))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('mTOR', 'Gene', '2475', (86, 90))	('vulnerabilities', 'MPA', (123, 138))	('glucose uptake', 'MPA', (198, 212))	('metabolism', 'biological_process', 'GO:0008152', ('149', '159'))	('mTOR', 'Gene', (86, 90))	('cancer', 'Disease', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('glucose uptake', 'biological_process', 'GO:0046323', ('198', '212'))	('glucose', 'Chemical', 'MESH:D005947', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('activating', 'PosReg', (187, 197))	('angiogenesis', 'biological_process', 'GO:0001525', ('62', '74'))	('cancer', 'Disease', (142, 148))
11048	28734735	And, genetic inhibition of autophagy in the PSCs blunts pancreatic tumor growth.	('genetic inhibition', 'Var', (5, 23))	('autophagy', 'CPA', (27, 36))	('autophagy', 'biological_process', 'GO:0016236', ('27', '36'))	('autophagy', 'biological_process', 'GO:0006914', ('27', '36'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (56, 72))	('PSCs blunts pancreatic tumor', 'Disease', (44, 72))	('PSCs blunts pancreatic tumor', 'Disease', 'MESH:D010190', (44, 72))
11078	28734735	First, local depletion of tryptophan by cancer cells and macrophages, through uptake and catabolism, suppresses antigen-specific T cell responses (Fig.	('uptake', 'biological_process', 'GO:0098739', ('78', '84'))	('suppresses', 'NegReg', (101, 111))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('depletion', 'Var', (13, 22))	('cancer', 'Disease', (40, 46))	('antigen-specific T cell responses', 'CPA', (112, 145))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tryptophan', 'Chemical', 'MESH:D014364', (26, 36))	('catabolism', 'biological_process', 'GO:0009056', ('89', '99'))	('uptake', 'biological_process', 'GO:0098657', ('78', '84'))
11088	28734735	The presence of arginine leads to arginine-sensor mediated activation of a gene expression program that enhances the bioenergetic profile of T cells, leading to a central memory like T cell state and improved anti-tumor activity.	('central memory', 'MPA', (163, 177))	('T cell state', 'MPA', (183, 195))	('arginine', 'Chemical', 'MESH:D001120', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('gene expression', 'Gene', (75, 90))	('arginine', 'Chemical', 'MESH:D001120', (34, 42))	('leading to', 'Reg', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('bioenergetic profile of', 'MPA', (117, 140))	('improved', 'PosReg', (200, 208))	('arginine-sensor', 'MPA', (34, 49))	('memory', 'biological_process', 'GO:0007613', ('171', '177'))	('tumor', 'Disease', (214, 219))	('arginine', 'Var', (16, 24))	('enhances', 'PosReg', (104, 112))	('activation', 'PosReg', (59, 69))	('gene expression', 'biological_process', 'GO:0010467', ('75', '90'))
11093	28734735	As these studies progress, it will be interesting to see whether manipulating the arginine concentration in the TME has a greater effect on cancer or T cell metabolism, both of which benefit from increased local arginine.	('increased', 'PosReg', (196, 205))	('T cell metabolism', 'CPA', (150, 167))	('arginine', 'Chemical', 'MESH:D001120', (82, 90))	('metabolism', 'biological_process', 'GO:0008152', ('157', '167'))	('arginine', 'Chemical', 'MESH:D001120', (212, 220))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('effect', 'Reg', (130, 136))	('manipulating', 'Var', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
11129	28734735	Gene signatures involved in anabolic glucose metabolism were significantly activated by acetylation.	('anabolic', 'MPA', (28, 36))	('activated', 'PosReg', (75, 84))	('glucose metabolism', 'biological_process', 'GO:0006006', ('37', '55'))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('acetylation', 'Var', (88, 99))	('Gene', 'MPA', (0, 4))
11130	28734735	It is tempting to speculate that these changes lead to increases in the Ac-CoA pools and thus act in a feed forward manner to potentiate an anabolic metabolic program.	('Ac-CoA pools', 'MPA', (72, 84))	('potentiate', 'PosReg', (126, 136))	('changes', 'Var', (39, 46))	('increases', 'PosReg', (55, 64))	('Ac-CoA', 'Chemical', 'MESH:D000105', (72, 78))	('anabolic metabolic program', 'MPA', (140, 166))
11143	28978057	Altered hyaluronoglucosaminidase 2 gene (HYAL2) DNA methylation in peripheral blood is known to be associated with malignancy at early stage but has not been evaluated in PDAC patients.	('patients', 'Species', '9606', (176, 184))	('hyaluronoglucosaminidase 2', 'Gene', '8692', (8, 34))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('malignancy', 'Disease', 'MESH:D009369', (115, 125))	('HYAL2', 'Gene', '8692', (41, 46))	('malignancy', 'Disease', (115, 125))	('methylation', 'Var', (52, 63))	('DNA methylation', 'biological_process', 'GO:0006306', ('48', '63'))	('hyaluronoglucosaminidase 2', 'Gene', (8, 34))	('HYAL2', 'Gene', (41, 46))	('associated', 'Reg', (99, 109))	('PDAC', 'Chemical', '-', (171, 175))
11145	28978057	Decreased methylation of all four investigated HYAL2 methylation sites showed highly significant association with PDAC (odds ratio (ORs) per -10% methylation ranging from 2.03 to 12.74, depending on the specific CpG site, p < 0.0001 for all).	('PDAC', 'Disease', (114, 118))	('methylation', 'MPA', (10, 21))	('Decreased', 'NegReg', (0, 9))	('HYAL2', 'Gene', (47, 52))	('PDAC', 'Chemical', '-', (114, 118))	('methylation', 'Var', (146, 157))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))	('HYAL2', 'Gene', '8692', (47, 52))	('methylation', 'biological_process', 'GO:0032259', ('146', '157'))
11158	28978057	Recently, inherited mutations in correlation with PDAC have gained focused attention, and a pathogenic BRCA1 and BRCA2 mutation was identified in a large cohort in 4.6% among pancreatic ductal adenocarcinoma patients.	('mutation', 'Var', (119, 127))	('patients', 'Species', '9606', (208, 216))	('BRCA1', 'Gene', '672', (103, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('pathogenic', 'Reg', (92, 102))	('BRCA1', 'Gene', (103, 108))	('pancreatic ductal adenocarcinoma', 'Disease', (175, 207))	('BRCA2', 'Gene', (113, 118))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (175, 207))	('PDAC', 'Chemical', '-', (50, 54))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (175, 207))	('BRCA2', 'Gene', '675', (113, 118))
11160	28978057	DNA methylation is described as one of the earliest and most common events in the process of cancer development, affecting control of gene transcription and the architecture of the cell nucleus.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('affecting', 'Reg', (113, 122))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('transcription', 'biological_process', 'GO:0006351', ('139', '152'))	('methylation', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cell nucleus', 'cellular_component', 'GO:0005634', ('181', '193'))	('control of gene transcription', 'MPA', (123, 152))
11161	28978057	Recent literature has reported the correlation between aberrant methylation of DNA from peripheral blood and multiple cancers, such as breast, ovarian, head and neck, as well as bladder cancer.	('ovarian', 'Disease', (143, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (178, 192))	('neck', 'cellular_component', 'GO:0044326', ('161', '165'))	('DNA', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('breast', 'Disease', (135, 141))	('multiple cancers', 'Disease', (109, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('bladder cancer', 'Disease', 'MESH:D001749', (178, 192))	('bladder cancer', 'Disease', (178, 192))	('aberrant methylation', 'Var', (55, 75))	('multiple cancers', 'Disease', 'MESH:D009369', (109, 125))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
11164	28978057	Whole exome sequencing discovered HYAL2 mutations in the recurrent B-cell lymphoma.	('HYAL2', 'Gene', '8692', (34, 39))	('lymphoma', 'Phenotype', 'HP:0002665', (74, 82))	('B-cell lymphoma', 'Disease', (67, 82))	('mutations', 'Var', (40, 49))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (67, 82))	('HYAL2', 'Gene', (34, 39))
11169	28978057	The HYAL2_CpG_3 site showed the most significantly lower methylation levels in PDAC cases than in controls (PDAC cases: median = 0.27 (inter quartile range (IQR) = 0.22-0.33); controls: median = 0.43 (IQR = 0.38-0.46); odds ratio (OR) per -10% methylation = 12.74, 95% C.I.	('methylation levels', 'MPA', (57, 75))	('HYAL2', 'Gene', '8692', (4, 9))	('PDAC', 'Chemical', '-', (79, 83))	('methylation', 'biological_process', 'GO:0032259', ('244', '255'))	('PDAC', 'Chemical', '-', (108, 112))	('lower', 'NegReg', (51, 56))	('HYAL2', 'Gene', (4, 9))	('methylation', 'Var', (244, 255))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('PDAC', 'Disease', (79, 83))
11199	28978057	Genetic analysis found several PDAC specific genes and identifies individuals with a germline mutation associated with predispositions for familial cancers.	('familial cancers', 'Disease', 'MESH:D009369', (139, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('associated', 'Reg', (103, 113))	('PDAC', 'Chemical', '-', (31, 35))	('familial cancers', 'Disease', (139, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('PDAC specific', 'Gene', (31, 44))	('germline mutation', 'Var', (85, 102))
11205	28978057	Here, we report HYAL2 hypomethylation in the blood of PDAC patients comparing to the healthy controls.	('PDAC', 'Disease', (54, 58))	('HYAL2', 'Gene', (16, 21))	('patients', 'Species', '9606', (59, 67))	('hypomethylation', 'Var', (22, 37))	('PDAC', 'Chemical', '-', (54, 58))	('HYAL2', 'Gene', '8692', (16, 21))
11206	28978057	It is possible that hypomethylation of HYAL2 may reflect a broader change in DNA methylation across many CpG sites in the genome that occurs in patients with certain cancer syndromes.	('DNA methylation', 'MPA', (77, 92))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('hypomethylation', 'Var', (20, 35))	('HYAL2', 'Gene', (39, 44))	('DNA methylation', 'biological_process', 'GO:0006306', ('77', '92'))	('cancer syndromes', 'Disease', 'MESH:D009369', (166, 182))	('patients', 'Species', '9606', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('HYAL2', 'Gene', '8692', (39, 44))	('cancer syndromes', 'Disease', (166, 182))	('change', 'Reg', (67, 73))
11210	28978057	In our previous study in breast cancer, we suggested that the change of leucocytes subpopulation proportion and the breast cancer associated differential HYAL2 methylation in leucocytes subpopulations (T cells and probably other cell types except B cells) are the main reasons for the origin of breast cancer associated differential methylation in blood.	('HYAL2', 'Gene', '8692', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('methylation', 'Var', (160, 171))	('breast cancer', 'Disease', (295, 308))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (295, 308))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('methylation', 'biological_process', 'GO:0032259', ('160', '171'))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (25, 38))	('HYAL2', 'Gene', (154, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('methylation', 'biological_process', 'GO:0032259', ('333', '344'))	('differential', 'Var', (141, 153))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('breast cancer', 'Disease', 'MESH:D001943', (295, 308))
11214	28978057	The mechanisms of cancer-related aberrant HYAL2 methylation in blood remain unknown.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('HYAL2', 'Gene', '8692', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('HYAL2', 'Gene', (42, 47))	('aberrant', 'Var', (33, 41))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
11216	28978057	Very recently, copy number variation in the gene region of HYAL2 was reported to be associated with diffuse large B-cell lymphoma, indicating that HYAL2 is functional in the malignancy of B cells.	('copy number variation', 'Var', (15, 36))	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('malignancy', 'Disease', (174, 184))	('HYAL2', 'Gene', '8692', (59, 64))	('HYAL2', 'Gene', '8692', (147, 152))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (114, 129))	('associated', 'Reg', (84, 94))	('diffuse large B-cell lymphoma', 'Disease', (100, 129))	('HYAL2', 'Gene', (59, 64))	('lymphoma', 'Phenotype', 'HP:0002665', (121, 129))	('HYAL2', 'Gene', (147, 152))
11222	28978057	The combination of HYAL2 methylation and other markers, especially the markers representing different pathway or mechanism, might provide a even better panel for the detection of early PDAC, and might even be useful for sub-classification and prognosis.	('PDAC', 'Chemical', '-', (185, 189))	('HYAL2', 'Gene', (19, 24))	('early PDAC', 'Disease', (179, 189))	('methylation', 'Var', (25, 36))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('HYAL2', 'Gene', '8692', (19, 24))	('combination', 'Interaction', (4, 15))
11223	28978057	To highlight, this study disclosed the correlation between altered DNA methylation in whole blood (mainly from blood cells) and PDAC, and suggested outstanding power for the detection of PDAC, and has great potential for the detection of early PDAC.	('DNA methylation', 'biological_process', 'GO:0006306', ('67', '82'))	('methylation', 'Var', (71, 82))	('altered', 'Var', (59, 66))	('PDAC', 'Chemical', '-', (244, 248))	('PDAC', 'Chemical', '-', (128, 132))	('PDAC', 'Disease', (128, 132))	('PDAC', 'Chemical', '-', (187, 191))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('DNA', 'MPA', (67, 70))	('PDAC', 'Disease', (187, 191))
11226	28978057	An additional remark also for our study is that the methylation difference has been compared to healthy controls but not to non-malignant pancreatic diseases or other cancers.	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancers', 'Disease', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('pancreatic diseases', 'Phenotype', 'HP:0001732', (138, 157))	('methylation', 'Var', (52, 63))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('pancreatic diseases', 'Disease', 'MESH:D010182', (138, 157))	('pancreatic diseases', 'Disease', (138, 157))
11246	28621712	Preclinical trials have shown that HCQ alone and in combination therapy leads to enhancement of tumor shrinkage.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('HCQ', 'Var', (35, 38))	('tumor', 'Disease', (96, 101))	('enhancement', 'PosReg', (81, 92))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('HCQ', 'Chemical', 'MESH:D006886', (35, 38))
11250	28621712	Dysfunction of autophagy has been associated with various disorders including inflammation and neoplastic conditions, as well as neurodegenerative diseases.	('inflammation', 'biological_process', 'GO:0006954', ('78', '90'))	('associated', 'Reg', (34, 44))	('autophagy', 'biological_process', 'GO:0006914', ('15', '24'))	('Dysfunction', 'Var', (0, 11))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (129, 155))	('inflammation', 'Disease', 'MESH:D007249', (78, 90))	('autophagy', 'CPA', (15, 24))	('inflammation', 'Disease', (78, 90))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (129, 155))	('neurodegenerative diseases', 'Disease', (129, 155))	('autophagy', 'biological_process', 'GO:0016236', ('15', '24'))
11257	28621712	Activation of mTORC1 inhibits autophagy via the regulation of autophagy-related gene 1(ATG1) activity in response to nutrient availability.	('mTORC1', 'Gene', (14, 20))	('response to nutrient availability', 'MPA', (105, 138))	('inhibits', 'NegReg', (21, 29))	('activity', 'MPA', (93, 101))	('autophagy', 'biological_process', 'GO:0016236', ('30', '39'))	('response to nutrient', 'biological_process', 'GO:0007584', ('105', '125'))	('mTORC1', 'Gene', '382056', (14, 20))	('regulation of autophagy', 'biological_process', 'GO:0010506', ('48', '71'))	('autophagy', 'biological_process', 'GO:0006914', ('30', '39'))	('mTORC1', 'cellular_component', 'GO:0031931', ('14', '20'))	('Activation', 'Var', (0, 10))	('ATG1', 'Gene', (87, 91))	('ATG1', 'Gene', '8408', (87, 91))	('autophagy', 'CPA', (30, 39))
11264	28621712	Inhibition of this step with PI3K inhibitors, such as 3-methyladenine (3-MA), wortmannin and LY294002, or with Vps34 inhibitors, such as SAR405, prevents the formation of autophagy vesicles.	('Vps34', 'Gene', '5289', (111, 116))	('LY294002', 'Chemical', 'MESH:C085911', (93, 101))	('PI3K', 'molecular_function', 'GO:0016303', ('29', '33'))	('autophagy', 'biological_process', 'GO:0016236', ('171', '180'))	('wortmannin', 'Chemical', 'MESH:D000077191', (78, 88))	('LY294002', 'Var', (93, 101))	('Vps34', 'Gene', (111, 116))	('3-methyladenine', 'Chemical', 'MESH:C025946', (54, 69))	('autophagy', 'biological_process', 'GO:0006914', ('171', '180'))	('formation of autophagy vesicles', 'CPA', (158, 189))	('SAR405', 'Chemical', 'MESH:C000594652', (137, 143))	('PI3K', 'Protein', (29, 33))	('3-MA', 'Chemical', 'MESH:C025946', (71, 75))	('formation', 'biological_process', 'GO:0009058', ('158', '167'))	('prevents', 'NegReg', (145, 153))
11285	28621712	In renal cell carcinoma lines, HCQ enhanced the cytotoxicity of temsirolimus, promoting apoptosis and causing the downregulation of phospho-S6 through a mechanism not found in other autophagy inhibitors, such as bafilomycin A1.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('apoptosis', 'CPA', (88, 97))	('renal cell carcinoma lines', 'Disease', (3, 29))	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('autophagy', 'biological_process', 'GO:0016236', ('182', '191'))	('phospho-S6', 'Protein', (132, 142))	('HCQ', 'Var', (31, 34))	('renal cell carcinoma lines', 'Disease', 'MESH:C538614', (3, 29))	('cytotoxicity', 'Disease', 'MESH:D064420', (48, 60))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (3, 23))	('autophagy', 'biological_process', 'GO:0006914', ('182', '191'))	('enhanced', 'PosReg', (35, 43))	('promoting', 'PosReg', (78, 87))	('cytotoxicity', 'Disease', (48, 60))	('temsirolimus', 'Chemical', 'MESH:C401859', (64, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))	('HCQ', 'Chemical', 'MESH:D006886', (31, 34))	('downregulation', 'NegReg', (114, 128))
11333	28621712	SBI-0206965 is a small molecule inhibitor of the autophagy kinase ULK1.	('ULK1', 'Gene', (66, 70))	('autophagy', 'biological_process', 'GO:0016236', ('49', '58'))	('ULK1', 'Gene', '8408', (66, 70))	('autophagy', 'biological_process', 'GO:0006914', ('49', '58'))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (0, 11))	('SBI-0206965', 'Var', (0, 11))
11334	28621712	SBI-0206965 suppressed ULK-1-mediated phosphorylation events in cells regulating autophagy.	('ULK-1', 'Gene', '8408', (23, 28))	('autophagy', 'biological_process', 'GO:0016236', ('81', '90'))	('ULK-1', 'Gene', (23, 28))	('autophagy', 'biological_process', 'GO:0006914', ('81', '90'))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (0, 11))	('autophagy', 'CPA', (81, 90))	('SBI-0206965', 'Var', (0, 11))	('suppressed', 'NegReg', (12, 22))
11335	28621712	show that when synergized with the mTOR inhibitor rapamycin, SBI-0206965 produced autophagy inhibition, leading to the death of tumor cells.	('autophagy inhibition', 'CPA', (82, 102))	('rapamycin', 'Chemical', 'MESH:D020123', (50, 59))	('autophagy', 'biological_process', 'GO:0016236', ('82', '91'))	('mTOR', 'Gene', (35, 39))	('mTOR', 'Gene', '2475', (35, 39))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (61, 72))	('autophagy', 'biological_process', 'GO:0006914', ('82', '91'))	('SBI-0206965', 'Var', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('death of tumor', 'Disease', 'MESH:D003643', (119, 133))	('death of tumor', 'Disease', (119, 133))
11336	28621712	SBI-0206965 should be considered a potential autophagy inhibitor when targeting ULK1/ATG1.	('autophagy', 'biological_process', 'GO:0006914', ('45', '54'))	('ULK1', 'Gene', (80, 84))	('ULK1', 'Gene', '8408', (80, 84))	('ATG1', 'Gene', '8408', (85, 89))	('ATG1', 'Gene', (85, 89))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (0, 11))	('SBI-0206965', 'Var', (0, 11))	('autophagy', 'biological_process', 'GO:0016236', ('45', '54'))
11341	28621712	SAR405 is a kinase inhibitor of Vps18 and Vps34.	('Vps18', 'Gene', (32, 37))	('SAR405', 'Var', (0, 6))	('Vps34', 'Gene', '5289', (42, 47))	('Vps18', 'Gene', '57617', (32, 37))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('12', '28'))	('SAR405', 'Chemical', 'MESH:C000594652', (0, 6))	('Vps34', 'Gene', (42, 47))
11342	28621712	Inhibiting Vps34 resulted in lysosomal function impairment, affecting vesicle trafficking between late endosome and the lysosome.	('Inhibiting', 'Var', (0, 10))	('Vps34', 'Gene', (11, 16))	('impairment', 'NegReg', (48, 58))	('affecting', 'Reg', (60, 69))	('lysosomal function', 'MPA', (29, 47))	('vesicle', 'cellular_component', 'GO:0031982', ('70', '77'))	('Vps34', 'Gene', '5289', (11, 16))	('late endosome', 'cellular_component', 'GO:0005770', ('98', '111'))	('lysosome', 'cellular_component', 'GO:0005764', ('120', '128'))	('vesicle trafficking', 'biological_process', 'GO:0016192', ('70', '89'))
11345	28621712	ATG4 inhibitors such as NSC185058 and NSC377071 have been used to inhibit ATG4B, LC3 lipidation and autophagy.	('ATG4B', 'Gene', '23192', (74, 79))	('NSC377071', 'Var', (38, 47))	('autophagy', 'CPA', (100, 109))	('NSC185058', 'Var', (24, 33))	('ATG4B', 'Gene', (74, 79))	('LC3', 'Gene', '84557', (81, 84))	('inhibit', 'NegReg', (66, 73))	('autophagy', 'biological_process', 'GO:0016236', ('100', '109'))	('autophagy', 'biological_process', 'GO:0006914', ('100', '109'))	('LC3', 'Gene', (81, 84))
11346	28621712	NSC185058 has been shown to suppress tumor growth in osteosarcoma without affecting the mTOR or PtdIns3K (class III phosphatidylinositol 3-kinase) pathways.	('suppress', 'NegReg', (28, 36))	('phosphatidylinositol 3-kinase', 'Gene', '5293', (116, 145))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('NSC185058', 'Var', (0, 9))	('mTOR', 'Gene', (88, 92))	('mTOR', 'Gene', '2475', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('phosphatidylinositol 3-kinase', 'Gene', (116, 145))	('osteosarcoma', 'Phenotype', 'HP:0002669', (53, 65))	('osteosarcoma', 'Disease', (53, 65))	('osteosarcoma', 'Disease', 'MESH:D012516', (53, 65))
11348	28621712	show that NSC185058 inhibits the C-terminal cleavage of LC3B by ATG4B in rapamycin-treated 293T cells and in amino acid-starved differentiated hepatocyte derived cellular carcinoma line (HuH7 cells), demonstrating that NSC185058 effectively inhibits ATGB activity in vitro and in vivo.	('ATG4B', 'Gene', (64, 69))	('carcinoma', 'Disease', (171, 180))	('LC3B', 'Gene', '81631', (56, 60))	('inhibits', 'NegReg', (20, 28))	('inhibits', 'NegReg', (241, 249))	('HuH7', 'CellLine', 'CVCL:0336', (187, 191))	('LC3B', 'Gene', (56, 60))	('NSC185058', 'Var', (10, 19))	('ATG4B', 'Gene', '23192', (64, 69))	('carcinoma', 'Disease', 'MESH:D002277', (171, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('C-terminal cleavage', 'MPA', (33, 52))	('ATGB', 'Chemical', '-', (250, 254))	('rapamycin', 'Chemical', 'MESH:D020123', (73, 82))	('activity', 'MPA', (255, 263))	('293T', 'CellLine', 'CVCL:0063', (91, 95))
11349	28621712	ATGB antagonists should be considered as useful autophagy inhibitors for treatment of aggressive cancers, such as osteosarcoma.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('ATGB', 'Chemical', '-', (0, 4))	('aggressive cancers', 'Disease', (86, 104))	('aggressive cancers', 'Disease', 'MESH:D009369', (86, 104))	('autophagy', 'biological_process', 'GO:0016236', ('48', '57'))	('osteosarcoma', 'Phenotype', 'HP:0002669', (114, 126))	('osteosarcoma', 'Disease', (114, 126))	('osteosarcoma', 'Disease', 'MESH:D012516', (114, 126))	('antagonists', 'Var', (5, 16))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('autophagy', 'biological_process', 'GO:0006914', ('48', '57'))	('ATGB', 'Protein', (0, 4))
11358	28621712	In vitro and in vivo studies in renal cell carcinoma showed that ROC325 induced the accumulation of autophagosomes with un-degraded cargo, lysosomal deacidification, P62 stabilization and disruption of autophagic flux, significantly better than HCQ.	('renal cell carcinoma', 'Disease', (32, 52))	('P62', 'Gene', (166, 169))	('HCQ', 'Chemical', 'MESH:D006886', (245, 248))	('lysosomal deacidification', 'CPA', (139, 164))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (32, 52))	('ROC325', 'Chemical', 'MESH:C000626512', (65, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('ROC325', 'Var', (65, 71))	('autophagosomes', 'CPA', (100, 114))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (32, 52))	('autophagic flux', 'CPA', (202, 217))	('P62', 'Gene', '23636', (166, 169))	('accumulation', 'PosReg', (84, 96))	('disruption', 'Reg', (188, 198))	('cargo', 'molecular_function', 'GO:0140355', ('132', '137'))
11360	28621712	Unlike HCQ, lys05 produces more potent antitumor activity as a single agent in vitro and in vivo in two melanoma xenograft models and a colon cancer xenograft model compared to HCQ.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('HCQ', 'Chemical', 'MESH:D006886', (177, 180))	('melanoma xenograft', 'Disease', 'MESH:D008545', (104, 122))	('lys05', 'Chemical', 'MESH:C573930', (12, 17))	('colon cancer', 'Phenotype', 'HP:0003003', (136, 148))	('colon cancer', 'Disease', 'MESH:D015179', (136, 148))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('HCQ', 'Chemical', 'MESH:D006886', (7, 10))	('colon cancer', 'Disease', (136, 148))	('lys05', 'Var', (12, 17))	('tumor', 'Disease', (43, 48))	('melanoma xenograft', 'Disease', (104, 122))
11361	28621712	The increased potency of lys05 can be associated with its bivalent aminoquinoline rings and carbon 7 chlorine.	('lys05', 'Chemical', 'MESH:C573930', (25, 30))	('aminoquinoline', 'Chemical', 'MESH:D000634', (67, 81))	('bivalent aminoquinoline rings', 'MPA', (58, 87))	('lys05', 'Var', (25, 30))	('potency', 'MPA', (14, 21))	('carbon 7 chlorine', 'Chemical', '-', (92, 109))	('increased', 'PosReg', (4, 13))
11362	28621712	The combination of lys05 with a BRAF inhibitor had significant inhibition activity in vivo.	('BRAF', 'Gene', '673', (32, 36))	('BRAF', 'Gene', (32, 36))	('lys05', 'Chemical', 'MESH:C573930', (19, 24))	('lys05', 'Var', (19, 24))	('combination', 'Interaction', (4, 15))	('inhibition', 'NegReg', (63, 73))
11363	28621712	Lys05 was also shown to enhance the antitumor activity of receptor tyrosine kinase inhibitors, such as sunitinib, in clear cell ovarian cancer.	('clear cell ovarian cancer', 'Disease', (117, 142))	('sunitinib', 'Chemical', 'MESH:D000077210', (103, 112))	('Lys05', 'Chemical', 'MESH:C573930', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('enhance', 'PosReg', (24, 31))	('clear cell ovarian cancer', 'Disease', 'MESH:D008649', (117, 142))	('Lys05', 'Var', (0, 5))	('ovarian cancer', 'Phenotype', 'HP:0100615', (128, 142))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
11368	28621712	HCQ's inhibitory interaction with the lysosome could be contributing to defective lysosomes function, which has been known to cause lysosomal storage disease.	('lysosomal storage disease', 'Disease', 'MESH:D016464', (132, 157))	('lysosome', 'cellular_component', 'GO:0005764', ('38', '46'))	('HCQ', 'Gene', (0, 3))	('cause', 'Reg', (126, 131))	('defective', 'Var', (72, 81))	('lysosomes function', 'MPA', (82, 100))	('inhibitory interaction', 'MPA', (6, 28))	('lysosomal storage disease', 'Disease', (132, 157))	('storage', 'biological_process', 'GO:0051235', ('142', '149'))	('HCQ', 'Chemical', 'MESH:D006886', (0, 3))
11388	28125014	15-LO-1 has been implicated as a tumour promoter of prostate cancer.	('tumour', 'Disease', (33, 39))	('15-LO-1', 'Var', (0, 7))	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('prostate cancer', 'Disease', (52, 67))
11389	28125014	In contrast, 15-LO-1 suppressed chronic myeloid leukaemia and colorectal cancer suggesting a protective role.	('chronic myeloid leukaemia', 'Phenotype', 'HP:0005506', (32, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('myeloid leukaemia', 'Disease', (40, 57))	('15-LO-1', 'Var', (13, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('suppressed', 'NegReg', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (40, 57))	('myeloid leukaemia', 'Disease', 'MESH:D007938', (40, 57))	('colorectal cancer', 'Disease', (62, 79))
11393	28125014	Overexpression of 12-LO and an association with disease has been reported in prostate cancer and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('prostate cancer', 'Disease', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('association', 'Interaction', (31, 42))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('Overexpression', 'Var', (0, 14))	('prostate cancer', 'Disease', 'MESH:D011471', (77, 92))	('breast cancer', 'Disease', (97, 110))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))
11403	28125014	We propose that manipulating LO-dependent AA metabolism in the TME could offer new strategies to block cancer-related inflammation and immune escape.	('inflammation', 'Disease', 'MESH:D007249', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('TME', 'Chemical', '-', (63, 66))	('inflammation', 'Disease', (118, 130))	('immune escape', 'CPA', (135, 148))	('inflammation', 'biological_process', 'GO:0006954', ('118', '130'))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('manipulating', 'Var', (16, 28))	('metabolism', 'biological_process', 'GO:0008152', ('45', '55'))
11414	28125014	LTC4, LTD4 and LTE4 are known collectively as the cysteinyl leukotrienes and are reported to have a role in inflammatory cell recruitment, smooth muscle contraction, vessel dilation and permeability (Figure 2).	('inflammatory cell recruitment', 'CPA', (108, 137))	('LTD4', 'Var', (6, 10))	('vessel dilation', 'CPA', (166, 181))	('cysteinyl leukotrienes', 'Chemical', 'MESH:C112381', (50, 72))	('smooth muscle contraction', 'biological_process', 'GO:0006939', ('139', '164'))	('LTD', 'biological_process', 'GO:0060292', ('6', '9'))	('smooth muscle contraction', 'CPA', (139, 164))	('permeability', 'CPA', (186, 198))	('LTC4', 'Var', (0, 4))	('LTD4', 'Chemical', 'MESH:D017998', (6, 10))	('LTE4', 'Var', (15, 19))	('LTE4', 'Chemical', 'MESH:D017999', (15, 19))
11419	28125014	In a study of colon adenomas (n = 111), 5-LO expression was found to correlate with typical high risk factors for malignant transformation to colorectal adenocarcinoma, suggesting its usefulness as a biomarker in early detection of this cancer type.	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('5-LO expression', 'Var', (40, 55))	('colorectal adenocarcinoma', 'Disease', (142, 167))	('colon adenomas', 'Disease', (14, 28))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (142, 167))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('cancer', 'Disease', (237, 243))	('colon adenomas', 'Disease', 'MESH:D000236', (14, 28))
11433	28125014	Treatment with MK886 (a FLAP inhibitor) and subsequent inhibition of 5-LO signalling led to massive apoptosis of prostate cancer cells as determined by the formation of nucleosomes using Cell Death Detection ELISAs.	('formation', 'biological_process', 'GO:0009058', ('156', '165'))	('apoptosis of prostate cancer', 'Disease', (100, 128))	('apoptosis of prostate cancer', 'Disease', 'MESH:D011471', (100, 128))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('FLAP', 'Gene', (24, 28))	('FLAP', 'Gene', '241', (24, 28))	('signalling', 'biological_process', 'GO:0023052', ('74', '84'))	('MK886', 'Var', (15, 20))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('MK886', 'Chemical', 'MESH:C060893', (15, 20))	('Cell Death', 'biological_process', 'GO:0008219', ('187', '197'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('5-LO signalling', 'Pathway', (69, 84))	('inhibition', 'NegReg', (55, 65))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))
11443	28125014	Several pancreatic cancer cell lines have also been shown to express 5-LO at both the gene and protein level, with little or no expression determined in normal pancreatic ductal cells.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (8, 25))	('pancreatic', 'Disease', (8, 18))	('pancreatic', 'Disease', 'MESH:D010195', (160, 170))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('5-LO', 'Var', (69, 73))	('pancreatic', 'Disease', (160, 170))	('pancreatic cancer', 'Disease', (8, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('pancreatic cancer', 'Disease', 'MESH:D010190', (8, 25))	('pancreatic', 'Disease', 'MESH:D010195', (8, 18))
11448	28125014	A report has demonstrated that 5-LO inhibitors can elicit cytotoxic and anti-proliferative effects on tumour cells, independently of 5-LO enzyme suppression and thus careful consideration must be taken when interpreting these pharmacological inhibitor data.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('inhibitors', 'Var', (36, 46))	('cytotoxic', 'CPA', (58, 67))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Disease', (102, 108))	('elicit', 'PosReg', (51, 57))	('anti-proliferative effects', 'CPA', (72, 98))
11450	28125014	Genetic or pharmacological inhibition of 5-LO in disease models, rendered the enzyme inactive and had the knock-on effect of suppressing Wnt signalling, a process critical for maintenance of the cancer stem cell population.	('Wnt signalling', 'MPA', (137, 151))	('cancer', 'Disease', (195, 201))	('inactive', 'NegReg', (85, 93))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('inhibition', 'Var', (27, 37))	('5-LO', 'Gene', (41, 45))	('signalling', 'biological_process', 'GO:0023052', ('141', '151'))	('suppressing', 'NegReg', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
11463	28125014	In concordance with this finding, blockage of 5-LO expression was shown to deplete neutrophil numbers infiltrating dysplastic lesions of the colon in a mouse model of polyposis.	('polyposis', 'Disease', (167, 176))	('5-LO expression', 'Protein', (46, 61))	('deplete neutrophil numbers', 'Phenotype', 'HP:0001875', (75, 101))	('lesions of the colon', 'Phenotype', 'HP:0100273', (126, 146))	('deplete', 'NegReg', (75, 82))	('mouse', 'Species', '10090', (152, 157))	('polyposis', 'Disease', 'MESH:D011125', (167, 176))	('dysplastic lesions of the colon', 'Disease', (115, 146))	('neutrophil numbers', 'CPA', (83, 101))	('dysplastic lesions of the colon', 'Disease', 'MESH:D003108', (115, 146))	('blockage', 'Var', (34, 42))
11476	28125014	Aberrant levels of 5-LO inflammatory leukotrienes have been extensively implicated in the pathogenesis of a variety of respiratory diseases including lung malignancies.	('respiratory diseases', 'Disease', (119, 139))	('Aberrant', 'Var', (0, 8))	('levels', 'MPA', (9, 15))	('leukotrienes', 'Chemical', 'MESH:D015289', (37, 49))	('lung malignancies', 'Disease', 'MESH:D009369', (150, 167))	('lung malignancies', 'Disease', (150, 167))	('lung malignancies', 'Phenotype', 'HP:0100526', (150, 167))	('respiratory diseases', 'Disease', 'MESH:D012131', (119, 139))	('pathogenesis', 'biological_process', 'GO:0009405', ('90', '102'))	('implicated', 'Reg', (72, 82))
11484	28125014	A murine study focusing on hematopoietic derived 5-LO, observed that specific deletion of this enzyme from bone marrow decreases polyp formation despite the presence of 5-LO proficient epithelial cells in these mice, indicating for the first time the importance of immune cell contribution to 5-LO activity.	('bone marrow decreases polyp', 'Disease', 'MESH:D011127', (107, 134))	('bone marrow decreases polyp', 'Disease', (107, 134))	('formation', 'biological_process', 'GO:0009058', ('135', '144'))	('murine', 'Species', '10090', (2, 8))	('deletion', 'Var', (78, 86))	('bone marrow decreases', 'Phenotype', 'HP:0005528', (107, 128))	('mice', 'Species', '10090', (211, 215))
11488	28125014	One recent study demonstrated an increased focal production of 5-LO LTB4 in human colon polyps compared to normal healthy adjacent tissues.	('human', 'Species', '9606', (76, 81))	('colon polyps', 'Disease', 'MESH:D003111', (82, 94))	('increased', 'PosReg', (33, 42))	('5-LO', 'Var', (63, 67))	('LTB4', 'Gene', (68, 72))	('LTB4', 'Chemical', 'MESH:D007975', (68, 72))	('colon polyps', 'Disease', (82, 94))	('focal production', 'MPA', (43, 59))
11495	28125014	In another study, pancreatic ductal adenocarcinoma lesions were significantly less frequent in 5-LO knockout mice and a decrease of infiltrating pancreatic mast cells was also noted.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('pancreatic', 'Disease', (145, 155))	('pancreatic ductal adenocarcinoma lesions', 'Disease', 'MESH:D021441', (18, 58))	('pancreatic', 'Disease', (18, 28))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (18, 50))	('less', 'NegReg', (78, 82))	('5-LO knockout', 'Var', (95, 108))	('decrease', 'NegReg', (120, 128))	('pancreatic ductal adenocarcinoma lesions', 'Disease', (18, 58))	('mice', 'Species', '10090', (109, 113))	('pancreatic', 'Disease', 'MESH:D010195', (145, 155))	('pancreatic', 'Disease', 'MESH:D010195', (18, 28))
11512	28125014	Production of 5-LO metabolites, namely LTB4 by non-metastatic breast cancer cells was shown to induce the activation of immunosuppressive tBregs via PPARalpha, promoting cancer escape and metastasis in a mouse model.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('tBregs', 'Chemical', '-', (138, 144))	('PPARalpha', 'Protein', (149, 158))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('LTB4', 'Var', (39, 43))	('promoting', 'PosReg', (160, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', (62, 75))	('mouse', 'Species', '10090', (204, 209))	('LTB4', 'Chemical', 'MESH:D007975', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('activation', 'PosReg', (106, 116))	('cancer', 'Disease', (69, 75))
11529	28125014	This subset of CD4+FOXP3+ cells express RORyt and are known to mediate pathogenic pro-tumorigenic effects in human tumours such as colorectal cancer.	('human', 'Species', '9606', (109, 114))	('tumours', 'Disease', 'MESH:D009369', (115, 122))	('tumours', 'Disease', (115, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('CD4+FOXP3+', 'Gene', (15, 25))	('RORyt', 'Protein', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('colorectal cancer', 'Disease', (131, 148))	('CD4+FOXP3+', 'Var', (15, 25))
11557	28125014	Aberrant lipid signalling is evident in many diseases with vascular pathology including cancer.	('cancer', 'Disease', (88, 94))	('lipid signalling', 'MPA', (9, 25))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Aberrant', 'Var', (0, 8))	('signalling', 'biological_process', 'GO:0023052', ('15', '25'))	('evident', 'Reg', (29, 36))	('lipid', 'Chemical', 'MESH:D008055', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
11560	28125014	These metabolites were found to upregulate a major pro-angiogenic factor, VEGF, in human malignant mesothelioma in vitro.	('upregulate', 'PosReg', (32, 42))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (89, 111))	('VEGF', 'Gene', (74, 78))	('human', 'Species', '9606', (83, 88))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (89, 111))	('metabolites', 'Var', (6, 17))	('malignant mesothelioma', 'Disease', (89, 111))
11563	28125014	An accompanied increase in MMP9 and VEGF, which could be blocked by pharmacologically inhibiting 5-LO, suggested that 5-LO expression in the inflamed colon may be involved in the angiogenic and inflammatory process of adenoma formation.	('MMP9', 'CPA', (27, 31))	('adenoma', 'Disease', (218, 225))	('increase', 'PosReg', (15, 23))	('MMP9', 'molecular_function', 'GO:0004229', ('27', '31'))	('VEGF', 'CPA', (36, 40))	('involved', 'Reg', (163, 171))	('formation', 'biological_process', 'GO:0009058', ('226', '235'))	('adenoma', 'Disease', 'MESH:D000236', (218, 225))	('5-LO', 'Var', (118, 122))
11568	28125014	DMBA-induced mammary gland tumours in mouse models were shown to progressively express 5-LO.	('mouse', 'Species', '10090', (38, 43))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('DMBA', 'Chemical', 'MESH:C082386', (0, 4))	('5-LO', 'Var', (87, 91))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('tumours', 'Disease', (27, 34))
11584	28125014	Although the studies mentioned here are not cancer specific, they do provide some insight into how immune cells or indeed tumour cells, and endothelial cells may interact through the 5-LO signalling pathways, and how dysfunctionally activated endothelial cells could play a role in pathological angiogenesis, inflammation and subsequent metastasis.	('inflammation', 'Disease', (309, 321))	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('signalling', 'biological_process', 'GO:0023052', ('188', '198'))	('5-LO signalling pathways', 'Pathway', (183, 207))	('interact', 'Interaction', (162, 170))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('role', 'Reg', (274, 278))	('dysfunctionally', 'Var', (217, 232))	('tumour', 'Disease', (122, 128))	('play', 'Reg', (267, 271))	('angiogenesis', 'biological_process', 'GO:0001525', ('295', '307'))	('inflammation', 'biological_process', 'GO:0006954', ('309', '321'))	('inflammation', 'Disease', 'MESH:D007249', (309, 321))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('metastasis', 'CPA', (337, 347))
11589	28125014	In a subsequent study by this group COX-2 inhibition was shown to result in an upregulation of 5-LO LTB4.	('LTB4', 'Chemical', 'MESH:D007975', (100, 104))	('upregulation', 'PosReg', (79, 91))	('inhibition', 'Var', (42, 52))	('5-LO LTB4', 'MPA', (95, 104))	('COX-2', 'Gene', (36, 41))	('COX-2', 'Gene', '5743', (36, 41))
11592	28125014	Knock-down of COX-2 showed only modest effects to cell proliferation in several cell lines but combined knock-down of both COX-2 and 5-LO had superior inhibitory effects on tumour cell proliferation and VEGF production.	('COX-2', 'Gene', '5743', (14, 19))	('COX-2', 'Gene', '5743', (123, 128))	('tumour', 'Disease', (173, 179))	('inhibitory effects', 'NegReg', (151, 169))	('cell proliferation', 'biological_process', 'GO:0008283', ('180', '198'))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('VEGF production', 'biological_process', 'GO:0010573', ('203', '218'))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('knock-down', 'Var', (104, 114))	('VEGF production', 'CPA', (203, 218))	('COX-2', 'Gene', (123, 128))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('COX-2', 'Gene', (14, 19))
11593	28125014	Additionally, genetic disruption of 5-LO in a mouse model of ethanol-induced oral carcinoma resulted in activation of COX-2 and an increase in COX-2 metabolites thought to be produced mainly by inflammatory cells This evidence suggests dual inhibition of both these pathways may have a superior anti-cancer effect in the suppression of angiogenesis.	('oral carcinoma', 'Disease', 'MESH:D020820', (77, 91))	('COX-2', 'Gene', '5743', (143, 148))	('activation', 'PosReg', (104, 114))	('genetic disruption', 'Var', (14, 32))	('5-LO', 'Gene', (36, 40))	('oral carcinoma', 'Disease', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('increase', 'PosReg', (131, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('COX-2', 'Gene', (118, 123))	('COX-2', 'Gene', '5743', (118, 123))	('mouse', 'Species', '10090', (46, 51))	('angiogenesis', 'CPA', (336, 348))	('ethanol', 'Chemical', 'MESH:D000431', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('COX-2', 'Gene', (143, 148))	('angiogenesis', 'biological_process', 'GO:0001525', ('336', '348'))	('cancer', 'Disease', (300, 306))
11607	28125014	Pharmacological inhibition or genetic deletion of 5-LO enzyme, FLAP or the 5-LO metabolite receptors in adipocytes or adipose tissue has been shown to cause an anti-inflammatory phenotype, with reduced chemotactic potential, lower adipose tissue macrophage (ATM) infiltration, decreased M1:M2 phenotype in the stromal vascular fraction and decreased FFA release.	('decreased', 'NegReg', (340, 349))	('M1:M2 phenotype in the stromal vascular fraction', 'MPA', (287, 335))	('chemotactic', 'MPA', (202, 213))	('genetic deletion', 'Var', (30, 46))	('anti-inflammatory phenotype', 'MPA', (160, 187))	('FLAP', 'Gene', '241', (63, 67))	('lower adipose tissue', 'Phenotype', 'HP:0040063', (225, 245))	('lower', 'NegReg', (225, 230))	('reduced', 'NegReg', (194, 201))	('FLAP', 'Gene', (63, 67))	('adipose', 'CPA', (231, 238))	('decreased', 'NegReg', (277, 286))	('FFA release', 'MPA', (350, 361))
11620	28125014	Similar to leukocytes, LTB4 has been shown to induce chemotaxis of normal fibroblasts in culture.	('chemotaxis', 'biological_process', 'GO:0006935', ('53', '63'))	('chemotaxis', 'CPA', (53, 63))	('LTB4', 'Var', (23, 27))	('LTB4', 'Chemical', 'MESH:D007975', (23, 27))	('induce', 'PosReg', (46, 52))
11629	28125014	Therefore, targeting MMPs and 5-LO may disturb important interactions between a growing tumour and the ECM and thus provide a potential therapeutic route in the treatment of metastatic disease.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('interactions', 'Interaction', (57, 69))	('tumour', 'Disease', (88, 94))	('disturb', 'NegReg', (39, 46))	('MMPs', 'Gene', '4313;17390;4316;17393;4318;17395', (21, 25))	('metastatic disease', 'Disease', (174, 192))	('MMPs', 'Gene', (21, 25))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('targeting', 'Var', (11, 20))
11643	28321402	However, the potential prognostic value of miR-200s in various human malignancies remains controversial.	('malignancies', 'Disease', (69, 81))	('miR-200s', 'Var', (43, 51))	('human', 'Species', '9606', (63, 68))	('malignancies', 'Disease', 'MESH:D009369', (69, 81))
11648	28321402	MiRNAs frequently reside in fragile sites and genomic regions involved in various cancers, suggesting that they play a potentially critical and complex role in cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MiRNAs', 'Var', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
11650	28321402	MiR-200b, miR-200c, and miR-429 have the same seed region (nucleotides 2-7), and miR-200a and miR-141 share a seed region with a difference in only the fourth nucleotide (U to C) among these regions.	('miR-429', 'Var', (24, 31))	('MiR-200b', 'Gene', '406984', (0, 8))	('miR-141', 'Var', (94, 101))	('miR-200c', 'Var', (10, 18))	('miR-200a', 'Var', (81, 89))	('MiR-200b', 'Gene', (0, 8))
11654	28321402	The articles were searched using the following keywords and MeSH vocabulary (Supplementary Table 1 in Supplementary Material available online at https://doi.org/10.1155/2017/1928021): miR-141, miR-200, or miR-429 combined with prognostic, prognosis, survival, tumor, cancer, neoplasm, or carcinoma.	('tumor', 'Disease', (260, 265))	('carcinoma', 'Disease', (288, 297))	('cancer', 'Disease', (267, 273))	('combined', 'Reg', (213, 221))	('neoplasm', 'Disease', 'MESH:D009369', (275, 283))	('neoplasm', 'Phenotype', 'HP:0002664', (275, 283))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('miR-429', 'Var', (205, 212))	('miR-200', 'Var', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('miR-141', 'Var', (184, 191))	('neoplasm', 'Disease', (275, 283))
11685	26805817	They demonstrated that FOLFIRINOX was associated with a median overall survival improvement of more than 10 months in comparison to gemcitabine.	('improvement', 'PosReg', (80, 91))	('FOLFIRINOX', 'Var', (23, 33))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (23, 33))	('gemcitabine', 'Chemical', 'MESH:C056507', (132, 143))
11687	26805817	In 2013, Von Hoff et al., reported that nab-paclitaxel with gemcitabine was more effective than gemcitabine alone, and that the combination resulted in an improvement in median overall survival that ranged from 6.7 to 8.5 months.	('improvement', 'PosReg', (155, 166))	('gemcitabine', 'Chemical', 'MESH:C056507', (60, 71))	('nab', 'Chemical', '-', (40, 43))	('gemcitabine', 'Chemical', 'MESH:C056507', (96, 107))	('overall survival', 'MPA', (177, 193))	('nab-paclitaxel', 'Var', (40, 54))	('paclitaxel', 'Chemical', 'MESH:D017239', (44, 54))
11698	26805817	Human HSP27 is phosphorylated mainly at three sites (Ser-15, Ser-78, and Ser-82), and the phosphorylation is catalyzed by various protein kinases including mitogen-activated protein (MAP) kinase activated protein kinase 2 (MAPKAPK-2).	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('Human', 'Species', '9606', (0, 5))	('Ser', 'cellular_component', 'GO:0005790', ('61', '64'))	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('phosphorylation', 'biological_process', 'GO:0016310', ('90', '105'))	('Ser', 'Chemical', 'MESH:D012694', (53, 56))	('MAPKAPK-2', 'Gene', '9261', (223, 232))	('Ser', 'Chemical', 'MESH:D012694', (73, 76))	('MAP', 'molecular_function', 'GO:0004239', ('183', '186'))	('MAPKAPK-2', 'Gene', (223, 232))	('Ser', 'cellular_component', 'GO:0005790', ('53', '56'))	('Ser', 'cellular_component', 'GO:0005790', ('73', '76'))	('HSP27', 'Gene', (6, 11))	('Ser', 'Chemical', 'MESH:D012694', (61, 64))	('Ser-82', 'Var', (73, 79))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('HSP27', 'Gene', '3315', (6, 11))
11702	26805817	Phosphorylated HSP27 expression also has been reported to play a suppressive role in the cell growth, chemosensitivity.	('Phosphorylated', 'Var', (0, 14))	('suppressive', 'NegReg', (65, 76))	('HSP27', 'Gene', (15, 20))	('HSP27', 'Gene', '3315', (15, 20))	('cell growth', 'CPA', (89, 100))	('chemosensitivity', 'CPA', (102, 118))	('cell growth', 'biological_process', 'GO:0016049', ('89', '100'))
11716	26805817	This article also reported that knockdown of the HSP27 expression using siRNA targeting HSP27 increased gemcitabine sensitivity even in the gemcitabine-resistant pancreatic cell line, KLM1-R.	('pancreatic', 'Disease', (162, 172))	('HSP27', 'Gene', '3315', (49, 54))	('HSP27', 'Gene', (49, 54))	('increased', 'PosReg', (94, 103))	('gemcitabine', 'Chemical', 'MESH:C056507', (104, 115))	('knockdown', 'Var', (32, 41))	('HSP27', 'Gene', (88, 93))	('HSP27', 'Gene', '3315', (88, 93))	('pancreatic', 'Disease', 'MESH:D010195', (162, 172))	('gemcitabine sensitivity', 'MPA', (104, 127))	('gemcitabine', 'Chemical', 'MESH:C056507', (140, 151))
11718	26805817	Zhang et al., also reported that SW1900/GEM, a gemcitabine-resistant cell line, exhibited increased gemcitabine sensitivity when the HSP27 expression was inhibited by shRNA specific for HSP27.	('gemcitabine', 'Chemical', 'MESH:C056507', (47, 58))	('increased', 'PosReg', (90, 99))	('HSP27', 'Gene', (186, 191))	('gemcitabine', 'Chemical', 'MESH:C056507', (100, 111))	('inhibited', 'NegReg', (154, 163))	('HSP27', 'Gene', (133, 138))	('HSP27', 'Gene', '3315', (186, 191))	('HSP27', 'Gene', '3315', (133, 138))	('expression', 'MPA', (139, 149))	('gemcitabine sensitivity', 'MPA', (100, 123))	('SW1900/GEM', 'Var', (33, 43))
11742	26805817	In order to elucidate the precise role of phosphorylated HSP27 in the sensitivity to gemcitabine, we established two types of mutant HSP27-transfected Panc1 pancreatic cell lines, overexpressed non-phosphorylatable HSP27 cells and phosphorylated HSP27 cells, and found that the cell growth of phosphorylated HSP27 cells was markedly retarded compared with that of non-phosphorylatable HSP27 cells, indicating that gemcitabine-induced HSP27 phosphorylation via the p38 MAPK-MAPKAP-2 pathway leads to the growth suppression of pancreatic cancer cells.	('MAPK', 'molecular_function', 'GO:0004707', ('468', '472'))	('HSP27', 'Gene', '3315', (246, 251))	('HSP27', 'Gene', '3315', (308, 313))	('HSP27', 'Gene', '3315', (133, 138))	('HSP27', 'Gene', '3315', (215, 220))	('phosphorylation', 'Var', (440, 455))	('HSP27-transfected Panc1 pancreatic', 'Disease', 'MESH:D010195', (133, 167))	('p38', 'Gene', (464, 467))	('HSP27', 'Gene', (385, 390))	('retarded', 'Disease', (333, 341))	('phosphorylation', 'biological_process', 'GO:0016310', ('440', '455'))	('growth suppression of pancreatic cancer', 'Disease', (503, 542))	('HSP27', 'Gene', '3315', (434, 439))	('retarded', 'Disease', 'MESH:D008607', (333, 341))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (525, 542))	('gemcitabine', 'Chemical', 'MESH:C056507', (414, 425))	('HSP27', 'Gene', (57, 62))	('mutant', 'Var', (126, 132))	('HSP27', 'Gene', (133, 138))	('p38', 'Gene', '1432', (464, 467))	('HSP27', 'Gene', (215, 220))	('HSP27-transfected Panc1 pancreatic', 'Disease', (133, 167))	('HSP27', 'Gene', (246, 251))	('HSP27', 'Gene', (308, 313))	('gemcitabine', 'Chemical', 'MESH:C056507', (85, 96))	('HSP27', 'Gene', '3315', (385, 390))	('cancer', 'Phenotype', 'HP:0002664', (536, 542))	('HSP27', 'Gene', (434, 439))	('growth suppression of pancreatic cancer', 'Disease', 'MESH:D010190', (503, 542))	('HSP27', 'Gene', '3315', (57, 62))	('cell growth', 'biological_process', 'GO:0016049', ('278', '289'))
11749	26633513	However, dysregulation or mutations in HH signaling leads to genomic instability (GI) and various cancers, for example, germline mutation in PTCH1 lead to Gorlin syndrome, a condition where patients develop numerous basal cell carcinomas and rarely rhabdomyosarcoma (RMS).	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('rhabdomyosarcoma', 'Disease', (249, 265))	('patients', 'Species', '9606', (190, 198))	('HH', 'Gene', '42737', (39, 41))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('numerous basal cell carcinomas', 'Disease', 'MESH:D002280', (207, 237))	('mutations', 'Var', (26, 35))	('germline mutation', 'Var', (120, 137))	('cancers', 'Disease', (98, 105))	('RMS', 'Phenotype', 'HP:0002859', (267, 270))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Gorlin syndrome', 'Disease', 'MESH:D001478', (155, 170))	('develop', 'PosReg', (199, 206))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (249, 265))	('lead to', 'Reg', (147, 154))	('PTCH1', 'Gene', (141, 146))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (249, 265))	('dysregulation', 'Var', (9, 22))	('Gorlin syndrome', 'Disease', (155, 170))	('genomic', 'MPA', (61, 68))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (216, 237))	('numerous basal cell carcinomas', 'Disease', (207, 237))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (216, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinomas', 'Phenotype', 'HP:0030731', (227, 237))	('sarcoma', 'Phenotype', 'HP:0100242', (258, 265))	('leads to', 'Reg', (52, 60))
11750	26633513	Activating mutations in SMO have also been recognized in sporadic cases of medulloblastoma and SMO is overexpressed in many other cancers.	('SMO', 'Gene', '6608', (24, 27))	('medulloblastoma', 'Phenotype', 'HP:0002885', (75, 90))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('Activating mutations', 'Var', (0, 20))	('cancers', 'Disease', (130, 137))	('medulloblastoma', 'Disease', (75, 90))	('SMO', 'Gene', (24, 27))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('SMO', 'Gene', '6608', (95, 98))	('SMO', 'Gene', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('medulloblastoma', 'Disease', 'MESH:D008527', (75, 90))
11752	26633513	In fact, this aberrantly regulated GLI1 has been linked to several non-canonical oncogenic growth signals such as Kirsten rat sarcoma viral oncogene homolog (KRAS), avian myelocytomatosis virus oncogene cellular homolog (C-MYC), transforming growth factor beta (TGFbeta), wingless-type MMTV integration site family (WNT) and beta-catenin.	('aberrantly', 'Var', (14, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('229', '260'))	('avian myelocytomatosis virus', 'Species', '11867', (165, 193))	('C-MYC', 'Gene', '4609', (221, 226))	('MMTV', 'Species', '11757', (286, 290))	('TGFbeta', 'Gene', '7040', (262, 269))	('linked', 'Reg', (49, 55))	('GLI1', 'Gene', (35, 39))	('sarcoma', 'Disease', 'MESH:D012509', (126, 133))	('beta-catenin', 'Gene', (325, 337))	('C-MYC', 'Gene', (221, 226))	('rat', 'Species', '10116', (122, 125))	('rat', 'Species', '10116', (296, 299))	('beta-catenin', 'Gene', '1499', (325, 337))	('TGFbeta', 'Gene', (262, 269))	('sarcoma', 'Disease', (126, 133))
11753	26633513	Recent studies from our lab and other independent studies demonstrate that aberrantly expressed GLI1 influences the integrity of several DNA damage response and repair signals, and if altered, these networks can contribute to GI and impact tumor response to chemo- and radiation therapies.	('DNA damage response', 'biological_process', 'GO:0006974', ('137', '156'))	('GLI1', 'Gene', (96, 100))	('impact tumor', 'Disease', 'MESH:D004834', (233, 245))	('aberrantly expressed', 'Var', (75, 95))	('contribute', 'Reg', (212, 222))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('impact tumor', 'Disease', (233, 245))	('influences', 'Reg', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('rat', 'Species', '10116', (65, 68))
11755	26633513	In this review, we focus on summarizing current understanding of the molecular, biochemical and cellular basis for aberrant GLI1 expression and discuss GLI1-mediated HH signaling on DNA damage responses, carcinogenesis and chemoresistance.	('carcinogenesis', 'Disease', (204, 218))	('DNA', 'cellular_component', 'GO:0005574', ('182', '185'))	('GLI1', 'Gene', (124, 128))	('HH', 'Gene', '42737', (166, 168))	('signaling', 'biological_process', 'GO:0023052', ('169', '178'))	('carcinogenesis', 'Disease', 'MESH:D063646', (204, 218))	('aberrant', 'Var', (115, 123))	('DNA damage', 'MPA', (182, 192))
11759	26633513	Dysregulation of HH signaling leads to numerous differentiation defects like segment polarity, holoprosencephaly, microencephaly or cyclopia, absent nose or cleft palate.	('leads to', 'Reg', (30, 38))	('cleft palate', 'Phenotype', 'HP:0000175', (157, 169))	('Dysregulation', 'Var', (0, 13))	('absent nose', 'Disease', (142, 153))	('holoprosencephaly', 'Disease', 'MESH:D016142', (95, 112))	('holoprosencephaly', 'Phenotype', 'HP:0001360', (95, 112))	('cyclopia', 'Phenotype', 'HP:0009914', (132, 140))	('cleft palate', 'Disease', 'MESH:D002972', (157, 169))	('HH', 'Gene', '42737', (17, 19))	('microencephaly or cyclopia', 'Disease', 'MESH:D016142', (114, 140))	('microencephaly or cyclopia', 'Disease', (114, 140))	('holoprosencephaly', 'Disease', (95, 112))	('segment polarity', 'Disease', (77, 93))	('cleft palate', 'Disease', (157, 169))	('absent nose', 'Phenotype', 'HP:0009927', (142, 153))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))
11763	26633513	While the balanced physiologic activation of GLI1 regulates differentiation and development of various organs, mutations in HH signaling genes or oncogenic signals upregulate the expression of GLI1 in a non-homeostatic manner (aberrant GLI1) leading to the development of neoplasm.	('mutations', 'Var', (111, 120))	('neoplasm', 'Disease', (272, 280))	('leading to', 'Reg', (242, 252))	('development of various organs', 'CPA', (80, 109))	('expression', 'MPA', (179, 189))	('HH', 'Gene', '42737', (124, 126))	('neoplasm', 'Disease', 'MESH:D009369', (272, 280))	('neoplasm', 'Phenotype', 'HP:0002664', (272, 280))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('GLI1', 'Gene', (193, 197))	('upregulate', 'PosReg', (164, 174))	('differentiation', 'CPA', (60, 75))	('regulates', 'Reg', (50, 59))
11764	26633513	Somatic or germline mutations of GLI1 have been reported in several cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('reported', 'Reg', (48, 56))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('GLI1', 'Gene', (33, 37))	('germline mutations', 'Var', (11, 29))
11769	26633513	Together these observations suggest an important role for aberrant GLI1 signaling in various stages of tumor development, from inducing mutagenic lesions, carcinogenesis, metastasis and resistance to cancer therapeutics.	('inducing', 'Reg', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('carcinogenesis', 'Disease', (155, 169))	('tumor', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('aberrant', 'Var', (58, 66))	('carcinogenesis', 'Disease', 'MESH:D063646', (155, 169))	('metastasis', 'CPA', (171, 181))	('resistance', 'CPA', (186, 196))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('mutagenic lesions', 'MPA', (136, 153))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))
11771	26633513	In this review we have discussed the role of aberrant GLI1 in DNA damage response (DDR), carcinogenesis and chemoresistance.	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('DNA damage response', 'biological_process', 'GO:0006974', ('62', '81'))	('aberrant', 'Var', (45, 53))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('DNA damage', 'Disease', (62, 72))	('carcinogenesis', 'Disease', (89, 103))	('GLI1', 'Gene', (54, 58))
11774	26633513	Phosphorylated SMO then facilitates the dissociation of GLI proteins from kinesin-family protein, kinesin superfamily 7 (Kif7), and suppressor of fused (SUFU).	('Phosphorylated', 'Var', (0, 14))	('Kif7', 'Gene', (121, 125))	('kinesin superfamily 7', 'Gene', '374654', (98, 119))	('facilitates', 'PosReg', (24, 35))	('dissociation', 'MPA', (40, 52))	('Kif7', 'Gene', '374654', (121, 125))	('GLI', 'Gene', '2735', (56, 59))	('kinesin superfamily 7', 'Gene', (98, 119))	('SMO', 'Gene', '6608', (15, 18))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('kinesin', 'molecular_function', 'GO:0003777', ('74', '81'))	('SMO', 'Gene', (15, 18))	('kinesin', 'molecular_function', 'GO:0003777', ('98', '105'))	('SUFU', 'Gene', (153, 157))	('SUFU', 'Gene', '51684', (153, 157))	('GLI', 'Gene', (56, 59))
11777	26633513	In addition to this, certain mutations in the HH signaling pathway members upstream of GLI1 induce its overexpression and alter the regulation of target genes that are involved in differentiation, DNA repair, and cell cycle checkpoint regulation.	('regulation', 'biological_process', 'GO:0065007', ('235', '245'))	('DNA', 'cellular_component', 'GO:0005574', ('197', '200'))	('alter', 'Reg', (122, 127))	('DNA repair', 'biological_process', 'GO:0006281', ('197', '207'))	('GLI1', 'Gene', (87, 91))	('mutations', 'Var', (29, 38))	('HH', 'Gene', '42737', (46, 48))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('213', '234'))	('regulation', 'biological_process', 'GO:0065007', ('132', '142'))	('regulation of', 'MPA', (132, 145))	('overexpression', 'MPA', (103, 117))	('HH signaling pathway', 'biological_process', 'GO:0007224', ('46', '66'))
11783	26633513	Activating mutations in KRAS have been linked to several cancers, including pancreatic, ovarian, lung and colon.	('Activating mutations', 'Var', (0, 20))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('linked', 'Reg', (39, 45))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('pancreatic, ovarian, lung and colon', 'Disease', 'MESH:D008175', (76, 111))	('KRAS', 'Gene', (24, 28))
11789	26633513	Similarly, aberrant expression of the transcription factor and oncogene EWS-FLI1, which is responsible for the Ewing sarcoma family of tumors, transcriptionally increases GLI1 expression.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (111, 124))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (111, 124))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('transcription factor', 'molecular_function', 'GO:0000981', ('38', '58'))	('transcription', 'biological_process', 'GO:0006351', ('38', '51'))	('EWS', 'Gene', '2130', (72, 75))	('EWS', 'Gene', (72, 75))	('FLI1', 'Gene', '2313', (76, 80))	('aberrant expression', 'Var', (11, 30))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('FLI1', 'Gene', (76, 80))	('Ewing sarcoma', 'Disease', (111, 124))	('expression', 'MPA', (176, 186))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('increases', 'PosReg', (161, 170))	('GLI1', 'Gene', (171, 175))
11797	26633513	Genetic analysis of pancreatic cancers showed mutations in GLI1 with clear functional relevance to neoplasia.	('neoplasia', 'Disease', 'MESH:D009369', (99, 108))	('GLI1', 'Gene', (59, 63))	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('neoplasia', 'Disease', (99, 108))	('pancreatic cancers', 'Disease', 'MESH:D010190', (20, 38))	('pancreatic cancers', 'Disease', (20, 38))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('neoplasia', 'Phenotype', 'HP:0002664', (99, 108))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (20, 38))
11798	26633513	Missense and nonsense mutations of GLI1 were also documented in melanoma and squamous cell carcinoma.	('nonsense mutations', 'Var', (13, 31))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('GLI1', 'Gene', (35, 39))	('documented', 'Reg', (50, 60))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Disease', (77, 100))	('Missense', 'Var', (0, 8))
11799	26633513	Additionally, the fusion of ACTB (beta-actin) with GLI1 t(7;12), has been associated in pericytoma.	('ACTB', 'Gene', '60', (28, 32))	('pericytoma', 'Disease', (88, 98))	('beta-actin', 'Gene', '728378', (34, 44))	('beta-actin', 'Gene', (34, 44))	('fusion', 'Var', (18, 24))	('ACTB', 'Gene', (28, 32))	('associated', 'Reg', (74, 84))
11801	26633513	Apart from cancers, mutations in GLI1 were found in Hirschsprung disease, which is characterized as abnormal neural crest cells differentiation.	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('Hirschsprung disease', 'Phenotype', 'HP:0002251', (52, 72))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('found', 'Reg', (43, 48))	('Hirschsprung disease', 'Disease', (52, 72))	('GLI1', 'Gene', (33, 37))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Disease', (11, 18))	('Hirschsprung disease', 'Disease', 'MESH:D006627', (52, 72))	('mutations', 'Var', (20, 29))
11803	26633513	The (GLI1DeltaN) variant acts on genes similarly to GLI1 in both normal and cancer cells.	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('GLI1DeltaN', 'Var', (5, 15))
11804	26633513	Interestingly, the tGLI1 variant is expressed only in the tumor tissues and has been characterized as a stronger promoter of epithelial-mesenchymal transition (EMT) phenotype, an important feature in carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('125', '158'))	('epithelial-mesenchymal transition', 'CPA', (125, 158))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('variant', 'Var', (25, 32))	('EMT', 'biological_process', 'GO:0001837', ('160', '163'))	('stronger promoter', 'PosReg', (104, 121))	('carcinogenesis', 'Disease', 'MESH:D063646', (200, 214))	('tGLI1', 'Gene', (19, 24))	('carcinogenesis', 'Disease', (200, 214))
11805	26633513	Overall, aberrant expression of GLI1 and its isoforms in the setting of either canonical or non-canonical signaling regulates genes that are involved in the repair of DNA damage, cell cycle, carcinogenesis, and multidrug resistance (MDR).	('carcinogenesis', 'Disease', (191, 205))	('regulates', 'Reg', (116, 125))	('MDR', 'molecular_function', 'GO:0004745', ('233', '236'))	('drug resistance', 'Phenotype', 'HP:0020174', (216, 231))	('genes', 'Gene', (126, 131))	('multidrug resistance', 'Disease', (211, 231))	('DNA', 'cellular_component', 'GO:0005574', ('167', '170'))	('GLI1', 'Gene', (32, 36))	('cell cycle', 'biological_process', 'GO:0007049', ('179', '189'))	('aberrant', 'Var', (9, 17))	('carcinogenesis', 'Disease', 'MESH:D063646', (191, 205))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
11808	26633513	Even though, many questions remain concerning how aberrant activation of GLI1 influences cell cycle checkpoints and DNA repair, there are few reports that clearly indicate potential mechanisms that GLI1 could control in order to protect tumor cells from oncogenic stress and chemotherapy.	('tumor', 'Disease', (237, 242))	('influences', 'Reg', (78, 88))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('GLI1', 'Gene', (73, 77))	('DNA repair', 'biological_process', 'GO:0006281', ('116', '126'))	('cell cycle checkpoints', 'CPA', (89, 111))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('aberrant', 'Var', (50, 58))	('cell cycle', 'biological_process', 'GO:0007049', ('89', '99'))	('activation', 'PosReg', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
11814	26633513	In this study, loss of either non-homologous end joining (NHEJ) gene DNA Ligase IV (Lig4), or genes involved in homologous recombination (HR) like X-ray cross complementation 2 (XRCC2), and breast cancer growth suppressor protein 2 (BRCA2), or (Lig4/XRCC2) in combination with p53 deficiency resulted in PTCH1 downregulation, GLI1 activation and rapid development of medulloblastoma.	('activation', 'PosReg', (331, 341))	('DNA Ligase IV', 'Gene', '3981', (69, 82))	('NHEJ', 'biological_process', 'GO:0006303', ('58', '62'))	('homologous recombination', 'biological_process', 'GO:0035825', ('112', '136'))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('GLI1', 'Gene', (326, 330))	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('XRCC2', 'Gene', '7516', (250, 255))	('BRCA2', 'Gene', '675', (233, 238))	('X-ray cross complementation 2', 'Gene', '7516', (147, 176))	('XRCC2', 'Gene', '7516', (178, 183))	('protein', 'cellular_component', 'GO:0003675', ('222', '229'))	('Lig4', 'Gene', (245, 249))	('deficiency', 'Var', (281, 291))	('X-ray cross complementation 2', 'Gene', (147, 176))	('DNA Ligase IV', 'Gene', (69, 82))	('Lig4', 'Gene', '3981', (245, 249))	('p53', 'Gene', (277, 280))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Lig4', 'Gene', (84, 88))	('PTCH1', 'Gene', (304, 309))	('medulloblastoma', 'Disease', 'MESH:D008527', (367, 382))	('XRCC2', 'Gene', (250, 255))	('medulloblastoma', 'Phenotype', 'HP:0002885', (367, 382))	('XRCC2', 'Gene', (178, 183))	('loss', 'NegReg', (15, 19))	('Lig4', 'Gene', '3981', (84, 88))	('medulloblastoma', 'Disease', (367, 382))	('BRCA2', 'Gene', (233, 238))	('downregulation', 'NegReg', (310, 324))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
11815	26633513	This study not only confirms a function link between DDR, repair and HH signaling, but reveals that DNA damage induced expression of GLI1 was kept in check by p53 and loss of p53 results in GLI1 overexpression, a novel regulation of GLI1 by tumor suppressor protein p53.	('tumor', 'Disease', (241, 246))	('HH', 'Gene', '42737', (69, 71))	('regulation', 'biological_process', 'GO:0065007', ('219', '229'))	('overexpression', 'PosReg', (195, 209))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('GLI1', 'Gene', (190, 194))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('241', '257'))	('p53', 'Gene', (175, 178))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('loss', 'Var', (167, 171))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('241', '257'))	('protein', 'cellular_component', 'GO:0003675', ('258', '265'))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
11816	26633513	The above observations were further supported by mechanistic studies that demonstrated p53 mediated regulation of GLI1 by post-translational modification in response to genotoxic stress.	('regulation', 'MPA', (100, 110))	('rat', 'Species', '10116', (81, 84))	('post-translational modification', 'biological_process', 'GO:0043687', ('122', '153'))	('post-translational modification', 'MPA', (122, 153))	('response to genotoxic stress', 'biological_process', 'GO:0006974', ('157', '185'))	('regulation', 'biological_process', 'GO:0065007', ('100', '110'))	('GLI1', 'Gene', (114, 118))	('p53', 'Var', (87, 90))
11821	26633513	It is interesting to note that GLI1 is one of the primary targets of p53 in response to genotoxic stress, and degradation of GLI1 prevents the proliferation of cells.	('degradation', 'biological_process', 'GO:0009056', ('110', '121'))	('degradation', 'Var', (110, 121))	('GLI1', 'Gene', (125, 129))	('rat', 'Species', '10116', (150, 153))	('prevents', 'NegReg', (130, 138))	('proliferation of cells', 'CPA', (143, 165))	('response to genotoxic stress', 'biological_process', 'GO:0006974', ('76', '104'))
11824	26633513	In human colon carcinoma cells, inhibition of GLI1 induced extensive cell death while the inhibition of HH signaling at the level of SMO did not.	('cell death', 'biological_process', 'GO:0008219', ('69', '79'))	('inhibition', 'Var', (32, 42))	('HH', 'Gene', '42737', (104, 106))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('human', 'Species', '9606', (3, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('GLI1', 'Gene', (46, 50))	('SMO', 'Gene', '6608', (133, 136))	('colon carcinoma', 'Disease', 'MESH:D015179', (9, 24))	('SMO', 'Gene', (133, 136))	('colon carcinoma', 'Disease', (9, 24))	('cell death', 'CPA', (69, 79))
11827	26633513	Thus, inhibition of GLI1 blocks the replication-associated checkpoints and therefore, cancer cells with high proliferation rate and without proper cell cycle arrest/regulation will undergo cell death.	('replication-associated checkpoints', 'CPA', (36, 70))	('GLI1', 'Gene', (20, 24))	('regulation', 'biological_process', 'GO:0065007', ('165', '175'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('147', '164'))	('undergo', 'Reg', (181, 188))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cell death', 'CPA', (189, 199))	('blocks', 'NegReg', (25, 31))	('rat', 'Species', '10116', (123, 126))	('rat', 'Species', '10116', (116, 119))	('inhibition', 'Var', (6, 16))	('arrest', 'Disease', 'MESH:D006323', (158, 164))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (147, 164))	('cell death', 'biological_process', 'GO:0008219', ('189', '199'))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('arrest', 'Disease', (158, 164))	('cancer', 'Disease', (86, 92))
11830	26633513	Under these conditions, the levels of pATM, pMDC1 and pNBS1Ser343 were increased and the level of gammaH2AX was found to be decreased, suggesting inhibition of GLI1 by GANT61 attenuates DDR and repair.	('pNBS1Ser343', 'Var', (54, 65))	('H2AX', 'Gene', (103, 107))	('ATM', 'Gene', (39, 42))	('decreased', 'NegReg', (124, 133))	('MDC1', 'Gene', '9656', (45, 49))	('increased', 'PosReg', (71, 80))	('Ser', 'cellular_component', 'GO:0005790', ('59', '62'))	('ATM', 'Gene', '472', (39, 42))	('MDC1', 'Gene', (45, 49))	('inhibition', 'Var', (146, 156))	('attenuates', 'NegReg', (175, 185))	('H2AX', 'Gene', '3014', (103, 107))
11831	26633513	The authors concluded that decreased pNBS1Ser343 mediated DNA repair in 48 h GANT61 exposed cells lead to the cell death, whereas in cells exposed to only 24 h GANT61 treatment recovered from GLI1 inhibition mediated DNA damage due to the pNBS1 ser343 reexpression and its mediated DNA repair.	('NBS1', 'Gene', '4683', (38, 42))	('cell death', 'biological_process', 'GO:0008219', ('110', '120'))	('reexpression', 'PosReg', (252, 264))	('NBS1', 'Gene', '4683', (240, 244))	('DNA', 'cellular_component', 'GO:0005574', ('217', '220'))	('decreased', 'NegReg', (27, 36))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('ser', 'cellular_component', 'GO:0005790', ('245', '248'))	('ser343', 'Chemical', '-', (245, 251))	('ser343', 'Var', (245, 251))	('NBS1', 'Gene', (240, 244))	('NBS1', 'Gene', (38, 42))	('Ser', 'cellular_component', 'GO:0005790', ('42', '45'))	('DNA repair', 'biological_process', 'GO:0006281', ('282', '292'))	('DNA repair', 'biological_process', 'GO:0006281', ('58', '68'))	('DNA', 'cellular_component', 'GO:0005574', ('282', '285'))
11832	26633513	These studies demonstrate an important role for aberrant GLI1 in regulation of the DDR and repair signaling in cancer cells, which could contribute to tumor cell survival from oncogenic stress and develop chemoresistance.	('GLI1', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('chemoresistance', 'CPA', (205, 220))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', (151, 156))	('aberrant', 'Var', (48, 56))	('rat', 'Species', '10116', (21, 24))	('contribute', 'Reg', (137, 147))	('develop', 'PosReg', (197, 204))	('regulation', 'biological_process', 'GO:0065007', ('65', '75'))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
11846	26633513	Impaired SHH signaling has been shown to induce spontaneous and ionizing radiation (IR)-induced genome instability and tumors development in mice.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('signaling', 'biological_process', 'GO:0023052', ('13', '22'))	('induce', 'Reg', (41, 47))	('SHH', 'Protein', (9, 12))	('mice', 'Species', '10090', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('genome instability', 'CPA', (96, 114))	('Impaired', 'Var', (0, 8))
11848	26633513	Although mutations in PTCH1 in humans and Ptc heterozygous mice (ptc+/-) known to develop increased spontaneous medulloblastoma; however, the mechanisms that lead to tumor development were not known.	('PTCH1', 'Gene', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('mice', 'Species', '10090', (59, 63))	('medulloblastoma', 'Phenotype', 'HP:0002885', (112, 127))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('medulloblastoma', 'Disease', 'MESH:D008527', (112, 127))	('increased', 'PosReg', (90, 99))	('mutations', 'Var', (9, 18))	('tumor', 'Disease', (166, 171))	('medulloblastoma', 'Disease', (112, 127))	('humans', 'Species', '9606', (31, 37))
11851	26633513	GLI1 expression abrogated IR-induced ATR-CHK1 signaling in these cells by disrupting DNA damage-induced binding of claspin to CHK1 and subsequent phosphorylation of CHK1 by ATR at Ser317 and Ser345 (Figure 2B).	('disrupting', 'NegReg', (74, 84))	('Ser317', 'Chemical', '-', (180, 186))	('phosphorylation', 'biological_process', 'GO:0016310', ('146', '161'))	('Ser345', 'Var', (191, 197))	('abrogated', 'NegReg', (16, 25))	('binding', 'molecular_function', 'GO:0005488', ('104', '111'))	('Ser317', 'Var', (180, 186))	('GLI1', 'Gene', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('expression', 'Var', (5, 15))	('Ser', 'cellular_component', 'GO:0005790', ('180', '183'))	('Ser', 'cellular_component', 'GO:0005790', ('191', '194'))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('claspin', 'Gene', (115, 122))	('DNA damage-induced', 'MPA', (85, 103))	('CHK1', 'Gene', (126, 130))	('CHK1', 'Gene', (165, 169))	('binding', 'Interaction', (104, 111))	('Ser345', 'Chemical', '-', (191, 197))	('claspin', 'Gene', '63967', (115, 122))	('phosphorylation', 'MPA', (146, 161))
11853	26633513	In contrast to above mechanism, our recent studies have revealed a tumor-specific role for aberrant GLI1 in regulation of S phase checkpoint.	('GLI1', 'Gene', (100, 104))	('S phase checkpoint', 'MPA', (122, 140))	('regulation', 'MPA', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('S phase checkpoint', 'biological_process', 'GO:0033314', ('122', '140'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('regulation of S phase', 'biological_process', 'GO:0033261', ('108', '129'))	('tumor', 'Disease', (67, 72))	('aberrant', 'Var', (91, 99))	('S phase checkpoint', 'biological_process', 'GO:0031573', ('122', '140'))
11854	26633513	Inhibition of GLI1 in several tumor cell lines originated from different tissues induced replication associated DNA damage as indicated by gammaH2AX and attenuated tumor cell growth.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('GLI1', 'Gene', (14, 18))	('tumor', 'Disease', (164, 169))	('induced', 'Reg', (81, 88))	('replication associated DNA damage', 'MPA', (89, 122))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('attenuated tumor', 'Disease', (153, 169))	('attenuated tumor', 'Disease', 'MESH:C538265', (153, 169))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('H2AX', 'Gene', '3014', (144, 148))	('cell growth', 'biological_process', 'GO:0016049', ('170', '181'))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))	('H2AX', 'Gene', (144, 148))	('tumor', 'Disease', (30, 35))
11855	26633513	Further analysis of replication stress-induced by DNA topoisomerase 1 (TOP 1) poison CPT revealed aberrant GLI1 important for the activation of S-phase checkpoint mediated by CHK1 in tumor cells.	('S-phase checkpoint', 'biological_process', 'GO:0031573', ('144', '162'))	('aberrant', 'Var', (98, 106))	('CPT', 'Gene', '56994', (85, 88))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('activation', 'PosReg', (130, 140))	('CPT', 'Gene', (85, 88))	('GLI1', 'Gene', (107, 111))	('DNA topoisomerase 1', 'Gene', '7150', (50, 69))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('CPT', 'molecular_function', 'GO:0004095', ('85', '88'))	('CPT', 'molecular_function', 'GO:0004142', ('85', '88'))	('S-phase checkpoint mediated', 'MPA', (144, 171))	('tumor', 'Disease', (183, 188))	('topoisomerase', 'molecular_function', 'GO:0003917', ('54', '67'))	('DNA topoisomerase 1', 'Gene', (50, 69))	('S-phase checkpoint', 'biological_process', 'GO:0033314', ('144', '162'))	('topoisomerase', 'molecular_function', 'GO:0003918', ('54', '67'))
11857	26633513	Furthermore, inhibition of GLI1 by either siRNAs or by pharmacological inhibitor GANT61 transcriptionally repressed the expression of BID, affected the association of RPA with the (ATRIP)-ATR complex, and compromised ATR-mediated phosphorylation/activation of CHK1.	('phosphorylation', 'biological_process', 'GO:0016310', ('230', '245'))	('affected', 'Reg', (139, 147))	('RPA', 'Gene', (167, 170))	('inhibition', 'Var', (13, 23))	('ATRIP', 'Gene', '84126', (181, 186))	('RPA', 'Gene', '6117', (167, 170))	('BID', 'Gene', '637', (134, 137))	('ATRIP', 'Gene', (181, 186))	('ATR-mediated phosphorylation/activation', 'MPA', (217, 256))	('association', 'Interaction', (152, 163))	('RPA', 'cellular_component', 'GO:0005662', ('167', '170'))	('compromised', 'NegReg', (205, 216))	('CHK1', 'Enzyme', (260, 264))	('BID', 'Gene', (134, 137))
11859	26633513	Similar to CHK1 inhibitors, pharmacological inhibition of aberrantly expressed GLI1 in tumor cells abrogated CPT-induced checkpoint responses, enhanced CPT-induced replication-mediated DNA damage and increased its cytotoxicity.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('DNA', 'cellular_component', 'GO:0005574', ('185', '188'))	('CPT', 'Gene', (109, 112))	('GLI1', 'Gene', (79, 83))	('CPT', 'molecular_function', 'GO:0004095', ('152', '155'))	('enhanced', 'PosReg', (143, 151))	('CPT', 'molecular_function', 'GO:0004095', ('109', '112'))	('CPT', 'Gene', '56994', (152, 155))	('aberrantly expressed', 'Var', (58, 78))	('cytotoxicity', 'Disease', (214, 226))	('increased', 'PosReg', (200, 209))	('tumor', 'Disease', (87, 92))	('cytotoxicity', 'Disease', 'MESH:D064420', (214, 226))	('replication-mediated DNA damage', 'MPA', (164, 195))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('abrogated', 'NegReg', (99, 108))	('CPT', 'Gene', (152, 155))	('CPT', 'Gene', '56994', (109, 112))	('CPT', 'molecular_function', 'GO:0004142', ('152', '155'))	('CPT', 'molecular_function', 'GO:0004142', ('109', '112'))
11862	26633513	), our studies suggests role for aberrant GLI1 during carcinogenesis, as well as their response to chemotherapy.	('carcinogenesis', 'Disease', 'MESH:D063646', (54, 68))	('carcinogenesis', 'Disease', (54, 68))	('aberrant', 'Var', (33, 41))
11865	26633513	Secondly, depletion of GLI1 causes a loss of BID which also leads to disruption of CHK1 activation.	('disruption', 'NegReg', (69, 79))	('BID', 'Gene', (45, 48))	('GLI1', 'Gene', (23, 27))	('depletion', 'Var', (10, 19))	('CHK1', 'Protein', (83, 87))	('loss', 'NegReg', (37, 41))	('activation', 'MPA', (88, 98))	('BID', 'Gene', '637', (45, 48))
11866	26633513	As disrupted DNA repair can directly lead to persistence of mutations that may promote carcinogenesis, studying GLI1 could lead to improved targeted therapies in repair-deficient tumors.	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('lead', 'Reg', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('deficient tumors', 'Disease', (169, 185))	('deficient tumors', 'Disease', 'MESH:D009369', (169, 185))	('DNA repair', 'biological_process', 'GO:0006281', ('13', '23'))	('promote', 'PosReg', (79, 86))	('carcinogenesis', 'Disease', (87, 101))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mutations', 'Var', (60, 69))
11867	26633513	As previously described, GLI1-mediated dysregulation of DNA repair can directly or indirectly lead to GI and such GI can promote carcinogenesis.	('dysregulation', 'Var', (39, 52))	('carcinogenesis', 'Disease', 'MESH:D063646', (129, 143))	('DNA repair', 'biological_process', 'GO:0006281', ('56', '66'))	('DNA repair', 'Gene', (56, 66))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('carcinogenesis', 'Disease', (129, 143))	('lead to', 'Reg', (94, 101))	('promote', 'PosReg', (121, 128))
11880	26633513	It is also necessary to analyze the roles of the different GLI1 mutations that are found in cancer on the development and progression of the cancer.	('GLI1', 'Gene', (59, 63))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (141, 147))
11882	26633513	Almost 90% of pancreatic ductal adenocarcinoma (PDA) has shown mutation in KRAS oncogene.	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (14, 46))	('KRAS oncogene', 'Gene', (75, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('mutation', 'Var', (63, 71))	('PDA', 'Phenotype', 'HP:0006725', (48, 51))	('pancreatic ductal adenocarcinoma', 'Disease', (14, 46))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (14, 46))
11892	26633513	Increased tumor growth was noticed in the GKO/KPC mice compared to KPC group alone.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('mice', 'Species', '10090', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('GKO/KPC', 'Var', (42, 49))
11902	26633513	It is important to highlight here again that in addition to GLI1 role in regulation of various mechanisms in tumor development, GLI1-induced disruption of ATR-CHK1 checkpoint signaling in the developing brain may generate the precursor lesions that lead to medulloblastoma formation.	('lead to', 'Reg', (249, 256))	('medulloblastoma', 'Disease', 'MESH:D008527', (257, 272))	('regulation', 'biological_process', 'GO:0065007', ('73', '83'))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('medulloblastoma', 'Phenotype', 'HP:0002885', (257, 272))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('formation', 'biological_process', 'GO:0009058', ('273', '282'))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('GLI1-induced', 'Gene', (128, 140))	('disruption', 'Var', (141, 151))	('medulloblastoma', 'Disease', (257, 272))	('rat', 'Species', '10116', (217, 220))	('tumor', 'Disease', (109, 114))
11907	26633513	Patients with nuclear GLI1 or FOXC2 typically exhibited diminished length of survival.	('FOXC2', 'Gene', '2303', (30, 35))	('length', 'MPA', (67, 73))	('Patients', 'Species', '9606', (0, 8))	('diminished', 'NegReg', (56, 66))	('FOXC2', 'Gene', (30, 35))	('nuclear GLI1', 'Var', (14, 26))
11911	26633513	Interestingly, silencing GLI1 expression in GLI1-induced tumors did not result in tumor regression, as the cells unexpectedly continued proliferation independent of GLI1.	('GLI1', 'Gene', (25, 29))	('continued', 'PosReg', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('silencing', 'Var', (15, 24))	('rat', 'Species', '10116', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', (82, 87))	('proliferation', 'CPA', (136, 149))
11912	26633513	The promoter region of the HH gene was found to be hypo-methylated in breast cancers and this correlated with increased HH and nuclear factor (NF)-kB expression, and nuclear accumulation of GLI1.	('HH', 'Gene', '42737', (27, 29))	('expression', 'MPA', (150, 160))	('increased HH', 'Phenotype', 'HP:0001900', (110, 122))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('nuclear accumulation', 'CPA', (166, 186))	('increased', 'PosReg', (110, 119))	('breast cancers', 'Phenotype', 'HP:0003002', (70, 84))	('HH', 'Gene', '42737', (120, 122))	('breast cancers', 'Disease', 'MESH:D001943', (70, 84))	('breast cancers', 'Disease', (70, 84))	('nuclear', 'Protein', (127, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('hypo-methylated', 'Var', (51, 66))
11920	26633513	Loss of E-cadherin causes beta-catenin to migrate into the nucleus, where it acts as a transcription factor and induces cell transformation.	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('nucleus', 'cellular_component', 'GO:0005634', ('59', '66'))	('beta-catenin', 'Gene', '1499', (26, 38))	('migrate', 'CPA', (42, 49))	('induces', 'Reg', (112, 119))	('cadherin', 'molecular_function', 'GO:0008014', ('10', '18'))	('beta-catenin', 'Gene', (26, 38))	('transcription factor', 'molecular_function', 'GO:0000981', ('87', '107'))	('Loss', 'Var', (0, 4))	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))	('rat', 'Species', '10116', (45, 48))	('cell transformation', 'CPA', (120, 139))
11923	26633513	Ectopic expression of GLI1 induced beta-catenin expression in the nuclei of endometrial cancer cell lines, and aberrant activation of this pathway may have a role in the development of endometrial cancer.	('beta-catenin', 'Gene', (35, 47))	('endometrial cancer', 'Phenotype', 'HP:0012114', (185, 203))	('endometrial cancer', 'Disease', 'MESH:D016889', (185, 203))	('endometrial cancer', 'Disease', (76, 94))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('expression', 'MPA', (48, 58))	('Ectopic expression', 'Var', (0, 18))	('activation', 'PosReg', (120, 130))	('beta-catenin', 'Gene', '1499', (35, 47))	('endometrial cancer', 'Phenotype', 'HP:0012114', (76, 94))	('induced', 'Reg', (27, 34))	('aberrant', 'Var', (111, 119))	('endometrial cancer', 'Disease', 'MESH:D016889', (76, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('GLI1', 'Gene', (22, 26))	('role', 'Reg', (158, 162))	('endometrial cancer', 'Disease', (185, 203))
11935	26633513	Aberrant expression of these DNMTs and dysregulation of DNA methylation has been reported in many cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('dysregulation', 'Var', (39, 52))	('DNMT', 'Gene', '1786', (29, 33))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('DNMT', 'Gene', (29, 33))	('DNA', 'Gene', (56, 59))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('expression', 'MPA', (9, 19))	('cancers', 'Disease', (98, 105))	('DNA methylation', 'biological_process', 'GO:0006306', ('56', '71'))	('reported', 'Reg', (81, 89))
11944	26633513	It has also been reported that GLI1 is over-expressed in more than 50% of hepatocellular carcinomas, and inhibition of HH signaling attenuated tumor growth and induced apoptosis.	('inhibition', 'Var', (105, 115))	('induced', 'Reg', (160, 167))	('attenuated tumor', 'Disease', (132, 148))	('GLI1', 'Gene', (31, 35))	('attenuated tumor', 'Disease', 'MESH:C538265', (132, 148))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('apoptosis', 'biological_process', 'GO:0097194', ('168', '177'))	('apoptosis', 'biological_process', 'GO:0006915', ('168', '177'))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (74, 99))	('apoptosis', 'CPA', (168, 177))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (74, 98))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (74, 99))	('over-expressed', 'PosReg', (39, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('HH', 'Gene', '42737', (119, 121))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('hepatocellular carcinomas', 'Disease', (74, 99))
11951	26633513	It will be interesting to note whether GLI1 alone is enough to induce tumor recurrence or if it works in combination with other oncogenic signals.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('induce', 'Reg', (63, 69))	('tumor', 'Disease', (70, 75))	('GLI1', 'Var', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
11963	26633513	On the other hand, inhibition of GLI1 signaling enhances the sensitivity of CD133 cells to temozolomide.	('signaling', 'biological_process', 'GO:0023052', ('38', '47'))	('inhibition', 'Var', (19, 29))	('CD133', 'Gene', (76, 81))	('CD133', 'Gene', '8842', (76, 81))	('temozolomide', 'Chemical', 'MESH:D000077204', (91, 103))	('enhances', 'PosReg', (48, 56))	('sensitivity', 'MPA', (61, 72))	('GLI1', 'Protein', (33, 37))
11974	26633513	Inhibition of GLI1 in ovarian cancer cells that are resistant to cisplatin caused an accumulation of cisplatin in the nucleus.	('ovarian cancer', 'Disease', 'MESH:D010051', (22, 36))	('cisplatin', 'MPA', (101, 110))	('GLI1', 'Gene', (14, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('nucleus', 'cellular_component', 'GO:0005634', ('118', '125'))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('accumulation', 'PosReg', (85, 97))	('ovarian cancer', 'Disease', (22, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (22, 36))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
11976	26633513	Inhibition of GLI1 not only suppresses tumor growth, but also sensitizes the cancer cells to chemotherapeutic agents.	('GLI1', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('suppresses', 'NegReg', (28, 38))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', (39, 44))	('sensitizes', 'Reg', (62, 72))
11982	26633513	Recently, it has been shown that in acute myeloid leukemia (AML) patients, GLI1 expression induces resistance to ribavirin by modifying the activity of the drug.	('AML', 'Disease', 'MESH:D015470', (60, 63))	('acute myeloid leukemia', 'Disease', (36, 58))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (36, 58))	('resistance to ribavirin', 'MPA', (99, 122))	('ribavirin', 'Chemical', 'MESH:D012254', (113, 122))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (36, 58))	('modifying', 'Reg', (126, 135))	('AML', 'Phenotype', 'HP:0004808', (60, 63))	('AML', 'Disease', (60, 63))	('patients', 'Species', '9606', (65, 73))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (42, 58))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))	('activity of the drug', 'MPA', (140, 160))	('GLI1', 'Gene', (75, 79))	('induces', 'Reg', (91, 98))	('expression', 'Var', (80, 90))
11985	26633513	Knocking down GLI1 affects the protein stability of UGT1A and sensitizes the cells to ribavirin.	('UGT1A', 'Gene', (52, 57))	('GLI1', 'Gene', (14, 18))	('Knocking down', 'Var', (0, 13))	('affects', 'Reg', (19, 26))	('ribavirin', 'Chemical', 'MESH:D012254', (86, 95))	('protein stability', 'MPA', (31, 48))	('UGT1A', 'Gene', '7361', (52, 57))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('sensitizes', 'Reg', (62, 72))
11992	26633513	Inhibition of SMO prevents UV-induced basal cell carcinomas through the regulation of Fas expression and apoptosis.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (38, 58))	('Fas', 'Protein', (86, 89))	('SMO', 'Gene', '6608', (14, 17))	('SMO', 'Gene', (14, 17))	('carcinomas', 'Phenotype', 'HP:0030731', (49, 59))	('apoptosis', 'CPA', (105, 114))	('apoptosis', 'biological_process', 'GO:0097194', ('105', '114'))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (38, 59))	('apoptosis', 'biological_process', 'GO:0006915', ('105', '114'))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (38, 59))	('Inhibition', 'Var', (0, 10))	('basal cell carcinomas', 'Disease', (38, 59))	('regulation', 'biological_process', 'GO:0065007', ('72', '82'))
12005	26633513	Overall, our review summarizes and updates the role of aberrant GLI1 activation in the DNA damage response, carcinogenesis and chemoresistance.	('DNA damage response', 'biological_process', 'GO:0006974', ('87', '106'))	('DNA damage', 'MPA', (87, 97))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('aberrant', 'Var', (55, 63))	('GLI1', 'Gene', (64, 68))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('carcinogenesis', 'Disease', (108, 122))	('activation', 'PosReg', (69, 79))
12007	26633513	The results may provide new directions for targeting aberrant GLI1 expression in cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('GLI1', 'Gene', (62, 66))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('aberrant', 'Var', (53, 61))
12011	26633513	In 2011, the authors appended two new hallmarks of cancer, dysregulated cellular metabolism and avoiding immune destruction.	('dysregulated', 'Var', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cellular metabolism', 'biological_process', 'GO:0044237', ('72', '91'))	('cellular metabolism', 'CPA', (72, 91))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
12014	26633513	Apart from these hallmarks, other important functions like epigenetic modification, angiogenesis, hypoxia, cancer stem cells, hTERT activity, DNA damage, repair and GI are induced or regulated by GLI1.	('hTERT', 'Gene', (126, 131))	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('angiogenesis', 'CPA', (84, 96))	('repair', 'CPA', (154, 160))	('hypoxia', 'Disease', (98, 105))	('hypoxia', 'Disease', 'MESH:D000860', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('hTERT', 'Gene', '7015', (126, 131))	('angiogenesis', 'biological_process', 'GO:0001525', ('84', '96'))	('cancer', 'Disease', (107, 113))	('epigenetic', 'Var', (59, 69))
12020	26633513	Inhibiting GLI1 alone or in combination with oncogenic signals will help to solve the complex roles of GLI1 in carcinogenesis.	('GLI1', 'Gene', (11, 15))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('carcinogenesis', 'Disease', (111, 125))	('Inhibiting', 'Var', (0, 10))
12027	26155170	Overexpression of TLR4, NOD1 and TRAF6 genes, and decreased MyD88 gene expression may contribute to chronic inflammation and tumor progression by up-regulation of the innate antibacterial response.	('expression', 'MPA', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('MyD88 gene', 'Gene', (60, 70))	('NOD1', 'Gene', (24, 28))	('up-regulation', 'PosReg', (146, 159))	('inflammation', 'Disease', (108, 120))	('TLR4', 'Gene', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('inflammation', 'biological_process', 'GO:0006954', ('108', '120'))	('tumor', 'Disease', (125, 130))	('TRAF6', 'Gene', (33, 38))	('decreased', 'NegReg', (50, 59))	('gene expression', 'biological_process', 'GO:0010467', ('66', '81'))	('Overexpression', 'Var', (0, 14))	('regulation', 'biological_process', 'GO:0065007', ('149', '159'))	('contribute', 'Reg', (86, 96))	('inflammation', 'Disease', 'MESH:D007249', (108, 120))
12046	26155170	The abnormal expression of TLR receptors may be associated with sepsis, and autoimmune diseases (lupus erythematosus, rheumatoid arthritis, type I diabetes).	('associated', 'Reg', (48, 58))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (118, 138))	('lupus erythematosus', 'Disease', 'MESH:D008180', (97, 116))	('lupus erythematosus', 'Phenotype', 'HP:0002725', (97, 116))	('sepsis', 'Phenotype', 'HP:0100806', (64, 70))	('sepsis', 'Disease', 'MESH:D018805', (64, 70))	('arthritis', 'Phenotype', 'HP:0001369', (129, 138))	('type I diabetes', 'Disease', 'MESH:D003922', (140, 155))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (118, 138))	('sepsis', 'Disease', (64, 70))	('abnormal', 'Var', (4, 12))	('type I diabetes', 'Disease', (140, 155))	('autoimmune diseases', 'Disease', 'MESH:D001327', (76, 95))	('autoimmune diseases', 'Disease', (76, 95))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (76, 95))	('TLR', 'Gene', (27, 30))	('expression', 'MPA', (13, 23))	('rheumatoid arthritis', 'Disease', (118, 138))	('type I diabetes', 'Phenotype', 'HP:0100651', (140, 155))	('lupus erythematosus', 'Disease', (97, 116))
12048	26155170	Toll-like receptors are involved in tumor cell proliferation, apoptosis and angiogenesis, while high expression of TLR4/MyD88 is correlated with poor prognosis in patients with colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (177, 194))	('TLR4/MyD88', 'Gene', (115, 125))	('tumor', 'Disease', (36, 41))	('colorectal cancer', 'Disease', (177, 194))	('involved', 'Reg', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('correlated', 'Reg', (129, 139))	('Toll', 'Gene', (0, 4))	('angiogenesis', 'biological_process', 'GO:0001525', ('76', '88'))	('patients', 'Species', '9606', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('colorectal cancer', 'Phenotype', 'HP:0003003', (177, 194))	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('Toll', 'Gene', '7099', (0, 4))	('high', 'Var', (96, 100))	('cell proliferation', 'biological_process', 'GO:0008283', ('42', '60'))	('expression', 'MPA', (101, 111))
12057	26155170	Nucleotide-binding oligomerization domain-containing protein 2 deficiency in mice can lead to a compromised epithelial barrier and impaired immune response to commensal microbiota.	('mice', 'Species', '10090', (77, 81))	('impaired', 'NegReg', (131, 139))	('immune response', 'CPA', (140, 155))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('deficiency', 'Var', (63, 73))	('immune response', 'biological_process', 'GO:0006955', ('140', '155'))	('Nucleotide-binding oligomerization domain-containing protein 2', 'Gene', '257632', (0, 62))	('Nucleotide-binding', 'molecular_function', 'GO:0000166', ('0', '18'))
12058	26155170	In turn, NOD1 deficiency results in increased tumor formation associated with the inflammation of the colon in mice.	('formation', 'biological_process', 'GO:0009058', ('52', '61'))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('inflammation of the colon', 'Disease', (82, 107))	('inflammation of the colon', 'Disease', 'MESH:D007249', (82, 107))	('tumor', 'Disease', (46, 51))	('mice', 'Species', '10090', (111, 115))	('increased', 'PosReg', (36, 45))	('deficiency', 'Var', (14, 24))	('NOD1', 'Gene', (9, 13))	('inflammation', 'biological_process', 'GO:0006954', ('82', '94'))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
12059	26155170	A recent study showed that NOD2 polymorphisms have been linked to gastric cancer that is induced by Helicobacter pylori infection.	('Helicobacter pylori infection', 'Disease', 'MESH:D016481', (100, 129))	('polymorphisms', 'Var', (32, 45))	('linked', 'Reg', (56, 62))	('NOD2', 'Gene', (27, 31))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (100, 129))	('NOD2', 'Gene', '64127', (27, 31))	('Helicobacter pylori infection', 'Disease', (100, 129))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
12073	26155170	The results were analyzed using the method of double delta, assuming that the expression of the gene in the treated groups is 2-DeltaDeltaCt, where DeltaDeltaCt = [Ct target gene - Ct GAPDH] is the treated sample, and [Ct target gene - Ct GAPDH] is the control sample.	('DeltaDeltaCt =', 'Var', (148, 162))	('GAPDH', 'Gene', '2597', (184, 189))	('GAPDH', 'Gene', (184, 189))	('GAPDH', 'Gene', '2597', (239, 244))	('GAPDH', 'Gene', (239, 244))
12084	26155170	Disorders of gene expression in peripheral blood leukocytes that infiltrate tumor cells have a major impact on the course of cancer disease by supporting chronic inflammation in the tumor microenvironment.	('Disorders', 'Var', (0, 9))	('inflammation', 'Disease', 'MESH:D007249', (162, 174))	('impact', 'Reg', (101, 107))	('cancer disease', 'Disease', 'MESH:D009369', (125, 139))	('inflammation', 'biological_process', 'GO:0006954', ('162', '174'))	('tumor', 'Disease', (182, 187))	('inflammation', 'Disease', (162, 174))	('gene expression', 'biological_process', 'GO:0010467', ('13', '28'))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', (76, 81))	('cancer disease', 'Disease', (125, 139))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('supporting', 'PosReg', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
12090	26155170	These findings suggest that the disorders of innate immunity gene expression, through various mediators, may cause dysfunction of the leukocyte immune response in malnourished pancreatic cancer patients, resulting in disease progression.	('leukocyte immune response', 'MPA', (134, 159))	('patients', 'Species', '9606', (194, 202))	('innate immunity', 'biological_process', 'GO:0045087', ('45', '60'))	('cause', 'Reg', (109, 114))	('pancreatic cancer', 'Disease', (176, 193))	('pancreatic cancer', 'Disease', 'MESH:D010190', (176, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('disorders', 'Var', (32, 41))	('dysfunction', 'MPA', (115, 126))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (176, 193))	('immune response', 'biological_process', 'GO:0006955', ('144', '159'))	('gene expression', 'biological_process', 'GO:0010467', ('61', '76'))
12111	26155170	It should be emphasized that synthetic inhibitors of MyD88 pathway were shown to exacerbate pancreatic fibro-inflammation and accelerate carcinogenesis, while mice deprived of TLR2 and the MyD88 adaptor protein were more susceptible to infections.	('inhibitors', 'Var', (39, 49))	('pancreatic fibro-inflammation', 'Disease', (92, 121))	('accelerate', 'PosReg', (126, 136))	('carcinogenesis', 'Disease', 'MESH:D063646', (137, 151))	('MyD88 pathway', 'Gene', (53, 66))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('pancreatic fibro-inflammation', 'Disease', 'MESH:D007249', (92, 121))	('inflammation', 'biological_process', 'GO:0006954', ('109', '121'))	('carcinogenesis', 'Disease', (137, 151))	('mice', 'Species', '10090', (159, 163))	('exacerbate', 'PosReg', (81, 91))
12115	26155170	Silencing the expression of MyD88 gene in peripheral blood leukocytes completely reversed the effects of LPS by activation of new signal pathways.	('activation', 'PosReg', (112, 122))	('Silencing', 'Var', (0, 9))	('LPS', 'Gene', '21898', (105, 108))	('new signal pathways', 'Pathway', (126, 145))	('LPS', 'Gene', (105, 108))	('MyD88', 'Gene', (28, 33))
12117	26155170	Other authors have shown that TLR4 is overexpressed in human pancreatic ductal adenocarcinoma (in 69-76% of the analyzed tumors), and inhibition of MyD88-dependent pathways clearly accelerated the development of pancreatic tumor and could induce the formation of aggressive cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (212, 228))	('pancreatic ductal adenocarcinoma', 'Disease', (61, 93))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('formation', 'biological_process', 'GO:0009058', ('250', '259'))	('aggressive cancer', 'Disease', 'MESH:D009369', (263, 280))	('pancreatic tumor', 'Disease', (212, 228))	('accelerated', 'PosReg', (181, 192))	('MyD88-dependent pathways', 'Pathway', (148, 172))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (61, 93))	('formation', 'CPA', (250, 259))	('pancreatic tumor', 'Disease', 'MESH:D010190', (212, 228))	('induce', 'Reg', (239, 245))	('development', 'CPA', (197, 208))	('inhibition', 'Var', (134, 144))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('human', 'Species', '9606', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('aggressive cancer', 'Disease', (263, 280))	('TLR4', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (61, 93))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
12119	26155170	Interestingly, inhibition of TLR4 in these mice had a protective effect against tumorigenesis (slower tumor growth).	('mice', 'Species', '10090', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (80, 85))	('TLR4', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('inhibition', 'Var', (15, 25))
12125	26155170	In addition, neutrophil infiltrations are reported in pancreatic adenocarcinomas and have been associated with the undifferentiated types of carcinoma and poor prognosis.	('carcinoma', 'Disease', 'MESH:D002277', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('carcinoma', 'Disease', 'MESH:D002277', (70, 79))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (54, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (54, 79))	('reported', 'Reg', (42, 50))	('carcinoma', 'Disease', (70, 79))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (54, 80))	('carcinoma', 'Disease', (141, 150))	('pancreatic adenocarcinomas', 'Disease', (54, 80))	('neutrophil', 'Var', (13, 23))	('associated', 'Reg', (95, 105))
12160	26155170	In summary, the results of our study clearly indicate an abnormal gene expression in the innate antibacterial signaling pathways in peripheral blood leukocytes of patients with pancreatic cancer, which may lead to leukocyte dysfunction.	('leukocyte dysfunction', 'Disease', (214, 235))	('abnormal gene expression', 'Var', (57, 81))	('patients', 'Species', '9606', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('innate antibacterial signaling pathways', 'Pathway', (89, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (177, 194))	('lead to', 'Reg', (206, 213))	('gene expression', 'biological_process', 'GO:0010467', ('66', '81'))	('pancreatic cancer', 'Disease', (177, 194))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (177, 194))	('leukocyte dysfunction', 'Disease', 'MESH:D007960', (214, 235))
12161	26155170	Overexpression of TLR4, NOD1 and TRAF6 genes, and a decreased MyD88 gene expression may contribute to chronic inflammation and tumor progression by up-regulation of the innate antibacterial response (e.g.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('contribute', 'Reg', (88, 98))	('up-regulation', 'PosReg', (148, 161))	('NOD1', 'Gene', (24, 28))	('inflammation', 'Disease', (110, 122))	('tumor', 'Disease', (127, 132))	('TLR4', 'Gene', (18, 22))	('decreased', 'NegReg', (52, 61))	('MyD88 gene', 'Gene', (62, 72))	('expression', 'MPA', (73, 83))	('regulation', 'biological_process', 'GO:0065007', ('151', '161'))	('Overexpression', 'Var', (0, 14))	('gene expression', 'biological_process', 'GO:0010467', ('68', '83'))	('TRAF6 genes', 'Gene', (33, 44))	('inflammation', 'biological_process', 'GO:0006954', ('110', '122'))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('inflammation', 'Disease', 'MESH:D007249', (110, 122))
12202	16295788	According to Ridwelski et al., monoclonal antibodies against cytokeratin may be more specific and reliable than CA 19-9 at detecting disseminated tumor cells in lymph nodes.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cytokeratin', 'Gene', (61, 72))	('tumor', 'Disease', (146, 151))	('monoclonal', 'Var', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
12243	23741220	Laboratory data on admission revealed no abnormalities in inflammation tests or tumor markers such as carcinoembryonic antigen, carbohydrate antigen (CA)19-9 and CA125.	('inflammation', 'biological_process', 'GO:0006954', ('58', '70'))	('carcinoembryonic', 'Disease', (102, 118))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('carcinoembryonic', 'Disease', 'None', (102, 118))	('tumor', 'Disease', (80, 85))	('inflammation', 'Disease', 'MESH:D007249', (58, 70))	('CA125', 'Var', (162, 167))	('inflammation', 'Disease', (58, 70))
12364	21647423	Figure 1 shows the real-time ultrasound acquired images of the USGI of 1x106 HCT116/deltaOR+ cells in a 20 microL bolus into the mouse pancreas.	('HCT116', 'CellLine', 'CVCL:0291', (77, 83))	('mouse', 'Species', '10090', (129, 134))	('HCT116/deltaOR+', 'Var', (77, 92))	('1x106 HCT116/deltaOR+', 'Var', (71, 92))
12370	21647423	Initially mice bearing orthotopic xenografts of HCT116/deltaOR+ via SOI and USGI were imaged weekly by ultrasound for up to 4 weeks to monitor tumor growth.	('HCT116/deltaOR+', 'Var', (48, 63))	('tumor', 'Disease', (143, 148))	('mice', 'Species', '10090', (10, 14))	('HCT116', 'CellLine', 'CVCL:0291', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
12380	21647423	The in vivo fluorescence images in Figure 3 showed uptake of the fluorescent probe in the area of the pancreas for both mouse models, indicating the presence of HCT116/deltaOR+ tumor cells.	('uptake', 'MPA', (51, 57))	('tumor', 'Disease', (177, 182))	('uptake', 'biological_process', 'GO:0098739', ('51', '57'))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('HCT116', 'CellLine', 'CVCL:0291', (161, 167))	('uptake', 'biological_process', 'GO:0098657', ('51', '57'))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('HCT116/deltaOR+', 'Var', (161, 176))	('mouse', 'Species', '10090', (120, 125))
12388	21647423	By histology, tumors were observed in 100% of pancreata that underwent USGI or SOI using HCT116/deltaOR+ cells.	('HCT116/deltaOR+ cells', 'Var', (89, 110))	('HCT116', 'CellLine', 'CVCL:0291', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
12406	21647423	This suggests that pancreatic cancer xenografts using HCT116/deltaOR+ cells are similar to pancreatic cancer cell xenografts.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('HCT116', 'CellLine', 'CVCL:0291', (54, 60))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (19, 36))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('HCT116/deltaOR+', 'Var', (54, 69))	('pancreatic cancer', 'Disease', (19, 36))	('pancreatic cancer', 'Disease', 'MESH:D010190', (19, 36))	('pancreatic cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))
12409	21647423	Although HCT116/deltaOR+ cells are human colorectal cancer cells, they are relevant for pancreatic xenograft models because they are known to form occult metastases in the pancreas.	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('HCT116', 'CellLine', 'CVCL:0291', (9, 15))	('pancreatic xenograft', 'Disease', 'MESH:D010195', (88, 108))	('colorectal cancer', 'Disease', (41, 58))	('human', 'Species', '9606', (35, 40))	('metastases', 'Disease', (154, 164))	('pancreatic xenograft', 'Disease', (88, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (41, 58))	('HCT116/deltaOR+ cells', 'Var', (9, 30))	('metastases', 'Disease', 'MESH:D009362', (154, 164))
12412	21647423	Based on ultrasound imaging, in vivo and ex vivo fluorescence imaging, and histological analysis, the xenograft take rate was 100% for both USGI and SOI using HCT116/deltaOR+ cells.	('HCT116/deltaOR+ cells', 'Var', (159, 180))	('HCT116', 'CellLine', 'CVCL:0291', (159, 165))	('xenograft take rate', 'CPA', (102, 121))
12434	21285251	siRNA-mediated knockdown of DCAMKL-1 in human pancreatic cancer cells induced microRNA miR-200a, an EMT inhibitor, along with down-regulation of EMT-associated transcription factors ZEB1, ZEB2, Snail, Slug and Twist.	('EMT', 'biological_process', 'GO:0001837', ('145', '148'))	('ZEB2', 'Gene', (188, 192))	('pancreatic cancer', 'Disease', (46, 63))	('Slug', 'Gene', '6591', (201, 205))	('EMT', 'biological_process', 'GO:0001837', ('100', '103'))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Snail', 'Gene', (194, 199))	('ZEB1', 'Gene', (182, 186))	('ZEB2', 'Gene', '9839', (188, 192))	('miR-200a', 'Gene', '406983', (87, 95))	('down-regulation', 'NegReg', (126, 141))	('human', 'Species', '9606', (40, 45))	('DCAMKL-1', 'Gene', (28, 36))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (46, 63))	('ZEB1', 'Gene', '6935', (182, 186))	('regulation', 'biological_process', 'GO:0065007', ('131', '141'))	('Slug', 'Gene', (201, 205))	('Snail', 'Gene', '6615', (194, 199))	('knockdown', 'Var', (15, 24))	('transcription', 'biological_process', 'GO:0006351', ('160', '173'))	('miR-200a', 'Gene', (87, 95))	('pancreatic cancer', 'Disease', 'MESH:D010190', (46, 63))
12435	21285251	Furthermore, DCAMKL-1 knockdown resulted in downregulation of c-Myc and KRAS through a let-7a microRNA-dependent mechanism, and downregulation of Notch-1 through a miR-144 microRNA-dependent mechanism.	('c-Myc', 'Gene', '4609', (62, 67))	('KRAS', 'Protein', (72, 76))	('c-Myc', 'Gene', (62, 67))	('downregulation', 'NegReg', (44, 58))	('knockdown', 'Var', (22, 31))	('let-7a', 'Gene', (87, 93))	('let-7a', 'Gene', '387244', (87, 93))	('DCAMKL-1', 'Gene', (13, 21))	('Notch-1', 'Gene', (146, 153))	('Notch-1', 'Gene', '4851', (146, 153))	('downregulation', 'NegReg', (128, 142))
12465	21285251	Furthermore, knockdown of DCAMKL-1 also resulted in downregulation of the proto-oncogenes c-Myc and KRAS via up regulation of pri-let-7a and inhibition of Notch-1 via miR-144 miRNA dependent mechanisms.	('KRAS', 'Gene', (100, 104))	('inhibition', 'NegReg', (141, 151))	('miR', 'Gene', '220972', (167, 170))	('c-Myc', 'Gene', '4609', (90, 95))	('miR', 'Gene', (167, 170))	('miR', 'Gene', '220972', (175, 178))	('c-Myc', 'Gene', (90, 95))	('miR', 'Gene', (175, 178))	('Notch-1', 'Gene', (155, 162))	('up regulation', 'PosReg', (109, 122))	('Notch-1', 'Gene', '4851', (155, 162))	('let-7a', 'Gene', '387244', (130, 136))	('downregulation', 'NegReg', (52, 66))	('DCAMKL-1', 'Gene', (26, 34))	('let-7a', 'Gene', (130, 136))	('knockdown', 'Var', (13, 22))	('regulation', 'biological_process', 'GO:0065007', ('112', '122'))
12472	21285251	The P48Cre-LSL-KRASG12D is a mouse model of pancreatic cancer that was initially developed by the Tyler Jacks laboratory.	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('P48Cre-LSL-KRASG12D', 'Var', (4, 23))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('mouse', 'Species', '10090', (29, 34))	('pancreatic cancer', 'Disease', (44, 61))
12474	21285251	When compared to 129V, the mutant mouse on the C57BL/6 genetic background develops more aggressive pancreatic lesions.	('mouse', 'Species', '10090', (34, 39))	('aggressive pancreatic lesions', 'Disease', 'MESH:D010182', (88, 117))	('aggressive pancreatic lesions', 'Disease', (88, 117))	('mutant', 'Var', (27, 33))
12477	21285251	Pancreatic tissues from 5-month-old P48Cre-LSL-KRASG12D and their wild-type (WT) littermates were immunostained for DCAMKL-1.	('Pancreatic', 'Disease', (0, 10))	('P48Cre-LSL-KRASG12D', 'Var', (36, 55))	('Pancreatic', 'Disease', 'MESH:D010195', (0, 10))
12482	21285251	These data suggest that DCAMKL-1 is upregulated in pancreas of P48Cre-LSL-KRASG12D mouse and may play an important role in mutated KRAS mediated tumorigenesis.	('play', 'Reg', (97, 101))	('DCAMKL-1', 'Gene', (24, 32))	('upregulated', 'PosReg', (36, 47))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('P48Cre-LSL-KRASG12D', 'Var', (63, 82))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mouse', 'Species', '10090', (83, 88))	('tumor', 'Disease', (145, 150))	('mutated', 'Var', (123, 130))
12487	21285251	However, in chronic pancreatitis, we observed DCAMKL-1 in the islets, ducts and a few intervening stromal cells (Supplementary Figure S1B-F).	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (12, 32))	('pancreatitis', 'Disease', (20, 32))	('observed', 'Reg', (37, 45))	('DCAMKL-1', 'Var', (46, 54))	('pancreatitis', 'Phenotype', 'HP:0001733', (20, 32))	('pancreatitis', 'Disease', 'MESH:D010195', (20, 32))
12518	21285251	Furthermore, DCAMKL-1 knockdown results in the downregulation of Snail, Slug and Twist (Fig.	('downregulation', 'NegReg', (47, 61))	('Snail', 'Gene', '6615', (65, 70))	('Snail', 'Gene', (65, 70))	('knockdown', 'Var', (22, 31))	('Slug', 'Gene', '6591', (72, 76))	('DCAMKL-1', 'Gene', (13, 21))	('Slug', 'Gene', (72, 76))
12520	21285251	These data taken together suggest that knockdown of DCAMKL-1 inhibits EMT via miR-200a dependent mechanism in human pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))	('miR-200a', 'Gene', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('miR-200a', 'Gene', '406983', (78, 86))	('EMT', 'CPA', (70, 73))	('DCAMKL-1', 'Gene', (52, 60))	('knockdown', 'Var', (39, 48))	('EMT', 'biological_process', 'GO:0001837', ('70', '73'))	('human', 'Species', '9606', (110, 115))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('pancreatic cancer', 'Disease', (116, 133))	('inhibits', 'NegReg', (61, 69))
12533	21285251	Similarly a reduction in c-Myc protein was observed following the knockdown of DCAMKL-1 (Fig.	('reduction', 'NegReg', (12, 21))	('c-Myc', 'Gene', (25, 30))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('knockdown', 'Var', (66, 75))	('c-Myc', 'Gene', '4609', (25, 30))	('DCAMKL-1', 'Gene', (79, 87))
12534	21285251	KRAS is a critical gene that is mutated in many cancers including pancreatic cancer and several studies have reported that up to 95% of pancreatic cancers contain KRAS mutations.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('pancreatic cancers', 'Disease', 'MESH:D010190', (136, 154))	('mutations', 'Var', (168, 177))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('KRAS', 'Gene', (163, 167))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancers', 'Disease', (48, 55))	('pancreatic cancer', 'Disease', 'MESH:D010190', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (136, 154))	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('pancreatic cancer', 'Disease', (66, 83))	('contain', 'Reg', (155, 162))	('pancreatic cancers', 'Disease', (136, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('cancers', 'Disease', 'MESH:D009369', (48, 55))
12536	21285251	Following knockdown of DCAMKL-1, we observed a 45% reduction in KRAS mRNA expression compared to control or AsPC-1-siSCR cells (Fig.	('reduction', 'NegReg', (51, 60))	('AsPC-1', 'CellLine', 'CVCL:0152', (108, 114))	('KRAS', 'Gene', (64, 68))	('DCAMKL-1', 'Gene', (23, 31))	('knockdown', 'Var', (10, 19))
12538	21285251	These data taken together demonstrate that DCAMKL-1 knockdown results in downregulation of c-Myc and KRAS, two key mediators of tumorigenesis in pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (145, 162))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('KRAS', 'Protein', (101, 105))	('pancreatic cancer', 'Disease', (145, 162))	('pancreatic cancer', 'Disease', 'MESH:D010190', (145, 162))	('c-Myc', 'Gene', '4609', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('DCAMKL-1', 'Gene', (43, 51))	('tumor', 'Disease', (128, 133))	('downregulation', 'NegReg', (73, 87))	('knockdown', 'Var', (52, 61))	('c-Myc', 'Gene', (91, 96))
12545	21285251	In this study, we observed a 50% reduction in Notch-1 mRNA in AsPC-1-siDCAMKL-1 cells compared to control AsPC-1 or AsPC-1-siSCR cells (Fig.	('Notch-1', 'Gene', '4851', (46, 53))	('reduction', 'NegReg', (33, 42))	('AsPC-1-siDCAMKL-1', 'CellLine', 'CVCL:3165', (62, 79))	('AsPC-1', 'CellLine', 'CVCL:0152', (116, 122))	('AsPC-1', 'CellLine', 'CVCL:0152', (106, 112))	('AsPC-1-siDCAMKL-1', 'Var', (62, 79))	('Notch-1', 'Gene', (46, 53))	('AsPC-1', 'CellLine', 'CVCL:0152', (62, 68))
12563	21285251	We have previously demonstrated that DCAMKL-1 is upregulated in human colorectal cancers and siRNA mediated knockdown of DCAMKL-1 results in tumor growth arrest via let-7a miRNA dependent manner.	('human', 'Species', '9606', (64, 69))	('tumor growth arrest', 'Disease', (141, 160))	('knockdown', 'Var', (108, 117))	('let-7a', 'Gene', (165, 171))	('let-7a', 'Gene', '387244', (165, 171))	('DCAMKL-1', 'Gene', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('miR', 'Gene', '220972', (172, 175))	('miR', 'Gene', (172, 175))	('colorectal cancers', 'Disease', 'MESH:D015179', (70, 88))	('DCAMKL-1', 'Gene', (37, 45))	('upregulated', 'PosReg', (49, 60))	('colorectal cancers', 'Disease', (70, 88))	('growth arrest', 'Phenotype', 'HP:0001510', (147, 160))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor growth arrest', 'Disease', 'MESH:D006323', (141, 160))
12577	21285251	Indeed in this report, knockdown of DCAMKL-1 induces pri-miR-200a resulting in down regulation of ZEB1, ZEB2, Snail, Slug and Twist in pancreatic cancer cell lines.	('pancreatic cancer', 'Disease', (135, 152))	('Twist', 'CPA', (126, 131))	('ZEB1', 'Gene', '6935', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('miR-200a', 'Gene', '406983', (57, 65))	('DCAMKL-1', 'Gene', (36, 44))	('induces', 'Reg', (45, 52))	('Slug', 'Gene', (117, 121))	('Snail', 'Gene', '6615', (110, 115))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (135, 152))	('regulation', 'biological_process', 'GO:0065007', ('84', '94'))	('ZEB1', 'Gene', (98, 102))	('ZEB2', 'Gene', (104, 108))	('miR-200a', 'Gene', (57, 65))	('down regulation', 'NegReg', (79, 94))	('knockdown', 'Var', (23, 32))	('ZEB2', 'Gene', '9839', (104, 108))	('Slug', 'Gene', '6591', (117, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (135, 152))	('Snail', 'Gene', (110, 115))
12582	21285251	DCAMKL-1 knockdown in AsPC-1 cells resulted in a marked decrease in Notch-1 mRNA (50%), which contains a putative predicted binding site for miR-144 in the 3'UTR.	('Notch-1', 'Gene', (68, 75))	('knockdown', 'Var', (9, 18))	('Notch-1', 'Gene', '4851', (68, 75))	('binding', 'Interaction', (124, 131))	('AsPC-1', 'CellLine', 'CVCL:0152', (22, 28))	('decrease', 'NegReg', (56, 64))	('binding', 'molecular_function', 'GO:0005488', ('124', '131'))	('DCAMKL-1', 'Gene', (0, 8))
12594	21285251	These data suggests that DCAMKL-1 disruption results in inhibition of the Notch-1 pathway thereby confirming its role as a potential target in anti-cancer strategies.	('cancer', 'Disease', (148, 154))	('inhibition', 'NegReg', (56, 66))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('Notch-1', 'Gene', (74, 81))	('Notch-1', 'Gene', '4851', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('disruption', 'Var', (34, 44))	('DCAMKL-1', 'Gene', (25, 33))
12598	33731188	Dysregulation of ECM dynamics leads to various pathological conditions and is crucial in cancer development and progression.	('leads to', 'Reg', (30, 38))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('pathological conditions', 'Disease', (47, 70))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
12605	33731188	During adult life an intense splicing activity of the FN1 gene occurs in angiogenesis, tissue repair, fibrosis and of relevance in cancer where FN1 modifications strongly contribute to the age-related alterations in the ECM biosynthesis and degradation, thus modulating the tumor microenvironment (TME) composition and cancer progression.	('biosynthesis', 'biological_process', 'GO:0009058', ('224', '236'))	('contribute', 'Reg', (171, 181))	('ECM biosynthesis', 'MPA', (220, 236))	('cancer', 'Disease', (319, 325))	('tumor', 'Disease', (274, 279))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('FN1', 'Gene', (144, 147))	('degradation', 'MPA', (241, 252))	('FN1', 'Gene', (54, 57))	('modifications', 'Var', (148, 161))	('alterations', 'Reg', (201, 212))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('modulating', 'Reg', (259, 269))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('degradation', 'biological_process', 'GO:0009056', ('241', '252'))	('cancer', 'Disease', (131, 137))	('fibrosis', 'Disease', 'MESH:D005355', (102, 110))	('fibrosis', 'Disease', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('splicing', 'biological_process', 'GO:0045292', ('29', '37'))	('angiogenesis', 'biological_process', 'GO:0001525', ('73', '85'))
12609	33731188	The role of EDA in pathological processes such as cancer has been demonstrated by the work of Manabe and colleagues who revealed the importance of EDA+ FN1 in promoting cell cycle progression through the induction of cyclin D1 expression, hyperphosphorylation of pRb, and activation of mitogen-activated protein kinase extracellular signal regulated kinase 2 (ERK2).	('cyclin', 'molecular_function', 'GO:0016538', ('217', '223'))	('cancer', 'Disease', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('activation', 'PosReg', (272, 282))	('cyclin D1', 'Gene', '595', (217, 226))	('ERK2', 'Gene', '5594', (360, 364))	('extracellular', 'cellular_component', 'GO:0005576', ('319', '332'))	('ERK2', 'Gene', (360, 364))	('ERK2', 'molecular_function', 'GO:0004707', ('360', '364'))	('cell cycle', 'biological_process', 'GO:0007049', ('169', '179'))	('extracellular signal regulated kinase 2', 'Gene', '5594', (319, 358))	('hyperphosphorylation', 'MPA', (239, 259))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('EDA+ FN1', 'Var', (147, 155))	('protein', 'cellular_component', 'GO:0003675', ('304', '311'))	('pRb', 'Gene', (263, 266))	('cell cycle progression', 'CPA', (169, 191))	('extracellular signal regulated kinase 2', 'Gene', (319, 358))	('promoting', 'PosReg', (159, 168))	('expression', 'MPA', (227, 237))	('pRb', 'Gene', '5925', (263, 266))	('hyperphosphorylation', 'biological_process', 'GO:0048151', ('239', '259'))	('cyclin D1', 'Gene', (217, 226))
12614	33731188	It has been shown that the activation of TLR4 by EDA+ FN in mesenchymal cells leads to a pro-fibrotic gene program characterized by the up-regulation of genes involved in wound healing, tissue repair and ECM remodelling.	('TLR4', 'Gene', (41, 45))	('pro-fibrotic gene program', 'MPA', (89, 114))	('wound healing', 'biological_process', 'GO:0042060', ('171', '184'))	('regulation', 'biological_process', 'GO:0065007', ('139', '149'))	('EDA+ FN', 'Var', (49, 56))	('genes', 'MPA', (153, 158))	('activation', 'PosReg', (27, 37))	('TLR4', 'Gene', '7099', (41, 45))	('up-regulation', 'PosReg', (136, 149))
12615	33731188	EDB deficient mice develop normally and are fertile.	('deficient', 'Var', (4, 13))	('mice', 'Species', '10090', (14, 18))	('EDB', 'Gene', (0, 3))	('develop', 'CPA', (19, 26))
12618	33731188	By the use of biologically active recombinant EDB+ cFN it was observed that EDB+ cFN is incorporated more efficiently into the ECM and EDB-/- embryonic fibroblasts (MEFs) grow slowly and produce thinner and shorter fibrils compared to control MEFs, indicating a role of this domain in the efficacious assembly of FN1 ECM.	('EDB+ cFN', 'Var', (76, 84))	('MEFs', 'CellLine', 'CVCL:9115', (243, 247))	('grow', 'CPA', (171, 175))	('MEFs', 'CellLine', 'CVCL:9115', (165, 169))	('EDB-/-', 'Var', (135, 141))	('slowly', 'NegReg', (176, 182))	('shorter', 'NegReg', (207, 214))
12620	33731188	The alpha5beta1 integrin is the primary receptor mediating the assembly process, as demonstrated by blocking antibodies against anti-integrin or anti-FN1.	('anti-FN1', 'Var', (145, 153))	('beta1 integrin', 'Gene', (10, 24))	('beta1 integrin', 'Gene', '3688', (10, 24))	('anti-integrin', 'Protein', (128, 141))
12628	33731188	The cryptic FN1 sites reside within the FNIII modules which, upon mechanical cell traction, expose cryptic binding sites allowing FN matrix assembly, as demonstrated by antibodies that recognize this region and by specific FN1 deletions, indicating that the III2 repeat is a critical module for fibrils formation.	('formation', 'biological_process', 'GO:0009058', ('303', '312'))	('cryptic', 'Gene', '55997', (99, 106))	('cryptic', 'Gene', (99, 106))	('deletions', 'Var', (227, 236))	('cryptic', 'Gene', '55997', (4, 11))	('FN1', 'Gene', (223, 226))	('cryptic', 'Gene', (4, 11))	('binding', 'molecular_function', 'GO:0005488', ('107', '114'))
12647	33731188	When fibrosis is in advanced stage, the high ECM stiffness induces fibroblasts to co-express EDA+ FN and LTBP-1 favoring their interaction in the ECM, suggesting that the inhibition of LTBP-1 and EDA+ FN interaction may reduce the TGF-beta1 reservoir in the ECM and fibrosis.	('inhibition', 'Var', (171, 181))	('fibrosis', 'Disease', 'MESH:D005355', (266, 274))	('LTBP-1', 'Gene', (185, 191))	('LTBP-1', 'Gene', '4052', (105, 111))	('TGF-beta1', 'Gene', '7040', (231, 240))	('LTBP-1', 'Gene', '4052', (185, 191))	('TGF-beta1', 'Gene', (231, 240))	('reduce', 'NegReg', (220, 226))	('LTBP-1', 'Gene', (105, 111))	('fibrosis', 'Disease', (266, 274))	('fibrosis', 'Disease', 'MESH:D005355', (5, 13))	('fibrosis', 'Disease', (5, 13))	('interaction', 'Interaction', (127, 138))
12648	33731188	The interference with the contractile function of myofibroblasts may be another potential therapeutic option for fibrosis, as suggested by Torr and coauthors who have differentiated human pulmonary fibroblasts in myofibroblasts by TGF-beta1 treatment and then inhibited fibrillogenesis by pharmacologic disruption of the transcription factor megakaryoblastic leukemia-1 (MKL1)/serum response factor (SRF), or by of the depletion of MKL1/SRF target gene, the alpha-SMA.	('disruption', 'Var', (303, 313))	('serum response factor', 'Gene', '6722', (377, 398))	('SRF', 'Gene', (437, 440))	('fibrillogenesis', 'CPA', (270, 285))	('alpha-SMA', 'Gene', (458, 467))	('inhibited', 'NegReg', (260, 269))	('MKL1', 'Gene', '57591', (371, 375))	('TGF-beta1', 'Gene', (231, 240))	('megakaryoblastic leukemia-1', 'Gene', (342, 369))	('fibrosis', 'Disease', 'MESH:D005355', (113, 121))	('fibrosis', 'Disease', (113, 121))	('alpha-SMA', 'Gene', '58', (458, 467))	('serum response factor', 'Gene', (377, 398))	('TGF-beta1', 'Gene', '7040', (231, 240))	('MKL1', 'Gene', '57591', (432, 436))	('MKL1', 'Gene', (371, 375))	('transcription', 'biological_process', 'GO:0006351', ('321', '334'))	('human', 'Species', '9606', (182, 187))	('megakaryoblastic leukemia-1', 'Gene', '57591', (342, 369))	('MKL1', 'Gene', (432, 436))	('SRF', 'Gene', '6722', (400, 403))	('depletion', 'MPA', (419, 428))	('SRF', 'Gene', (400, 403))	('transcription factor', 'molecular_function', 'GO:0000981', ('321', '341'))	('SRF', 'Gene', '6722', (437, 440))	('leukemia', 'Phenotype', 'HP:0001909', (359, 367))
12652	33731188	FN1 assembly has been suggested as a new hallmark of CAFs that promote tumor invasion as indicated in colon cancer-derived CAFs, where CAF contractility induces FN1 assembly and tumor cell invasion.	('tumor', 'Disease', (178, 183))	('contractility', 'Var', (139, 152))	('assembly', 'MPA', (165, 173))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colon cancer', 'Disease', 'MESH:D015179', (102, 114))	('FN1', 'Protein', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('promote', 'PosReg', (63, 70))	('colon cancer', 'Disease', (102, 114))	('induces', 'Reg', (153, 160))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
12674	33731188	These data have a strong clinical implication since in primary tumors high hMENA11a correlates with low stromal FN1 and a favorable clinical outcome of early node-negative non-small-cell lung cancer (NSCLC) patients, providing a new tool for the stratification of patient risk, guiding their clinical management.	('hMENA', 'Gene', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('patients', 'Species', '9606', (207, 215))	('hMENA', 'Gene', '55740', (75, 80))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('SCLC', 'Phenotype', 'HP:0030357', (201, 205))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('NSCLC', 'Disease', (200, 205))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('low', 'NegReg', (100, 103))	('patient', 'Species', '9606', (264, 271))	('high', 'Var', (70, 74))	('patient', 'Species', '9606', (207, 214))	('lung cancer', 'Disease', (187, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
12677	33731188	Moreover, FN1 also induces cell proliferation regulating cancerous inhibitor of protein phosphatase 2A (CIP2A) expression via its stabilization mediated by beta catenin in bladder cancer.	('beta catenin', 'Gene', (156, 168))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('cell proliferation', 'CPA', (27, 45))	('CIP2A', 'Gene', (104, 109))	('FN1', 'Var', (10, 13))	('cancerous inhibitor of protein phosphatase 2A', 'Gene', (57, 102))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('expression', 'MPA', (111, 121))	('cell proliferation', 'biological_process', 'GO:0008283', ('27', '45'))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('bladder cancer', 'Disease', 'MESH:D001749', (172, 186))	('protein phosphatase 2A', 'molecular_function', 'GO:0050115', ('80', '102'))	('bladder cancer', 'Disease', (172, 186))	('stabilization', 'MPA', (130, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (172, 186))	('cancerous inhibitor of protein phosphatase 2A', 'Gene', '57650', (57, 102))	('induces', 'PosReg', (19, 26))	('CIP2A', 'Gene', '57650', (104, 109))	('beta catenin', 'Gene', '1499', (156, 168))
12690	33731188	Indeed, in the absence of TLR3, FN1 and the other upregulated genes, neutrophil recruitment and lung metastasis are reduced.	('FN1', 'Gene', (32, 35))	('absence', 'Var', (15, 22))	('TLR3', 'Gene', '142980', (26, 30))	('lung metastasis', 'CPA', (96, 111))	('reduced', 'NegReg', (116, 123))	('TLR3', 'Gene', (26, 30))	('neutrophil recruitment', 'CPA', (69, 91))
12722	33731188	Mechanistically, FN1 sustains the cell viability and proliferation and in parallel reduces the docetaxel-induced apoptosis inhibiting the caspase 8.	('caspase 8', 'Gene', '841', (138, 147))	('inhibiting', 'NegReg', (123, 133))	('caspase 8', 'Gene', (138, 147))	('reduces', 'NegReg', (83, 90))	('FN1', 'Var', (17, 20))	('docetaxel-induced apoptosis', 'MPA', (95, 122))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('docetaxel', 'Chemical', 'MESH:D000077143', (95, 104))	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))	('cell viability', 'CPA', (34, 48))
12734	33731188	In human lung cancer cells unfolded type III domain of FN1 inhibited TRAIL induced apoptosis through the activation of a PI3K/Akt/alphavbeta5 signaling pathway.	('human', 'Species', '9606', (3, 8))	('inhibited', 'NegReg', (59, 68))	('PI3', 'Gene', '5266', (121, 124))	('Akt', 'Gene', (126, 129))	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('activation', 'PosReg', (105, 115))	('Akt', 'Gene', '207', (126, 129))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('FN1', 'Gene', (55, 58))	('apoptosis', 'CPA', (83, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))	('PI3K', 'molecular_function', 'GO:0016303', ('121', '125'))	('TRAIL', 'Gene', '8743', (69, 74))	('PI3', 'Gene', (121, 124))	('domain', 'Var', (45, 51))	('signaling pathway', 'biological_process', 'GO:0007165', ('142', '159'))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('TRAIL', 'Gene', (69, 74))	('lung cancer', 'Disease', (9, 20))
12842	33275621	We categorized the participants based on their BMI at enrolment as: underweight (BMI < 18.5), normal (18.5 <= BMI < 25), overweight (25 <= BMI < 30), and obese (BMI >= 30).	('obese', 'Disease', 'MESH:D009765', (154, 159))	('participants', 'Species', '9606', (19, 31))	('obese', 'Disease', (154, 159))	('25 <= BMI <', 'Var', (133, 144))	('overweight', 'Phenotype', 'HP:0025502', (121, 131))	('18.5 <=', 'Var', (102, 109))
12916	33275621	Additionally, opioid receptors have been found in PC tissues and the experimental studies have shown that inhibiting these receptors results in the inhibition of PC progression, as the development and progression of PC are shown to be related to opioid receptor pathways.	('inhibition', 'NegReg', (148, 158))	('inhibiting', 'Var', (106, 116))	('PC', 'Gene', '5091', (216, 218))	('PC', 'Gene', '5091', (162, 164))	('PC', 'Gene', '5091', (50, 52))
13007	33194580	3D-PSPBT resulted in a significant dose reduction for GI-OARs in both the low-intermediate dose range (below 30 GyE) and the highest dose region (Dmax and V50 GyE) in comparison with IMRT and VMAT (P < 0.05).	('GI-OARs', 'Disease', (54, 61))	('GI-OARs', 'Disease', 'MESH:D005767', (54, 61))	('a', 'Gene', '351', (21, 22))	('a', 'Gene', '351', (188, 189))	('a', 'Gene', '351', (117, 118))	('a', 'Gene', '351', (31, 32))	('a', 'Gene', '351', (151, 152))	('a', 'Gene', '351', (87, 88))	('A', 'Gene', '351', (58, 59))	('dose', 'MPA', (35, 39))	('a', 'Gene', '351', (97, 98))	('Dmax', 'Chemical', '-', (146, 150))	('3D-PSPBT', 'Chemical', '-', (0, 8))	('reduction', 'NegReg', (40, 49))	('A', 'Gene', '351', (194, 195))	('a', 'Gene', '351', (148, 149))	('a', 'Gene', '351', (171, 172))	('3D-PSPBT', 'Var', (0, 8))
13008	33194580	Based on the NTCP evaluation, the NTCP reduction for GI-OARs by 3D-PSPBT was minimal in comparison with IMRT and VMAT.	('a', 'Gene', '351', (20, 21))	('3D-PSPBT', 'Chemical', '-', (64, 72))	('NTCP', 'Chemical', '-', (13, 17))	('NTCP', 'Chemical', '-', (34, 38))	('a', 'Gene', '351', (74, 75))	('a', 'Gene', '351', (1, 2))	('3D-PSPBT', 'Var', (64, 72))	('A', 'Gene', '351', (115, 116))	('a', 'Gene', '351', (23, 24))	('a', 'Gene', '351', (82, 83))	('A', 'Gene', '351', (57, 58))	('a', 'Gene', '351', (92, 93))	('a', 'Gene', '351', (109, 110))	('GI-OARs', 'Disease', (53, 60))	('GI-OARs', 'Disease', 'MESH:D005767', (53, 60))
13009	33194580	Conclusion: 3D-PSPBT results in minimal NTCP reduction and has less potential to substantially reduce the toxicity risk of upper GI bleeding, ulceration, obstruction, and perforation endpoints compared to IMRT and VMAT.	('a', 'Gene', '351', (177, 178))	('reduce', 'NegReg', (95, 101))	('toxicity', 'Disease', (106, 114))	('GI bleeding', 'Phenotype', 'HP:0002239', (129, 140))	('reduction', 'NegReg', (45, 54))	('3D-PSPBT', 'Chemical', '-', (12, 20))	('NTCP', 'MPA', (40, 44))	('a', 'Gene', '351', (55, 56))	('a', 'Gene', '351', (86, 87))	('upper GI bleeding', 'Disease', 'MESH:D006470', (123, 140))	('a', 'Gene', '351', (37, 38))	('a', 'Gene', '351', (197, 198))	('NTCP', 'Chemical', '-', (40, 44))	('A', 'Gene', '351', (216, 217))	('3D-PSPBT', 'Var', (12, 20))	('obstruction', 'Disease', 'MESH:D000402', (154, 165))	('a', 'Gene', '351', (75, 76))	('a', 'Gene', '351', (60, 61))	('toxicity', 'Disease', 'MESH:D064420', (106, 114))	('a', 'Gene', '351', (147, 148))	('a', 'Gene', '351', (90, 91))	('a', 'Gene', '351', (210, 211))	('upper GI bleeding', 'Disease', (123, 140))	('obstruction', 'Disease', (154, 165))	('a', 'Gene', '351', (167, 168))
13010	33194580	3D-PSPBT may have the potential to reduce acute dose-limiting toxicity in the form of nausea, vomiting, and diarrhea by reducing the GI-OAR treated volume in the low-to-intermediate dose range.	('a', 'Gene', '351', (87, 88))	('a', 'Gene', '351', (104, 105))	('diarrhea', 'Disease', (108, 116))	('3D-PSPBT', 'Var', (0, 8))	('a', 'Gene', '351', (143, 144))	('vomiting', 'Disease', 'MESH:D014839', (94, 102))	('a', 'Gene', '351', (14, 15))	('reducing', 'NegReg', (120, 128))	('toxicity', 'Disease', 'MESH:D064420', (62, 70))	('nausea', 'Phenotype', 'HP:0002018', (86, 92))	('diarrhea', 'Disease', 'MESH:D003967', (108, 116))	('a', 'Gene', '351', (110, 111))	('a', 'Gene', '351', (29, 30))	('vomiting', 'Phenotype', 'HP:0002013', (94, 102))	('vomiting', 'Disease', (94, 102))	('A', 'Gene', '351', (137, 138))	('a', 'Gene', '351', (188, 189))	('nausea', 'Disease', (86, 92))	('a', 'Gene', '351', (115, 116))	('toxicity', 'Disease', (62, 70))	('a', 'Gene', '351', (91, 92))	('a', 'Gene', '351', (10, 11))	('a', 'Gene', '351', (178, 179))	('a', 'Gene', '351', (42, 43))	('diarrhea', 'Phenotype', 'HP:0002014', (108, 116))	('3D-PSPBT', 'Chemical', '-', (0, 8))	('nausea', 'Disease', 'MESH:D009325', (86, 92))
13075	33194580	For the stomach, the dose constraints were V50 GyE <=2% and V45 GyE <=25%, respectively.	('V50 GyE <', 'Var', (43, 52))	('a', 'Gene', '351', (56, 57))	('a', 'Gene', '351', (12, 13))	('a', 'Gene', '351', (32, 33))	('V45 GyE <', 'Var', (60, 69))
13078	33194580	For the small bowel, the dose constraints were V50 GyE <=2% and V45 GyE <=25%, respectively.	('a', 'Gene', '351', (10, 11))	('V50 GyE <', 'Var', (47, 56))	('a', 'Gene', '351', (36, 37))	('V45 GyE <', 'Var', (64, 73))	('a', 'Gene', '351', (60, 61))
13079	33194580	For both kidneys, the dose constraints were V18 GyE <=50% and V23 GyE <=30%, respectively.	('a', 'Gene', '351', (33, 34))	('a', 'Gene', '351', (58, 59))	('V23 GyE <', 'Var', (62, 71))	('V18 GyE <=50', 'Var', (44, 56))
13090	33194580	D2%, D98%, and D50% are the doses received by 2, 98, and 50%, respectively, of the target volume.	('a', 'Gene', '351', (20, 21))	('a', 'Gene', '351', (11, 12))	('D50%', 'Var', (15, 19))	('D98%', 'Var', (5, 9))	('a', 'Gene', '351', (53, 54))	('a', 'Gene', '351', (84, 85))	('D2%', 'Var', (0, 3))
13114	33194580	3D-PSPBT decreased the stomach, duodenum, and small bowel doses in low-intermediate regions (P < 0.05) and showed a clear dosimetric benefit below 30 GyE compared to IMRT and VMAT.	('a', 'Gene', '351', (27, 28))	('a', 'Gene', '351', (158, 159))	('a', 'Gene', '351', (103, 104))	('a', 'Gene', '351', (14, 15))	('a', 'Gene', '351', (48, 49))	('a', 'Gene', '351', (42, 43))	('duodenum', 'MPA', (32, 40))	('3D-PSPBT', 'Chemical', '-', (0, 8))	('a', 'Gene', '351', (80, 81))	('a', 'Gene', '351', (114, 115))	('A', 'Gene', '351', (177, 178))	('a', 'Gene', '351', (171, 172))	('3D-PSPBT', 'Var', (0, 8))	('a', 'Gene', '351', (119, 120))
13121	33194580	The Dmean to the liver with IMRT was significantly lower,  41% lower, in comparison with VMAT (2.20 vs. 3.75 GyE, P < 0.001).	('a', 'Gene', '351', (34, 35))	('lower', 'NegReg', (63, 68))	('a', 'Gene', '351', (7, 8))	('a', 'Gene', '351', (45, 46))	('Dmean', 'Chemical', '-', (4, 9))	('lower', 'NegReg', (51, 56))	('A', 'Gene', '351', (91, 92))	('IMRT', 'Var', (28, 32))	('a', 'Gene', '351', (77, 78))
13122	33194580	3D-PSPBT reduced the spinal cord Dmax significantly in comparison with IMRT (14.9 vs. 20.6 GyE, P = 0.03) and VMAT (14.9 vs. 19.3 GyE, P = 0.04).	('a', 'Gene', '351', (59, 60))	('a', 'Gene', '351', (106, 107))	('a', 'Gene', '351', (25, 26))	('a', 'Gene', '351', (35, 36))	('3D-PSPBT', 'Chemical', '-', (0, 8))	('reduced', 'NegReg', (9, 16))	('Dmax', 'Chemical', '-', (33, 37))	('a', 'Gene', '351', (46, 47))	('A', 'Gene', '351', (112, 113))	('3D-PSPBT', 'Var', (0, 8))
13125	33194580	The dose reduction of the GI-OARs in the high-dose region of V50 GyE and Dmax obtained using 3D-PSPBT did not result in a substantial NTCP reduction in comparison with IMRT and VMAT (Figures 5A-D).	('A', 'Gene', '351', (30, 31))	('a', 'Gene', '351', (120, 121))	('A', 'Gene', '351', (179, 180))	('3D-PSPBT', 'Chemical', '-', (93, 101))	('GI-OARs', 'Disease', (26, 33))	('GI-OARs', 'Disease', 'MESH:D005767', (26, 33))	('a', 'Gene', '351', (127, 128))	('reduction', 'NegReg', (139, 148))	('a', 'Gene', '351', (173, 174))	('A', 'Gene', '351', (192, 193))	('a', 'Gene', '351', (69, 70))	('a', 'Gene', '351', (131, 132))	('a', 'Gene', '351', (156, 157))	('V50', 'Var', (61, 64))	('a', 'Gene', '351', (75, 76))	('NTCP', 'MPA', (134, 138))	('Dmax', 'Chemical', '-', (73, 77))	('NTCP', 'Chemical', '-', (134, 138))	('a', 'Gene', '351', (81, 82))
13135	33194580	In our study, the observed dosimetric differences in the Dmax and V50GyE for the stomach, duodenum, small bowel, and stoduo were statistically significant with the 3D-PSPBT plan in comparison with the IMRT and VMAT plans.	('a', 'Gene', '351', (59, 60))	('A', 'Gene', '351', (212, 213))	('3D-PSPBT', 'Var', (164, 172))	('a', 'Gene', '351', (185, 186))	('a', 'Gene', '351', (206, 207))	('a', 'Gene', '351', (151, 152))	('V50GyE', 'Var', (66, 72))	('a', 'Gene', '351', (138, 139))	('a', 'Gene', '351', (62, 63))	('a', 'Gene', '351', (131, 132))	('3D-PSPBT', 'Chemical', '-', (164, 172))	('Dmax', 'Chemical', '-', (57, 61))	('a', 'Gene', '351', (217, 218))	('a', 'Gene', '351', (102, 103))	('a', 'Gene', '351', (85, 86))	('a', 'Gene', '351', (113, 114))	('a', 'Gene', '351', (175, 176))
13136	33194580	However, in our study, 3D-PSPBT results in minimal NTCP reduction and has less potential to substantially reduce the toxicity risk of the upper GI bleeding, ulceration, obstruction, and perforation endpoints in comparison with IMRT and VMAT.	('3D-PSPBT', 'Chemical', '-', (23, 31))	('obstruction', 'Disease', (169, 180))	('a', 'Gene', '351', (192, 193))	('a', 'Gene', '351', (48, 49))	('NTCP', 'Chemical', '-', (51, 55))	('upper GI bleeding', 'Disease', 'MESH:D006470', (138, 155))	('a', 'Gene', '351', (71, 72))	('a', 'Gene', '351', (215, 216))	('GI bleeding', 'Phenotype', 'HP:0002239', (144, 155))	('a', 'Gene', '351', (182, 183))	('a', 'Gene', '351', (86, 87))	('a', 'Gene', '351', (101, 102))	('toxicity', 'Disease', 'MESH:D064420', (117, 125))	('3D-PSPBT', 'Var', (23, 31))	('a', 'Gene', '351', (162, 163))	('A', 'Gene', '351', (238, 239))	('toxicity', 'Disease', (117, 125))	('upper GI bleeding', 'Disease', (138, 155))	('reduction', 'NegReg', (56, 65))	('obstruction', 'Disease', 'MESH:D000402', (169, 180))	('a', 'Gene', '351', (66, 67))	('a', 'Gene', '351', (97, 98))	('reduce', 'NegReg', (106, 112))	('a', 'Gene', '351', (232, 233))	('NTCP', 'MPA', (51, 55))
13139	33194580	The 3D-PSPBT plan resulted in a significantly reduced dose to GI-OARs in the low-intermediate dose range (below 30 GyE) than did the IMRT and VMAT plans, as shown in Table 3 and Figures 3C-E.	('a', 'Gene', '351', (15, 16))	('a', 'Gene', '351', (40, 41))	('a', 'Gene', '351', (174, 175))	('3D-PSPBT', 'Chemical', '-', (4, 12))	('A', 'Gene', '351', (66, 67))	('a', 'Gene', '351', (149, 150))	('a', 'Gene', '351', (30, 31))	('A', 'Gene', '351', (144, 145))	('a', 'Gene', '351', (138, 139))	('GI-OARs', 'Disease', (62, 69))	('a', 'Gene', '351', (100, 101))	('GI-OARs', 'Disease', 'MESH:D005767', (62, 69))	('dose', 'MPA', (54, 58))	('reduced', 'NegReg', (46, 53))	('a', 'Gene', '351', (154, 155))	('a', 'Gene', '351', (122, 123))	('3D-PSPBT', 'Var', (4, 12))	('a', 'Gene', '351', (90, 91))	('a', 'Gene', '351', (167, 168))
13166	33194580	3D-PSPBT decreased the volume of GI-OARs receiving radiation doses at 50 GyE and the highest dose region.	('GI-OARs', 'Disease', (33, 40))	('GI-OARs', 'Disease', 'MESH:D005767', (33, 40))	('a', 'Gene', '351', (14, 15))	('a', 'Gene', '351', (52, 53))	('a', 'Gene', '351', (55, 56))	('3D-PSPBT', 'Chemical', '-', (0, 8))	('a', 'Gene', '351', (67, 68))	('3D-PSPBT', 'Var', (0, 8))	('a', 'Gene', '351', (77, 78))
13167	33194580	However, as per NTCP reduction, 3D-PSPBT does not have the potential to reduce radiation-related upper GI bleeding, ulceration, obstruction, or perforation in comparison with IMRT and VMAT.	('A', 'Gene', '351', (186, 187))	('3D-PSPBT', 'Var', (32, 40))	('a', 'Gene', '351', (80, 81))	('a', 'Gene', '351', (150, 151))	('obstruction', 'Disease', (128, 139))	('a', 'Gene', '351', (180, 181))	('a', 'Gene', '351', (92, 93))	('upper GI bleeding', 'Disease', 'MESH:D006470', (97, 114))	('a', 'Gene', '351', (83, 84))	('GI bleeding', 'Phenotype', 'HP:0002239', (103, 114))	('a', 'Gene', '351', (163, 164))	('3D-PSPBT', 'Chemical', '-', (32, 40))	('NTCP', 'Chemical', '-', (16, 20))	('a', 'Gene', '351', (121, 122))	('a', 'Gene', '351', (66, 67))	('a', 'Gene', '351', (9, 10))	('a', 'Gene', '351', (51, 52))	('upper GI bleeding', 'Disease', (97, 114))	('obstruction', 'Disease', 'MESH:D000402', (128, 139))
13183	33077737	In this review, we present the role of exosomes in the TME and the underlying mechanism of how exosomes exacerbate tumor development through metabolic reprogramming.	('exosomes', 'Var', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('exacerbate', 'PosReg', (104, 114))	('metabolic reprogramming', 'CPA', (141, 164))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
13201	33077737	Another study showed that KIBRA could regulate exosome secretion by inhibiting proteasome degradation of Rab27a, and KIBRA depletion could increase the number and size of MVBs.	('KIBRA', 'Gene', (117, 122))	('KIBRA', 'Gene', '23286', (26, 31))	('inhibiting', 'NegReg', (68, 78))	('proteasome', 'molecular_function', 'GO:0004299', ('79', '89'))	('proteasome', 'cellular_component', 'GO:0000502', ('79', '89'))	('Rab27a', 'Gene', '5873', (105, 111))	('proteasome degradation', 'biological_process', 'GO:1903009', ('79', '101'))	('KIBRA', 'Gene', '23286', (117, 122))	('secretion', 'biological_process', 'GO:0046903', ('55', '64'))	('increase', 'PosReg', (139, 147))	('depletion', 'Var', (123, 132))	('exosome', 'cellular_component', 'GO:0070062', ('47', '54'))	('KIBRA', 'Gene', (26, 31))	('Rab27a', 'Gene', (105, 111))	('proteasome degradation', 'MPA', (79, 101))	('exosome secretion', 'MPA', (47, 64))
13224	33077737	Inhibition of these enzymes can suppress tumor growth both in vivo and in vitro.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('suppress', 'NegReg', (32, 40))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
13257	33077737	Moreover, Michael and colleagues found that knockdown of Cav-1 resulted in significant upregulation of glycolytic enzymes, including lactate dehydrogenase and pyruvate kinase.	('Cav-1', 'Gene', (57, 62))	('pyruvate', 'Chemical', 'MESH:D019289', (159, 167))	('lactate', 'Chemical', 'MESH:D019344', (133, 140))	('Cav-1', 'Gene', '857', (57, 62))	('upregulation', 'PosReg', (87, 99))	('knockdown', 'Var', (44, 53))	('lactate dehydrogenase', 'MPA', (133, 154))	('pyruvate kinase', 'MPA', (159, 174))	('glycolytic enzymes', 'MPA', (103, 121))
13313	33077737	Exosomal miR-1246 secreted from mutp53 colon cancer cells triggered M2 type polarization of macrophages.	('miR-1246', 'Gene', (9, 17))	('colon cancer', 'Disease', 'MESH:D015179', (39, 51))	('colon cancer', 'Phenotype', 'HP:0003003', (39, 51))	('mutp53', 'Var', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('triggered', 'Reg', (58, 67))	('colon cancer', 'Disease', (39, 51))	('miR-1246', 'Gene', '100302142', (9, 17))	('M2 type polarization of macrophages', 'CPA', (68, 103))
13336	33077737	Another study found that miR-105-containing exosomes derived from breast cancer cells could induce metabolic reprogramming in the CAFs.	('metabolic reprogramming in the', 'CPA', (99, 129))	('miR-105', 'Chemical', '-', (25, 32))	('CAF', 'Disease', 'None', (130, 133))	('miR-105-containing', 'Var', (25, 43))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('CAF', 'Disease', (130, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('induce', 'PosReg', (92, 98))
13358	33077737	Cells detachment induce a large amount of ROS, and excessive ROS can cause cell death, namely anoikis, which is an obstacle to metastasis.	('ROS', 'MPA', (42, 45))	('ROS', 'Var', (61, 64))	('anoikis', 'Disease', (94, 101))	('cell death', 'CPA', (75, 85))	('ROS', 'Chemical', 'MESH:D017382', (42, 45))	('cell death', 'biological_process', 'GO:0008219', ('75', '85'))	('cause', 'Reg', (69, 74))	('anoikis', 'biological_process', 'GO:0043276', ('94', '101'))	('ROS', 'Chemical', 'MESH:D017382', (61, 64))
13369	33077737	Furthermore, EVs packaged LMP1 markedly increased the important pre-metastatic niche factors (S100A8, VEGFR1 and fibronectin) levels by stimulating CAFs in vivo favored the establishment of pre-metastatic niche in nasopharyngeal carcinoma.	('CAF', 'Disease', (148, 151))	('EVs packaged', 'Var', (13, 25))	('CAF', 'Disease', 'None', (148, 151))	('fibronectin', 'Gene', '2335', (113, 124))	('LMP1', 'Gene', '9260', (26, 30))	('pre', 'molecular_function', 'GO:0003904', ('64', '67'))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('carcinoma', 'Disease', (229, 238))	('S100A8', 'Gene', (94, 100))	('favored', 'PosReg', (161, 168))	('S100A8', 'Gene', '6279', (94, 100))	('VEGFR1', 'Gene', '2321', (102, 108))	('VEGFR1', 'Gene', (102, 108))	('establishment of pre-metastatic niche', 'CPA', (173, 210))	('pre', 'molecular_function', 'GO:0003904', ('190', '193'))	('carcinoma', 'Disease', 'MESH:D009369', (229, 238))	('stimulating', 'PosReg', (136, 147))	('LMP1', 'Gene', (26, 30))	('increased', 'PosReg', (40, 49))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (214, 238))	('fibronectin', 'Gene', (113, 124))
13380	33077737	It is currently known that tumor drug resistance mechanisms include drug efflux, altered drug metabolism, altered energy programming, DNA damage repair, cancer stem cells, and epigenetic alterations.	('altered', 'Reg', (106, 113))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('efflux', 'biological_process', 'GO:0140115', ('73', '79'))	('tumor', 'Disease', (27, 32))	('energy programming', 'MPA', (114, 132))	('drug resistance', 'biological_process', 'GO:0009315', ('33', '48'))	('efflux', 'biological_process', 'GO:0140352', ('73', '79'))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('drug resistance', 'biological_process', 'GO:0042493', ('33', '48'))	('epigenetic alterations', 'Var', (176, 198))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('DNA damage repair', 'MPA', (134, 151))	('drug metabolism', 'biological_process', 'GO:0017144', ('89', '104'))	('drug resistance', 'Phenotype', 'HP:0020174', (33, 48))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('drug efflux', 'MPA', (68, 79))	('altered', 'Reg', (81, 88))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))
13410	33077737	However, inhibition of glycolysis improved the anti-tumor immunity of T cells.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('improved', 'PosReg', (34, 42))	('tumor', 'Disease', (52, 57))	('inhibition of glycolysis', 'biological_process', 'GO:0045820', ('9', '33'))	('glycolysis', 'MPA', (23, 33))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('inhibition', 'Var', (9, 19))
13430	33077737	showed that enriched PKM2 and GLUT1 were secreted in exosomes from activated hepatic stellate cells (HSCs), which induced the "Warburg effect" of quiescent HSCs, Kupffer cells (KCs) and liver sinusoidal endothelial cells (LSECs); meanwhile, inhibition of Hif-1 by 2-ME (an inhibitor of Hif-1) or specific siRNA suppressed the expression of PKM2 and GLUT1 in exosomes from LPS- or hypoxia-activated LX-2 cells.	('suppressed', 'NegReg', (311, 321))	('GLUT1', 'Gene', (30, 35))	('LPS', 'Disease', 'MESH:C536528', (372, 375))	('inhibition', 'Var', (241, 251))	('expression', 'MPA', (326, 336))	('Hif-1', 'Gene', '3091', (255, 260))	('PKM2', 'Gene', (340, 344))	('Hif-1', 'Gene', '3091', (286, 291))	('PKM2', 'Gene', (21, 25))	('hypoxia', 'Disease', (380, 387))	('PKM2', 'Gene', '5315', (21, 25))	('GLUT1', 'Gene', '6513', (349, 354))	('Hif-1', 'Gene', (255, 260))	('Hif-1', 'Gene', (286, 291))	('PKM2', 'Gene', '5315', (340, 344))	('hypoxia', 'Disease', 'MESH:D000860', (380, 387))	('GLUT1', 'Gene', '6513', (30, 35))	('LX-2', 'CellLine', 'CVCL:5792', (398, 402))	('GLUT1', 'Gene', (349, 354))	('LPS', 'Disease', (372, 375))
13447	33077737	Meanwhile, inhibition of exosomal miR-122 could rescue glucose metabolism in distant organs, such as lungs and brain, and decreased the incidence of tumor metastasis in vivo, which demonstrated that exosomal miR-122 was able to remodel systemic energy metabolism to promote tumor progression.	('rescue', 'PosReg', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('metabolism', 'biological_process', 'GO:0008152', ('252', '262'))	('inhibition', 'Var', (11, 21))	('tumor', 'Disease', (274, 279))	('remodel', 'Reg', (228, 235))	('tumor metastasis', 'Disease', (149, 165))	('exosomal', 'Var', (199, 207))	('miR-122', 'Gene', '406906', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('miR-122', 'Gene', '406906', (208, 215))	('glucose metabolism', 'biological_process', 'GO:0006006', ('55', '73'))	('glucose metabolism', 'Disease', (55, 73))	('miR-122', 'Gene', (34, 41))	('miR-122', 'Gene', (208, 215))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('promote', 'PosReg', (266, 273))	('glucose metabolism', 'Disease', 'MESH:D044882', (55, 73))	('tumor', 'Disease', (149, 154))	('tumor metastasis', 'Disease', 'MESH:D009362', (149, 165))	('decreased', 'NegReg', (122, 131))
13450	33077737	In contrast, glycolysis was not significantly influenced by the exosomal miR-155 in the cancer cells.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('miR-155', 'Gene', '406947', (73, 80))	('glycolysis', 'biological_process', 'GO:0006096', ('13', '23'))	('exosomal', 'Var', (64, 72))	('glycolysis', 'MPA', (13, 23))	('miR-155', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
13457	33077737	Moreover, inhibition of miR-126 or miR-144 decreased adipocyte-induced tumor progression in vivo, which revealed exosomal miR-126 and miR-144 from the tumor-adipocyte crosstalk remodeled systemic energy metabolism to promote tumor progression.	('miR-126', 'Gene', '406913', (24, 31))	('tumor', 'Disease', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('remodeled', 'Reg', (177, 186))	('miR-144', 'Gene', '406936', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('decreased adipocyte', 'Phenotype', 'HP:0040063', (43, 62))	('miR-126', 'Gene', (122, 129))	('miR-144', 'Gene', (35, 42))	('inhibition', 'Var', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('metabolism', 'biological_process', 'GO:0008152', ('203', '213'))	('miR-126', 'Gene', (24, 31))	('tumor', 'Disease', (71, 76))	('miR-144', 'Gene', (134, 141))	('miR-126', 'Gene', '406913', (122, 129))	('promote', 'PosReg', (217, 224))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('miR-144', 'Gene', '406936', (35, 42))	('decreased', 'NegReg', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
13468	33077737	Meanwhile, it also indicated that exosomal si-ciRS-122 reversed the oxaliplatin resistance through inhibiting the ciRS-122/miR-122/PKM2 axis in vivo and in vitro.	('oxaliplatin resistance', 'MPA', (68, 90))	('si-ciRS-122', 'Var', (43, 54))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (68, 79))	('inhibiting', 'NegReg', (99, 109))	('miR-122', 'Gene', '406906', (123, 130))	('PKM2', 'Gene', (131, 135))	('PKM2', 'Gene', '5315', (131, 135))	('ciRS', 'Chemical', '-', (46, 50))	('miR-122', 'Gene', (123, 130))	('ciRS', 'Chemical', '-', (114, 118))
13471	33077737	Moreover, the enrichment of specific lipids in exosomes significantly increases the membrane stiffness of the exosomes.	('enrichment', 'Var', (14, 24))	('membrane stiffness', 'MPA', (84, 102))	('increases', 'PosReg', (70, 79))	('lipids', 'Chemical', 'MESH:D008055', (37, 43))	('membrane', 'cellular_component', 'GO:0016020', ('84', '92'))
13490	33077737	The nSMase2 inhibitor, GW4869, is widely used to suppress the secretion of exosomes, which significantly inhibit the production of exosomes.	('nSMase2', 'Gene', (4, 11))	('GW4869', 'Var', (23, 29))	('inhibit', 'NegReg', (105, 112))	('secretion', 'biological_process', 'GO:0046903', ('62', '71'))	('secretion of exosomes', 'MPA', (62, 83))	('GW4869', 'Chemical', 'MESH:C468773', (23, 29))	('production of exosomes', 'MPA', (117, 139))	('suppress', 'NegReg', (49, 57))	('nSMase2', 'Gene', '55512', (4, 11))
13496	33077737	However, the GW4869 could reverse the metabolic changes of breast cancer cells, which in turn led to inhibit the cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('inhibit', 'NegReg', (101, 108))	('metabolic changes', 'CPA', (38, 55))	('GW4869', 'Var', (13, 19))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('GW4869', 'Chemical', 'MESH:C468773', (13, 19))	('cancer', 'Disease', (66, 72))
13497	33077737	Another study also showed that the secretion of exosomes was blocking by GW4869, which inhibited the glycolysis and activation of recipient cells.	('secretion', 'biological_process', 'GO:0046903', ('35', '44'))	('glycolysis', 'MPA', (101, 111))	('GW4869', 'Chemical', 'MESH:C468773', (73, 79))	('secretion of exosomes', 'MPA', (35, 56))	('glycolysis', 'biological_process', 'GO:0006096', ('101', '111'))	('inhibited', 'NegReg', (87, 96))	('GW4869', 'Var', (73, 79))
13517	33000262	Altered tricellulin expression could promote tumor cell invasions and metastasis in human cancers.	('cancers', 'Disease', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('expression', 'MPA', (20, 30))	('promote', 'PosReg', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', (45, 50))	('Altered', 'Var', (0, 7))	('tricellulin', 'Gene', '153562', (8, 19))	('tricellulin', 'Gene', (8, 19))	('human', 'Species', '9606', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
13520	33000262	Colorectal cell lines were used to overexpress or knockdown tricellulin expression in various assays.	('knockdown', 'Var', (50, 59))	('Colorectal', 'Disease', (0, 10))	('tricellulin', 'Gene', '153562', (60, 71))	('tricellulin', 'Gene', (60, 71))	('Colorectal', 'Disease', 'MESH:D015179', (0, 10))
13522	33000262	In contrast, tricellulin knockdown had positive effects on the tumor cells.	('tumor', 'Disease', (63, 68))	('tricellulin', 'Gene', '153562', (13, 24))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tricellulin', 'Gene', (13, 24))	('knockdown', 'Var', (25, 34))
13535	33000262	Accumulating evidence has revealed that aberrant expression of the tight junction proteins contributes to the development and metastasis of numerous epithelial-derived cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('aberrant expression', 'Var', (40, 59))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('tight junction proteins', 'Protein', (67, 90))	('development', 'CPA', (110, 121))	('metastasis', 'CPA', (126, 136))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('contributes', 'Reg', (91, 102))	('tight junction', 'cellular_component', 'GO:0070160', ('67', '81'))
13552	33000262	The efficiency of tricellulin knockdown or overexpression was confirmed by RT-qPCR and western blotting.	('overexpression', 'PosReg', (43, 57))	('tricellulin', 'Gene', '153562', (18, 29))	('knockdown', 'Var', (30, 39))	('tricellulin', 'Gene', (18, 29))
13572	33000262	15071S; 1:1,000) (all from Cell Signaling Technology, Inc.) overnight at 4 C. Subsequently, the membranes were incubated with a secondary antibody (1:10,000; LI-COR IRDye  680RD Goat anti-Rabbit P/N 926-68071 or LI-COR IRDye  680RD Goat anti-Mouse P/N 926-68070; LI-COR Biosciences) at room temperature for 1 h. The protein bands were quantified by using Odyssey infrared imaging (LI-COR Biosciences).	('P/N 926', 'SUBSTITUTION', 'None', (195, 202))	('P/N 926', 'Var', (195, 202))	('P/N 926', 'SUBSTITUTION', 'None', (248, 255))	('antibody', 'cellular_component', 'GO:0042571', ('138', '146'))	('Mouse', 'Species', '10090', (242, 247))	('P/N 926', 'Var', (248, 255))	('protein', 'cellular_component', 'GO:0003675', ('316', '323'))	('antibody', 'cellular_component', 'GO:0019815', ('138', '146'))	('antibody', 'cellular_component', 'GO:0019814', ('138', '146'))	('antibody', 'molecular_function', 'GO:0003823', ('138', '146'))	('Signaling', 'biological_process', 'GO:0023052', ('32', '41'))
13586	33000262	It was revealed that the level of tricellulin protein was higher in HT29, HCT116, and SW620 cells than in other all cancerous and normal cells (Fig.	('cancerous', 'Disease', 'MESH:D009369', (116, 125))	('HCT116', 'CellLine', 'CVCL:0291', (74, 80))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('HT29', 'CellLine', 'CVCL:0320', (68, 72))	('level', 'MPA', (25, 30))	('SW620', 'CellLine', 'CVCL:0547', (86, 91))	('cancerous', 'Disease', (116, 125))	('higher', 'PosReg', (58, 64))	('SW620', 'Var', (86, 91))	('HCT116', 'Var', (74, 80))	('HT29', 'Var', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tricellulin', 'Gene', '153562', (34, 45))	('tricellulin', 'Gene', (34, 45))
13588	33000262	Tricellulin knockdown (TRIC-KD) or overexpression (TRIC-OE) was confirmed by RT-qPCR and western blotting (Fig.	('TRIC', 'cellular_component', 'GO:0005832', ('51', '55'))	('TRIC', 'Gene', '153562', (51, 55))	('TRIC', 'Gene', (23, 27))	('knockdown', 'Var', (12, 21))	('Tricellulin', 'Gene', '153562', (0, 11))	('TRIC', 'Gene', (51, 55))	('Tricellulin', 'Gene', (0, 11))	('TRIC-KD', 'Disease', 'MESH:C537017', (23, 30))	('TRIC', 'Gene', '153562', (23, 27))	('TRIC', 'cellular_component', 'GO:0005832', ('23', '27'))	('TRIC-KD', 'Disease', (23, 30))
13604	33000262	In contrast, knockdown of tricellulin expression decreased vimentin and Snail, but increased E-cadherin, which was also not completely activated by an NF-kappaB activator TNF-alpha (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('95', '103'))	('vimentin', 'Gene', (59, 67))	('E-cadherin', 'Gene', (93, 103))	('increased', 'PosReg', (83, 92))	('E-cadherin', 'Gene', '999', (93, 103))	('vimentin', 'cellular_component', 'GO:0045098', ('59', '67'))	('vimentin', 'Gene', '7431', (59, 67))	('NF-kappaB', 'Gene', '4790', (151, 160))	('decreased', 'NegReg', (49, 58))	('vimentin', 'cellular_component', 'GO:0045099', ('59', '67'))	('Snail', 'Gene', (72, 77))	('tricellulin', 'Gene', (26, 37))	('TNF-alpha', 'Gene', '7124', (171, 180))	('Snail', 'Gene', '6615', (72, 77))	('tricellulin', 'Gene', '153562', (26, 37))	('NF-kappaB', 'Gene', (151, 160))	('knockdown', 'Var', (13, 22))	('TNF-alpha', 'Gene', (171, 180))
13609	33000262	Assessment of the levels of apoptosis-related proteins revealed that tricellulin overexpression reduced caspase-3 and increased Bcl-2 and survivin levels, whereas knockdown of tricellulin expression reduced Bcl-2 and survivin levels and enhanced caspase-3 levels (Fig.	('Bcl-2', 'Gene', '596', (128, 133))	('increased', 'PosReg', (118, 127))	('Bcl-2', 'Gene', '596', (207, 212))	('tricellulin', 'Gene', '153562', (176, 187))	('caspase-3', 'Gene', '836', (104, 113))	('caspase-3', 'Gene', '836', (246, 255))	('caspase-3', 'Gene', (104, 113))	('reduced', 'NegReg', (96, 103))	('survivin levels', 'MPA', (217, 232))	('survivin levels', 'MPA', (138, 153))	('knockdown', 'Var', (163, 172))	('tricellulin', 'Gene', (69, 80))	('Bcl-2', 'molecular_function', 'GO:0015283', ('207', '212'))	('caspase-3', 'Gene', (246, 255))	('reduced', 'NegReg', (199, 206))	('Bcl-2', 'molecular_function', 'GO:0015283', ('128', '133'))	('tricellulin', 'Gene', '153562', (69, 80))	('apoptosis', 'biological_process', 'GO:0097194', ('28', '37'))	('enhanced', 'PosReg', (237, 245))	('apoptosis', 'biological_process', 'GO:0006915', ('28', '37'))	('Bcl-2', 'Gene', (128, 133))	('Bcl-2', 'Gene', (207, 212))	('tricellulin', 'Gene', (176, 187))
13611	33000262	Aberrant expression and functions of the tight junction-related proteins contribute to the development of various human cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('contribute', 'Reg', (73, 83))	('Aberrant', 'Var', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('expression', 'MPA', (9, 19))	('cancers', 'Disease', (120, 127))	('human', 'Species', '9606', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('tight junction', 'cellular_component', 'GO:0070160', ('41', '55'))	('functions', 'MPA', (24, 33))	('tight junction-related proteins', 'Protein', (41, 72))
13616	33000262	Using in vitro functional assays, it was revealed that knockdown of tricellulin expression inhibited colorectal cancer cell invasion and migration, whereas tricellulin overexpression enhanced tumor cell invasion and migration.	('tricellulin', 'Gene', '153562', (68, 79))	('knockdown', 'Var', (55, 64))	('tumor', 'Disease', (192, 197))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('inhibited', 'NegReg', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('enhanced', 'PosReg', (183, 191))	('tricellulin', 'Gene', (156, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tricellulin', 'Gene', '153562', (156, 167))	('tricellulin', 'Gene', (68, 79))	('colorectal cancer', 'Disease', (101, 118))
13623	33000262	For example, knockdown of tricellulin expression using RNAi compromised the epithelial barrier and tricellular contacts and disorganized the bicellular tight-junction.	('bicellular tight-junction', 'cellular_component', 'GO:0005923', ('141', '166'))	('RNAi', 'biological_process', 'GO:0016246', ('55', '59'))	('tricellular contacts', 'CPA', (99, 119))	('tricellulin', 'Gene', (26, 37))	('epithelial barrier', 'CPA', (76, 94))	('bicellular', 'MPA', (141, 151))	('disorganized', 'NegReg', (124, 136))	('tricellulin', 'Gene', '153562', (26, 37))	('knockdown', 'Var', (13, 22))	('compromised', 'NegReg', (60, 71))
13636	33000262	In contrast, knockdown of tricellulin expression decreased vimentin and Snail, but increased E-cadherin, which was also not completely activated by an NF-kappaB activator TNF-alpha, thus indicating that tricellulin may regulate the EMT in colorectal cancer cells through the canonical NF-kappaB signaling pathway.	('vimentin', 'Gene', (59, 67))	('colorectal cancer', 'Disease', 'MESH:D015179', (239, 256))	('signaling pathway', 'biological_process', 'GO:0007165', ('295', '312'))	('TNF-alpha', 'Gene', '7124', (171, 180))	('Snail', 'Gene', '6615', (72, 77))	('vimentin', 'cellular_component', 'GO:0045099', ('59', '67'))	('knockdown', 'Var', (13, 22))	('colorectal cancer', 'Disease', (239, 256))	('TNF-alpha', 'Gene', (171, 180))	('E-cadherin', 'Gene', (93, 103))	('increased', 'PosReg', (83, 92))	('E-cadherin', 'Gene', '999', (93, 103))	('decreased', 'NegReg', (49, 58))	('regulate', 'Reg', (219, 227))	('NF-kappaB', 'Gene', (151, 160))	('NF-kappaB', 'Gene', (285, 294))	('tricellulin', 'Gene', (203, 214))	('NF-kappaB', 'Gene', '4790', (151, 160))	('EMT', 'CPA', (232, 235))	('EMT', 'biological_process', 'GO:0001837', ('232', '235'))	('Snail', 'Gene', (72, 77))	('tricellulin', 'Gene', (26, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (239, 256))	('NF-kappaB', 'Gene', '4790', (285, 294))	('vimentin', 'cellular_component', 'GO:0045098', ('59', '67'))	('tricellulin', 'Gene', '153562', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cadherin', 'molecular_function', 'GO:0008014', ('95', '103'))	('tricellulin', 'Gene', '153562', (26, 37))	('vimentin', 'Gene', '7431', (59, 67))
13641	33000262	In summary, the present study demonstrated that tricellulin expression was associated with colorectal cancer metastasis and poor prognosis, while tricellulin expression promoted colorectal cancer cell invasion and EMT in vitro.	('colorectal cancer', 'Phenotype', 'HP:0003003', (178, 195))	('promoted', 'PosReg', (169, 177))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('EMT', 'biological_process', 'GO:0001837', ('214', '217'))	('colorectal cancer', 'Disease', 'MESH:D015179', (178, 195))	('expression', 'Var', (60, 70))	('colorectal cancer', 'Disease', (178, 195))	('tricellulin', 'Gene', (48, 59))	('tricellulin', 'Gene', (146, 157))	('tricellulin', 'Gene', '153562', (48, 59))	('tricellulin', 'Gene', '153562', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('colorectal cancer metastasis', 'Disease', 'MESH:D015179', (91, 119))	('EMT', 'CPA', (214, 217))	('associated', 'Reg', (75, 85))	('colorectal cancer metastasis', 'Disease', (91, 119))
13650	31843922	We demonstrate using RNA-sequencing and RNA-in situ hybridization (RNA-ISH) that FOLFIRINOX combination chemotherapy induces a common shift of both E and QM PDAC toward a more QM state in cell lines and patient tumors.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('RNA', 'cellular_component', 'GO:0005562', ('21', '24'))	('RNA', 'cellular_component', 'GO:0005562', ('67', '70'))	('QM', 'Chemical', '-', (176, 178))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (81, 91))	('QM', 'Chemical', '-', (154, 156))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('PDAC', 'Phenotype', 'HP:0006725', (157, 161))	('patient', 'Species', '9606', (203, 210))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('FOLFIRINOX', 'Var', (81, 91))	('tumors', 'Disease', (211, 217))	('PDAC', 'Chemical', '-', (157, 161))
13711	31843922	Western blot analysis confirmed a specific increase in FN1 protein levels exclusively in QM type CalT-treated PDAC cells (Fig.	('CalT', 'Chemical', 'MESH:D002117', (97, 101))	('PDAC', 'Chemical', '-', (110, 114))	('FN1', 'Gene', '2335', (55, 58))	('increase', 'PosReg', (43, 51))	('FN1', 'Gene', (55, 58))	('PDAC', 'Phenotype', 'HP:0006725', (110, 114))	('QM type', 'Var', (89, 96))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('QM', 'Chemical', '-', (89, 91))
13723	31843922	Consistent with this hypothesis, direct intravascular inoculation of cells from dissociated QM tumorspheres pretreated with CalT into the tail vein of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice demonstrated a significant increase in the rate and number of lung metastases compared with control-treated dissociated tumorspheres from 2 different cell lines (Fig.	('lung metastases', 'Disease', 'MESH:D009362', (257, 272))	('CalT', 'Chemical', 'MESH:D002117', (124, 128))	('QM tumorspheres', 'Disease', (92, 107))	('tumors', 'Disease', (315, 321))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (315, 321))	('Il2rgtm1Wjl/SzJ', 'Var', (168, 183))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('Il2', 'molecular_function', 'GO:0005134', ('168', '171'))	('increase', 'PosReg', (222, 230))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mice', 'Species', '10090', (190, 194))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('QM tumorspheres', 'Disease', 'None', (92, 107))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumors', 'Disease', (95, 101))	('lung metastases', 'Disease', (257, 272))
13757	31843922	Here, we have shown that the combination chemotherapy FOLFIRINOX results in a consistent shift toward the QM state for all PDAC cell lines and a general intrinsic chemoresistance profile seen in QM compared to E cell lines.	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (54, 64))	('shift', 'Reg', (89, 94))	('PDAC', 'Phenotype', 'HP:0006725', (123, 127))	('QM', 'Chemical', '-', (195, 197))	('FOLFIRINOX', 'Var', (54, 64))	('PDAC', 'Chemical', '-', (123, 127))	('QM', 'Chemical', '-', (106, 108))
13766	31843922	The poor survival outcomes of patients with QM tumors demonstrating high tumor CYP24A1 expression, which is not seen in E tumors, support this possibility and suggest that Vit D supplementation could be ineffective or may even result in disease progression and metastasis in these patients.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (122, 127))	('result in', 'Reg', (227, 236))	('CYP24A1', 'Gene', (79, 86))	('metastasis', 'CPA', (261, 271))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('patients', 'Species', '9606', (30, 38))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('E tumors', 'Disease', 'MESH:D016751', (120, 128))	('CYP24A1', 'Gene', '1591', (79, 86))	('high', 'Var', (68, 72))	('patients', 'Species', '9606', (281, 289))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (47, 52))	('disease progression', 'CPA', (237, 256))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('E tumors', 'Disease', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('QM tumors', 'Disease', (44, 53))	('QM tumors', 'Disease', 'MESH:D009369', (44, 53))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
13786	31843922	Components of FOLFIRINOX including 5-fluorouracil (14416), oxaliplatin (13106), and irinotecan (14180) were purchased from Cayman Chemicals.	('14416', 'Var', (51, 56))	('13106', 'Var', (72, 77))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (35, 49))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (14, 24))	('irinotecan', 'Chemical', 'MESH:D000077146', (84, 94))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (59, 70))
13823	31843922	Samples were stratified between high and low CYP24A1 expression using a threshold defined by the Ostu method of minimizing the within-class variance.	('CYP24A1', 'Gene', (45, 52))	('high', 'Var', (32, 36))	('CYP24A1', 'Gene', '1591', (45, 52))	('low', 'NegReg', (41, 44))	('expression', 'MPA', (53, 63))
13831	31843922	This was followed by a series of signal amplification steps: Amp 1 was added to bind to the target-specific probe, followed by Amp 2 to Amp 10, which were subsequently added to bind each other one after the other.	('bind', 'Interaction', (80, 84))	('Amp', 'Chemical', 'MESH:D000249', (61, 64))	('Amp', 'Chemical', 'MESH:D000249', (127, 130))	('Amp', 'Chemical', 'MESH:D000249', (136, 139))	('Amp 2', 'Var', (127, 132))
13856	31495721	Taiwan Academia Sinica (AS-107-TP-L15 and AS-105-TP-B15), Ministry of Science and Technology (MOST 106-2321-B-001-048, 106-0210-01-15-02, 106-2321-B-002-034, and 106-2314-B-007-004-MY2), and Taiwan National Health Research Institutes (NHRI EX107-10524EI).	('106-2314-B-007-004-MY2', 'Var', (162, 184))	('106-2321-B', 'Chemical', 'MESH:C511599', (138, 148))	('106-2314-B-007-004', 'Chemical', 'MESH:C097674', (162, 180))	('Academia Sinica', 'Disease', 'None', (7, 22))	('106-2321-B-002-034', 'Chemical', 'MESH:C545088', (138, 156))	('106-2321-B', 'Chemical', 'MESH:C511599', (99, 109))	('Academia Sinica', 'Disease', (7, 22))	('106-2321-B-002-034', 'Var', (138, 156))	('106-0210-01-15-02', 'Var', (119, 136))
13870	31495721	This process is often associated with inflammation (pancreatitis) and oncogenic Kras mutation, causing potential acinar-to-ductal metaplasia and unregulated epithelial proliferation, which in turn remodels the pancreatic microenvironment.	('metaplasia', 'biological_process', 'GO:0036074', ('130', '140'))	('pancreatitis', 'Disease', 'MESH:D010195', (52, 64))	('turn remodels the pancreatic', 'Disease', 'MESH:D020257', (192, 220))	('inflammation', 'biological_process', 'GO:0006954', ('38', '50'))	('mutation', 'Var', (85, 93))	('turn remodels the pancreatic', 'Disease', (192, 220))	('pancreatitis', 'Disease', (52, 64))	('rat', 'Species', '10116', (175, 178))	('inflammation', 'Disease', 'MESH:D007249', (38, 50))	('causing', 'Reg', (95, 102))	('acinar-to-ductal metaplasia', 'Disease', (113, 140))	('Kras', 'Gene', (80, 84))	('inflammation', 'Disease', (38, 50))	('pancreatitis', 'Phenotype', 'HP:0001733', (52, 64))
13934	31495721	Oncogenic Kras mutation often occurs in human PDAC.	('mutation', 'Var', (15, 23))	('PDAC', 'Phenotype', 'HP:0006725', (46, 50))	('human', 'Species', '9606', (40, 45))	('Kras', 'Gene', (10, 14))
13946	31495721	Furthermore, when the large-scale duct lesion formation is induced under the background of p53 mutation (elastase-CreER;LSL-KrasG12D;p53+/-, the EKP mice), we identify the lymphatic luminal invasion in five of the seven examined animals (Fig.	('p53', 'Gene', '22059', (133, 136))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '22059', (91, 94))	('mice', 'Species', '10090', (149, 153))	('p53', 'Gene', (133, 136))	('formation', 'biological_process', 'GO:0009058', ('46', '55'))	('lymphatic luminal invasion', 'CPA', (172, 198))	('mutation', 'Var', (95, 103))
13948	31495721	Quantitation of the Lyve1+ signals shows that the density of the pancreatic lymphatic vessels in the EK and EKP mice increases 5.5-fold (P < .01) and 4.9-fold (P < .01) against the wild-type B6 mice, respectively.	('density', 'CPA', (50, 57))	('Lyve1', 'Gene', '114332', (20, 25))	('Lyve1', 'Gene', (20, 25))	('increases', 'PosReg', (117, 126))	('EKP', 'Var', (108, 111))	('mice', 'Species', '10090', (194, 198))	('mice', 'Species', '10090', (112, 116))
13950	31495721	4h), indicating that the increased incidence of the luminal invasion in the EKP mice compared with the EK mice (Fig.	('EKP', 'Var', (76, 79))	('mice', 'Species', '10090', (106, 110))	('mice', 'Species', '10090', (80, 84))	('luminal invasion', 'CPA', (52, 68))
13977	31495721	In experimental PanIN and PDAC, mutations (Kras or Kras and p53) and the cerulein-induced pancreatitis were systematically introduced to mice to investigate the early and advanced duct lesion formation.	('pancreatitis', 'Phenotype', 'HP:0001733', (90, 102))	('cerulein', 'Chemical', 'MESH:D002108', (73, 81))	('pancreatitis', 'Disease', 'MESH:D010195', (90, 102))	('PDAC', 'Phenotype', 'HP:0006725', (26, 30))	('p53', 'Gene', (60, 63))	('formation', 'biological_process', 'GO:0009058', ('192', '201'))	('p53', 'Gene', '22059', (60, 63))	('pancreatitis', 'Disease', (90, 102))	('Kras', 'Var', (43, 47))	('mice', 'Species', '10090', (137, 141))
13993	31103629	HNF1A inhibition induces the resistance of pancreatic cancer cells to gemcitabine by targeting ABCB1 Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis, and gemcitabine-based chemotherapy remains an effective option for the majority of PDAC patients.	('induces', 'PosReg', (17, 24))	('PDAC', 'Phenotype', 'HP:0006725', (135, 139))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (43, 60))	('Pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (101, 133))	('aggressive disease', 'Disease', (147, 165))	('patients', 'Species', '9606', (275, 283))	('Pancreatic ductal adenocarcinoma', 'Disease', (101, 133))	('aggressive disease', 'Disease', 'MESH:D001523', (147, 165))	('gemcitabine', 'Chemical', 'MESH:C056507', (191, 202))	('inhibition', 'NegReg', (6, 16))	('pancreatic cancer', 'Disease', 'MESH:D010190', (43, 60))	('HNF1A', 'Gene', '6927', (0, 5))	('Pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (101, 133))	('ABCB1', 'Gene', (95, 100))	('gemcitabine', 'Chemical', 'MESH:C056507', (70, 81))	('HNF1A', 'Gene', (0, 5))	('PDAC', 'Chemical', '-', (270, 274))	('pancreatic cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('PDAC', 'Phenotype', 'HP:0006725', (270, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('targeting', 'Var', (85, 94))	('PDAC', 'Chemical', '-', (135, 139))
13995	31103629	The function of HNF1A in gemcitabine was detected by overexpression and knockdown of HNF1A in vitro and in vitro.	('overexpression', 'PosReg', (53, 67))	('gemcitabine', 'Chemical', 'MESH:C056507', (25, 36))	('knockdown', 'Var', (72, 81))	('HNF1A', 'Gene', (85, 90))
13996	31103629	The regulatory network between HNF1A and ABCB1 was further demonstrated by luciferase assays, deletion/mutation reporter construct assays and CHIP assays.	('deletion/mutation', 'Var', (94, 111))	('HNF1A', 'Gene', (31, 36))	('ABCB1', 'Gene', (41, 46))	('ABCB1', 'Gene', '5243', (41, 46))
14036	31103629	For the roles of HNF1a in pancreas-associated diseases, mutation of HNF1A in the germline has been identified as the cause of maturity onset diabetes of the young 3 (MODY3), which account for 21-64% of all MODY3 cases.	('MODY3', 'Gene', '6927', (206, 211))	('MODY3', 'Gene', '6927', (166, 171))	('diabetes', 'Disease', (141, 149))	('MODY3', 'Gene', (206, 211))	('cause', 'Reg', (117, 122))	('HNF1a', 'Gene', (17, 22))	('MODY3', 'Gene', (166, 171))	('HNF1A', 'Gene', (68, 73))	('HNF1a', 'Gene', '6927', (17, 22))	('mutation', 'Var', (56, 64))	('diabetes', 'Disease', 'MESH:D003920', (141, 149))	('maturity onset diabetes of the young', 'Phenotype', 'HP:0004904', (126, 162))
14037	31103629	In addition, a nonsynonymous variant (rs1169288, I27L) in the HNF1A gene associated with type-2 diabetes risk was reported by a genome wide association study (GWAS).	('HNF1A', 'Gene', (62, 67))	('diabetes', 'Disease', (96, 104))	('diabetes', 'Disease', 'MESH:D003920', (96, 104))	('associated', 'Reg', (73, 83))	('rs1169288', 'Var', (38, 47))	('rs1169288', 'Mutation', 'rs1169288', (38, 47))	('type-2 diabetes', 'Phenotype', 'HP:0005978', (89, 104))	('I27L', 'Mutation', 'rs1169288', (49, 53))	('I27L', 'Var', (49, 53))
14076	31103629	Primary antibodies were rabbit anti-human HNF1A antibody (1:1000, #ab96777, Abcam), rabbit anti-human ABCB1 antibody (1:1000, #ab170904, Abcam), rabbit anti-human ABCC1 antibody (1:1000, #ab32574, Abcam), rabbit anti-human ABCC3 antibody (1:1000, #ab226804, Abcam), rabbit anti-human ABCC5 antibody (1:1000, #ab24107, Abcam) and rabbit anti-human GAPDH antibody (1:1000, #ab18162, Abcam).	('human', 'Species', '9606', (217, 222))	('1:1000', 'Var', (179, 185))	('antibody', 'cellular_component', 'GO:0019815', ('108', '116'))	('antibody', 'cellular_component', 'GO:0019814', ('169', '177'))	('rabbit', 'Species', '9986', (266, 272))	('rabbit', 'Species', '9986', (329, 335))	('antibody', 'cellular_component', 'GO:0019815', ('290', '298'))	('ABCC1', 'Gene', (163, 168))	('antibody', 'cellular_component', 'GO:0019815', ('48', '56'))	('antibody', 'cellular_component', 'GO:0019814', ('229', '237'))	('rabbit', 'Species', '9986', (145, 151))	('human', 'Species', '9606', (96, 101))	('antibody', 'cellular_component', 'GO:0019815', ('353', '361'))	('human', 'Species', '9606', (278, 283))	('antibody', 'cellular_component', 'GO:0019814', ('108', '116'))	('antibody', 'molecular_function', 'GO:0003823', ('169', '177'))	('human', 'Species', '9606', (341, 346))	('rabbit', 'Species', '9986', (24, 30))	('antibody', 'cellular_component', 'GO:0042571', ('169', '177'))	('antibody', 'cellular_component', 'GO:0019814', ('290', '298'))	('antibody', 'cellular_component', 'GO:0019814', ('48', '56'))	('antibody', 'molecular_function', 'GO:0003823', ('229', '237'))	('human', 'Species', '9606', (157, 162))	('1:1000', 'Var', (239, 245))	('GAPDH', 'Gene', '2597', (347, 352))	('ABCB1', 'Gene', (102, 107))	('antibody', 'cellular_component', 'GO:0042571', ('229', '237'))	('ABCB1', 'Gene', '5243', (102, 107))	('ABCC3', 'Gene', (223, 228))	('1:1000', 'Var', (300, 306))	('1:1000', 'Var', (118, 124))	('antibody', 'cellular_component', 'GO:0019814', ('353', '361'))	('antibody', 'molecular_function', 'GO:0003823', ('108', '116'))	('1:1000', 'Var', (363, 369))	('ABCC5', 'Gene', '10057', (284, 289))	('antibody', 'molecular_function', 'GO:0003823', ('48', '56'))	('ABCC1', 'Gene', '4363', (163, 168))	('antibody', 'molecular_function', 'GO:0003823', ('290', '298'))	('antibody', 'cellular_component', 'GO:0019815', ('169', '177'))	('antibody', 'cellular_component', 'GO:0042571', ('108', '116'))	('rabbit', 'Species', '9986', (84, 90))	('GAPDH', 'Gene', (347, 352))	('ABCC3', 'Gene', '8714', (223, 228))	('rabbit', 'Species', '9986', (205, 211))	('antibody', 'cellular_component', 'GO:0042571', ('48', '56'))	('antibody', 'cellular_component', 'GO:0042571', ('290', '298'))	('antibody', 'molecular_function', 'GO:0003823', ('353', '361'))	('antibody', 'cellular_component', 'GO:0019815', ('229', '237'))	('ABCC5', 'Gene', (284, 289))	('human', 'Species', '9606', (36, 41))	('antibody', 'cellular_component', 'GO:0042571', ('353', '361'))
14093	31103629	The loss of HNF1A expression has been reported to promote the progression of pancreatic cancer, and HNF1A was identified as a possible tumor suppressor in pancreatic cancer.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('135', '151'))	('promote', 'PosReg', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('tumor', 'Disease', (135, 140))	('pancreatic cancer', 'Disease', (155, 172))	('progression', 'CPA', (62, 73))	('HNF1A', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('pancreatic cancer', 'Disease', 'MESH:D010190', (155, 172))	('tumor suppressor', 'biological_process', 'GO:0051726', ('135', '151'))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('pancreatic cancer', 'Disease', (77, 94))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (155, 172))	('loss', 'Var', (4, 8))
14112	31103629	Moreover, when treated with various concentrations of gemcitabine (10 nM, 100 nM, 1 muM, 10 muM, 100 muM), the proliferation capacity was much more significantly lower in HNF1A cells (Fig.	('muM', 'Gene', (92, 95))	('muM', 'Gene', '56925', (101, 104))	('lower', 'NegReg', (162, 167))	('muM', 'Gene', '56925', (84, 87))	('muM', 'Gene', '56925', (92, 95))	('proliferation capacity', 'CPA', (111, 133))	('muM', 'Gene', (101, 104))	('10 nM', 'Var', (67, 72))	('HNF1A', 'Disease', (171, 176))	('muM', 'Gene', (84, 87))	('gemcitabine', 'Chemical', 'MESH:C056507', (54, 65))
14129	31103629	These results implied that HNF1A inhibition enhances gemcitabine resistance by inducing ABCB1 expression in pancreatic cancer cells.	('inhibition', 'Var', (33, 43))	('ABCB1', 'Gene', (88, 93))	('ABCB1', 'Gene', '5243', (88, 93))	('inducing', 'Reg', (79, 87))	('enhances', 'PosReg', (44, 52))	('pancreatic cancer', 'Disease', (108, 125))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('expression', 'MPA', (94, 104))	('gemcitabine', 'Chemical', 'MESH:C056507', (53, 64))	('gemcitabine resistance', 'MPA', (53, 75))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))	('HNF1A', 'Gene', (27, 32))
14131	31103629	To identify the transcriptional suppression elements in the ABCB1 promoter responsive to HNF1A, we generated and cotransfected a series of deletion/mutation reporter constructs into PANC-1 cells together with either the constitutively active HNF1A or an empty control vector.	('ABCB1', 'Gene', '5243', (60, 65))	('deletion/mutation', 'Var', (139, 156))	('PANC-1', 'CellLine', 'CVCL:0480', (182, 188))	('ABCB1', 'Gene', (60, 65))
14134	31103629	Consistent with this idea, the suppressive effect on ABCB1 promoter activity was abrogated when the binding sequence was mutant (Fig.	('mutant', 'Var', (121, 127))	('binding', 'Interaction', (100, 107))	('binding', 'molecular_function', 'GO:0005488', ('100', '107'))	('abrogated', 'NegReg', (81, 90))	('promoter activity', 'MPA', (59, 76))	('ABCB1', 'Gene', (53, 58))	('ABCB1', 'Gene', '5243', (53, 58))
14136	31103629	Consistent with the cotransfection studies, ChIP analysis showed that HNF1A binding was confined to the specific region of the ABCB1 promoter (-989 bp to -747 sbp, Fig.	('ABCB1', 'Gene', (127, 132))	('ABCB1', 'Gene', '5243', (127, 132))	('binding', 'molecular_function', 'GO:0005488', ('76', '83'))	('-989', 'Var', (143, 147))	('binding', 'Interaction', (76, 83))
14142	31103629	By univariate analyses, we found that OS was lower in patients in the moderate/low HNF1A groups than that in the high HNF1A group (Table 2).	('HNF1A', 'Gene', (83, 88))	('moderate/low', 'Var', (70, 82))	('patients', 'Species', '9606', (54, 62))	('lower', 'NegReg', (45, 50))	('OS', 'Chemical', '-', (38, 40))
14144	31103629	In addition, the survival analyses demonstrated an improvement in OS for patients in high HNF1A group compared with the moderate/low HNF1A groups (Fig.	('OS', 'Chemical', '-', (66, 68))	('HNF1A', 'Gene', (90, 95))	('improvement', 'PosReg', (51, 62))	('high', 'Var', (85, 89))	('patients', 'Species', '9606', (73, 81))
14167	31103629	We found that knockdown of HNF1A led to increased IC50 values of gemcitabine and enhanced proliferation in gemcitabine resistant cell lines in vitro.	('enhanced', 'PosReg', (81, 89))	('proliferation', 'CPA', (90, 103))	('gemcitabine', 'Chemical', 'MESH:C056507', (65, 76))	('IC50 values of gemcitabine', 'MPA', (50, 76))	('gemcitabine', 'Chemical', 'MESH:C056507', (107, 118))	('increased', 'PosReg', (40, 49))	('knockdown', 'Var', (14, 23))	('HNF1A', 'Gene', (27, 32))
14175	31103629	described the development of genomic signatures and revealed a strong association between gemcitabine resistance and ABCB1 copy number in breast cancer cell lines.	('gemcitabine', 'Chemical', 'MESH:C056507', (90, 101))	('copy number', 'Var', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('ABCB1', 'Gene', (117, 122))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('ABCB1', 'Gene', '5243', (117, 122))	('gemcitabine resistance', 'MPA', (90, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancer', 'Disease', (138, 151))
14185	31103629	Furthermore, the responses of PDAC cell lines to gemcitabine decreased after transfection with ABCB1.	('responses', 'MPA', (17, 26))	('PDAC', 'Chemical', '-', (30, 34))	('transfection', 'Var', (77, 89))	('ABCB1', 'Gene', (95, 100))	('ABCB1', 'Gene', '5243', (95, 100))	('gemcitabine', 'Chemical', 'MESH:C056507', (49, 60))	('PDAC', 'Phenotype', 'HP:0006725', (30, 34))	('decreased', 'NegReg', (61, 70))
14190	31103629	Moreover, by bioinformatic analyses, specific sequence mutation experiments and ChIP analysis, we confirmed that HNF1A regulates ABCB1 expression through binding to its specific promoter region (-989 bp to -747 bp) and inhibiting its transcription.	('ABCB1', 'Gene', '5243', (129, 134))	('transcription', 'biological_process', 'GO:0006351', ('234', '247'))	('binding', 'Interaction', (154, 161))	('transcription', 'MPA', (234, 247))	('inhibiting', 'NegReg', (219, 229))	('binding', 'molecular_function', 'GO:0005488', ('154', '161'))	('expression', 'MPA', (135, 145))	('-989', 'Var', (195, 199))	('HNF1A', 'Gene', (113, 118))	('ABCB1', 'Gene', (129, 134))
14195	31103629	Additionally, the p.Q511L mutation of HNF1A may suppress the transcriptional activity of HNF1A in hepatocellular carcinoma, which needed further study in pancreatic cancer and can expand our work.	('suppress', 'NegReg', (48, 56))	('transcriptional activity', 'MPA', (61, 85))	('pancreatic cancer', 'Disease', 'MESH:D010190', (154, 171))	('p.Q511L', 'Mutation', 'p.Q511L', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (154, 171))	('HNF1A', 'Gene', (89, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('p.Q511L', 'Var', (18, 25))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (98, 122))	('HNF1A', 'Gene', (38, 43))	('hepatocellular carcinoma', 'Disease', (98, 122))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (98, 122))	('pancreatic cancer', 'Disease', (154, 171))
14198	31103629	By univariate and multivariate analyses, we revealed that patients with high/moderate HNF1A staining were significantly associated with both OS and DFS compared with low level groups.	('HNF1A', 'Gene', (86, 91))	('associated', 'Reg', (120, 130))	('high/moderate', 'Var', (72, 85))	('OS', 'Chemical', '-', (141, 143))	('patients', 'Species', '9606', (58, 66))	('DFS', 'Disease', (148, 151))
14199	31103629	Consistently, analyses of TCGA database showed that high HNF1A levels were significantly correlated to the improvement of OS and DFS in pancreatic adenocarcinoma patients (Fig.	('patients', 'Species', '9606', (162, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (136, 161))	('pancreatic adenocarcinoma', 'Disease', (136, 161))	('DFS', 'MPA', (129, 132))	('improvement', 'PosReg', (107, 118))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (136, 161))	('HNF1A', 'Gene', (57, 62))	('high', 'Var', (52, 56))	('OS', 'Chemical', '-', (122, 124))
14214	30587546	At 24 hours after a single injection of PEGPH20, Ktrans, a DCE MRI derived marker that measures how fast a unit volume of contrast media is transferred from capillaries to interstitial space, increased 56% and 50% from baseline in the orthotopic and xenograft tumors respectively, compared to a 4% and 6% decrease in vehicle groups (both P<0.05).	('PEGPH20', 'Var', (40, 47))	('DCE', 'Gene', (59, 62))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('PEGPH20', 'Chemical', '-', (40, 47))	('Ktrans', 'Chemical', '-', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('DCE', 'Gene', '1718', (59, 62))	('tumors', 'Disease', (260, 266))	('increased', 'PosReg', (192, 201))
14216	30587546	Consistently, after a single injection of PEGPH20, tumor hyaluronan content assessed by immunohistochemistry, was reduced substantially in all three models while drug delivery (measured by paclitaxel accumulation in tumor) was increased by 2.6-fold.	('tumor', 'Disease', (216, 221))	('increased', 'PosReg', (227, 236))	('paclitaxel', 'Chemical', 'MESH:D017239', (189, 199))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('drug delivery', 'MPA', (162, 175))	('PEGPH20', 'Chemical', '-', (42, 49))	('reduced', 'NegReg', (114, 121))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('PEGPH20', 'Var', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('hyaluronan', 'Chemical', 'MESH:D006820', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
14240	30587546	A genetically-engineered mouse model harboring a pancreas-specific Cre allele with p53 and Kras mutations referred to as the KPC mouse, was maintained at the Mouse Hospital of Pancreatic Cancer Research Center of our institution.	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (176, 193))	('p53', 'Gene', (83, 86))	('Mouse', 'Species', '10090', (158, 163))	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (176, 193))	('Kras', 'Gene', (91, 95))	('Kras', 'Gene', '16653', (91, 95))	('mouse', 'Species', '10090', (25, 30))	('p53', 'Gene', '22060', (83, 86))	('Pancreatic Cancer', 'Disease', (176, 193))	('mouse', 'Species', '10090', (129, 134))	('Cancer', 'Phenotype', 'HP:0002664', (187, 193))	('mutations', 'Var', (96, 105))
14265	30587546	injection of PEGPH20 (1 mg/kg) or vehicle in mice bearing orthotopic tumor (4662-KPC) or human PDA xenograft.	('4662-KPC', 'CellLine', 'CVCL:M532', (76, 84))	('human', 'Species', '9606', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mice', 'Species', '10090', (45, 49))	('tumor', 'Disease', (69, 74))	('PEGPH20', 'Var', (13, 20))	('PDA', 'Chemical', '-', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('PEGPH20', 'Chemical', '-', (13, 20))	('PDA', 'Phenotype', 'HP:0006725', (95, 98))
14274	30587546	The rate constant, kep, also exhibited a large increase after PEGPH20 treatment; however, variations in kep changes were greater than those in Ktrans.	('PEGPH20', 'Chemical', '-', (62, 69))	('Ktrans', 'Chemical', '-', (143, 149))	('kep', 'MPA', (19, 22))	('PEGPH20', 'Var', (62, 69))	('increase', 'PosReg', (47, 55))
14276	30587546	The paired Ktrans values revealed a substantial increase 24 h after PEGPH20 injection from the baseline, while partial recovery (reduction of Ktrans) was observed between injections (Supplemental Fig 1).	('Ktrans', 'Chemical', '-', (11, 17))	('PEGPH20', 'Var', (68, 75))	('Ktrans', 'Chemical', '-', (142, 148))	('PEGPH20', 'Chemical', '-', (68, 75))	('increase', 'PosReg', (48, 56))
14277	30587546	The pattern of Ktrans change is consistent with the reversible degradation of tumor hyaluronan by PEGPH20.	('PEGPH20', 'Var', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('Ktrans', 'MPA', (15, 21))	('degradation', 'NegReg', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('hyaluronan', 'Chemical', 'MESH:D006820', (84, 94))	('PEGPH20', 'Chemical', '-', (98, 105))	('degradation', 'biological_process', 'GO:0009056', ('63', '74'))	('tumor', 'Disease', (78, 83))	('Ktrans', 'Chemical', '-', (15, 21))
14279	30587546	After three treatments of PEGPH20 + gemcitabine, Ktrans in KPC tumors increased 54% from baseline compared to 4% decrease in vehicle + gemcitabine group (Fig 2C, F), suggesting that PEGPH20+gemcitabine treatments led to a sustained improvement of perfusion.	('Ktrans', 'MPA', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('KPC tumors', 'Disease', (59, 69))	('PEGPH20', 'Var', (26, 33))	('increased', 'PosReg', (70, 79))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('PEGPH20', 'Chemical', '-', (26, 33))	('KPC tumors', 'Disease', 'MESH:C565455', (59, 69))	('Ktrans', 'Chemical', '-', (49, 55))	('improvement', 'PosReg', (232, 243))	('perfusion', 'MPA', (247, 256))	('gemcitabine', 'Chemical', 'MESH:C056507', (36, 47))	('gemcitabine', 'Chemical', 'MESH:C056507', (190, 201))	('gemcitabine', 'Chemical', 'MESH:C056507', (135, 146))	('PEGPH20', 'Chemical', '-', (182, 189))
14286	30587546	In response to a single injection of PEGPH20, the orthotopic model showed a remarkable redistribution of Ktrans (red), which was right-shifted relative to the baseline (black) or to vehicle treatment (blue).	('redistribution', 'MPA', (87, 101))	('PEGPH20', 'Var', (37, 44))	('Ktrans', 'MPA', (105, 111))	('PEGPH20', 'Chemical', '-', (37, 44))	('Ktrans', 'Chemical', '-', (105, 111))
14298	30587546	By counting the % of HA-positive pixels in the viable tumor regions, a significant difference of HA-content was found between PEGPH20 versus VEH treated tumors (Fig 4G).	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('PEGPH20', 'Chemical', '-', (126, 133))	('PEGPH20', 'Var', (126, 133))	('tumor', 'Disease', (153, 158))	('HA', 'Chemical', 'MESH:C034124', (21, 23))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', (54, 59))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('HA', 'Chemical', 'MESH:C034124', (97, 99))
14301	30587546	Our results demonstrated that PEGPH20 treatment resulted in > 2-fold greater paclitaxel accumulation in the tumor (Fig 5 and supplemental Fig 3), consistent with improved perfusion/permeability revealed by Ktrans results.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('PEGPH20', 'Var', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Ktrans', 'Chemical', '-', (206, 212))	('paclitaxel accumulation', 'MPA', (77, 100))	('greater', 'PosReg', (69, 76))	('tumor', 'Disease', (108, 113))	('PEGPH20', 'Chemical', '-', (30, 37))	('paclitaxel', 'Chemical', 'MESH:D017239', (77, 87))
14303	30587546	Conflicting results may reflect the complexity of these interactions, since genetic ablation of stromal fibroblasts or the sonic hedgehog (SHH) pathway appeared to enhance tumor aggressiveness.	('enhance', 'PosReg', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('genetic ablation', 'Var', (76, 92))	('sonic hedgehog', 'Gene', (123, 137))	('SHH', 'Gene', '20423', (139, 142))	('tumor aggressiveness', 'Disease', (172, 192))	('aggressiveness', 'Phenotype', 'HP:0000718', (178, 192))	('SHH', 'Gene', (139, 142))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (172, 192))	('sonic hedgehog', 'Gene', '20423', (123, 137))
14304	30587546	Conversely, reversal of desmoplastic stroma by stroma-directed drugs including PEGPH20, vitamin-D analogs, SHH inhibitors and CD40 agonist antibody have shown promise to overcome gemcitabine resistance, and to extend the survival of KPC mice.	('gemcitabine', 'Chemical', 'MESH:C056507', (179, 190))	('antibody', 'molecular_function', 'GO:0003823', ('139', '147'))	('SHH', 'Gene', (107, 110))	('mice', 'Species', '10090', (237, 241))	('antibody', 'cellular_component', 'GO:0042571', ('139', '147'))	('survival', 'CPA', (221, 229))	('extend', 'PosReg', (210, 216))	('CD40', 'Gene', '21939', (126, 130))	('desmoplastic stroma', 'Disease', (24, 43))	('vitamin-D', 'Chemical', 'MESH:D014807', (88, 97))	('SHH', 'Gene', '20423', (107, 110))	('PEGPH20', 'Chemical', '-', (79, 86))	('antibody', 'cellular_component', 'GO:0019815', ('139', '147'))	('gemcitabine resistance', 'MPA', (179, 201))	('overcome', 'PosReg', (170, 178))	('PEGPH20', 'Var', (79, 86))	('desmoplastic stroma', 'Disease', 'MESH:D018220', (24, 43))	('CD40', 'Gene', (126, 130))	('antibody', 'cellular_component', 'GO:0019814', ('139', '147'))
14306	30587546	For example, PEGPH20 selectively degrades HA in the extracellular matrix, whereas calcitriol/paricalcitol activates the vitamin-D receptors on pancreatic stellate cells.	('vitamin-D', 'Chemical', 'MESH:D014807', (120, 129))	('paricalcitol', 'Chemical', 'MESH:C084656', (93, 105))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('52', '72'))	('degrades', 'NegReg', (33, 41))	('PEGPH20', 'Var', (13, 20))	('HA in the extracellular matrix', 'MPA', (42, 72))	('HA', 'Chemical', 'MESH:C034124', (42, 44))	('calcitriol', 'Chemical', 'MESH:D002117', (82, 92))	('PEGPH20', 'Chemical', '-', (13, 20))
14310	30587546	A major effect of PEGPH20 on tumor stroma is to degrade extracellular HA, leading to relief of IFP and reopening of otherwise collapsed microvasculature.	('tumor stroma', 'Disease', (29, 41))	('PEGPH20', 'Chemical', '-', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('IFP', 'MPA', (95, 98))	('extracellular', 'cellular_component', 'GO:0005576', ('56', '69'))	('relief', 'MPA', (85, 91))	('HA', 'Chemical', 'MESH:C034124', (70, 72))	('tumor stroma', 'Disease', 'MESH:D009369', (29, 41))	('degrade', 'NegReg', (48, 55))	('extracellular HA', 'MPA', (56, 72))	('PEGPH20', 'Var', (18, 25))
14314	30587546	Taken together, the effects of PEGPH20 and treatment-induced DCE-MRI changes were robustly achieved in a variety of stroma-dense tumors.	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('stroma-dense tumors', 'Disease', (116, 135))	('stroma-dense tumors', 'Disease', 'MESH:D015432', (116, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('DCE', 'Gene', '1718', (61, 64))	('PEGPH20', 'Var', (31, 38))	('DCE', 'Gene', (61, 64))	('PEGPH20', 'Chemical', '-', (31, 38))
14403	30631808	Abnormalities of the third stage of intestinal rotation can lead to an excessively floppy cecum, which can predispose patients to the development of a cecal bascule or cecal volvulus.	('predispose', 'Reg', (107, 117))	('volvulus', 'Phenotype', 'HP:0002580', (174, 182))	('Abnormalities', 'Var', (0, 13))	('lead to', 'Reg', (60, 67))	('cecal bascule', 'Disease', (151, 164))	('intestinal rotation', 'Disease', 'MESH:D009069', (36, 55))	('intestinal rotation', 'Disease', (36, 55))	('patients', 'Species', '9606', (118, 126))	('cecal', 'Disease', (168, 173))
14421	30324084	A Scalable Method for Squalenoylation and Assembly of Multifunctional 64Cu-Labeled Squalenoylated Gemcitabine Nanoparticles Squalenoylation of gemcitabine, a front-line therapy for pancreatic cancer, allows for improved cellular-level and system-wide drug delivery.	('pancreatic cancer', 'Disease', 'MESH:D010190', (181, 198))	('pancreatic cancer', 'Disease', (181, 198))	('gemcitabine', 'Chemical', 'MESH:C056507', (143, 154))	('Squalenoylation', 'Var', (124, 139))	('64Cu', 'Chemical', 'MESH:C000615411', (70, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (181, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('Gemcitabine', 'Chemical', 'MESH:C056507', (98, 109))
14434	30324084	In addition, pancreatic tumors can quickly develop resistance to gemcitabine, and chemical modification of gemcitabine with squalene alters gemcitabine's transport on the cellular level, bypassing one mechanism of gemcitabine resistance.	('pancreatic tumors', 'Disease', (13, 30))	('gemcitabine', 'Chemical', 'MESH:C056507', (140, 151))	('gemcitabine', 'Chemical', 'MESH:C056507', (214, 225))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('squalene', 'Chemical', 'MESH:D013185', (124, 132))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('transport on the cellular level', 'MPA', (154, 185))	('alters', 'Reg', (133, 139))	('gemcitabine', 'Chemical', 'MESH:C056507', (65, 76))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (13, 30))	('gemcitabine', 'Chemical', 'MESH:C056507', (107, 118))	('transport', 'biological_process', 'GO:0006810', ('154', '163'))	('chemical modification', 'Var', (82, 103))	('pancreatic tumors', 'Disease', 'MESH:D010190', (13, 30))	('resistance', 'MPA', (51, 61))	('gemcitabine', 'MPA', (140, 151))
14454	30324084	2,3-Oxidosqualene (3) is then converted into 1,1',2-tris-norsqualene aldehyde (4), through the direct cleavage of the epoxide by periodic acid.	('2,3-Oxidosqualene', 'Chemical', 'MESH:C002821', (0, 17))	('periodic acid', 'Chemical', 'MESH:D010504', (129, 142))	("1,1',2-tris-norsqualene aldehyde", 'Chemical', '-', (45, 77))	('epoxide', 'Protein', (118, 125))	('cleavage', 'Var', (102, 110))	('epoxide', 'Chemical', 'MESH:D004852', (118, 125))
14465	30324084	TBDMS-gemcitabine has increased solubility in dimethylformamide and reduced side reactions during squalenoylation compared to gemcitabine.	('solubility in dimethylformamide', 'MPA', (32, 63))	('gemcitabine', 'Chemical', 'MESH:C056507', (6, 17))	('gemcitabine', 'Chemical', 'MESH:C056507', (126, 137))	('increased', 'PosReg', (22, 31))	('TBDMS-gemcitabine', 'Chemical', '-', (0, 17))	('side reactions', 'MPA', (76, 90))	('TBDMS-gemcitabine', 'Var', (0, 17))	('dimethylformamide', 'Chemical', 'MESH:D004126', (46, 63))
14479	30324084	Cholesterol inclusion did not alter the size of the resulting SqGem:CholPEG:Chol NPs, but cholesterol inclusion at 15 mol% was observed to yield a lower PDI (Figure 1C).	('lower', 'NegReg', (147, 152))	('Chol', 'Chemical', 'MESH:D002784', (0, 4))	('Chol', 'Chemical', 'MESH:D002784', (68, 72))	('Cholesterol', 'Chemical', 'MESH:D002784', (0, 11))	('PDI', 'MPA', (153, 156))	('cholesterol inclusion', 'Var', (90, 111))	('cholesterol', 'Chemical', 'MESH:D002784', (90, 101))	('Chol', 'Chemical', 'MESH:D002784', (76, 80))	('CholPEG', 'Chemical', '-', (68, 75))
14514	30324084	SqNOTA-SqGem NPs exhibit slower blood clearance than free SqNOTA.	('blood clearance', 'CPA', (32, 47))	('SqNOTA', 'Chemical', '-', (58, 64))	('SqNOTA', 'Chemical', '-', (0, 6))	('SqNOTA-SqGem', 'Var', (0, 12))	('slower', 'NegReg', (25, 31))
14528	30324084	We found that addition of CholPEG was required for SqGem-based NPs to form in 5% aqueous dextrose (w/v), but that large amounts of Chol-PEG lead to a wider distribution of particle sizes.	('Chol-PEG', 'Var', (131, 139))	('lead to', 'Reg', (140, 147))	('Chol-PEG', 'Chemical', '-', (131, 139))	('dextrose', 'Chemical', 'MESH:D005947', (89, 97))	('CholPEG', 'Chemical', '-', (26, 33))
14535	30324084	As shown previously using liquid chromatography-tandem mass spectrometry, squalenoylation of gemcitabine can increase its half-life 3.9-fold (based on two-exponential decay).	('squalenoylation', 'Var', (74, 89))	('half-life', 'MPA', (122, 131))	('gemcitabine', 'Chemical', 'MESH:C056507', (93, 104))	('increase', 'PosReg', (109, 117))
14639	29888283	Using CRISPR/Cas9 to Knock out Amylase in Acinar Cells Decreases Pancreatitis-Induced Autophagy Pancreatic cancer is a malignant neoplasm that originates from acinar cells.	('Acinar Cells Decreases Pancreatitis-Induced Autophagy', 'Disease', 'MESH:D010190', (42, 95))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Autophagy', 'biological_process', 'GO:0016236', ('86', '95'))	('Autophagy', 'biological_process', 'GO:0006914', ('86', '95'))	('Pancreatic cancer', 'Disease', (96, 113))	('Pancreatitis', 'Phenotype', 'HP:0001733', (65, 77))	('Knock out', 'Var', (21, 30))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('malignant neoplasm', 'Disease', (119, 137))	('neoplasm', 'Phenotype', 'HP:0002664', (129, 137))	('Amylase', 'Protein', (31, 38))	('malignant neoplasm', 'Disease', 'MESH:D009369', (119, 137))	('Cas', 'cellular_component', 'GO:0005650', ('13', '16'))
14645	29888283	Here, we knocked out ATG12 in a pancreatic cancer cells and acinar cells using CRISPR/Cas9.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (32, 49))	('knocked out', 'Var', (9, 20))	('Cas', 'cellular_component', 'GO:0005650', ('86', '89'))	('pancreatic cancer', 'Disease', (32, 49))	('ATG12', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('pancreatic cancer', 'Disease', 'MESH:D010190', (32, 49))
14655	29888283	Acinar cells undergo reprogramming known as "acinar-to-ductal metaplasia" because of inflammation caused by pancreatitis and genetic mutations.	('metaplasia', 'Disease', (62, 72))	('pancreatitis', 'Disease', 'MESH:D010195', (108, 120))	('pancreatitis', 'Disease', (108, 120))	('metaplasia', 'Disease', 'MESH:D008679', (62, 72))	('inflammation', 'Disease', 'MESH:D007249', (85, 97))	('pancreatitis', 'Phenotype', 'HP:0001733', (108, 120))	('genetic mutations', 'Var', (125, 142))	('inflammation', 'Disease', (85, 97))
14661	29888283	Furthermore, autophagy deletion increases acinar-to-ductal metaplasia in mice.	('metaplasia', 'biological_process', 'GO:0036074', ('59', '69'))	('deletion', 'Var', (23, 31))	('mice', 'Species', '10090', (73, 77))	('autophagy', 'biological_process', 'GO:0016236', ('13', '22'))	('autophagy', 'biological_process', 'GO:0006914', ('13', '22'))	('metaplasia', 'Disease', (59, 69))	('increases', 'PosReg', (32, 41))	('autophagy', 'CPA', (13, 22))	('metaplasia', 'Disease', 'MESH:D008679', (59, 69))
14671	29888283	To reevaluate the relationship between autophagy and pancreatic cancer, we used the CRISPR/Cas9 system to knock out autophagy in a human pancreatic cancer cell line.	('autophagy', 'biological_process', 'GO:0016236', ('116', '125'))	('autophagy', 'CPA', (116, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (53, 70))	('autophagy', 'biological_process', 'GO:0006914', ('116', '125'))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('human', 'Species', '9606', (131, 136))	('knock', 'Var', (106, 111))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (137, 154))	('autophagy', 'biological_process', 'GO:0016236', ('39', '48'))	('pancreatic cancer', 'Disease', (53, 70))	('pancreatic cancer', 'Disease', (137, 154))	('autophagy', 'biological_process', 'GO:0006914', ('39', '48'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (53, 70))	('pancreatic cancer', 'Disease', 'MESH:D010190', (137, 154))	('Cas', 'cellular_component', 'GO:0005650', ('91', '94'))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
14691	29888283	To clarify the role of autophagy in pancreatic cancer, we established an autophagy deletion MIA PaCa-2 cell line.	('autophagy', 'CPA', (73, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (36, 53))	('autophagy', 'biological_process', 'GO:0016236', ('23', '32'))	('autophagy', 'biological_process', 'GO:0016236', ('73', '82'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('deletion', 'Var', (83, 91))	('pancreatic cancer', 'Disease', (36, 53))	('autophagy', 'biological_process', 'GO:0006914', ('73', '82'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (36, 53))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (92, 102))	('autophagy', 'biological_process', 'GO:0006914', ('23', '32'))
14700	29888283	Next, to evaluate the influence of autophagy deletion on inducing the duct phenotype, we measured the mRNA expression of the duct cell marker CK19 (KRT19).	('autophagy', 'biological_process', 'GO:0016236', ('35', '44'))	('KRT19', 'Gene', (148, 153))	('autophagy', 'biological_process', 'GO:0006914', ('35', '44'))	('KRT19', 'Gene', '3880', (148, 153))	('deletion', 'Var', (45, 53))
14702	29888283	This suggests that autophagy deletion strengthened the duct phenotype of pancreatic cancer.	('deletion', 'Var', (29, 37))	('duct', 'MPA', (55, 59))	('pancreatic cancer', 'Disease', (73, 90))	('strengthened', 'PosReg', (38, 50))	('autophagy', 'biological_process', 'GO:0016236', ('19', '28'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('autophagy', 'CPA', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('autophagy', 'biological_process', 'GO:0006914', ('19', '28'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))
14703	29888283	Next, we evaluated whether autophagy deletion influences pancreatic cancer cell viability using alamarBlue.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('autophagy', 'CPA', (27, 36))	('autophagy', 'biological_process', 'GO:0016236', ('27', '36'))	('deletion', 'Var', (37, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (57, 74))	('autophagy', 'biological_process', 'GO:0006914', ('27', '36'))	('pancreatic cancer', 'Disease', (57, 74))	('influences', 'Reg', (46, 56))	('pancreatic cancer', 'Disease', 'MESH:D010190', (57, 74))
14708	29888283	However, in autophagy deletion pancreatic cancer cells, mitochondria remained localized in the perinuclear region and were generally fused (Figure 1(g)).	('autophagy', 'biological_process', 'GO:0016236', ('12', '21'))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('mitochondria', 'CPA', (56, 68))	('deletion', 'Var', (22, 30))	('pancreatic cancer', 'Disease', (31, 48))	('autophagy', 'biological_process', 'GO:0006914', ('12', '21'))	('autophagy', 'CPA', (12, 21))	('pancreatic cancer', 'Disease', 'MESH:D010190', (31, 48))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (31, 48))	('mitochondria', 'cellular_component', 'GO:0005739', ('56', '68'))
14710	29888283	Next, to investigate the differences in responsiveness to anticancer agents following autophagy deletion, a common anti-pancreatic cancer drug, gemcitabine, was administered.	('gemcitabine', 'Chemical', 'MESH:C056507', (144, 155))	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('autophagy', 'CPA', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('autophagy', 'biological_process', 'GO:0016236', ('86', '95'))	('deletion', 'Var', (96, 104))	('autophagy', 'biological_process', 'GO:0006914', ('86', '95'))	('pancreatic cancer', 'Disease', (120, 137))
14713	29888283	Pancreatic cancer showed increased cell viability after gemcitabine treatment because of autophagy deletion and the altered mitochondria morphology.	('mitochondria morphology', 'CPA', (124, 147))	('Pancreatic cancer', 'Disease', (0, 17))	('increased', 'PosReg', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cell viability', 'CPA', (35, 49))	('autophagy', 'biological_process', 'GO:0016236', ('89', '98'))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))	('mitochondria', 'cellular_component', 'GO:0005739', ('124', '136'))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('autophagy', 'biological_process', 'GO:0006914', ('89', '98'))	('deletion', 'Var', (99, 107))	('gemcitabine', 'Chemical', 'MESH:C056507', (56, 67))	('autophagy', 'CPA', (89, 98))	('altered', 'Reg', (116, 123))
14720	29888283	Autophagy deletion decreased the mRNA expression of Ptf1, an acinar cell marker, compared to the expression in wild-type cells (Figure 2(b)).	('Autophagy', 'biological_process', 'GO:0006914', ('0', '9'))	('Autophagy', 'biological_process', 'GO:0016236', ('0', '9'))	('mRNA expression', 'MPA', (33, 48))	('Ptf1', 'Gene', (52, 56))	('Ptf1', 'Species', '32651', (52, 56))	('deletion', 'Var', (10, 18))	('decreased', 'NegReg', (19, 28))	('Autophagy', 'CPA', (0, 9))
14721	29888283	Loss of Ptf1 causes the loss of acinar cells in vivo.	('Loss', 'Var', (0, 4))	('loss', 'NegReg', (24, 28))	('Ptf1', 'Species', '32651', (8, 12))	('Ptf1', 'Gene', (8, 12))
14723	29888283	The results in AR42J and MIA PaCa-2 cells suggest that autophagy deletion is necessary to strengthen the duct phenotype in pancreatic cancer cells and decrease the acinar phenotype in acinar cells.	('duct phenotype', 'CPA', (105, 119))	('pancreatic cancer', 'Disease', (123, 140))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (25, 35))	('pancreatic cancer', 'Disease', 'MESH:D010190', (123, 140))	('autophagy', 'CPA', (55, 64))	('decrease', 'NegReg', (151, 159))	('autophagy', 'biological_process', 'GO:0016236', ('55', '64'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (123, 140))	('strengthen', 'PosReg', (90, 100))	('acinar phenotype in acinar cells', 'CPA', (164, 196))	('autophagy', 'biological_process', 'GO:0006914', ('55', '64'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('deletion', 'Var', (65, 73))
14728	29888283	Next, we investigated whether amylase deletion influences the increase in autophagy caused by rapamycin and cerulein.	('autophagy', 'biological_process', 'GO:0006914', ('74', '83'))	('amylase', 'Protein', (30, 37))	('autophagy', 'CPA', (74, 83))	('deletion', 'Var', (38, 46))	('autophagy', 'biological_process', 'GO:0016236', ('74', '83'))	('rapamycin', 'Chemical', 'MESH:D020123', (94, 103))	('increase', 'PosReg', (62, 70))
14733	29888283	Compared to the wild-type, the amylase deletion clone showed a decrease in LC3 puncta (Figure 4(b), Supp.	('deletion', 'Var', (39, 47))	('decrease', 'NegReg', (63, 71))	('LC3', 'Gene', '84557', (75, 78))	('amylase', 'Protein', (31, 38))	('LC3', 'Gene', (75, 78))
14738	29888283	Finally, we evaluated whether attenuation of autophagy by Amy2 deficiency affects cell function.	('autophagy', 'CPA', (45, 54))	('autophagy', 'biological_process', 'GO:0006914', ('45', '54'))	('attenuation', 'NegReg', (30, 41))	('deficiency', 'Var', (63, 73))	('Amy2', 'Gene', (58, 62))	('Amy2', 'Gene', '279', (58, 62))	('autophagy', 'biological_process', 'GO:0016236', ('45', '54'))
14741	29888283	In this study, we found that autophagy deletion in a pancreatic cancer cell line increased the duct phenotype in pancreatic cancer cells and decreased the acinar phenotype in acinar cells; morphological changes in the mitochondria were also observed.	('autophagy', 'biological_process', 'GO:0016236', ('29', '38'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (53, 70))	('duct phenotype', 'CPA', (95, 109))	('acinar', 'MPA', (155, 161))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('deletion', 'Var', (39, 47))	('autophagy', 'biological_process', 'GO:0006914', ('29', '38'))	('autophagy', 'CPA', (29, 38))	('decreased', 'NegReg', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('pancreatic cancer', 'Disease', (113, 130))	('mitochondria', 'cellular_component', 'GO:0005739', ('218', '230'))	('pancreatic cancer', 'Disease', (53, 70))	('pancreatic cancer', 'Disease', 'MESH:D010190', (113, 130))	('increased', 'PosReg', (81, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
14742	29888283	To further elucidate the influence of autophagy deletion on pancreatic cancer cells in vivo, xenograft experiments and assessments of mitochondrial metabolism need to be performed.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('metabolism', 'biological_process', 'GO:0008152', ('148', '158'))	('pancreatic cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('autophagy', 'biological_process', 'GO:0016236', ('38', '47'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('deletion', 'Var', (48, 56))	('autophagy', 'biological_process', 'GO:0006914', ('38', '47'))
14751	29888283	We found that autophagy in acinar cells is controlled by amylase, suggesting that loss of amylase expression contributes to pancreatic cancer development through autophagy.	('autophagy', 'biological_process', 'GO:0016236', ('162', '171'))	('contributes', 'Reg', (109, 120))	('autophagy', 'biological_process', 'GO:0006914', ('14', '23'))	('autophagy', 'CPA', (162, 171))	('pancreatic cancer', 'Disease', (124, 141))	('autophagy', 'biological_process', 'GO:0006914', ('162', '171'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('amylase', 'Protein', (90, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (124, 141))	('loss', 'Var', (82, 86))	('autophagy', 'biological_process', 'GO:0016236', ('14', '23'))
14761	29551917	The high Tim-3 expression in pancreatic cancer tissues may be closely related to cell invasion, metastasis, and the recurrence of pancreatic cancer.	('metastasis', 'CPA', (96, 106))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Tim-3', 'Gene', (9, 14))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (130, 147))	('expression', 'MPA', (15, 25))	('pancreatic cancer', 'Disease', (29, 46))	('high', 'Var', (4, 8))	('Tim-3', 'Gene', '84868', (9, 14))	('pancreatic cancer', 'Disease', 'MESH:D010190', (29, 46))	('related', 'Reg', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('pancreatic cancer', 'Disease', (130, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (130, 147))	('cell invasion', 'CPA', (81, 94))
14787	29551917	Among the 36 patients that showed positive Tim-3 expression, 8.2 months was revealed as the median survival time.	('Tim-3', 'Gene', (43, 48))	('patients', 'Species', '9606', (13, 21))	('expression', 'Var', (49, 59))	('Tim-3', 'Gene', '84868', (43, 48))
14810	29551917	The inactivation of oncogenes, tumor suppressor, and apoptotic genes has been observed to lead to the uncontrolled proliferation of pancreatic cells, which can lead to the formation of pancreatic tumor entities.	('lead to', 'Reg', (160, 167))	('pancreatic tumor', 'Disease', 'MESH:D010190', (185, 201))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('inactivation', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('formation', 'biological_process', 'GO:0009058', ('172', '181'))	('tumor', 'Disease', (196, 201))	('tumor suppressor', 'biological_process', 'GO:0051726', ('31', '47'))	('tumor', 'Disease', (31, 36))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('31', '47'))	('pancreatic tumor', 'Disease', (185, 201))	('oncogenes', 'Gene', (20, 29))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (185, 201))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('lead to', 'Reg', (90, 97))	('apoptotic genes', 'Gene', (53, 68))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('uncontrolled', 'MPA', (102, 114))
14811	29551917	Interestingly, the site mutation of the 12th codon of K-ras genes is observed to accompany 90% of pancreatic cancers.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (98, 115))	('pancreatic cancers', 'Disease', (98, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (98, 116))	('pancreatic cancers', 'Disease', 'MESH:D010190', (98, 116))	('accompany', 'Reg', (81, 90))	('K-ras', 'Gene', (54, 59))	('K-ras', 'Gene', '3845', (54, 59))	('site mutation', 'Var', (19, 32))
14819	29551917	The survival curves further indicated that the median survival time of patients with Tim-3 positive expression was significantly shorter than those patients with a negative expression.	('patients', 'Species', '9606', (148, 156))	('Tim-3', 'Gene', '84868', (85, 90))	('positive expression', 'Var', (91, 110))	('patients', 'Species', '9606', (71, 79))	('Tim-3', 'Gene', (85, 90))	('shorter', 'NegReg', (129, 136))
14820	29551917	The patients with high Tim-3 expression were observed to have a lower overall survival rate and worse prognosis than those patients with a low Tim-3 expression.	('expression', 'Var', (29, 39))	('overall survival', 'MPA', (70, 86))	('Tim-3', 'Gene', '84868', (143, 148))	('lower', 'NegReg', (64, 69))	('patients', 'Species', '9606', (123, 131))	('Tim-3', 'Gene', (23, 28))	('high', 'Var', (18, 22))	('patients', 'Species', '9606', (4, 12))	('Tim-3', 'Gene', '84868', (23, 28))	('Tim-3', 'Gene', (143, 148))
14843	29068423	The proteogenomic profiling of biomarker signatures in cancer biopsies could be used to monitor response to therapy and at the same time disease progression, as the outcome of a particular treatment is not uniform among affected patients due to specific genomic and epigenomic alterations.	('patients', 'Species', '9606', (229, 237))	('epigenomic alterations', 'Var', (266, 288))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
14846	29068423	Recent investigations on human colon cancer have shown that there is a poor correlation between expressed proteome and protein abundance and DNA mutation in the colon cancer genome.	('colon cancer', 'Disease', (31, 43))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('colon cancer', 'Phenotype', 'HP:0003003', (161, 173))	('colon cancer', 'Disease', 'MESH:D015179', (161, 173))	('human', 'Species', '9606', (25, 30))	('N', 'Chemical', 'MESH:D009584', (142, 143))	('colon cancer', 'Phenotype', 'HP:0003003', (31, 43))	('colon cancer', 'Disease', 'MESH:D015179', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('colon cancer', 'Disease', (161, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('mutation', 'Var', (145, 153))
14847	29068423	These studies have shown that tumor-associated somatic mutations or copy number variations might be accountable for these outcomes.	('copy number variations', 'Var', (68, 90))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (30, 35))
14861	29068423	Genomic alterations due to somatic and inherited mutations, copy number variations, and epigenetic changes in cancer genome alter cellular function at the protein level by modulating its abundance and protein-protein interaction.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('mutations', 'Var', (49, 58))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('modulating', 'Reg', (172, 182))	('abundance', 'MPA', (187, 196))	('protein-protein interaction', 'MPA', (201, 228))	('cellular function at the protein', 'MPA', (130, 162))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('copy number variations', 'Var', (60, 82))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('alter', 'Reg', (124, 129))	('protein', 'cellular_component', 'GO:0003675', ('209', '216'))	('epigenetic changes', 'Var', (88, 106))
14864	29068423	Furthermore, a complimentary effort using both the genomic and proteomic-based approaches can be employed to accurately identify genetic variants and their role in tumorigenesis at the protein level.	('tumor', 'Disease', (164, 169))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('variants', 'Var', (137, 145))
14866	29068423	Thus, the proteogenomic analysis of clinical samples may better delineate the functional consequences of somatic mutations and may accurately map driver mutations in significantly larger deletions and amplified regions in chromosomes.	('mutations', 'Var', (153, 162))	('mutations', 'Var', (113, 122))	('clinical samples', 'Species', '191496', (36, 52))
14870	29068423	Further, an understanding of how somatic mutations in a cancer patient's genome alter the pathways in proteome is crucial, which as a result present different clinical phenotypes and therapeutic targets.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('clinical', 'Species', '191496', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('patient', 'Species', '9606', (63, 70))	('cancer', 'Disease', (56, 62))	('alter', 'Reg', (80, 85))	('pathways in proteome', 'Pathway', (90, 110))
14874	29068423	Recently, a comprehensive genetic analysis of multiple cancer genomes in pancreatic cancer has shown 63 genetic alterations, the majority of which are point mutations.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('pancreatic cancer', 'Disease', (73, 90))	('cancer', 'Disease', (84, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('point mutations', 'Var', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('alterations', 'Reg', (112, 123))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))	('cancer', 'Disease', (55, 61))
14875	29068423	Interestingly, these alterations have been shown to affect 12 signaling pathways leading to pancreatic tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('12 signaling pathways', 'Pathway', (59, 80))	('pancreatic tumorigenesis', 'Disease', 'MESH:D010190', (92, 116))	('signaling', 'biological_process', 'GO:0023052', ('62', '71'))	('affect', 'Reg', (52, 58))	('leading', 'Reg', (81, 88))	('pancreatic tumorigenesis', 'Disease', (92, 116))	('alterations', 'Var', (21, 32))
14884	29068423	In another pan-cancer study, researchers found discordance between HER2 copy number variation, mRNA expression, and protein expression level in colorectal and serous endometrial cancer, which demonstrates that a simple protein-based analysis of patients' samples across tumor subtypes could highlight potential therapeutic targets.	('colorectal and serous endometrial cancer', 'Disease', 'MESH:D016889', (144, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('patients', 'Species', '9606', (245, 253))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('serous endometrial cancer', 'Phenotype', 'HP:0012887', (159, 184))	('HER2', 'Gene', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('copy number variation', 'Var', (72, 93))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('mRNA expression', 'MPA', (95, 110))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('cancer', 'Disease', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('protein', 'cellular_component', 'GO:0003675', ('219', '226'))	('tumor', 'Disease', (270, 275))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('endometrial cancer', 'Phenotype', 'HP:0012114', (166, 184))	('cancer', 'Disease', (178, 184))	('HER2', 'Gene', '2064', (67, 71))	('protein expression level', 'MPA', (116, 140))
14887	29068423	In addition, HGSC is the most common subtype of ovarian cancer associated with breast cancer susceptibility gene (BRCA) germline mutation in patients.	('HGSC', 'Disease', (13, 17))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('associated', 'Reg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('subtype of ovarian cancer', 'Disease', (37, 62))	('breast cancer', 'Disease', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('subtype of ovarian cancer', 'Disease', 'MESH:D010051', (37, 62))	('germline mutation', 'Var', (120, 137))	('BRCA', 'Gene', '672', (114, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('BRCA', 'Gene', (114, 118))	('patients', 'Species', '9606', (141, 149))
14891	29068423	A clinical proteogenomic analysis of 100 pancreatic ductal adenocarcinoma samples was able to precisely identify mutations in TP53, KRAS, SMAD4, CDKN2A, ARID1A, and ROBO2, including mutations in the KDM6A and PREX2 driver genes, which drive PDAC tumorigenesis.	('KRAS', 'Gene', (132, 136))	('TP53', 'Gene', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('mutations', 'Var', (113, 122))	('clinical', 'Species', '191496', (2, 10))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (41, 73))	('ARID1A', 'Gene', (153, 159))	('PDAC', 'Disease', (241, 245))	('CDKN2A', 'Gene', (145, 151))	('N', 'Chemical', 'MESH:D009584', (148, 149))	('ROBO2', 'Gene', (165, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('pancreatic ductal adenocarcinoma', 'Disease', (41, 73))	('SMAD4', 'Gene', (138, 143))	('TP53', 'Gene', '7157', (126, 130))	('PDAC', 'Chemical', '-', (241, 245))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (41, 73))	('tumor', 'Disease', (246, 251))	('PDAC', 'Phenotype', 'HP:0006725', (241, 245))	('KRAS', 'Gene', '3845', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (246, 251))
14896	29068423	A proteogenomic analysis of 77 breast cancer samples has shown that 43% of PIK3CA is mutated in luminal breast cancer tumors, and 83% of TP53 is mutated in basal-like tumors (TCGA, 2012).	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('mutated', 'Var', (85, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('PIK3CA', 'Gene', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('breast cancer', 'Disease', (31, 44))	('tumors', 'Disease', (118, 124))	('TP53', 'Gene', (137, 141))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('luminal breast cancer tumors', 'Disease', 'MESH:D001943', (96, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('PIK3CA', 'Gene', '5290', (75, 81))	('luminal breast cancer tumors', 'Disease', (96, 124))	('basal-like tumors', 'Phenotype', 'HP:0002671', (156, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('TP53', 'Gene', '7157', (137, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('tumors', 'Disease', (167, 173))
14900	29068423	It has been observed that the copy number variation (CNV) of these genes has been found in a higher percentage of CRC patients, which always alters the gene expression pattern in those patients and has promiscuous impact in treatment response.	('N', 'Chemical', 'MESH:D009584', (54, 55))	('copy number variation', 'Var', (30, 51))	('gene expression', 'biological_process', 'GO:0010467', ('152', '167'))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('alters', 'Reg', (141, 147))	('gene expression pattern', 'MPA', (152, 175))	('patients', 'Species', '9606', (185, 193))	('patients', 'Species', '9606', (118, 126))	('CRC', 'Disease', (114, 117))
14908	29068423	It is a well-established fact that cancer is triggered due to mutations and epigenetic alterations in the genome; however, the molecular impact of these changes transpire at the proteome level by dysregulating signaling pathways.	('cancer', 'Disease', (35, 41))	('epigenetic alterations', 'Var', (76, 98))	('signaling', 'biological_process', 'GO:0023052', ('210', '219'))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('dysregulating', 'Reg', (196, 209))	('signaling pathways', 'Pathway', (210, 228))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('changes', 'Var', (153, 160))	('mutations', 'Var', (62, 71))
14913	29068423	During tumorigenesis, genetic alterations in signaling molecules lead to over-activated cell surface receptors, which as a consequence affect downstream signaling pathways.	('downstream signaling pathways', 'Pathway', (142, 171))	('over-activated', 'PosReg', (73, 87))	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('cell surface', 'cellular_component', 'GO:0009986', ('88', '100'))	('tumor', 'Disease', (7, 12))	('affect', 'Reg', (135, 141))	('genetic alterations', 'Var', (22, 41))	('cell surface receptors', 'Protein', (88, 110))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
14915	29068423	Interestingly, post-translational modification, such as the phosphorylation of STY residues in these kinases, also transiently controls and propagates abnormal signals during tumorigenesis, and as a consequence a cell faces altered signaling pathways.	('controls', 'Reg', (127, 135))	('phosphorylation', 'MPA', (60, 75))	('tumor', 'Disease', (175, 180))	('STY', 'Protein', (79, 82))	('faces altered', 'Reg', (218, 231))	('abnormal signals', 'MPA', (151, 167))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('post-translational', 'Var', (15, 33))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('post-translational modification', 'biological_process', 'GO:0043687', ('15', '46'))	('signaling', 'biological_process', 'GO:0023052', ('232', '241'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('signaling pathways', 'Pathway', (232, 250))
14917	29068423	The TCGA data set analysis of 3185 genomes, which covered 12 tumor types, showed phosphorylated Single Nucleotide Polymorphism variants in 90% of tumors, which could influence cancer susceptibility by modifying the phosphorylation kinase network.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('N', 'Chemical', 'MESH:D009584', (103, 104))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('modifying', 'Reg', (201, 210))	('phosphorylation', 'biological_process', 'GO:0016310', ('215', '230'))	('tumor', 'Disease', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Single Nucleotide Polymorphism variants', 'Var', (96, 135))	('cancer', 'Disease', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Disease', (146, 152))	('influence', 'Reg', (166, 175))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('tumor', 'Disease', (61, 66))	('phosphorylation kinase network', 'Pathway', (215, 245))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
14918	29068423	A recent study in non-small cell lung carcinoma cancer patients has shown a fourfold upregulation of phosphorylation of Akt in lung tumor samples, In addition, analogous studies have also suggested that the phosphorylated form of Akt has been associated with a poor prognosis and tumor aggression.	('tumor aggression', 'Disease', 'MESH:D001523', (280, 296))	('Akt', 'Gene', '207', (120, 123))	('Akt', 'Gene', '207', (230, 233))	('upregulation of phosphorylation', 'biological_process', 'GO:0042327', ('85', '116'))	('non-small cell lung carcinoma cancer', 'Disease', 'MESH:D002289', (18, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('patients', 'Species', '9606', (55, 63))	('lung tumor', 'Disease', (127, 137))	('aggression', 'Phenotype', 'HP:0000718', (286, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (18, 47))	('non-small cell lung carcinoma cancer', 'Disease', (18, 54))	('lung tumor', 'Phenotype', 'HP:0100526', (127, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('aggression', 'biological_process', 'GO:0002118', ('286', '296'))	('upregulation', 'PosReg', (85, 97))	('phosphorylated', 'Var', (207, 221))	('phosphorylation', 'MPA', (101, 116))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (22, 47))	('tumor aggression', 'Disease', (280, 296))	('lung carcinoma cancer', 'Phenotype', 'HP:0030078', (33, 54))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('lung tumor', 'Disease', 'MESH:D008175', (127, 137))	('Akt', 'Gene', (120, 123))	('Akt', 'Gene', (230, 233))
14928	29068423	A recent study on the role of Ybx1 phosphorylation in colon cancer has shown that S176 phosphorylation is responsible for an aggressive form of colon cancer, and its inhibition could be an important treatment option for colon cancer.	('colon cancer', 'Disease', (54, 66))	('colon cancer', 'Disease', (220, 232))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))	('responsible for', 'Reg', (106, 121))	('colon cancer', 'Phenotype', 'HP:0003003', (144, 156))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('phosphorylation', 'MPA', (87, 102))	('Ybx1', 'Gene', '4904', (30, 34))	('Ybx1', 'Gene', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('colon cancer', 'Phenotype', 'HP:0003003', (54, 66))	('S176', 'Var', (82, 86))	('colon cancer', 'Phenotype', 'HP:0003003', (220, 232))	('colon cancer', 'Disease', 'MESH:D015179', (144, 156))	('colon cancer', 'Disease', 'MESH:D015179', (54, 66))	('colon cancer', 'Disease', 'MESH:D015179', (220, 232))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('colon cancer', 'Disease', (144, 156))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
14929	29068423	Aberrant alterations in glycosylation patterns have been linked with tumor aggression and tumor microenvironment heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('glycosylation patterns', 'MPA', (24, 46))	('glycosylation', 'biological_process', 'GO:0070085', ('24', '37'))	('aggression', 'biological_process', 'GO:0002118', ('75', '85'))	('tumor', 'Disease', (69, 74))	('aggression', 'Phenotype', 'HP:0000718', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('linked', 'Reg', (57, 63))	('tumor aggression', 'Disease', (69, 85))	('Aberrant alterations', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor aggression', 'Disease', 'MESH:D001523', (69, 85))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
14932	29068423	In ovarian cancer, many membrane proteins have been found to be aberrantly glycosylated and modified, including CA125 and KLK6, which qualify as potential biomarkers for an early diagnosis.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('KLK6', 'Gene', '5653', (122, 126))	('modified', 'Var', (92, 100))	('CA125', 'Gene', (112, 117))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('KLK6', 'Gene', (122, 126))	('membrane proteins', 'Protein', (24, 41))	('membrane', 'cellular_component', 'GO:0016020', ('24', '32'))	('ovarian cancer', 'Disease', (3, 17))	('CA125', 'Gene', '94025', (112, 117))
14933	29068423	Further, MUC-4:a transmembrane protein:expression has been observed in pancreatic ductal adenocarcinoma, and it is aberrantly glycosylated, which is involved in cancer progression and neoplast cancer aggression.	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('aggression', 'biological_process', 'GO:0002118', ('200', '210'))	('cancer', 'Disease', (161, 167))	('aggression', 'Phenotype', 'HP:0000718', (200, 210))	('transmembrane', 'cellular_component', 'GO:0016021', ('17', '30'))	('neoplast cancer aggression', 'Disease', 'MESH:D009369', (184, 210))	('aberrantly', 'Var', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (71, 103))	('MUC-4', 'Gene', '4585', (9, 14))	('transmembrane', 'cellular_component', 'GO:0044214', ('17', '30'))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('pancreatic ductal adenocarcinoma', 'Disease', (71, 103))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('observed', 'Reg', (59, 67))	('MUC-4', 'Gene', (9, 14))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (71, 103))	('neoplast cancer aggression', 'Disease', (184, 210))
14939	29068423	The detection of aberrant glycosylated MUC1-specific autoantibodies correlates with colorectal cancer, which has the capability to predict cancer with 95% specificity.	('colorectal cancer', 'Disease', (84, 101))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('aberrant', 'Var', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('colorectal cancer', 'Disease', 'MESH:D015179', (84, 101))	('MUC1', 'Gene', (39, 43))	('MUC1', 'Gene', '4582', (39, 43))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (139, 145))
14943	29068423	Lysine N-acetylation precisely regulates the function of histone and non-histone proteins, and, especially, histone acetyltransferase (HAT) are dysregulated as a result of numerous genetic or epigenetic alterations.	('histone', 'MPA', (108, 115))	('histone', 'Protein', (57, 64))	('Lysine N', 'Chemical', '-', (0, 8))	('function', 'MPA', (45, 53))	('epigenetic alterations', 'Var', (192, 214))	('regulates', 'Reg', (31, 40))
14945	29068423	However, abnormal acetylation could activate malignant proteins and trigger tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('abnormal', 'Var', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('malignant proteins', 'Protein', (45, 63))	('activate', 'PosReg', (36, 44))	('acetylation', 'MPA', (18, 29))	('trigger', 'PosReg', (68, 75))
14948	29068423	Further, epigenetic therapy, employing histone deacetylase inhibitors and acetylation modulators, shows promise in treating some forms of cancers.	('epigenetic', 'Var', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
14950	29068423	In conclusion, post-translational modifications play an extremely important role in cancer activation by altering signaling pathways controlled by kinases.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('post-translational modifications', 'Var', (15, 47))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('altering', 'Reg', (105, 113))	('signaling pathways controlled', 'Pathway', (114, 143))
14957	29068423	Earlier studies have reported the use of a single biomarker which has shown significance in the early diagnosis of cancer, and by employing a proteogenomic approach, the APEX1 gene has been identified as biomarker which could monitor damaged DNA repair, and its deletion triggered radiosensitivity in cell lines inherently expressing radio resistance phenotypes.	('APEX', 'cellular_component', 'GO:0097683', ('170', '174'))	('cancer', 'Disease', (115, 121))	('DNA', 'cellular_component', 'GO:0005574', ('242', '245'))	('damaged DNA repair', 'MPA', (234, 252))	('triggered', 'Reg', (271, 280))	('APEX1', 'Gene', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('N', 'Chemical', 'MESH:D009584', (243, 244))	('DNA repair', 'biological_process', 'GO:0006281', ('242', '252'))	('deletion', 'Var', (262, 270))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('radiosensitivity', 'CPA', (281, 297))	('APEX1', 'Gene', '328', (170, 175))
14959	29068423	Additionally, a number of gene variations have also been associated with radiotoxicity.	('radiotoxicity', 'Disease', (73, 86))	('gene variations', 'Var', (26, 41))	('radiotoxicity', 'Disease', 'None', (73, 86))	('associated', 'Reg', (57, 67))
14970	29068423	In another elegant study based on Reverse Phase Protein Array (RPPA) analysis of a cohort of 118 stage II colon cancer patients, an upregulation of three components of an activated PIK3/Akt pathway, namely phospho-Akt, S6RP, and phospho-4E-BP1, served as novel biomarkers for stage II colon cancer recurrence.	('PIK3', 'Gene', (181, 185))	('Akt', 'Gene', '207', (186, 189))	('upregulation', 'PosReg', (132, 144))	('Akt', 'Gene', '207', (214, 217))	('PIK3', 'Gene', '5294', (181, 185))	('patients', 'Species', '9606', (119, 127))	('Akt', 'Gene', (186, 189))	('II colon cancer', 'Disease', (282, 297))	('colon cancer', 'Phenotype', 'HP:0003003', (106, 118))	('S6RP', 'Gene', (219, 223))	('phospho-4E-BP1', 'Var', (229, 243))	('II colon cancer', 'Disease', (103, 118))	('Akt', 'Gene', (214, 217))	('II colon cancer', 'Disease', 'MESH:D015179', (103, 118))	('II colon cancer', 'Disease', 'MESH:D015179', (282, 297))	('colon cancer', 'Phenotype', 'HP:0003003', (285, 297))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))
14974	29068423	A large number of cancer genome sequence analyses have shown that each patient's tumor contains specific genetic alterations and that these alterations drive tumorigenesis.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('genetic alterations', 'Var', (105, 124))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('drive', 'Reg', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('patient', 'Species', '9606', (71, 78))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Disease', (81, 86))
14975	29068423	Interestingly, a clear landscape of genomic alterations in a specific cancer subtype may lead to an individualized medical treatment that is precisely based on the specific genetic alterations of an individual cancer patient.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('lead to', 'Reg', (89, 96))	('patient', 'Species', '9606', (217, 224))	('alterations', 'Var', (44, 55))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (210, 216))
14979	29068423	A large-scale cancer genome atlas (TCGA) analysis has clearly established that a large number of genetic alterations and aberrations in an individual genome and epigenome accumulate over time and activate malignant transformations.	('activate', 'PosReg', (196, 204))	('aberrations', 'Var', (121, 132))	('genetic alterations', 'Var', (97, 116))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer genome atlas', 'Disease', 'MESH:D009369', (14, 33))	('malignant transformations', 'CPA', (205, 230))	('cancer genome atlas', 'Disease', (14, 33))
14982	29068423	The well-established examples of a precision medicine approach are the mutational profile of the EGFR receptor gene, which triggers uncontrolled growth and at the same time blocks apoptotic signals.	('triggers', 'PosReg', (123, 131))	('mutational profile', 'Var', (71, 89))	('EGFR', 'Gene', '1956', (97, 101))	('apoptotic signals', 'CPA', (180, 197))	('blocks', 'NegReg', (173, 179))	('EGFR', 'Gene', (97, 101))	('uncontrolled growth', 'MPA', (132, 151))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))
14983	29068423	Thus, Tarceva is designed to block mutant EGFR activity.	('EGFR', 'Gene', '1956', (42, 46))	('Tarceva', 'Chemical', 'MESH:D000069347', (6, 13))	('EGFR', 'Gene', (42, 46))	('mutant', 'Var', (35, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('activity', 'MPA', (47, 55))
14984	29068423	In a corollary finding, Cetuximab therapy in colorectal cancer patients based on a KRAS mutational profile has been quite promising.	('KRAS', 'Gene', (83, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (45, 62))	('KRAS', 'Gene', '3845', (83, 87))	('mutational', 'Var', (88, 98))	('colorectal cancer', 'Disease', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('patients', 'Species', '9606', (63, 71))	('Cetuximab', 'Chemical', 'MESH:D000068818', (24, 33))	('colorectal cancer', 'Disease', 'MESH:D015179', (45, 62))
14987	29068423	Interestingly, the genetic profiling of tumor samples helps us to understand the link between specific genetic variants and the important clinical state of the patient, which could serve as an important step in personalized medicine (Figure 2).	('clinical', 'Species', '191496', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('variants', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('patient', 'Species', '9606', (160, 167))
15000	29068423	Cancer genomic alterations, combined with cutting-edge proteomic technologies and bioinformatics tools, are beginning to reveal patients' specific cancer landscapes.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('alterations', 'Var', (15, 26))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', (147, 153))	('patients', 'Species', '9606', (128, 136))
15001	29068423	Thus, an onco-proteogenomic approach can precisely identify point mutations, splice variants, copy number variation, and gene fusions in a patient's genome, which could be complimented with changes in the proteome and its post-translational modifications, which could immensely facilitate the early diagnosis, prognosis, and treatment of cancer.	('cancer', 'Disease', (338, 344))	('facilitate', 'PosReg', (278, 288))	('point mutations', 'Var', (60, 75))	('patient', 'Species', '9606', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('cancer', 'Disease', 'MESH:D009369', (338, 344))	('copy number variation', 'Var', (94, 115))
15005	29068423	Advances in Next-Gen sequencing have facilitated the RNA-Seq-based transcriptomic analysis of cancer samples, and it allows us to precisely quantify mRNA transcripts and helps us to identify the various genetic variants which might be responsible for cancer progression.	('N', 'Chemical', 'MESH:D009584', (12, 13))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('mRNA transcripts', 'MPA', (149, 165))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('RNA', 'cellular_component', 'GO:0005562', ('53', '56'))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('N', 'Chemical', 'MESH:D009584', (151, 152))	('variants', 'Var', (211, 219))	('cancer', 'Disease', (251, 257))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
15016	28446878	Mutations mediated by the KRAS or MYC oncogenes, found in 95% of cases of PDAC (Almoguera et al.,; Uemura et al.,; Lohr et al.,; Hezel et al.,; Kimmelman,), promote reprogramming of the cellular metabolism, enabling the cancer cells to optimally use available resources (Ying et al.,).	('MYC', 'Gene', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('PDAC', 'Phenotype', 'HP:0006725', (74, 78))	('promote', 'PosReg', (157, 164))	('reprogramming of the cellular metabolism', 'CPA', (165, 205))	('enabling', 'PosReg', (207, 215))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cellular metabolism', 'biological_process', 'GO:0044237', ('186', '205'))	('KRAS', 'Gene', (26, 30))	('cancer', 'Disease', (220, 226))	('PDAC', 'Chemical', '-', (74, 78))	('KRAS', 'Gene', '3845', (26, 30))	('PDAC', 'Gene', (74, 78))
15022	28446878	Moreover, the metabolic stress that occurs as a result of KRAS-mediated metabolic alterations can lead to further mutations and continued cell proliferation and tumor progression (Cairns et al.,; Misale et al.,).	('KRAS', 'Gene', (58, 62))	('KRAS', 'Gene', '3845', (58, 62))	('metabolic stress', 'MPA', (14, 30))	('lead to', 'Reg', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('mutations', 'CPA', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cell proliferation', 'biological_process', 'GO:0008283', ('138', '156'))	('cell proliferation', 'CPA', (138, 156))	('alterations', 'Var', (82, 93))	('tumor', 'Disease', (161, 166))
15036	28446878	For example, knocking down GOT1 activity alters the cells reductive capacity and is shown to inhibit cell proliferation in vitro and tumor growth in vivo (Son et al.,).	('inhibit', 'NegReg', (93, 100))	('cells reductive capacity', 'MPA', (52, 76))	('knocking down', 'Var', (13, 26))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('activity', 'MPA', (32, 40))	('cell proliferation', 'biological_process', 'GO:0008283', ('101', '119'))	('alters', 'Reg', (41, 47))	('GOT1', 'Gene', '2805', (27, 31))	('tumor', 'Disease', (133, 138))	('cell proliferation', 'CPA', (101, 119))	('GOT1', 'Gene', (27, 31))
15069	28446878	Son and coworkers sought to understand the non-canonical glutamine metabolism in pancreatic cancer cells following the knockdown of GOT1, a major enzyme in glutamine metabolism.	('GOT1', 'Gene', (132, 136))	('glutamine', 'Chemical', 'MESH:D005973', (156, 165))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('57', '77'))	('non-canonical glutamine metabolism', 'MPA', (43, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('GOT1', 'Gene', '2805', (132, 136))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('156', '176'))	('glutamine', 'Chemical', 'MESH:D005973', (57, 66))	('knockdown', 'Var', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('pancreatic cancer', 'Disease', (81, 98))
15070	28446878	The metabolite concentrations were measured when the GOT1 enzyme was knocked down, relative to the no knockdown condition.	('GOT1', 'Gene', '2805', (53, 57))	('GOT1', 'Gene', (53, 57))	('knocked', 'Var', (69, 76))	('metabolite concentrations', 'MPA', (4, 29))
15073	28446878	They measure the number of cells with and without GOT1 knockdown and in the presence of varying extracellular nutrient concentrations.	('GOT1', 'Gene', '2805', (50, 54))	('knockdown', 'Var', (55, 64))	('extracellular', 'cellular_component', 'GO:0005576', ('96', '109'))	('GOT1', 'Gene', (50, 54))
15074	28446878	The model simulations to optimize for cell growth were conducted such that the same set of seven growth parameters could fit the experimental growth curve for both no knockdown and GOT1 knockdown conditions.	('cell growth', 'biological_process', 'GO:0016049', ('38', '49'))	('knockdown', 'Var', (186, 195))	('GOT1', 'Gene', '2805', (181, 185))	('GOT1', 'Gene', (181, 185))
15075	28446878	Training data includes the fold-change in metabolite concentrations and cell number under GOT1 knockdown.	('knockdown', 'Var', (95, 104))	('GOT1', 'Gene', '2805', (90, 94))	('metabolite concentrations', 'MPA', (42, 67))	('GOT1', 'Gene', (90, 94))
15078	28446878	Through glycolysis, glucose is metabolized to pyruvate, which enters the tricarboxylic acid cycle (in the mitochondria), or pyruvate can form lactate (in the cytoplasm), which is excreted from the cell.	('mitochondria', 'cellular_component', 'GO:0005739', ('106', '118'))	('tricarboxylic', 'MPA', (73, 86))	('tricarboxylic acid cycle', 'biological_process', 'GO:0006099', ('73', '97'))	('pyruvate', 'Chemical', 'MESH:D019289', (124, 132))	('pyruvate', 'Chemical', 'MESH:D019289', (46, 54))	('pyruvate', 'Var', (124, 132))	('cytoplasm', 'cellular_component', 'GO:0005737', ('158', '167'))	('glycolysis', 'biological_process', 'GO:0006096', ('8', '18'))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (73, 91))	('lactate', 'Chemical', 'MESH:D019344', (142, 149))	('glucose', 'Chemical', 'MESH:D005947', (20, 27))
15079	28446878	Glycolysis and pentose phosphate pathway take place in the cytoplasm and are linked through three metabolites: G6P, F6P and G3P.	('F6P', 'Var', (116, 119))	('pentose phosphate', 'Chemical', 'MESH:D010428', (15, 32))	('G3P', 'Var', (124, 127))	('pentose', 'Enzyme', (15, 22))	('Glycolysis', 'biological_process', 'GO:0006096', ('0', '10'))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('15', '40'))	('G6P', 'Var', (111, 114))	('cytoplasm', 'cellular_component', 'GO:0005737', ('59', '68'))
15098	28446878	Therefore, we applied the model to predict the dynamic reaction fluxes through the metabolic reactions both in the baseline model with no GOT1 knockdown (Figure 6A) and under GOT1 knockdown (Figure 6B).	('GOT1', 'Gene', (138, 142))	('knockdown', 'Var', (180, 189))	('metabolic', 'MPA', (83, 92))	('GOT1', 'Gene', '2805', (175, 179))	('GOT1', 'Gene', (175, 179))	('GOT1', 'Gene', '2805', (138, 142))
15099	28446878	The model predicts that GOT1 knockdown influences the magnitude and direction of the adenylate kinase (AK) reaction.	('knockdown', 'Var', (29, 38))	('magnitude', 'MPA', (54, 63))	('influences', 'Reg', (39, 49))	('GOT1', 'Gene', '2805', (24, 28))	('GOT1', 'Gene', (24, 28))
15101	28446878	With GOT1 knockdown, the flux through the AK reaction switches after 24 h of cell growth.	('GOT1', 'Gene', '2805', (5, 9))	('GOT1', 'Gene', (5, 9))	('cell growth', 'biological_process', 'GO:0016049', ('77', '88'))	('AK reaction', 'Enzyme', (42, 53))	('switches', 'Reg', (54, 62))	('knockdown', 'Var', (10, 19))	('flux', 'MPA', (25, 29))
15103	28446878	Additionally, GOT1 knockdown causes the glutamate-pyruvate transaminase (GPT) reaction to proceed in the opposite direction, as compared to the no knockdown case.	('glutamate', 'Chemical', 'MESH:D018698', (40, 49))	('knockdown', 'Var', (19, 28))	('glutamate-pyruvate transaminase', 'MPA', (40, 71))	('GPT', 'Gene', '2875', (73, 76))	('GOT1', 'Gene', '2805', (14, 18))	('GPT', 'Gene', (73, 76))	('GPT', 'molecular_function', 'GO:0004021', ('73', '76'))	('pyruvate', 'Chemical', 'MESH:D019289', (50, 58))	('GOT1', 'Gene', (14, 18))
15104	28446878	This means that with GOT1 knockdown, the GPT reaction works to produce glutamate rather than consume it, compensating for the lower glutamate production that occurs when the GOT1 enzyme is not fully active.	('GPT', 'Gene', '2875', (41, 44))	('GPT', 'Gene', (41, 44))	('produce glutamate', 'MPA', (63, 80))	('GOT1', 'Gene', '2805', (174, 178))	('GOT1', 'Gene', '2805', (21, 25))	('knockdown', 'Var', (26, 35))	('glutamate production', 'MPA', (132, 152))	('glutamate', 'Chemical', 'MESH:D018698', (132, 141))	('GPT', 'molecular_function', 'GO:0004021', ('41', '44'))	('GOT1', 'Gene', (174, 178))	('GOT1', 'Gene', (21, 25))	('glutamate', 'Chemical', 'MESH:D018698', (71, 80))	('lower glutamate production', 'Phenotype', 'HP:0500150', (126, 152))
15106	28446878	We implemented enzyme knockdowns by decreasing the forward reaction velocity (Vf) by 85%, either alone or in combination with GOT1 knockdown.	('knockdowns', 'Var', (22, 32))	('decreasing', 'NegReg', (36, 46))	('GOT1', 'Gene', '2805', (126, 130))	('GOT1', 'Gene', (126, 130))	('forward reaction velocity', 'MPA', (51, 76))
15109	28446878	GLUT1 knockdown alone is not as effective in reducing cell growth as GOT1 knockdown (Figure 7A).	('GLUT1', 'Gene', (0, 5))	('cell growth', 'CPA', (54, 65))	('GLUT1', 'Gene', '6513', (0, 5))	('knockdown', 'Var', (6, 15))	('cell growth', 'biological_process', 'GO:0016049', ('54', '65'))	('GOT1', 'Gene', '2805', (69, 73))	('GOT1', 'Gene', (69, 73))
15110	28446878	Moreover, knockdown of both GLUT1 and GOT1 is as effective in reducing cell growth as GOT1 knockdown alone.	('GOT1', 'Gene', '2805', (86, 90))	('GOT1', 'Gene', (86, 90))	('cell growth', 'biological_process', 'GO:0016049', ('71', '82'))	('GLUT1', 'Gene', (28, 33))	('cell growth', 'CPA', (71, 82))	('GOT1', 'Gene', (38, 42))	('reducing', 'NegReg', (62, 70))	('GLUT1', 'Gene', '6513', (28, 33))	('GOT1', 'Gene', '2805', (38, 42))	('knockdown', 'Var', (10, 19))
15112	28446878	In comparison, OXPHOS knockdown leads to lower cell proliferation compared to GOT1 knockdown (Figure 7B).	('OXPHOS', 'biological_process', 'GO:0002082', ('15', '21'))	('OXPHOS knockdown', 'Var', (15, 31))	('GOT1', 'Gene', '2805', (78, 82))	('lower', 'NegReg', (41, 46))	('GOT1', 'Gene', (78, 82))	('cell proliferation', 'biological_process', 'GO:0008283', ('47', '65'))	('cell proliferation', 'CPA', (47, 65))
15113	28446878	Also, under GLS knockdown, cell growth is significantly reduced (Figure 7C), alone or in combination with GOT1 knockdown.	('GLS', 'Gene', '2744', (12, 15))	('cell growth', 'CPA', (27, 38))	('GLS', 'Gene', (12, 15))	('reduced', 'NegReg', (56, 63))	('knockdown', 'Var', (16, 25))	('GOT1', 'Gene', '2805', (106, 110))	('cell growth', 'biological_process', 'GO:0016049', ('27', '38'))	('GOT1', 'Gene', (106, 110))
15115	28446878	Reducing the reaction velocity in the GOT1 reaction showed an expected direct correlation of decrease in cell growth with increasing effect of knockdown (Figure S7).	('Reducing', 'NegReg', (0, 8))	('cell growth', 'biological_process', 'GO:0016049', ('105', '116'))	('cell growth', 'CPA', (105, 116))	('reaction velocity', 'MPA', (13, 30))	('GOT1', 'Gene', '2805', (38, 42))	('decrease', 'NegReg', (93, 101))	('knockdown', 'Var', (143, 152))	('GOT1', 'Gene', (38, 42))
15116	28446878	Therefore, we identified how knockdown (reducing the reaction velocity by 85%) for a target enzyme influences the predicted cell growth, alone and in combination with GOT1 knockdown.	('influences', 'Reg', (99, 109))	('cell growth', 'biological_process', 'GO:0016049', ('124', '135'))	('cell growth', 'CPA', (124, 135))	('knockdown', 'Var', (29, 38))	('GOT1', 'Gene', '2805', (167, 171))	('GOT1', 'Gene', (167, 171))	('reaction', 'MPA', (53, 61))
15118	28446878	Knockdown of the target enzyme alone is not as effective as GOT1, but its knockdown synergizes with GOT1 knockdown to further decrease cell count.	('cell count', 'CPA', (135, 145))	('GOT1', 'Gene', '2805', (60, 64))	('GOT1', 'Gene', (60, 64))	('knockdown', 'Var', (74, 83))	('decrease', 'NegReg', (126, 134))	('GOT1', 'Gene', '2805', (100, 104))	('GOT1', 'Gene', (100, 104))
15124	28446878	This behavior is illustrated in the case of targeting GAPDH, the enzyme responsible for converting G3P to BPG, accompanied by the reduction of NAD to NADH.	('NAD', 'Chemical', 'MESH:D009243', (143, 146))	('G3P', 'Var', (99, 102))	('NADH', 'Chemical', 'MESH:D009243', (150, 154))	('NAD', 'MPA', (143, 146))	('NAD', 'Chemical', 'MESH:D009243', (150, 153))	('GAPDH', 'Gene', '2597', (54, 59))	('GAPDH', 'Gene', (54, 59))
15126	28446878	Inhibiting GAPDH would decrease the production of downstream metabolites, hence reducing the formation of lipids and amino acids, which are required for cell proliferation (Pereira et al.,).	('decrease', 'NegReg', (23, 31))	('lipids', 'Chemical', 'MESH:D008055', (106, 112))	('GAPDH', 'Gene', '2597', (11, 16))	('Inhibiting', 'Var', (0, 10))	('formation', 'biological_process', 'GO:0009058', ('93', '102'))	('GAPDH', 'Gene', (11, 16))	('reducing', 'NegReg', (80, 88))	('production of downstream metabolites', 'MPA', (36, 72))	('cell proliferation', 'biological_process', 'GO:0008283', ('153', '171'))
15128	28446878	Knockdown of the target enzyme alone is very effective in reducing cell proliferation, and combining it with GOT1 knockdown does not have any additional effect.	('Knockdown', 'Var', (0, 9))	('GOT1', 'Gene', '2805', (109, 113))	('GOT1', 'Gene', (109, 113))	('reducing', 'NegReg', (58, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('cell proliferation', 'CPA', (67, 85))
15158	28446878	Interestingly, inhibitors of GLS are being explored: BPTES (DeLaBarre et al.,; Hartwick and Curthoys,) and CB839 (Gross et al.,) have been shown to induce apoptosis in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('CB839', 'Var', (107, 112))	('apoptosis', 'biological_process', 'GO:0006915', ('155', '164'))	('GLS', 'Gene', '2744', (29, 32))	('GLS', 'Gene', (29, 32))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('induce', 'PosReg', (148, 154))	('apoptosis', 'CPA', (155, 164))	('apoptosis', 'biological_process', 'GO:0097194', ('155', '164'))
15175	28294968	In particular, diets low in folate and high in fruits, vegetables, red/processed meat, and saturated fat have been identified as pancreatic cancer risk factors with a proposed mechanism involving epigenetic modifications or gene regulation.	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('saturated fat', 'Chemical', 'MESH:D005227', (91, 104))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('folate', 'Chemical', 'MESH:D005492', (28, 34))	('low', 'NegReg', (21, 24))	('regulation', 'biological_process', 'GO:0065007', ('229', '239'))	('folate', 'MPA', (28, 34))	('gene regulation', 'Var', (224, 239))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('pancreatic cancer', 'Disease', (129, 146))	('epigenetic', 'Var', (196, 206))	('low in folate', 'Phenotype', 'HP:0100507', (21, 34))
15209	28294968	Activation through mutations of KRAS oncogene, inactivation of tumor-suppressor genes such as CDKN2A, TP53, SMAD4, and BRCA2, telomere shortening, gene amplification, and chromosomal loss are the most frequent genetic mutations.	('inactivation', 'Var', (47, 59))	('telomere', 'cellular_component', 'GO:0000781', ('126', '134'))	('TP53', 'Gene', (102, 106))	('CDKN2A', 'Gene', '1029', (94, 100))	('telomere', 'cellular_component', 'GO:0005696', ('126', '134'))	('telomere', 'CPA', (126, 134))	('tumor-suppressor', 'Gene', '7248', (63, 79))	('KRAS', 'Gene', '3845', (32, 36))	('telomere shortening', 'Phenotype', 'HP:0031413', (126, 145))	('BRCA2', 'Gene', (119, 124))	('TP53', 'Gene', '7157', (102, 106))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('63', '79'))	('SMAD4', 'Gene', (108, 113))	('tumor-suppressor', 'Gene', (63, 79))	('KRAS', 'Gene', (32, 36))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('63', '79'))	('Activation', 'PosReg', (0, 10))	('CDKN2A', 'Gene', (94, 100))	('BRCA2', 'Gene', '675', (119, 124))	('gene amplification', 'Var', (147, 165))	('mutations', 'Var', (19, 28))	('SMAD4', 'Gene', '4089', (108, 113))	('chromosomal', 'CPA', (171, 182))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
15210	28294968	In addition to the mutations in genes, epigenetic alterations in DNA methylation, histone modification, and non-coding RNA can change gene function in pancreatic cancers; this topic will be further discussed below.	('gene function', 'MPA', (134, 147))	('DNA methylation', 'biological_process', 'GO:0006306', ('65', '80'))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (151, 169))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('epigenetic alterations', 'Var', (39, 61))	('histone', 'Protein', (82, 89))	('change', 'Reg', (127, 133))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('histone modification', 'biological_process', 'GO:0016570', ('82', '102'))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('pancreatic cancers', 'Disease', (151, 169))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('RNA', 'cellular_component', 'GO:0005562', ('119', '122'))	('pancreatic cancers', 'Disease', 'MESH:D010190', (151, 169))
15214	28294968	We conducted a search of the published scientific literature using Pubmed, SpringerLink, Google Scholar, EBSCO, Elsevier, and Wiley Online Library (with the search terms "pancreatic cancer" and "epigenetics" or "nutrition" or "diet" or "epigenetic modifications").	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('epigenetics', 'Var', (195, 206))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (171, 188))	('epigenetic modifications"', 'Var', (237, 262))	('pancreatic cancer', 'Disease', (171, 188))	('pancreatic cancer', 'Disease', 'MESH:D010190', (171, 188))
15223	28294968	Folate donates dietary methyl groups involved in DNA synthesis and repair and DNA methylation and irregularities and these pathways may contribute to cancer.	('DNA methylation', 'biological_process', 'GO:0006306', ('78', '93'))	('Folate', 'Chemical', 'MESH:D005492', (0, 6))	('contribute', 'Reg', (136, 146))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('irregularities', 'Var', (98, 112))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('cancer', 'Disease', (150, 156))	('DNA synthesis', 'biological_process', 'GO:0071897', ('49', '62'))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
15224	28294968	Low folate or defective folate metabolism leads to methyl group deficiency.	('methyl group deficiency', 'MPA', (51, 74))	('folate', 'Chemical', 'MESH:D005492', (24, 30))	('folate', 'Enzyme', (24, 30))	('leads to', 'Reg', (42, 50))	('defective', 'Var', (14, 23))	('folate', 'Chemical', 'MESH:D005492', (4, 10))	('Low folate', 'Phenotype', 'HP:0100507', (0, 10))	('folate metabolism', 'biological_process', 'GO:0046655', ('24', '41'))	('Low', 'NegReg', (0, 3))
15225	28294968	According to McCabe and Cadudill deficiencies in folate and their methyl supplying ability can either independently or interactively reduce the potential for DNA methylation.	('DNA methylation', 'MPA', (158, 173))	('reduce', 'NegReg', (133, 139))	('folate', 'Chemical', 'MESH:D005492', (49, 55))	('DNA', 'cellular_component', 'GO:0005574', ('158', '161'))	('DNA methylation', 'biological_process', 'GO:0006306', ('158', '173'))	('methyl supplying', 'MPA', (66, 82))	('deficiencies', 'Var', (33, 45))	('folate', 'MPA', (49, 55))
15229	28294968	Genetic changes in this enzyme may result in an increased risk of pancreatic cancer because MTHFR works by directing folate metabolites towards the DNA methylation pathway.	('result in', 'Reg', (35, 44))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (48, 83))	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('DNA methylation', 'biological_process', 'GO:0006306', ('148', '163'))	('pancreatic cancer', 'Disease', (66, 83))	('folate', 'Chemical', 'MESH:D005492', (117, 123))	('Genetic changes', 'Var', (0, 15))	('MTHFR', 'Gene', (92, 97))	('pancreatic cancer', 'Disease', 'MESH:D010190', (66, 83))	('directing', 'PosReg', (107, 116))	('MTHFR', 'Gene', '4524', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('folate metabolites', 'MPA', (117, 135))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (66, 83))
15230	28294968	MTHFR is also involved in DNA methylation and abnormal DNA methylation is associated with many types of cancer, including pancreatic.	('MTHFR', 'Gene', '4524', (0, 5))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('DNA methylation', 'biological_process', 'GO:0006306', ('26', '41'))	('pancreatic', 'Disease', 'MESH:D010195', (122, 132))	('MTHFR', 'Gene', (0, 5))	('DNA methylation', 'biological_process', 'GO:0006306', ('55', '70'))	('abnormal', 'Var', (46, 54))	('DNA methylation', 'MPA', (55, 70))	('pancreatic', 'Disease', (122, 132))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('associated', 'Reg', (74, 84))
15238	28294968	In addition, isothicyanates, an enzymatic product of a plant enzyme called myrosinase, has been shown in laboratory studies to inhibit the growth of human pancreatic cancer cell lines.	('isothicyanates', 'Var', (13, 27))	('growth', 'CPA', (139, 145))	('pancreatic cancer', 'Disease', (155, 172))	('human', 'Species', '9606', (149, 154))	('pancreatic cancer', 'Disease', 'MESH:D010190', (155, 172))	('inhibit', 'NegReg', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('isothicyanates', 'Chemical', '-', (13, 27))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (155, 172))
15260	28294968	An analysis of a large cohort study of male smokers reported a significant positive association for pancreatic cancer and saturated fat intake.	('saturated fat', 'Chemical', 'MESH:D005227', (122, 135))	('pancreatic cancer', 'Disease', (100, 117))	('positive', 'PosReg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('pancreatic cancer', 'Disease', 'MESH:D010190', (100, 117))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (100, 117))	('saturated', 'Var', (122, 131))
15266	28294968	In addition to the known genetic modifications, the role of epigenetic alterations has become more apparent in the development and progression of cancer.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('epigenetic alterations', 'Var', (60, 82))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('men', 'Species', '9606', (122, 125))
15268	28294968	Two main hypothesis currently exist around how dietary intake influences development and progression of pancreatic cancer: (1) certain dietary components affect pathways involved in insulin resistance and insulin insensitivity; and (2) dietary components reduce oxidative stress and inflammation by reducing DNA damage and mutation.	('inflammation', 'Disease', 'MESH:D007249', (283, 295))	('pancreatic cancer', 'Disease', (104, 121))	('inflammation', 'biological_process', 'GO:0006954', ('283', '295'))	('dietary', 'Var', (236, 243))	('oxidative stress', 'Phenotype', 'HP:0025464', (262, 278))	('insulin insensitivity', 'Phenotype', 'HP:0008189', (205, 226))	('inflammation', 'Disease', (283, 295))	('affect', 'Reg', (154, 160))	('insulin', 'Gene', '3630', (182, 189))	('DNA', 'cellular_component', 'GO:0005574', ('308', '311'))	('insulin', 'molecular_function', 'GO:0016088', ('205', '212'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('insulin', 'Gene', '3630', (205, 212))	('reducing', 'NegReg', (299, 307))	('men', 'Species', '9606', (80, 83))	('oxidative stress', 'MPA', (262, 278))	('insulin', 'molecular_function', 'GO:0016088', ('182', '189'))	('pathways', 'Pathway', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('insulin', 'Gene', (182, 189))	('reduce', 'NegReg', (255, 261))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('insulin resistance', 'Phenotype', 'HP:0000855', (182, 200))	('DNA damage', 'MPA', (308, 318))	('mutation', 'Var', (323, 331))	('insulin', 'Gene', (205, 212))
15272	28294968	DNA methylation patterns have been associated with carcinogenesis and are known to interfere with the gene stability and transcription.	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('associated', 'Reg', (35, 45))	('gene stability', 'CPA', (102, 116))	('transcription', 'MPA', (121, 134))	('transcription', 'biological_process', 'GO:0006351', ('121', '134'))	('interfere', 'NegReg', (83, 92))	('carcinogenesis', 'Disease', 'MESH:D063646', (51, 65))	('carcinogenesis', 'Disease', (51, 65))	('methylation patterns', 'Var', (4, 24))
15274	28294968	CDKN2A/p16 was one of the first recognized tumor suppressor genes to undergo hypermethylation at the promoter region and lead to gene silencing in pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('gene silencing', 'biological_process', 'GO:0016458', ('129', '143'))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('p16', 'Gene', (7, 10))	('gene', 'MPA', (129, 133))	('p16', 'Gene', '1029', (7, 10))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('CDKN2A', 'Gene', (0, 6))	('tumor', 'Disease', (43, 48))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))	('pancreatic cancer', 'Disease', (147, 164))	('hypermethylation', 'Var', (77, 93))	('CDKN2A', 'Gene', '1029', (0, 6))
15275	28294968	Hypomethylation has also been implicated in pancreatic adenocarcinomas.	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (44, 70))	('Hypomethylation', 'Var', (0, 15))	('implicated', 'Reg', (30, 40))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (44, 70))	('pancreatic adenocarcinomas', 'Disease', (44, 70))
15277	28294968	A pathway analysis involved in pancreatic ductal adenocarcinoma, revealed 25 pathways that are significantly influenced by DNA methylation.	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('methylation', 'Var', (127, 138))	('DNA methylation', 'biological_process', 'GO:0006306', ('123', '138'))	('influenced', 'Reg', (109, 119))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (31, 63))	('DNA', 'Var', (123, 126))	('pancreatic ductal adenocarcinoma', 'Disease', (31, 63))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (31, 63))
15279	28294968	Additionally, stellate cell activation and axon guidance were significantly affected by DNA methylation in adenocarcinomas.	('stellate cell activation', 'CPA', (14, 38))	('axon', 'cellular_component', 'GO:0030424', ('43', '47'))	('cell activation', 'biological_process', 'GO:0001775', ('23', '38'))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('DNA methylation', 'Var', (88, 103))	('adenocarcinomas', 'Disease', 'MESH:D000230', (107, 122))	('adenocarcinomas', 'Disease', (107, 122))	('DNA methylation', 'biological_process', 'GO:0006306', ('88', '103'))	('affected', 'Reg', (76, 84))	('axon guidance', 'CPA', (43, 56))	('axon guidance', 'biological_process', 'GO:0007411', ('43', '56'))
15280	28294968	Also, DNA methylation has been implicated in the development of diabetes, influencing islets, beta and alpha cells, contributing to malignant cell transformation.	('DNA methylation', 'biological_process', 'GO:0006306', ('6', '21'))	('implicated', 'Reg', (31, 41))	('men', 'Species', '9606', (56, 59))	('DNA', 'cellular_component', 'GO:0005574', ('6', '9'))	('diabetes', 'Disease', 'MESH:D003920', (64, 72))	('methylation', 'Var', (10, 21))	('malignant cell transformation', 'CPA', (132, 161))	('diabetes', 'Disease', (64, 72))	('influencing', 'Reg', (74, 85))	('contributing', 'Reg', (116, 128))
15282	28294968	However, few studies have examined the specific genes regulated by histone modifications in cancers of the pancreas.	('cancers of the pancreas', 'Disease', 'MESH:D010190', (92, 115))	('cancers of the pancreas', 'Disease', (92, 115))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers of the pancreas', 'Phenotype', 'HP:0002894', (92, 115))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('histone modifications', 'Var', (67, 88))
15291	28294968	Other miRNAs were found to effect pathways involved in cell cycle and proliferation, DNA repair, apoptosis, invasivity, and metastasis in cancers of the pancreas.	('apoptosis', 'CPA', (97, 106))	('DNA repair', 'biological_process', 'GO:0006281', ('85', '95'))	('cancers of the pancreas', 'Phenotype', 'HP:0002894', (138, 161))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('cell cycle', 'biological_process', 'GO:0007049', ('55', '65'))	('DNA repair', 'MPA', (85, 95))	('pathways', 'Pathway', (34, 42))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('proliferation', 'CPA', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cell cycle', 'CPA', (55, 65))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('invasivity', 'MPA', (108, 118))	('miRNAs', 'Var', (6, 12))	('metastasis in cancers of the pancreas', 'Disease', (124, 161))	('effect', 'Reg', (27, 33))	('metastasis in cancers of the pancreas', 'Disease', 'MESH:D009362', (124, 161))
15292	28294968	Several miRNAs have also been implicated in beta-cell dysfunction, thereby affecting insulin regulation in association with type 2 diabetes and potentially pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (156, 173))	('regulation', 'biological_process', 'GO:0065007', ('93', '103'))	('affecting', 'Reg', (75, 84))	('miRNAs', 'Var', (8, 14))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (124, 139))	('pancreatic cancer', 'Disease', (156, 173))	('insulin', 'Gene', (85, 92))	('diabetes', 'Disease', (131, 139))	('pancreatic cancer', 'Disease', 'MESH:D010190', (156, 173))	('insulin', 'Gene', '3630', (85, 92))	('beta-cell dysfunction', 'Phenotype', 'HP:0006279', (44, 65))	('implicated', 'Reg', (30, 40))	('insulin', 'molecular_function', 'GO:0016088', ('85', '92'))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('diabetes', 'Disease', 'MESH:D003920', (131, 139))
15307	28294968	There is still much research needed to explore the connection between epigenetic modification and dietary intake and their association with pancreatic cancer.	('association', 'Interaction', (123, 134))	('pancreatic cancer', 'Disease', 'MESH:D010190', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('epigenetic modification', 'Var', (70, 93))	('pancreatic cancer', 'Disease', (140, 157))
15348	28503090	As a matter of fact, PG490-88, a derivative of triptolide, is part of a phase I clinical trial for treatment of prostate cancer in the USA.	('triptolide', 'Chemical', 'MESH:C001899', (47, 57))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('PG490-88', 'Var', (21, 29))	('prostate cancer', 'Disease', (112, 127))	('prostate cancer', 'Disease', 'MESH:D011471', (112, 127))
15363	28503090	Pristimerin was found to induce apoptosis in hormone-sensitive (LNCaP) and hormone-refractory (PC-3) prostate cancer cell lines.	('Pristimerin', 'Chemical', 'MESH:C009043', (0, 11))	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('apoptosis', 'CPA', (32, 41))	('prostate cancer', 'Disease', (101, 116))	('induce', 'PosReg', (25, 31))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('Pristimerin', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('LNCaP', 'CellLine', 'CVCL:0395', (64, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (101, 116))	('PC-3', 'CellLine', 'CVCL:0035', (95, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (101, 116))
15364	28503090	Pristimerin increased annexin V-binding and cleavage of PARP-1, procaspases-3 and -9-induced mitochondrial depolarization, cytochrome c release from mitochondria, generation of reactive oxygen species (ROS), and downregulation of BCL-2 and survivin expression via proteasome-dependent degradation.	('cleavage', 'MPA', (44, 52))	('degradation', 'biological_process', 'GO:0009056', ('285', '296'))	('degradation', 'MPA', (285, 296))	('depolarization', 'NegReg', (107, 121))	('Pristimerin', 'Chemical', 'MESH:C009043', (0, 11))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (177, 200))	('generation', 'MPA', (163, 173))	('cytochrome c', 'Gene', (123, 135))	('proteasome', 'cellular_component', 'GO:0000502', ('264', '274'))	('cytochrome c', 'molecular_function', 'GO:0009461', ('123', '135'))	('expression', 'MPA', (249, 259))	('BCL-2', 'Gene', '596', (230, 235))	('BCL-2', 'Gene', (230, 235))	('Pristimerin', 'Var', (0, 11))	('increased', 'PosReg', (12, 21))	('mitochondria', 'cellular_component', 'GO:0005739', ('149', '161'))	('downregulation', 'NegReg', (212, 226))	('BCL-2', 'molecular_function', 'GO:0015283', ('230', '235'))	('annexin V', 'Gene', (22, 31))	('PARP-1, procaspases-3 and -9', 'Gene', '142;836', (56, 84))	('mitochondrial', 'MPA', (93, 106))	('annexin V', 'Gene', '308', (22, 31))	('binding', 'molecular_function', 'GO:0005488', ('32', '39'))	('mitochondrial depolarization', 'biological_process', 'GO:0051882', ('93', '121'))	('survivin', 'Protein', (240, 248))	('cytochrome c', 'Gene', '54205', (123, 135))	('ROS', 'Chemical', 'MESH:D017382', (202, 205))	('cytochrome c', 'molecular_function', 'GO:0045155', ('123', '135'))	('proteasome', 'molecular_function', 'GO:0004299', ('264', '274'))
15372	28503090	The work reported that treatment of pancreatic cancer cells with pristimerin resulted in G1-phase arrest associated with a marked decrease in the level of cyclins CCND1 and CCNE, and cyclin-dependent kinases (CDK-2, -4 and -6) with concomitant induction of CDK inhibitors, CDKN1A (p21WAF1) and CDKN1B (p27KIP1).	('CCND1', 'Gene', (163, 168))	('CDKN1A', 'Gene', (273, 279))	('CCNE', 'Gene', '898', (173, 177))	('CDKN1A', 'Gene', '1026', (273, 279))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (36, 53))	('level', 'MPA', (146, 151))	('CDKN1B', 'Gene', '1027', (294, 300))	('pristimerin', 'Chemical', 'MESH:C009043', (65, 76))	('p27KIP1', 'Gene', '1027', (302, 309))	('cyclin', 'Gene', (183, 189))	('G1-phase', 'biological_process', 'GO:0051318', ('89', '97'))	('p27KIP1', 'Gene', (302, 309))	('G1-phase arrest', 'CPA', (89, 104))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('p21', 'Gene', '1026', (281, 284))	('cyclin', 'Gene', '5111', (155, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (36, 53))	('cyclin', 'molecular_function', 'GO:0016538', ('183', '189'))	('decrease', 'NegReg', (130, 138))	('induction', 'PosReg', (244, 253))	('cyclin', 'Gene', '5111', (183, 189))	('CDKN1B', 'Gene', (294, 300))	('pancreatic cancer', 'Disease', (36, 53))	('cyclin', 'Gene', (155, 161))	('CDK-2, -4 and -6', 'Gene', '1017;1019;1021', (209, 225))	('CDK', 'molecular_function', 'GO:0004693', ('257', '260'))	('CDK', 'molecular_function', 'GO:0004693', ('209', '212'))	('CCND1', 'Gene', '595', (163, 168))	('pristimerin', 'Var', (65, 76))	('CCNE', 'Gene', (173, 177))	('p21', 'Gene', (281, 284))
15374	28503090	In human pancreatic ductal adenocarcinoma cells (MiaPaCa-2 and Panc-1) pristimerin inhibited the proliferation and induced apoptosis.	('pancreatic ductal adenocarcinoma', 'Disease', (9, 41))	('human', 'Species', '9606', (3, 8))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (9, 41))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (9, 41))	('proliferation', 'CPA', (97, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('inhibited', 'NegReg', (83, 92))	('Panc-1', 'CellLine', 'CVCL:0480', (63, 69))	('apoptosis', 'CPA', (123, 132))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (49, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('pristimerin', 'Var', (71, 82))	('pristimerin', 'Chemical', 'MESH:C009043', (71, 82))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))	('induced', 'Reg', (115, 122))
15376	28503090	The induction of apoptosis was associated with the inhibition of the pro-survival AKT, NF-kappaB and mTOR proteins and downstream targets, such as FOXO3A, CCND1, COX-2, VEGF, p-70S6K1, p-4E-BP1, and protein kinase C-epsilon (PKCepsilon), as well as of anti-apoptotic BCL-2 and survivin (also known as BIRC5) but not BCL-xL.	('mTOR', 'Gene', '2475', (101, 105))	('AKT', 'Gene', '207', (82, 85))	('pro-survival', 'biological_process', 'GO:0043066', ('69', '81'))	('survivin', 'Protein', (277, 285))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('4', '26'))	('NF-kappaB', 'Gene', (87, 96))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('225', '235'))	('protein kinase C-epsilon', 'Gene', '5581', (199, 223))	('BCL-xL', 'Gene', '598', (316, 322))	('NF-kappaB', 'Gene', '4790', (87, 96))	('protein kinase C-epsilon', 'Gene', (199, 223))	('PKCepsilon', 'Gene', '5581', (225, 235))	('FOXO3A', 'Gene', (147, 153))	('apoptosis', 'Disease', (17, 26))	('4E-BP1', 'Gene', '1978', (187, 193))	('COX-2', 'Gene', (162, 167))	('protein', 'cellular_component', 'GO:0003675', ('199', '206'))	('BCL-xL', 'Gene', (316, 322))	('p-70S6K1', 'Var', (175, 183))	('BCL-2', 'Gene', '596', (267, 272))	('AKT', 'Gene', (82, 85))	('COX-2', 'Gene', '4513', (162, 167))	('inhibition', 'NegReg', (51, 61))	('BCL-2', 'Gene', (267, 272))	('BCL-2', 'molecular_function', 'GO:0015283', ('267', '272'))	('anti-apoptotic', 'CPA', (252, 266))	('mTOR', 'Gene', (101, 105))	('4E-BP1', 'Gene', (187, 193))	('BIRC5', 'Gene', '332', (301, 306))	('BIRC5', 'Gene', (301, 306))	('CCND1', 'Gene', '595', (155, 160))	('PKCepsilon', 'Gene', (225, 235))	('FOXO3A', 'Gene', '2309', (147, 153))	('CCND1', 'Gene', (155, 160))
15378	28503090	Pristimerin was found to possess potent cytotoxic effects, inducing apoptosis and inhibiting proliferation in U87 human glioma cells.	('U87', 'Gene', (110, 113))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('Pristimerin', 'Chemical', 'MESH:C009043', (0, 11))	('inducing', 'NegReg', (59, 67))	('inhibiting', 'NegReg', (82, 92))	('proliferation', 'CPA', (93, 106))	('apoptosis', 'CPA', (68, 77))	('Pristimerin', 'Var', (0, 11))	('U87', 'Gene', '677775', (110, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('68', '77'))	('human', 'Species', '9606', (114, 119))	('glioma', 'Disease', (120, 126))	('apoptosis', 'biological_process', 'GO:0006915', ('68', '77'))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
15381	28503090	In ovarian cancer cells, pristimerin also induced apoptosis through cleavage of PARP-1, procaspases-3, -8 and -9 activity and enhanced mitochondrial depolarization.	('PARP-1, procaspases-3, -8 and -9', 'Gene', '142;836', (80, 112))	('mitochondrial depolarization', 'biological_process', 'GO:0051882', ('135', '163'))	('apoptosis', 'biological_process', 'GO:0006915', ('50', '59'))	('cleavage', 'MPA', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('enhanced', 'PosReg', (126, 134))	('pristimerin', 'Var', (25, 36))	('pristimerin', 'Chemical', 'MESH:C009043', (25, 36))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('mitochondrial depolarization', 'MPA', (135, 163))	('ovarian cancer', 'Disease', (3, 17))	('activity', 'MPA', (113, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('50', '59'))	('apoptosis', 'CPA', (50, 59))
15383	28503090	In a somewhat different approach, pristimerin was shown to inhibit human telomerase reverse transcriptase (hTERT) expression and activity in human pancreatic cancer cells.	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('hTERT', 'Gene', '7015', (107, 112))	('transcriptase', 'molecular_function', 'GO:0003899', ('92', '105'))	('pristimerin', 'Var', (34, 45))	('pristimerin', 'Chemical', 'MESH:C009043', (34, 45))	('transcriptase', 'molecular_function', 'GO:0003968', ('92', '105'))	('transcriptase', 'molecular_function', 'GO:0034062', ('92', '105'))	('hTERT', 'Gene', (107, 112))	('telomerase reverse transcriptase', 'Gene', (73, 105))	('telomerase reverse transcriptase', 'Gene', '7015', (73, 105))	('human', 'Species', '9606', (141, 146))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('activity', 'MPA', (129, 137))	('expression', 'MPA', (114, 124))	('inhibit', 'NegReg', (59, 66))	('human', 'Species', '9606', (67, 72))	('pancreatic cancer', 'Disease', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
15389	28503090	On the one hand, silencing of SENP1 or c-JUN in PC-3 prostate cancer cells decreased cellular viability, suggesting that the cytotoxicity of triptolide could result from triptolide-induced downregulation of SENP1, or c-JUN.	('triptolide', 'Chemical', 'MESH:C001899', (170, 180))	('SENP1', 'Gene', (30, 35))	('downregulation', 'NegReg', (189, 203))	('c-JUN', 'Gene', '3725', (39, 44))	('c-JUN', 'Gene', (39, 44))	('triptolide', 'Chemical', 'MESH:C001899', (141, 151))	('PC-3', 'CellLine', 'CVCL:0035', (48, 52))	('cellular viability', 'CPA', (85, 103))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('SENP1', 'Gene', '29843', (207, 212))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('cytotoxicity', 'Disease', (125, 137))	('prostate cancer', 'Disease', (53, 68))	('SENP1', 'Gene', (207, 212))	('cytotoxicity', 'Disease', 'MESH:D064420', (125, 137))	('c-JUN', 'Gene', '3725', (217, 222))	('c-JUN', 'Gene', (217, 222))	('SENP1', 'Gene', '29843', (30, 35))	('silencing', 'Var', (17, 26))	('decreased', 'NegReg', (75, 84))
15390	28503090	On the other hand, ectopic expression of SENP1, or c-JUN significantly increased the viability of prostate cancer cells upon triptolide exposure, indicating that rescuing these triptolide downregulated proteins could inhibit cell toxicity induced by triptolide.	('toxicity', 'Disease', 'MESH:D064420', (230, 238))	('prostate cancer', 'Disease', 'MESH:D011471', (98, 113))	('proteins', 'Protein', (202, 210))	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('ectopic expression', 'Var', (19, 37))	('toxicity', 'Disease', (230, 238))	('prostate cancer', 'Disease', (98, 113))	('triptolide', 'Chemical', 'MESH:C001899', (125, 135))	('viability', 'CPA', (85, 94))	('downregulated', 'NegReg', (188, 201))	('SENP1', 'Gene', '29843', (41, 46))	('inhibit', 'NegReg', (217, 224))	('SENP1', 'Gene', (41, 46))	('triptolide', 'Chemical', 'MESH:C001899', (250, 260))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('c-JUN', 'Gene', '3725', (51, 56))	('increased', 'PosReg', (71, 80))	('c-JUN', 'Gene', (51, 56))	('triptolide', 'Chemical', 'MESH:C001899', (177, 187))
15399	28503090	After low-dose combined treatments with triptolide and cisplatin, a decrease in viability with a concomitant increase in apoptosis was observed in SC-M1 cells but not in normal cells.	('triptolide', 'Chemical', 'MESH:C001899', (40, 50))	('decrease', 'NegReg', (68, 76))	('increase', 'PosReg', (109, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('SC-M1', 'CellLine', 'CVCL:G299', (147, 152))	('viability', 'CPA', (80, 89))	('apoptosis', 'biological_process', 'GO:0097194', ('121', '130'))	('apoptosis', 'CPA', (121, 130))	('cisplatin', 'Var', (55, 64))	('apoptosis', 'biological_process', 'GO:0006915', ('121', '130'))
15442	28503090	HNSCC arises from premalignant progenitor cells that progress to invasive malignancy due to cumulative genetic alterations.	('genetic alterations', 'Var', (103, 122))	('invasive malignancy', 'Disease', (65, 84))	('HNSCC', 'Disease', (0, 5))	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))	('invasive malignancy', 'Disease', 'MESH:D009369', (65, 84))	('progress', 'PosReg', (53, 61))
15449	28503090	However, despite the abundant expression in HNSCC, only a subset of patients responds to EGFR inhibitors since alternative downstream signaling pathways may remain activated.	('responds to', 'MPA', (77, 88))	('EGFR', 'Gene', (89, 93))	('HNSCC', 'Gene', (44, 49))	('signaling', 'biological_process', 'GO:0023052', ('134', '143'))	('patients', 'Species', '9606', (68, 76))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('HNSCC', 'Phenotype', 'HP:0012288', (44, 49))	('EGFR', 'Gene', '1956', (89, 93))	('inhibitors', 'Var', (94, 104))
15451	28503090	Loss of heterozygosity at the chromosomal region 9p21 is found in 70-80% of HNSCC cases, representing the most common genetic alteration in this type of cancer and in early pre-invasive lesions.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('chromosomal region', 'cellular_component', 'GO:0098687', ('30', '48'))	('Loss of heterozygosity', 'Var', (0, 22))	('cancer', 'Disease', (153, 159))	('HNSCC', 'Disease', (76, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('p21', 'Gene', '1026', (50, 53))	('pre', 'molecular_function', 'GO:0003904', ('173', '176'))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('p21', 'Gene', (50, 53))
15476	28503090	Thus, crosstalk by TGF-beta via TAK1 and NF-kappaB promotes the malignant phenotype of HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('malignant phenotype of', 'CPA', (64, 86))	('TAK1', 'Gene', '6885', (32, 36))	('NF-kappaB', 'Gene', '4790', (41, 50))	('promotes', 'PosReg', (51, 59))	('TAK1', 'Gene', (32, 36))	('NF-kappaB', 'Gene', (41, 50))	('TGF-beta', 'Gene', (19, 27))	('crosstalk', 'Var', (6, 15))	('HNSCC', 'Disease', (87, 92))
15497	27591765	Mutations in the tumor suppressor genes TP53 and p16/CDKN2A have also been shown to occur commonly in IPMNs  although mostly in regions of high grade dysplasia.	('tumor suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('tumor', 'Disease', (17, 22))	('CDKN2A', 'Gene', (53, 59))	('CDKN2A', 'Gene', '1029', (53, 59))	('p16', 'Gene', (49, 52))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('TP53', 'Gene', '7157', (40, 44))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (40, 44))	('occur', 'Reg', (84, 89))	('dysplasia', 'Disease', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('dysplasia', 'Disease', 'MESH:D004476', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('p16', 'Gene', '1029', (49, 52))	('IPMNs', 'Disease', (102, 107))
15499	27591765	In addition, activating mutations in GNAS  and inactivating mutations in RNF43  have been identified in at least half of IPMNs, especially intestinal-type, and are relatively specific for the "IPMN pathway" .	('GNAS', 'Gene', (37, 41))	('RNF43', 'Gene', (73, 78))	('activating', 'PosReg', (13, 23))	('identified', 'Reg', (90, 100))	('IPMNs', 'Disease', (121, 126))	('GNAS', 'Gene', '2778', (37, 41))	('inactivating mutations', 'Var', (47, 69))	('RNF43', 'Gene', '54894', (73, 78))
15501	27591765	Several other studies have investigated mucin expression and selected gene mutations in IOPNs and showed that IOPNs generally do not have specific patterns of mucin protein expression (except for MUC6 ), and they do not harbor the same genetic alterations commonly seen in DAs and IPMNs .	('investigated', 'Reg', (27, 39))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('DAs', 'Disease', (273, 276))	('MUC6', 'Gene', '4588', (196, 200))	('mucin', 'Gene', (40, 45))	('mucin', 'Gene', '100508689', (159, 164))	('mucin', 'Gene', (159, 164))	('mutations', 'Var', (75, 84))	('MUC6', 'Gene', (196, 200))	('IPMNs', 'Disease', (281, 286))	('mucin', 'Gene', '100508689', (40, 45))
15503	27591765	identified mutations in codon 12 of the KRAS gene in three of eighteen (17%) IOPNs.	('mutations in', 'Var', (11, 23))	('KRAS', 'Gene', '3845', (40, 44))	('KRAS', 'Gene', (40, 44))
15504	27591765	Therefore, it is quite possible that the three cases they reported as KRAS mutated may have exhibited heterogeneity in differentiation, and that the oncocytic features were a morphologic variation within a non-oncocytic IPMN.	('mutated', 'Var', (75, 82))	('KRAS', 'Gene', (70, 74))	('KRAS', 'Gene', '3845', (70, 74))
15505	27591765	reported that twelve of twelve (100%) intestinal-type, five of seven (71%) pancreatobiliary-type, and twenty-seven of fifty-three (51%) gastric-type IPMNs harbored a codon 201 GNAS mutation, while two of two (100%) IOPNs in their series were found to be GNAS wild type .	('GNAS', 'Gene', '2778', (176, 180))	('GNAS', 'Gene', '2778', (254, 258))	('GNAS', 'Gene', (254, 258))	('harbored', 'Reg', (155, 163))	('codon 201', 'Var', (166, 175))	('gastric-type IPMN', 'Disease', 'MESH:D000077779', (136, 153))	('GNAS', 'Gene', (176, 180))	('gastric-type IPMN', 'Disease', (136, 153))
15507	27591765	Instead, ARHGAP26, ASXL1, EPHA8, and ERBB4 genes were mutated in more than one IOPN .	('ERBB4', 'Gene', (37, 42))	('ASXL1', 'Gene', '171023', (19, 24))	('EPHA8', 'Gene', '2046', (26, 31))	('EPHA8', 'Gene', (26, 31))	('ASXL1', 'Gene', (19, 24))	('ARHGAP26', 'Gene', '23092', (9, 17))	('ARHGAP26', 'Gene', (9, 17))	('mutated', 'Var', (54, 61))	('ERBB4', 'Gene', '2066', (37, 42))
15540	27591765	A higher proportion of IOPNs labeled with antibodies to mesothelin [21/24 (87.5%) of IOPNs vs 6/22 (27%) of IPMNs, p<0.001], while the reverse was true for claudin-4 [2/23 (9%) of IOPNs vs 9/22 (41%) of IPMNs, p=0.01].	('claudin-4', 'Gene', '1364', (156, 165))	('mesothelin', 'Gene', '10232', (56, 66))	('claudin-4', 'Gene', (156, 165))	('higher proportion of IOPNs', 'Phenotype', 'HP:0007906', (2, 28))	('antibodies', 'Var', (42, 52))	('mesothelin', 'Gene', (56, 66))
15554	27591765	6), but only 6/21(29%) IPMNs revealed MUC6 expression (p=0.002) in their papillae and the degree of expression was much stronger in IOPNs compared to IPMNs.	('MUC6', 'Gene', (38, 42))	('stronger', 'PosReg', (120, 128))	('MUC6', 'Gene', '4588', (38, 42))	('IOPNs', 'Var', (132, 137))	('expression', 'MPA', (43, 53))
15578	27591765	Alterations in the adenomatous polyposis coli (APC)/ beta-catenin pathway have been reported in non-ductal pancreatic lesions such as acinar cell carcinoma, solid-pseudopapillary neoplasm and pancreatoblastoma but are only rarely found in DA .	('Alterations', 'Var', (0, 11))	('pancreatic lesions', 'Disease', 'MESH:D010182', (107, 125))	('APC)', 'Gene', '324', (47, 51))	('APC', 'Phenotype', 'HP:0005227', (47, 50))	('solid-pseudopapillary neoplasm and pancreatoblastoma', 'Disease', 'MESH:C537162', (157, 209))	('APC', 'cellular_component', 'GO:0005680', ('47', '50'))	('neoplasm', 'Phenotype', 'HP:0002664', (179, 187))	('pancreatoblastoma', 'Phenotype', 'HP:0100757', (192, 209))	('APC', 'Gene', (47, 50))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (19, 45))	('beta-catenin', 'Gene', (53, 65))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (19, 45))	('adenomatous polyposis coli', 'Disease', (19, 45))	('beta-catenin', 'Gene', '1499', (53, 65))	('acinar cell carcinoma', 'Disease', (134, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('pancreatic lesions', 'Disease', (107, 125))	('acinar cell carcinoma', 'Disease', 'MESH:D018267', (134, 155))	('reported', 'Reg', (84, 92))
15582	27591765	In previous studies, TP53 gene mutations have been identified in 0-38% (weighted mean, 21%) of IPMNs, with most cases showing mutation only in high-grade dysplasia and invasive carcinoma .	('TP53', 'Gene', (21, 25))	('mutations', 'Var', (31, 40))	('invasive carcinoma', 'Disease', (168, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('invasive carcinoma', 'Disease', 'MESH:D009361', (168, 186))	('dysplasia', 'Disease', (154, 163))	('IPMNs', 'Disease', (95, 100))	('dysplasia', 'Disease', 'MESH:D004476', (154, 163))	('TP53', 'Gene', '7157', (21, 25))
15583	27591765	In pancreatic DA and PanIN, abnormalities in p53 expression are detected more often in invasive carcinomas (60%) and PanIN3 and rarely in lower-grade lesions .	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('p53', 'Gene', (45, 48))	('abnormalities', 'Var', (28, 41))	('p53', 'Gene', '7157', (45, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('invasive carcinomas', 'Disease', (87, 106))	('invasive carcinomas', 'Disease', 'MESH:D009361', (87, 106))	('expression', 'MPA', (49, 59))	('detected', 'Reg', (64, 72))	('pancreatic', 'Disease', 'MESH:D010195', (3, 13))	('PanIN3', 'Disease', (117, 123))	('pancreatic', 'Disease', (3, 13))
15598	27591765	Also, in accordance with previous findings was a high proportion of MUC2 positivity in intestinal-type IPMN versus than in pancreatobiliary-type IPMN or gastric-type IPMN.	('intestinal-type IPMN', 'Disease', (87, 107))	('gastric-type IPMN', 'Disease', 'MESH:D000077779', (153, 170))	('pancreatobiliary-type IPMN', 'Disease', (123, 149))	('pancreatobiliary-type IPMN', 'Disease', 'MESH:D000077779', (123, 149))	('positivity', 'Var', (73, 83))	('gastric-type IPMN', 'Disease', (153, 170))	('MUC2', 'Gene', (68, 72))	('MUC2', 'Gene', '4583', (68, 72))
15599	27591765	The unexpected finding was that a high percentage (52%) of IOPNs labeled with antibodies to MUC1 (Fig.	('antibodies', 'Var', (78, 88))	('MUC1', 'Gene', '4582', (92, 96))	('MUC1', 'Gene', (92, 96))
15649	27240355	It was found that like nafamostat, PD98059 also suppressed the proliferative effect of MCT (Figure 2C).	('nafamostat', 'Chemical', 'MESH:C032855', (23, 33))	('MCT', 'Gene', '23430', (87, 90))	('PD98059', 'Var', (35, 42))	('suppressed', 'NegReg', (48, 58))	('PD98059', 'Chemical', 'MESH:C093973', (35, 42))	('MCT', 'biological_process', 'GO:0120197', ('87', '90'))	('MCT', 'Gene', (87, 90))
15650	27240355	Moreover, Western blot experiments showed that the phosphorylated-ERK (p-ERK) protein levels were increased in HUVEC cells after stimulation with 1 and 10 ng/mL MCT for 24 h, while PD98095 blocked the promoting effect of MCT on ERK phosphorylation (Figure 2D).	('ERK', 'molecular_function', 'GO:0004707', ('73', '76'))	('MCT', 'Gene', (161, 164))	('ERK', 'molecular_function', 'GO:0004707', ('228', '231'))	('ERK', 'Gene', (66, 69))	('ERK', 'Gene', '5594', (73, 76))	('MCT', 'biological_process', 'GO:0120197', ('161', '164'))	('HUVEC', 'CellLine', 'CVCL:2959', (111, 116))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('increased', 'PosReg', (98, 107))	('MCT', 'Gene', '23430', (161, 164))	('ERK', 'Gene', '5594', (228, 231))	('MCT', 'Gene', (221, 224))	('ERK', 'Gene', (73, 76))	('PD98095', 'Var', (181, 188))	('phosphorylation', 'biological_process', 'GO:0016310', ('232', '247'))	('ERK', 'molecular_function', 'GO:0004707', ('66', '69'))	('ERK', 'Gene', (228, 231))	('MCT', 'Gene', '23430', (221, 224))	('MCT', 'biological_process', 'GO:0120197', ('221', '224'))	('ERK', 'Gene', '5594', (66, 69))
15660	27240355	Finally, tube formation assays showed that TIE2 inhibitor ab141270 could partly block MCT-induced tube formation as well as the MCT inhibitor nafamostat (Figure 3E).	('TIE2', 'Gene', '7010', (43, 47))	('MCT', 'biological_process', 'GO:0120197', ('128', '131'))	('MCT', 'Gene', '23430', (86, 89))	('MCT', 'Gene', '23430', (128, 131))	('block', 'NegReg', (80, 85))	('ab141270', 'Var', (58, 66))	('MCT', 'biological_process', 'GO:0120197', ('86', '89'))	('tube formation', 'biological_process', 'GO:0035148', ('98', '112'))	('tube formation', 'biological_process', 'GO:0035148', ('9', '23'))	('MCT', 'Gene', (86, 89))	('nafamostat', 'Chemical', 'MESH:C032855', (142, 152))	('MCT', 'Gene', (128, 131))	('ab141270', 'Chemical', '-', (58, 66))	('TIE2', 'Gene', (43, 47))
15705	27240355	Next, slides were incubated with human-specific monoclonal antibodies anti-tryptase (SantaCruz Biotechnology) diluted 1:100 for 1 h and anti-CD31 (Cell Signaling Technology, Beverly, MA, USA) diluted 1:100 for 12 h at room temperature.	('diluted', 'Var', (110, 117))	('anti-tryptase', 'Var', (70, 83))	('human', 'Species', '9606', (33, 38))	('Signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('anti-CD31', 'Var', (136, 145))
15820	25848351	A recent study illustrated that it takes about 12 years for the initiating mutation to result in the nonmetastatic founder cell; another 7 years to acquire the metastatic ability, and then 3 more years to cause death.	('death', 'Disease', (211, 216))	('metastatic ability', 'CPA', (160, 178))	('mutation', 'Var', (75, 83))	('nonmetastatic founder cell', 'CPA', (101, 127))	('result in', 'Reg', (87, 96))	('death', 'Disease', 'MESH:D003643', (211, 216))
15851	25441307	Instead, there is striking genomic instability, and a subset of cases has mutations in the APC/beta-catenin pathway, mutations in SMAD4, RAF gene family fusions, or microsatellite instability.	('RAF', 'Gene', (137, 140))	('RAF', 'Gene', '22882', (137, 140))	('mutations', 'Var', (117, 126))	('APC', 'Disease', (91, 94))	('APC', 'cellular_component', 'GO:0005680', ('91', '94'))	('SMAD4', 'Gene', (130, 135))	('mutations', 'Var', (74, 83))	('microsatellite', 'MPA', (165, 179))	('beta-catenin', 'Gene', (95, 107))	('SMAD4', 'Gene', '4089', (130, 135))	('APC', 'Disease', 'MESH:D011125', (91, 94))	('beta-catenin', 'Gene', '1499', (95, 107))
15859	25441307	Although acinar cell carcinoma is not firmly associated with any known genetic syndromes, cases have been reported in patients with Lynch syndrome (hereditary non-polyposis colon cancer or HNPCC), as well as in patients with germline BRCA1 and BRCA2 mutations.	('BRCA1', 'Gene', '672', (234, 239))	('hereditary non-polyposis colon cancer', 'Disease', 'MESH:D015179', (148, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('BRCA1', 'Gene', (234, 239))	('patients', 'Species', '9606', (211, 219))	('Lynch syndrome', 'Disease', (132, 146))	('acinar cell carcinoma', 'Disease', (9, 30))	('BRCA2', 'Gene', (244, 249))	('genetic syndromes', 'Disease', (71, 88))	('genetic syndromes', 'Disease', 'MESH:D030342', (71, 88))	('Lynch syndrome', 'Disease', 'MESH:D003123', (132, 146))	('acinar cell carcinoma', 'Disease', 'MESH:D018267', (9, 30))	('hereditary non-polyposis colon cancer', 'Phenotype', 'HP:0006716', (148, 185))	('HNPCC', 'Disease', 'None', (189, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('HNPCC', 'Disease', (189, 194))	('colon cancer', 'Phenotype', 'HP:0003003', (173, 185))	('BRCA2', 'Gene', '675', (244, 249))	('hereditary non-polyposis colon cancer', 'Disease', (148, 185))	('mutations', 'Var', (250, 259))	('patients', 'Species', '9606', (118, 126))
15893	25441307	In acinar cell carcinomas, molecular alterations in the APC-beta-catenin pathway occur in approximately 20% of tumors, including inactivating mutations in APC and activating mutations in CTNNB1.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('APC', 'Disease', 'MESH:D011125', (56, 59))	('APC', 'Disease', (56, 59))	('CTNNB1', 'Gene', (187, 193))	('activating mutations', 'Var', (163, 183))	('APC', 'cellular_component', 'GO:0005680', ('155', '158'))	('carcinomas', 'Phenotype', 'HP:0030731', (15, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('APC', 'Disease', 'MESH:D011125', (155, 158))	('acinar cell carcinomas', 'Disease', (3, 25))	('alterations', 'Reg', (37, 48))	('APC', 'Disease', (155, 158))	('inactivating mutations', 'Var', (129, 151))	('APC', 'cellular_component', 'GO:0005680', ('56', '59'))	('beta-catenin', 'Gene', (60, 72))	('beta-catenin', 'Gene', '1499', (60, 72))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (3, 25))	('CTNNB1', 'Gene', '1499', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))
15894	25441307	Copy number alterations and promoter hypermethylation of APC have also been reported.	('promoter', 'MPA', (28, 36))	('APC', 'Disease', 'MESH:D011125', (57, 60))	('APC', 'Disease', (57, 60))	('Copy number alterations', 'Var', (0, 23))	('APC', 'cellular_component', 'GO:0005680', ('57', '60'))
15896	25441307	Some studies have reported rare mutations in KRAS and TP53 as well as rare loss of SMAD4 expression, though several studies have also reported no alterations in these genes in acinar neoplasms.	('acinar neoplasms', 'Disease', (176, 192))	('KRAS', 'Gene', '3845', (45, 49))	('neoplasms', 'Phenotype', 'HP:0002664', (183, 192))	('expression', 'MPA', (89, 99))	('SMAD4', 'Gene', '4089', (83, 88))	('acinar neoplasms', 'Disease', 'MESH:D018267', (176, 192))	('neoplasm', 'Phenotype', 'HP:0002664', (183, 191))	('TP53', 'Gene', '7157', (54, 58))	('mutations', 'Var', (32, 41))	('loss', 'NegReg', (75, 79))	('SMAD4', 'Gene', (83, 88))	('TP53', 'Gene', (54, 58))	('KRAS', 'Gene', (45, 49))
15898	25441307	Large chromosomal gains and losses in acinar cell carcinomas have been reported in several previous studies, including several regions that are altered in multiple tumors; however, the target genes (if any) in most of these alterations remain to be identified.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (38, 60))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('multiple tumors', 'Disease', (155, 170))	('multiple tumors', 'Disease', 'MESH:D009369', (155, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('acinar cell carcinomas', 'Disease', (38, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('chromosomal gains', 'Var', (6, 23))	('losses', 'NegReg', (28, 34))
15899	25441307	However, some of these alterations have compelling potential to be drivers, for example, trisomy 3 with gain of CTNNB1 occurred in 5 of 5 acinar cell carcinomas in a study.	('CTNNB1', 'Gene', (112, 118))	('gain', 'PosReg', (104, 108))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (138, 160))	('trisomy 3', 'Var', (89, 98))	('CTNNB1', 'Gene', '1499', (112, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('acinar cell carcinomas', 'Disease', (138, 160))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))
15901	25441307	Loss of chromosome 11p (at the locus affected in Beckwith-Wiedemann syndrome) occurs in more than 80% of pancreatoblastomas:this loss of 11p has also been reported in other embryonal neoplasms (such as hepatoblastoma and Wilms tumor), suggesting the possibility of a common genetic pathway in embryonal tumors.	('Wilms tumor', 'Disease', (221, 232))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('pancreatoblastomas', 'Disease', (105, 123))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('Beckwith-Wiedemann syndrome', 'Disease', (49, 76))	('pancreatoblastomas', 'Disease', 'MESH:C537162', (105, 123))	('hepatoblastoma', 'Disease', (202, 216))	('embryonal neoplasms', 'Phenotype', 'HP:0002898', (173, 192))	('Loss', 'NegReg', (0, 4))	('pancreatoblastoma', 'Phenotype', 'HP:0100757', (105, 122))	('hepatoblastoma', 'Disease', 'MESH:D018197', (202, 216))	('Wilms tumor', 'Disease', 'MESH:D009396', (221, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('Beckwith-Wiedemann syndrome', 'Disease', 'MESH:D001506', (49, 76))	('embryonal tumors', 'Phenotype', 'HP:0002898', (293, 309))	('embryonal neoplasms', 'Disease', 'MESH:D009373', (173, 192))	('embryonal tumors', 'Disease', (293, 309))	('neoplasm', 'Phenotype', 'HP:0002664', (183, 191))	('loss', 'Var', (129, 133))	('embryonal tumors', 'Disease', 'MESH:D009373', (293, 309))	('Wilms tumor', 'Phenotype', 'HP:0002667', (221, 232))	('neoplasms', 'Phenotype', 'HP:0002664', (183, 192))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (202, 216))	('embryonal neoplasms', 'Disease', (173, 192))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))
15902	25441307	Although loss of 11p also occurs in almost 50% of acinar cell carcinomas, it is not clear whether this region is unique among the numerous regions recurrently lost in this tumor type.	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('acinar cell carcinomas', 'Disease', (50, 72))	('11p', 'Protein', (17, 20))	('tumor', 'Disease', (172, 177))	('loss', 'Var', (9, 13))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (50, 72))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
15903	25441307	Pancreatoblastomas also have frequent alterations of the APC-beta-catenin pathway; unlike acinar cell carcinomas (which more frequently have inactivating APC mutations), pancreatoblastomas more frequently have activating CTNNB1 mutations, though mutations in both genes have been identified.	('APC', 'Disease', 'MESH:D011125', (57, 60))	('APC', 'Disease', (57, 60))	('APC', 'cellular_component', 'GO:0005680', ('154', '157'))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('pancreatoblastoma', 'Phenotype', 'HP:0100757', (170, 187))	('acinar cell carcinomas', 'Disease', (90, 112))	('APC', 'Disease', 'MESH:D011125', (154, 157))	('APC', 'Disease', (154, 157))	('CTNNB1', 'Gene', '1499', (221, 227))	('Pancreatoblastomas', 'Disease', (0, 18))	('mutations', 'Var', (228, 237))	('beta-catenin', 'Gene', (61, 73))	('APC', 'cellular_component', 'GO:0005680', ('57', '60'))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('pancreatoblastomas', 'Disease', (170, 188))	('beta-catenin', 'Gene', '1499', (61, 73))	('Pancreatoblastomas', 'Disease', 'MESH:C537162', (0, 18))	('activating', 'PosReg', (210, 220))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (90, 112))	('pancreatoblastomas', 'Disease', 'MESH:C537162', (170, 188))	('CTNNB1', 'Gene', (221, 227))
15905	25441307	Mutations in genes frequently altered in pancreatic ductal adenocarcinoma are uncommon in pancreatoblastoma; in a study, loss of SMAD4 was infrequent, and no alterations in KRAS or TP53 were identified.	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (41, 73))	('TP53', 'Gene', (181, 185))	('SMAD4', 'Gene', (129, 134))	('pancreatoblastoma', 'Disease', (90, 107))	('loss', 'Var', (121, 125))	('pancreatoblastoma', 'Disease', 'MESH:C537162', (90, 107))	('KRAS', 'Gene', (173, 177))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', '3845', (173, 177))	('pancreatoblastoma', 'Phenotype', 'HP:0100757', (90, 107))	('pancreatic ductal adenocarcinoma', 'Disease', (41, 73))	('SMAD4', 'Gene', '4089', (129, 134))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (41, 73))	('TP53', 'Gene', '7157', (181, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
15909	25441307	Approximately 10% of the analyzed neoplasms had microsatellite instability, and although one carcinoma had a somatic mutation in MSH2, the mechanistic basis for the microsatellite instability in the remaining tumors was unclear, as none of the other tumors with microsatellite instability had methylation of MLH1 or mutations in other genes in the mismatch repair pathway.	('MSH2', 'Gene', '4436', (129, 133))	('neoplasms', 'Disease', (34, 43))	('MLH1', 'Gene', (308, 312))	('mismatch repair', 'biological_process', 'GO:0006298', ('348', '363'))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('methylation', 'Var', (293, 304))	('microsatellite instability', 'MPA', (48, 74))	('MLH1', 'Gene', '4292', (308, 312))	('neoplasms', 'Phenotype', 'HP:0002664', (34, 43))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('neoplasm', 'Phenotype', 'HP:0002664', (34, 42))	('carcinoma', 'Disease', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('methylation', 'biological_process', 'GO:0032259', ('293', '304'))	('tumors', 'Disease', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('MSH2', 'Gene', (129, 133))	('mutations', 'Reg', (316, 325))	('neoplasms', 'Disease', 'MESH:D009369', (34, 43))	('tumors', 'Disease', (209, 215))	('mutation', 'Var', (117, 125))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('carcinoma', 'Disease', 'MESH:D002277', (93, 102))
15913	25441307	Intriguingly, in a small subset of cases, mutations were identified in genes commonly altered in other pancreatic neoplasms, including those frequently altered in ductal adenocarcinoma (SMAD4 and TP53), cystic neoplasms (GNAS and RNF43), and neuroendocrine neoplasms (MEN1).	('TP53', 'Gene', (196, 200))	('altered', 'Reg', (152, 159))	('RNF43', 'Gene', (230, 235))	('ductal adenocarcinoma', 'Disease', (163, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('cystic neoplasms', 'Phenotype', 'HP:0010576', (203, 219))	('GNAS', 'Gene', (221, 225))	('pancreatic neoplasms', 'Phenotype', 'HP:0002894', (103, 123))	('neoplasm', 'Phenotype', 'HP:0002664', (257, 265))	('neoplasm', 'Phenotype', 'HP:0002664', (210, 218))	('MEN1', 'Gene', '4221', (268, 272))	('neoplasm', 'Phenotype', 'HP:0002664', (114, 122))	('GNAS', 'Gene', '2778', (221, 225))	('TP53', 'Gene', '7157', (196, 200))	('neoplasms', 'Phenotype', 'HP:0002664', (257, 266))	('neoplasms', 'Phenotype', 'HP:0002664', (210, 219))	('neuroendocrine neoplasms', 'Disease', 'MESH:D018358', (242, 266))	('SMAD4', 'Gene', (186, 191))	('neoplasms', 'Phenotype', 'HP:0002664', (114, 123))	('MEN1', 'Gene', (268, 272))	('ductal adenocarcinoma', 'Disease', 'MESH:D044584', (163, 184))	('pancreatic neoplasms', 'Disease', 'MESH:D010190', (103, 123))	('cystic neoplasms', 'Disease', (203, 219))	('pancreatic neoplasms', 'Disease', (103, 123))	('pancreatic neoplasm', 'Phenotype', 'HP:0002894', (103, 122))	('cystic neoplasms', 'Disease', 'MESH:D052177', (203, 219))	('neuroendocrine neoplasms', 'Disease', (242, 266))	('RNF43', 'Gene', '54894', (230, 235))	('neuroendocrine neoplasms', 'Phenotype', 'HP:0100634', (242, 266))	('SMAD4', 'Gene', '4089', (186, 191))	('mutations', 'Var', (42, 51))
15914	25441307	SMAD4 was the most frequently altered gene in this series, with mutations in approximately 25% of tumors.	('SMAD4', 'Gene', '4089', (0, 5))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('SMAD4', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutations', 'Var', (64, 73))
15917	25441307	These included mutations in APC and CTNNB1, confirming previously reported findings.	('CTNNB1', 'Gene', (36, 42))	('APC', 'cellular_component', 'GO:0005680', ('28', '31'))	('mutations', 'Var', (15, 24))	('CTNNB1', 'Gene', '1499', (36, 42))	('APC', 'Disease', 'MESH:D011125', (28, 31))	('APC', 'Disease', (28, 31))
15918	25441307	Other known driver genes with mutations in acinar neoplasms included JAK1, BRAF, RB1, PTEN, ARID1A, MLL3, and BAP1.	('MLL3', 'Gene', '58508', (100, 104))	('BAP1', 'Gene', '8314', (110, 114))	('PTEN', 'Gene', (86, 90))	('JAK', 'molecular_function', 'GO:0004713', ('69', '72'))	('acinar neoplasms', 'Disease', (43, 59))	('neoplasms', 'Phenotype', 'HP:0002664', (50, 59))	('PTEN', 'Gene', '5728', (86, 90))	('BAP1', 'Gene', (110, 114))	('MLL3', 'Gene', (100, 104))	('neoplasm', 'Phenotype', 'HP:0002664', (50, 58))	('JAK1', 'Gene', (69, 73))	('RB1', 'Gene', (81, 84))	('mutations', 'Var', (30, 39))	('ARID1A', 'Gene', (92, 98))	('JAK1', 'Gene', '3716', (69, 73))	('acinar neoplasms', 'Disease', 'MESH:D018267', (43, 59))	('BRAF', 'Gene', '673', (75, 79))	('BRAF', 'Gene', (75, 79))	('RB1', 'Gene', '5925', (81, 84))	('ARID1A', 'Gene', '8289', (92, 98))
15919	25441307	Although the types of mutations identified (such as oncogenic hotspot mutations in BRAF and inactivating mutations in RB1) strongly support that these alterations are drivers, each occurred in no more than 20% of tumors.	('mutations', 'Var', (70, 79))	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('RB1', 'Gene', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('RB1', 'Gene', '5925', (118, 121))	('inactivating mutations', 'Var', (92, 114))	('BRAF', 'Gene', '673', (83, 87))	('BRAF', 'Gene', (83, 87))
15922	25441307	Importantly, almost half of the carcinomas sequenced had somatic mutations that are potentially targetable by existing therapeutics, including mutations in JAK1, BRAF, and the Fanconi anemia pathway.	('Fanconi anemia', 'Disease', (176, 190))	('JAK1', 'Gene', (156, 160))	('JAK1', 'Gene', '3716', (156, 160))	('Fanconi anemia', 'Disease', 'MESH:D005199', (176, 190))	('anemia', 'Phenotype', 'HP:0001903', (184, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (32, 42))	('carcinomas', 'Disease', 'MESH:D002277', (32, 42))	('JAK', 'molecular_function', 'GO:0004713', ('156', '159'))	('BRAF', 'Gene', '673', (162, 166))	('carcinomas', 'Disease', (32, 42))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (176, 190))	('mutations', 'Var', (143, 152))	('BRAF', 'Gene', (162, 166))
15926	25441307	Second, both pancreatoblastomas contained mutations in CTNNB1, which agrees with previous studies showing frequent alteration of the APC-beta-catenin pathway (and specifically activating CTNNB1 mutations) in pancreatoblastoma.	('beta-catenin', 'Gene', '1499', (137, 149))	('pancreatoblastoma', 'Disease', 'MESH:C537162', (208, 225))	('CTNNB1', 'Gene', (187, 193))	('APC', 'Disease', 'MESH:D011125', (133, 136))	('pancreatoblastoma', 'Phenotype', 'HP:0100757', (13, 30))	('pancreatoblastoma', 'Disease', (208, 225))	('APC', 'Disease', (133, 136))	('APC', 'cellular_component', 'GO:0005680', ('133', '136'))	('CTNNB1', 'Gene', '1499', (55, 61))	('contained', 'Reg', (32, 41))	('pancreatoblastoma', 'Phenotype', 'HP:0100757', (208, 225))	('pancreatoblastomas', 'Disease', (13, 31))	('pancreatoblastoma', 'Disease', 'MESH:C537162', (13, 30))	('CTNNB1', 'Gene', '1499', (187, 193))	('pancreatoblastomas', 'Disease', 'MESH:C537162', (13, 31))	('activating', 'PosReg', (176, 186))	('CTNNB1', 'Gene', (55, 61))	('beta-catenin', 'Gene', (137, 149))	('mutations', 'Var', (42, 51))	('pancreatoblastoma', 'Disease', (13, 30))
15927	25441307	In addition, the mixed acinar-ductal carcinomas were also unique:they contained a higher frequency of P16/CDKN2A and oncogenic BRAF mutations compared to other acinar cell carcinomas.	('P16', 'Gene', (102, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('acinar cell carcinomas', 'Disease', (160, 182))	('BRAF', 'Gene', '673', (127, 131))	('mutations', 'Var', (132, 141))	('P16', 'Gene', '1029', (102, 105))	('acinar-ductal carcinomas', 'Disease', 'MESH:D018267', (23, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('BRAF', 'Gene', (127, 131))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (30, 46))	('CDKN2A', 'Gene', (106, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('acinar-ductal carcinomas', 'Disease', (23, 47))	('CDKN2A', 'Gene', '1029', (106, 112))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (160, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))
15930	25441307	In addition to the recent whole exome sequencing study, a targeted DNA and RNA sequencing study revealed recurrent chromosomal rearrangements in acinar cell carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('chromosomal rearrangements', 'Var', (115, 141))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (145, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('acinar cell carcinomas', 'Disease', (145, 167))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('RNA', 'cellular_component', 'GO:0005562', ('75', '78'))	('men', 'Species', '9606', (136, 139))
15932	25441307	The most common fusion involved the SND1 and BRAF genes on chromosome 7q, occurring in 6 cases.	('SND1', 'Gene', (36, 40))	('SND1', 'Gene', '27044', (36, 40))	('BRAF', 'Gene', '673', (45, 49))	('BRAF', 'Gene', (45, 49))	('fusion', 'Var', (16, 22))	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))
15934	25441307	Functional analyses of the SND1-BRAF fusion revealed that it leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, which can be reversed, at least in vitro, by targeted MEK inhibitors.	('BRAF', 'Gene', '673', (32, 36))	('MEK', 'Gene', '5609', (204, 207))	('MAPK', 'molecular_function', 'GO:0004707', ('135', '139'))	('BRAF', 'Gene', (32, 36))	('MEK', 'Gene', (204, 207))	('SND1', 'Gene', (27, 31))	('fusion', 'Var', (37, 43))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('SND1', 'Gene', '27044', (27, 31))	('activation', 'PosReg', (83, 93))
15936	25441307	In addition, this study confirmed many of the findings of the previous whole exome sequencing, including infrequent mutations in genes in the APC/beta-catenin pathway (APC and CTNNB1), genes frequently altered in ductal adenocarcinoma (SMAD4, TP53, and CDKN2A), and driver genes from other tumor types (BRAF and RB1).	('RB1', 'Gene', '5925', (312, 315))	('CTNNB1', 'Gene', '1499', (176, 182))	('APC', 'cellular_component', 'GO:0005680', ('168', '171'))	('APC', 'Disease', 'MESH:D011125', (142, 145))	('CDKN2A', 'Gene', '1029', (253, 259))	('TP53', 'Gene', (243, 247))	('APC', 'Disease', (142, 145))	('tumor', 'Disease', (290, 295))	('ductal adenocarcinoma', 'Disease', 'MESH:D044584', (213, 234))	('SMAD4', 'Gene', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('CTNNB1', 'Gene', (176, 182))	('mutations', 'Var', (116, 125))	('RB1', 'Gene', (312, 315))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('TP53', 'Gene', '7157', (243, 247))	('SMAD4', 'Gene', '4089', (236, 241))	('APC', 'cellular_component', 'GO:0005680', ('142', '145'))	('altered', 'Reg', (202, 209))	('ductal adenocarcinoma', 'Disease', (213, 234))	('APC', 'Disease', 'MESH:D011125', (168, 171))	('CDKN2A', 'Gene', (253, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('beta-catenin', 'Gene', (146, 158))	('APC', 'Disease', (168, 171))	('beta-catenin', 'Gene', '1499', (146, 158))	('BRAF', 'Gene', '673', (303, 307))	('BRAF', 'Gene', (303, 307))
15937	25441307	Inactivating alteration in DNA repair genes (including BRCA1, ATM, and PALB2) occurred in almost half of the cases in this study.	('ATM', 'Gene', '472', (62, 65))	('Inactivating alteration', 'Var', (0, 23))	('PALB2', 'Gene', (71, 76))	('PALB2', 'Gene', '79728', (71, 76))	('BRCA1', 'Gene', '672', (55, 60))	('DNA repair genes', 'Gene', (27, 43))	('ATM', 'Gene', (62, 65))	('BRCA1', 'Gene', (55, 60))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))	('DNA repair', 'biological_process', 'GO:0006281', ('27', '37'))
15938	25441307	The occurrence of these BRAF fusions in addition to oncogenic hotspot point mutations in BRAF strongly suggests that BRAF and MEK inhibitors are a promising potential therapeutic target in acinar cell carcinomas.	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (189, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('fusions', 'Var', (29, 36))	('MEK', 'Gene', (126, 129))	('MEK', 'Gene', '5609', (126, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (201, 211))	('acinar cell carcinomas', 'Disease', (189, 211))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', '673', (117, 121))	('BRAF', 'Gene', (89, 93))	('BRAF', 'Gene', (117, 121))
15941	25441307	Acinar cell carcinomas demonstrate striking genomic instability (at both the base pair and chromosomal level); ductal adenocarcinomas have SMAD4, TP53, KRAS, and P16/CDKN2A mutations; pancreatic neuroendocrine tumors have MEN1, DAXX, ATRX, and mTOR pathway mutations; solid-pseudopapillary neoplasms have CTNNB1 mutations; serous cystadenomas have VHL mutations; intraductal papillary mucinous neoplasms have GNAS and RNF43 mutations (in addition to mutations in some genes altered in ductal adenocarcinomas); and mucinous cystic neoplasms have RNF43 mutations (in addition to mutations in some genes altered in ductal adenocarcinomas).	('ductal adenocarcinomas', 'Disease', 'MESH:D044584', (485, 507))	('mutations', 'Var', (257, 266))	('ductal adenocarcinomas', 'Disease', 'MESH:D044584', (111, 133))	('mucinous neoplasms', 'Phenotype', 'HP:0031495', (385, 403))	('CDKN2A', 'Gene', '1029', (166, 172))	('ductal adenocarcinomas', 'Disease', 'MESH:D044584', (612, 634))	('neoplasm', 'Phenotype', 'HP:0002664', (530, 538))	('ductal adenocarcinomas', 'Disease', (485, 507))	('intraductal papillary mucinous neoplasms', 'Disease', (363, 403))	('neoplasms', 'Phenotype', 'HP:0002664', (394, 403))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (184, 216))	('ductal adenocarcinomas', 'Disease', (111, 133))	('mucinous cystic neoplasms', 'Disease', (514, 539))	('DAXX', 'Gene', (228, 232))	('MEN1', 'Gene', '4221', (222, 226))	('ductal adenocarcinomas', 'Disease', (612, 634))	('neoplasm', 'Phenotype', 'HP:0002664', (290, 298))	('CTNNB1', 'Gene', (305, 311))	('VHL', 'Gene', '7428', (348, 351))	('ATRX', 'Gene', (234, 238))	('neoplasm', 'Phenotype', 'HP:0002664', (394, 402))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (195, 216))	('TP53', 'Gene', (146, 150))	('RNF43', 'Gene', '54894', (545, 550))	('pancreatic neuroendocrine tumors', 'Disease', (184, 216))	('DAXX', 'Gene', '1616', (228, 232))	('RNF43', 'Gene', '54894', (418, 423))	('KRAS', 'Gene', '3845', (152, 156))	('ATRX', 'Gene', '546', (234, 238))	('solid-pseudopapillary neoplasms', 'Disease', (268, 299))	('intraductal papillary mucinous neoplasms', 'Disease', 'MESH:D000077779', (363, 403))	('MEN1', 'Gene', (222, 226))	('neoplasms', 'Phenotype', 'HP:0002664', (290, 299))	('serous cystadenomas', 'Phenotype', 'HP:0012887', (323, 342))	('SMAD4', 'Gene', (139, 144))	('Acinar cell carcinomas', 'Disease', 'MESH:D018267', (0, 22))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('KRAS', 'Gene', (152, 156))	('GNAS', 'Gene', (409, 413))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (497, 506))	('carcinomas', 'Phenotype', 'HP:0030731', (497, 507))	('RNF43', 'Gene', (545, 550))	('RNF43', 'Gene', (418, 423))	('GNAS', 'Gene', '2778', (409, 413))	('carcinoma', 'Phenotype', 'HP:0030731', (624, 633))	('carcinomas', 'Phenotype', 'HP:0030731', (624, 634))	('CDKN2A', 'Gene', (166, 172))	('mTOR', 'Gene', (244, 248))	('mutations', 'Var', (551, 560))	('P16', 'Gene', '1029', (162, 165))	('TP53', 'Gene', '7157', (146, 150))	('neoplasms', 'Phenotype', 'HP:0002664', (530, 539))	('Acinar cell carcinomas', 'Disease', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('cystic neoplasms', 'Phenotype', 'HP:0010576', (523, 539))	('mutations', 'Var', (424, 433))	('mucinous cystic neoplasms', 'Disease', 'MESH:D018297', (514, 539))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (12, 22))	('CTNNB1', 'Gene', '1499', (305, 311))	('serous cystadenomas', 'Disease', (323, 342))	('serous cystadenomas', 'Disease', 'MESH:D018293', (323, 342))	('mutations', 'Var', (312, 321))	('solid-pseudopapillary neoplasms', 'Disease', 'MESH:D018250', (268, 299))	('P16', 'Gene', (162, 165))	('SMAD4', 'Gene', '4089', (139, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('mTOR', 'Gene', '2475', (244, 248))	('VHL', 'Gene', (348, 351))
15944	25441307	For example, APC-beta-catenin pathway alterations in acinar cell carcinomas and pancreatoblastomas may result in aberrant nuclear accumulation of beta-catenin in immunohistochemical assays.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('APC', 'cellular_component', 'GO:0005680', ('13', '16'))	('beta-catenin', 'Gene', '1499', (17, 29))	('acinar cell carcinomas', 'Disease', (53, 75))	('nuclear accumulation', 'MPA', (122, 142))	('APC', 'Disease', 'MESH:D011125', (13, 16))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('APC', 'Disease', (13, 16))	('beta-catenin', 'Gene', (146, 158))	('beta-catenin', 'Gene', '1499', (146, 158))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (53, 75))	('pancreatoblastomas', 'Disease', 'MESH:C537162', (80, 98))	('pancreatoblastoma', 'Phenotype', 'HP:0100757', (80, 97))	('alterations', 'Var', (38, 49))	('result in', 'Reg', (103, 112))	('beta-catenin', 'Gene', (17, 29))	('pancreatoblastomas', 'Disease', (80, 98))
15946	25441307	In addition, loss of SMAD4 protein expression by immunohistochemistry can be used as evidence for pancreatic ductal adenocarcinoma; SMAD4 mutations in acinar cell carcinomas occur less frequently than in ductal adenocarcinoma but should still be considered when interpreting results of SMAD4 immunohistochemical staining in a pancreatic tumor.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('pancreatic tumor', 'Disease', (326, 342))	('ductal adenocarcinoma', 'Disease', 'MESH:D044584', (109, 130))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (98, 130))	('pancreatic tumor', 'Disease', 'MESH:D010190', (326, 342))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (151, 173))	('ductal adenocarcinoma', 'Disease', 'MESH:D044584', (204, 225))	('pancreatic ductal adenocarcinoma', 'Disease', (98, 130))	('SMAD4', 'Gene', '4089', (286, 291))	('SMAD4', 'Gene', (21, 26))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('SMAD4', 'Gene', (132, 137))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (98, 130))	('mutations', 'Var', (138, 147))	('SMAD4', 'Gene', '4089', (21, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (326, 342))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('ductal adenocarcinoma', 'Disease', (204, 225))	('acinar cell carcinomas', 'Disease', (151, 173))	('SMAD4', 'Gene', '4089', (132, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('SMAD4', 'Gene', (286, 291))
15947	25441307	The identification of targetable genetic alterations in a significant proportion of acinar cell carcinomas points to another potential clinical use for genetic data.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('clinical', 'Species', '191496', (135, 143))	('genetic alterations', 'Var', (33, 52))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (84, 106))	('acinar cell carcinomas', 'Disease', (84, 106))
15949	25441307	Current data supports further exploration of JAK inhibitors, BRAF inhibitors, MEK inhibitors, and PARP inhibitors (which are particularly effective in tumors with mutations in the Fanconi anemia pathway) in acinar neoplasms.	('acinar neoplasms', 'Disease', 'MESH:D018267', (207, 223))	('MEK', 'Gene', '5609', (78, 81))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('PARP', 'Gene', '1302', (98, 102))	('acinar neoplasms', 'Disease', (207, 223))	('MEK', 'Gene', (78, 81))	('Fanconi anemia', 'Disease', (180, 194))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Fanconi anemia', 'Disease', 'MESH:D005199', (180, 194))	('tumors', 'Disease', (151, 157))	('JAK', 'molecular_function', 'GO:0004713', ('45', '48'))	('anemia', 'Phenotype', 'HP:0001903', (188, 194))	('PARP', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (61, 65))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('BRAF', 'Gene', (61, 65))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (180, 194))	('neoplasms', 'Phenotype', 'HP:0002664', (214, 223))	('mutations', 'Var', (163, 172))	('neoplasm', 'Phenotype', 'HP:0002664', (214, 222))
15950	25441307	However, considering the large number of alterations in each acinar cell carcinoma and the overlap between acinar cell carcinomas and other tumor types, these tumors may be amenable to additional therapies as they are developed.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('acinar cell carcinomas', 'Disease', (107, 129))	('acinar cell carcinoma', 'Disease', 'MESH:D018267', (61, 82))	('acinar cell carcinoma', 'Disease', 'MESH:D018267', (107, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('men', 'Species', '9606', (174, 177))	('alterations', 'Var', (41, 52))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (107, 129))	('tumor', 'Disease', (140, 145))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('acinar cell carcinoma', 'Disease', (61, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
15967	24624093	Increasing knowledge of inherited genetic mutations is leading to a better understanding of pancreatic cancer risk, as these genetic variations are known to contribute to both familial and non-familial (sporadic) PDAC.	('variations', 'Var', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('PDAC', 'Chemical', '-', (213, 217))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))	('contribute to', 'Reg', (157, 170))	('PDAC', 'Phenotype', 'HP:0006725', (213, 217))	('pancreatic cancer', 'Disease', (92, 109))	('non-familial', 'Disease', (189, 201))	('genetic variations', 'Var', (125, 143))
15974	24624093	Peutz-Jeghers Syndrome (PJS), which is associated with germline mutations in the STK11/LKB1 gene, leads to a 36% lifetime risk for pancreatic cancer (Hahn et al.,); similarly, Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, which results due to germline mutations in the p16/CDKN2A gene, leads to an approximate 17% lifetime risk for pancreatic cancer (Hahn et al.,); other syndromes include Hereditary Breast-Ovarian Cancer (HBOC) syndrome (BRCA1/2 genes), Hereditary Non-polyposis Colorectal Cancer (HNPCC; mismatch repair genes), and Familial Adenomatous Polyposis (FAP) syndrome (APC gene) (Table 1).	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('HNPCC', 'Disease', 'None', (513, 518))	('Mole', 'Phenotype', 'HP:0003764', (203, 207))	('HNPCC', 'Disease', (513, 518))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (421, 435))	('Hereditary Non-polyposis Colorectal Cancer', 'Phenotype', 'HP:0006716', (469, 511))	('Hereditary Breast-Ovarian Cancer (HBOC) syndrome', 'Disease', 'MESH:D061325', (403, 451))	('p16', 'Gene', (282, 285))	('APC', 'Disease', 'MESH:D011125', (595, 598))	('APC', 'Disease', (595, 598))	('mismatch repair', 'biological_process', 'GO:0006298', ('520', '535'))	('germline', 'Var', (256, 264))	('p16', 'Gene', '1029', (282, 285))	('Cancer', 'Phenotype', 'HP:0002664', (429, 435))	('Non-polyposis Colorectal Cancer', 'Disease', (480, 511))	('pancreatic cancer', 'Disease', 'MESH:D010190', (345, 362))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('LKB1', 'Gene', '6794', (87, 91))	('Melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('Multiple Mole', 'Phenotype', 'HP:0001054', (194, 207))	('CDKN2A', 'Gene', (286, 292))	('STK11', 'Gene', (81, 86))	('BRCA1/2', 'Gene', (453, 460))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome', 'Disease', 'MESH:D004416', (176, 233))	('HNPCC', 'Phenotype', 'HP:0006716', (513, 518))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('pancreatic cancer', 'Disease', (345, 362))	('pancreatic cancer', 'Disease', (131, 148))	('Familial Adenomatous Polyposis (FAP) syndrome', 'Disease', 'MESH:D011125', (548, 593))	('Adenomatous Polyposis', 'Phenotype', 'HP:0005227', (557, 578))	('Non-polyposis Colorectal Cancer', 'Disease', 'MESH:D015179', (480, 511))	('CDKN2A', 'Gene', '1029', (286, 292))	('LKB1', 'Gene', (87, 91))	('STK11', 'Gene', '6794', (81, 86))	('BRCA1/2', 'Gene', '672;675', (453, 460))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (494, 511))	('STK11', 'molecular_function', 'GO:0033868', ('81', '86'))	('Atypical Multiple Mole', 'Phenotype', 'HP:0001062', (185, 207))	('Cancer', 'Phenotype', 'HP:0002664', (505, 511))	('APC', 'cellular_component', 'GO:0005680', ('595', '598'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (345, 362))
15975	24624093	Secondly, hereditary causes of pancreatitis, such as the autosomal dominant form caused by germline mutations of the cationic trypsinogen gene, PRSS1, have been indirectly linked to PDAC through early onset chronic pancreatitis with an associated 53-fold increased incidence and approximately 40% of hereditary pancreatitis patients noted to develop pancreatic cancer by age 70 (Hahn et al.,; Hezel et al.,; Koorstra et al.,).	('chronic pancreatitis', 'Disease', 'MESH:D050500', (207, 227))	('PDAC', 'Chemical', '-', (182, 186))	('pancreatitis', 'Disease', 'MESH:D010195', (215, 227))	('PDAC', 'Phenotype', 'HP:0006725', (182, 186))	('pancreatitis', 'Disease', 'MESH:D010195', (311, 323))	('pancreatitis', 'Disease', 'MESH:D010195', (31, 43))	('cationic trypsinogen', 'Gene', (117, 137))	('pancreatitis', 'Disease', (215, 227))	('develop', 'PosReg', (342, 349))	('patients', 'Species', '9606', (324, 332))	('hereditary pancreatitis', 'Disease', 'MESH:C537262', (300, 323))	('pancreatitis', 'Disease', (311, 323))	('pancreatitis', 'Disease', (31, 43))	('hereditary pancreatitis', 'Disease', (300, 323))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (350, 367))	('chronic pancreatitis', 'Disease', (207, 227))	('cationic trypsinogen', 'Gene', '5644', (117, 137))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (207, 227))	('PRSS1', 'Gene', (144, 149))	('PRSS1', 'Gene', '5644', (144, 149))	('pancreatic cancer', 'Disease', 'MESH:D010190', (350, 367))	('mutations', 'Var', (100, 109))	('linked', 'Reg', (172, 178))	('pancreatitis', 'Phenotype', 'HP:0001733', (215, 227))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('pancreatitis', 'Phenotype', 'HP:0001733', (311, 323))	('pancreatic cancer', 'Disease', (350, 367))	('pancreatitis', 'Phenotype', 'HP:0001733', (31, 43))
15986	24624093	The inheritance pattern of FPC is mostly autosomal dominant and demonstrates a heterogenous phenotype (Slater et al.,) The genetic mutations responsible for the majority of clustering in families with PDAC have yet to be identified, although germline mutations in high-penetrance genes such as BRCA2 and PALB2 have been established along with mutations in p16/CDKN2A, STK11/LKB1, PRSS1, BRCA1, mismatch repair genes (hMLH1, hMSH2, hMSH6), VHL, and ATM (Table 1).	('hMSH2', 'Gene', (424, 429))	('FPC', 'Disease', 'MESH:D011125', (27, 30))	('ATM', 'Gene', (448, 451))	('STK11', 'Gene', (368, 373))	('CDKN2A', 'Gene', (360, 366))	('hMSH', 'molecular_function', 'GO:0018775', ('431', '435'))	('mutations', 'Var', (343, 352))	('hMSH', 'molecular_function', 'GO:0018775', ('424', '428'))	('FPC', 'cellular_component', 'GO:1990900', ('27', '30'))	('LKB1', 'Gene', '6794', (374, 378))	('hMSH6', 'Gene', (431, 436))	('VHL', 'Gene', (439, 442))	('PDAC', 'Chemical', '-', (201, 205))	('BRCA2', 'Gene', (294, 299))	('CDKN2A', 'Gene', '1029', (360, 366))	('STK11', 'Gene', '6794', (368, 373))	('hMLH1', 'Gene', (417, 422))	('mismatch repair', 'biological_process', 'GO:0006298', ('394', '409'))	('PDAC', 'Phenotype', 'HP:0006725', (201, 205))	('hMLH1', 'Gene', '4292', (417, 422))	('FPC', 'Disease', (27, 30))	('PALB2', 'Gene', (304, 309))	('hMSH6', 'Gene', '2956', (431, 436))	('VHL', 'Gene', '7428', (439, 442))	('ATM', 'Gene', '472', (448, 451))	('BRCA1', 'Gene', '672', (387, 392))	('hMSH2', 'Gene', '4436', (424, 429))	('BRCA2', 'Gene', '675', (294, 299))	('BRCA1', 'Gene', (387, 392))	('LKB1', 'Gene', (374, 378))	('PRSS1', 'Gene', (380, 385))	('PALB2', 'Gene', '79728', (304, 309))	('p16', 'Gene', (356, 359))	('STK11', 'molecular_function', 'GO:0033868', ('368', '373'))	('p16', 'Gene', '1029', (356, 359))	('PRSS1', 'Gene', '5644', (380, 385))
15987	24624093	Despite sharing many of the same genetic mutations associated with well-established familial cancer syndromes, FPC patients must not fulfill criteria for one of the familial cancer syndromes, and thus likely represent phenotypic variants with the associated influence of environmental risk factors.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (115, 123))	('men', 'Species', '9606', (278, 281))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (84, 109))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (165, 190))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('familial cancer syndromes', 'Disease', (84, 109))	('FPC', 'Disease', 'MESH:D011125', (111, 114))	('FPC', 'cellular_component', 'GO:1990900', ('111', '114'))	('FPC', 'Disease', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('familial cancer syndromes', 'Disease', (165, 190))
15992	24624093	Some studies have suggested a younger age of onset (8-10 years younger) in individuals with a family history or known germline mutation (i.e., BRCA2), while other studies have shown no association with age of onset in those with a hereditary predisposition (Lynch et al.,; Phelan et al.,; Ozcelik et al.,; Hruban et al.,; Silverman et al.,; Lal et al.,; Schenk et al.,; Hahn et al.,; James et al.,; Hezel et al.,; Brune et al.,; Schneider et al.,; Klein,).	('mutation', 'Var', (127, 135))	('BRCA2', 'Gene', '675', (143, 148))	('BRCA2', 'Gene', (143, 148))
15995	24624093	Additionally, BRCA1/2 mutations carriers may be more likely to die from aggressive breast or ovarian cancer at an early age, thereby masking an underlying diagnosis of pancreatic cancer.	('BRCA1/2', 'Gene', (14, 21))	('pancreatic cancer', 'Disease', 'MESH:D010190', (168, 185))	('pancreatic cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('BRCA1/2', 'Gene', '672;675', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (22, 31))	('aggressive breast or ovarian cancer', 'Disease', (72, 107))	('aggressive breast or ovarian cancer', 'Disease', 'MESH:D010051', (72, 107))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (168, 185))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))
16002	24624093	Genes with germline mutations that have been identified in FPC kindred include BRCA2 (and other Fanconi anemia DNA repair pathway genes, including FANCC and FANCG genes), PALB2, PTEN, STK11/LKB1, p16/CDKN2A, TP53, ATM, and PRSS1 (Table 1).	('FPC', 'cellular_component', 'GO:1990900', ('59', '62'))	('Fanconi anemia', 'Disease', 'MESH:D005199', (96, 110))	('anemia', 'Phenotype', 'HP:0001903', (104, 110))	('FPC', 'Disease', 'MESH:D011125', (59, 62))	('TP53', 'Gene', '7157', (208, 212))	('BRCA2', 'Gene', (79, 84))	('ATM', 'Gene', '472', (214, 217))	('CDKN2A', 'Gene', (200, 206))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('PALB2', 'Gene', (171, 176))	('FANCG', 'Gene', (157, 162))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (96, 110))	('STK11', 'Gene', (184, 189))	('LKB1', 'Gene', '6794', (190, 194))	('PTEN', 'Gene', (178, 182))	('BRCA2', 'Gene', '675', (79, 84))	('CDKN2A', 'Gene', '1029', (200, 206))	('PALB2', 'Gene', '79728', (171, 176))	('ATM', 'Gene', (214, 217))	('FPC', 'Disease', (59, 62))	('DNA repair', 'biological_process', 'GO:0006281', ('111', '121'))	('FANCC', 'Gene', '2176', (147, 152))	('PRSS1', 'Gene', (223, 228))	('TP53', 'Gene', (208, 212))	('mutations', 'Var', (20, 29))	('PRSS1', 'Gene', '5644', (223, 228))	('STK11', 'Gene', '6794', (184, 189))	('PTEN', 'Gene', '5728', (178, 182))	('p16', 'Gene', (196, 199))	('FANCC', 'Gene', (147, 152))	('FANCG', 'Gene', '2189', (157, 162))	('STK11', 'molecular_function', 'GO:0033868', ('184', '189'))	('LKB1', 'Gene', (190, 194))	('Fanconi anemia', 'Disease', (96, 110))	('p16', 'Gene', '1029', (196, 199))
16004	24624093	Notably, genetically engineered mouse models have been created for many of these mutations (across a wide range of malignancies), thereby allowing for a tractable in vivo system to help determine the biologic impact of oncogenic mutations as well as helping establish genotype-phenotype relationships.	('mouse', 'Species', '10090', (32, 37))	('malignancies', 'Disease', (115, 127))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))	('mutations', 'Var', (81, 90))
16008	24624093	Therefore, BRCA2 mutant cells exhibit defective HR repair, proliferation arrest, impaired cytokinesis, radioresistant DNA synthesis (due to impairment of intra-S phase DNA damage checkpoint control), genomic instability, and hypersensitivity to DNA damaging agents (e.g., PARP inhibitors, mitomycin, platinum, etc.)	('mitomycin', 'Chemical', 'MESH:D016685', (289, 298))	('hypersensitivity', 'Disease', 'MESH:D004342', (225, 241))	('proliferation arrest', 'Disease', (59, 79))	('DNA damage checkpoint', 'biological_process', 'GO:0000077', ('168', '189'))	('mutant', 'Var', (17, 23))	('DNA', 'cellular_component', 'GO:0005574', ('245', '248'))	('impairment of intra-S', 'Disease', (140, 161))	('BRCA2', 'Gene', '675', (11, 16))	('DNA synthesis', 'biological_process', 'GO:0071897', ('118', '131'))	('impaired cytokinesis', 'CPA', (81, 101))	('cytokinesis', 'biological_process', 'GO:0000910', ('90', '101'))	('S phase', 'biological_process', 'GO:0051320', ('160', '167'))	('DNA', 'cellular_component', 'GO:0005574', ('168', '171'))	('proliferation arrest', 'Disease', 'MESH:D006323', (59, 79))	('PARP', 'Gene', '142', (272, 276))	('hypersensitivity', 'biological_process', 'GO:0002524', ('225', '241'))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('genomic instability', 'CPA', (200, 219))	('HR repair', 'CPA', (48, 57))	('defective', 'NegReg', (38, 47))	('radioresistant DNA synthesis', 'MPA', (103, 131))	('PARP', 'Gene', (272, 276))	('impairment of intra-S', 'Disease', 'MESH:D009422', (140, 161))	('platinum', 'Chemical', 'MESH:D010984', (300, 308))	('hypersensitivity', 'Disease', (225, 241))	('BRCA2', 'Gene', (11, 16))
16009	24624093	The majority (80%) of BRCA2 germline mutations are nonsense or frameshift mutations, such as the 6174delT mutation and other exon 11 mutations, which lead to the development of premature stop codons and result in truncated and non-functional BRCA2 proteins similar to what is seen in BRCA2-mutated breast cancers (Hahn et al.,).	('men', 'Species', '9606', (169, 172))	('BRCA2', 'Gene', '675', (242, 247))	('BRCA2', 'Gene', '675', (284, 289))	('breast cancers', 'Disease', 'MESH:D001943', (298, 312))	('breast cancers', 'Disease', (298, 312))	('non-functional', 'MPA', (227, 241))	('truncated', 'MPA', (213, 222))	('germline mutations', 'Var', (28, 46))	('breast cancers', 'Phenotype', 'HP:0003002', (298, 312))	('premature stop codons', 'MPA', (177, 198))	('proteins', 'Protein', (248, 256))	('BRCA2', 'Gene', (284, 289))	('BRCA2', 'Gene', (22, 27))	('6174delT', 'Mutation', 'rs786204278', (97, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (298, 311))	('6174delT mutation', 'Var', (97, 114))	('frameshift', 'Var', (63, 73))	('cancers', 'Phenotype', 'HP:0002664', (305, 312))	('BRCA2', 'Gene', (242, 247))	('BRCA2', 'Gene', '675', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
16010	24624093	Of note, it is estimated that 1% of the Ashkenazi Jewish population in North America harbors the germline BRCA2 6174delT founder mutation, which has been associated with a 10-fold increased risk of developing pancreatic, breast, prostate, and ovarian cancers (Oddoux et al.,; Ozcelik et al.,) Interestingly though, the BRCA2 6174delT mutation has been described to have independent origins in both Ashkenazi Jewish and non-Jewish populations (Berman et al.,; Hahn et al.,).	('ovarian cancers', 'Phenotype', 'HP:0100615', (243, 258))	('6174delT mutation', 'Var', (325, 342))	('pancreatic', 'Disease', 'MESH:D010195', (209, 219))	('breast', 'Disease', (221, 227))	('BRCA2', 'Gene', (319, 324))	('BRCA2', 'Gene', '675', (106, 111))	('prostate', 'Disease', (229, 237))	('pancreatic', 'Disease', (209, 219))	('BRCA2', 'Gene', '675', (319, 324))	('ovarian cancer', 'Phenotype', 'HP:0100615', (243, 257))	('ovarian cancers', 'Disease', (243, 258))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('ovarian cancers', 'Disease', 'MESH:D010051', (243, 258))	('6174delT', 'Mutation', 'rs786204278', (325, 333))	('associated', 'Reg', (154, 164))	('6174delT', 'Mutation', 'rs786204278', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('6174delT', 'Var', (112, 120))	('BRCA2', 'Gene', (106, 111))
16012	24624093	In this setting, biallelic loss of BRCA2 alone and certainly in conjunction with p53 deregulation, has been shown to induce the spectrum of pancreatic ductal neoplasia although after a fairly long latency period (Skoulidis et al.,; Feldmann et al.,; Rowley et al.,).	('loss', 'Var', (27, 31))	('pancreatic ductal neoplasia', 'Disease', 'MESH:D021441', (140, 167))	('BRCA2', 'Gene', '675', (35, 40))	('spectrum', 'MPA', (128, 136))	('induce', 'PosReg', (117, 123))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('pancreatic ductal neoplasia', 'Disease', (140, 167))	('neoplasia', 'Phenotype', 'HP:0002664', (158, 167))	('BRCA2', 'Gene', (35, 40))
16014	24624093	Previous studies analyzing families with known BRCA2 mutations found young-onset breast and/or ovarian cancer BRCA2 mutation carriers to have a 3.5- to 10-fold increased risk and estimated 5% lifetime risk of developing PDAC relative to non-BRCA2 carriers (Breast Cancer Linkage Consortium,; van Asperen et al.,).	('PDAC', 'Chemical', '-', (220, 224))	('mutation', 'Var', (116, 124))	('PDAC', 'Phenotype', 'HP:0006725', (220, 224))	('breast and/or ovarian cancer', 'Disease', 'MESH:D010051', (81, 109))	('Breast Cancer', 'Disease', 'MESH:D001943', (257, 270))	('BRCA2', 'Gene', '675', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BRCA2', 'Gene', (47, 52))	('Breast Cancer', 'Disease', (257, 270))	('breast and/or ovarian cancer', 'Disease', (81, 109))	('Cancer', 'Phenotype', 'HP:0002664', (264, 270))	('BRCA2', 'Gene', (110, 115))	('Breast Cancer', 'Phenotype', 'HP:0003002', (257, 270))	('mutations', 'Var', (53, 62))	('PDAC', 'Disease', (220, 224))	('BRCA2', 'Gene', '675', (47, 52))	('BRCA2', 'Gene', '675', (110, 115))	('BRCA2', 'Gene', (241, 246))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))
16017	24624093	The overall prevalence of BRCA2 mutations in moderate-risk (two or more affected first-degree relatives) and high-risk (three or more affected first-degree relatives) pancreatic cancer families, was noted by Couch et al to be approximately 6% with a frequency ranging from 3 to 15% for families depending on the number of affected family members (Couch et al.,).	('pancreatic cancer', 'Disease', 'MESH:D010190', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (167, 184))	('BRCA2', 'Gene', (26, 31))	('mutations', 'Var', (32, 41))	('BRCA2', 'Gene', '675', (26, 31))	('pancreatic cancer', 'Disease', (167, 184))
16018	24624093	Other studies have suggested the prevalence of BRCA2 germline mutations to be significantly higher (12-19%) among individuals with a family history of PDAC, albeit those specifically fulfilling criteria for FPC (Murphy et al.,; Hahn et al.,).	('germline mutations', 'Var', (53, 71))	('higher', 'PosReg', (92, 98))	('PDAC', 'Chemical', '-', (151, 155))	('BRCA2', 'Gene', (47, 52))	('FPC', 'cellular_component', 'GO:1990900', ('207', '210'))	('PDAC', 'Disease', (151, 155))	('FPC', 'Disease', 'MESH:D011125', (207, 210))	('PDAC', 'Phenotype', 'HP:0006725', (151, 155))	('BRCA2', 'Gene', '675', (47, 52))	('FPC', 'Disease', (207, 210))
16019	24624093	Thus, BRCA2 germline mutations are currently the most frequently identified genetic alteration in FPC even in the absence of breast and/or ovarian cancer (Goggins et al.,; Ozcelik et al.,; Hahn et al.,).	('FPC', 'Disease', (98, 101))	('BRCA2', 'Gene', '675', (6, 11))	('FPC', 'Disease', 'MESH:D011125', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast and/or ovarian cancer', 'Disease', (125, 153))	('absence of breast', 'Phenotype', 'HP:0100783', (114, 131))	('breast and/or ovarian cancer', 'Disease', 'MESH:D010051', (125, 153))	('ovarian cancer', 'Phenotype', 'HP:0100615', (139, 153))	('BRCA2', 'Gene', (6, 11))	('FPC', 'cellular_component', 'GO:1990900', ('98', '101'))	('germline', 'Var', (12, 20))
16022	24624093	Although prophylactic surgical intervention to reduce the risk of breast and ovarian cancer onset is acceptable for BRCA2 mutated female carriers from families with numerous individuals affected with breast and/or ovarian cancers, it is unclear whether there would be risk reduction conferred by similar surgeries in women with BRCA2 mutations from families that only display a history of pancreatic cancer (Couch et al.,).	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (66, 91))	('pancreatic cancer', 'Disease', (389, 406))	('cancer', 'Phenotype', 'HP:0002664', (400, 406))	('BRCA2', 'Gene', '675', (328, 333))	('women', 'Species', '9606', (317, 322))	('ovarian cancer', 'Phenotype', 'HP:0100615', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('ovarian cancers', 'Phenotype', 'HP:0100615', (214, 229))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (389, 406))	('breast and/or ovarian cancers', 'Disease', 'MESH:D010051', (200, 229))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('BRCA2', 'Gene', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutated', 'Var', (122, 129))	('BRCA2', 'Gene', (328, 333))	('pancreatic cancer', 'Disease', 'MESH:D010190', (389, 406))	('ovarian cancer', 'Phenotype', 'HP:0100615', (214, 228))	('breast and/or ovarian cancers', 'Disease', (200, 229))	('BRCA2', 'Gene', '675', (116, 121))
16023	24624093	HBOC is commonly associated with an inherited germline mutation in one of the BRCA1 or BRCA2 alleles with the remaining functional/wildtype allele lost via somatic mutation (Bryant et al.,).	('germline mutation', 'Var', (46, 63))	('associated', 'Reg', (17, 27))	('BRCA2', 'Gene', '675', (87, 92))	('BRCA1', 'Gene', '672', (78, 83))	('HBOC', 'Disease', (0, 4))	('BRCA1', 'Gene', (78, 83))	('BRCA2', 'Gene', (87, 92))
16024	24624093	As previously noted, BRCA2 mutation carriers far outnumber BRCA1 mutation carriers in both HBOC-associated pancreatic cancer and FPC (Hruban et al.,; Hahn et al.,; Bartsch et al.,).	('FPC', 'Disease', (129, 132))	('FPC', 'Disease', 'MESH:D011125', (129, 132))	('BRCA2', 'Gene', '675', (21, 26))	('BRCA1', 'Gene', '672', (59, 64))	('pancreatic cancer', 'Disease', (107, 124))	('pancreatic cancer', 'Disease', 'MESH:D010190', (107, 124))	('BRCA1', 'Gene', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mutation', 'Var', (27, 35))	('FPC', 'cellular_component', 'GO:1990900', ('129', '132'))	('BRCA2', 'Gene', (21, 26))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))
16025	24624093	The majority of studies examining the prevalence of pancreatic cancer in BRCA1 mutated patients have shown no increased risk, however, others have estimated a 2- to 2.5-fold increased risk (Thompson et al.,; Ferrone et al.,).	('mutated', 'Var', (79, 86))	('pancreatic cancer', 'Disease', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (52, 69))	('BRCA1', 'Gene', '672', (73, 78))	('Ferrone', 'Chemical', 'MESH:C031621', (208, 215))	('BRCA1', 'Gene', (73, 78))	('patients', 'Species', '9606', (87, 95))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (52, 69))
16026	24624093	Ferrone et al examined 145 Ashkenazi Jewish pancreatic cancer patients and found no increase in frequency of BRCA1 mutations among this group (Ferrone et al.,).	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('mutations', 'Var', (115, 124))	('BRCA1', 'Gene', (109, 114))	('Ferrone', 'Chemical', 'MESH:C031621', (143, 150))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('Ferrone', 'Chemical', 'MESH:C031621', (0, 7))	('BRCA1', 'Gene', '672', (109, 114))	('patients', 'Species', '9606', (62, 70))	('pancreatic cancer', 'Disease', (44, 61))
16028	24624093	In examining whether BRCA1 mutations confer an increased risk of pancreatic cancer, Moran et al studied 268 British BRCA1 mutation-associated HBOC families to determine whether BRCA-mutations conferred an increased risk of PDAC and found no overall increased risk (Moran et al.,).	('mutations', 'Var', (27, 36))	('BRCA1', 'Gene', (116, 121))	('BRCA1', 'Gene', '672', (21, 26))	('BRCA1', 'Gene', (21, 26))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('BRCA', 'Gene', '672', (116, 120))	('BRCA', 'Gene', (21, 25))	('PDAC', 'Disease', (223, 227))	('BRCA', 'Gene', (116, 120))	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (47, 82))	('BRCA', 'Gene', '672', (177, 181))	('pancreatic cancer', 'Disease', (65, 82))	('PDAC', 'Chemical', '-', (223, 227))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('BRCA1', 'Gene', '672', (116, 121))	('PDAC', 'Phenotype', 'HP:0006725', (223, 227))	('BRCA', 'Gene', '672', (21, 25))	('BRCA', 'Gene', (177, 181))
16029	24624093	In addition, when specifically analyzing for the BRCA1 185delAG founder mutation in pancreatic cancer patients, it was suggested that BRCA1 germline mutations do not contribute to an increased risk of pancreatic cancer (Schnall and Macdonald,).	('pancreatic cancer', 'Phenotype', 'HP:0002894', (201, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('BRCA1', 'Gene', (134, 139))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (84, 101))	('185delAG', 'Var', (55, 63))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (183, 218))	('BRCA1', 'Gene', '672', (49, 54))	('pancreatic cancer', 'Disease', (201, 218))	('patients', 'Species', '9606', (102, 110))	('pancreatic cancer', 'Disease', 'MESH:D010190', (201, 218))	('pancreatic cancer', 'Disease', (84, 101))	('BRCA1', 'Gene', (49, 54))	('pancreatic cancer', 'Disease', 'MESH:D010190', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BRCA1', 'Gene', '672', (134, 139))	('185delAG', 'Mutation', 'c.185delAG', (55, 63))
16030	24624093	Germline truncating mutations in the "partner and localizer of BRCA2" (PALB2) gene, which is located on chromosome 16p12 have been identified in approximately 3% of patients with FPC (Jones et al.,; Slater et al.,).	('BRCA2', 'Gene', '675', (63, 68))	('PALB2', 'Gene', (71, 76))	('FPC', 'Disease', 'MESH:D011125', (179, 182))	('PALB2', 'Gene', '79728', (71, 76))	('identified', 'Reg', (131, 141))	('FPC', 'Disease', (179, 182))	('Germline', 'Var', (0, 8))	('patients', 'Species', '9606', (165, 173))	('BRCA2', 'Gene', (63, 68))
16034	24624093	Germline BRCA2 missense mutations within the PALB2-binding motif have been shown to disrupt PALB2 binding, thereby disabling BRCA2 function, and PALB2-depleted cells share a phenotype similar to those deficient in BRCA2 function, further highlighting the importance of this complex (Xia et al.,).	('PALB2', 'Gene', '79728', (145, 150))	('BRCA2', 'Gene', (9, 14))	('disabling', 'NegReg', (115, 124))	('disrupt', 'NegReg', (84, 91))	('missense mutations', 'Var', (15, 33))	('PALB2', 'Gene', (92, 97))	('BRCA2', 'Gene', (214, 219))	('BRCA2', 'Gene', '675', (9, 14))	('binding', 'molecular_function', 'GO:0005488', ('98', '105'))	('PALB2', 'Gene', (45, 50))	('BRCA2', 'Gene', (125, 130))	('binding', 'Interaction', (98, 105))	('binding', 'molecular_function', 'GO:0005488', ('51', '58'))	('PALB2', 'Gene', '79728', (92, 97))	('BRCA2', 'Gene', '675', (214, 219))	('PALB2', 'Gene', '79728', (45, 50))	('PALB2', 'Gene', (145, 150))	('BRCA2', 'Gene', '675', (125, 130))	('function', 'MPA', (131, 139))
16035	24624093	Although mutated PALB2 has been linked with HBOC syndrome and Fanconi Anemia, its role in the pathogenesis of PDAC has only recently been shown.	('HBOC syndrome', 'Disease', (44, 57))	('PDAC', 'Chemical', '-', (110, 114))	('Fanconi Anemia', 'Disease', (62, 76))	('mutated', 'Var', (9, 16))	('Fanconi Anemia', 'Phenotype', 'HP:0001994', (62, 76))	('Fanconi Anemia', 'Disease', 'MESH:D005199', (62, 76))	('pathogenesis', 'biological_process', 'GO:0009405', ('94', '106'))	('PALB2', 'Gene', '79728', (17, 22))	('linked', 'Reg', (32, 38))	('Anemia', 'Phenotype', 'HP:0001903', (70, 76))	('PDAC', 'Phenotype', 'HP:0006725', (110, 114))	('PALB2', 'Gene', (17, 22))	('HBOC syndrome', 'Disease', 'MESH:D061325', (44, 57))
16036	24624093	Indeed, according to Slater et al, PALB2 mutation carriers in FPC families demonstrated a 10- to 32-fold increased risk for the development of pancreatic cancer depending on the number of affected family members (Brand et al.,; Rahman et al.,; Jones et al.,; Slater et al.,).	('FPC', 'Disease', (62, 65))	('FPC', 'Disease', 'MESH:D011125', (62, 65))	('men', 'Species', '9606', (135, 138))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (143, 160))	('mutation', 'Var', (41, 49))	('FPC', 'cellular_component', 'GO:1990900', ('62', '65'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (143, 160))	('pancreatic cancer', 'Disease', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('PALB2', 'Gene', (35, 40))	('PALB2', 'Gene', '79728', (35, 40))
16037	24624093	Using whole-exome sequencing to examine patients with FPC, Jones et al identified a total of four PALB2 truncating mutations in 3.1% of patients with pancreatic cancer (Jones et al.,).	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('FPC', 'cellular_component', 'GO:1990900', ('54', '57'))	('PALB2', 'Gene', '79728', (98, 103))	('patients', 'Species', '9606', (40, 48))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('PALB2', 'Gene', (98, 103))	('patients', 'Species', '9606', (136, 144))	('truncating mutations', 'Var', (104, 124))	('FPC', 'Disease', 'MESH:D011125', (54, 57))	('FPC', 'Disease', (54, 57))	('pancreatic cancer', 'Disease', (150, 167))
16039	24624093	Further studies have identified additional PALB2 mutations in 1-3% of FPC kindred (Tischkowitz et al.,; Slater et al.,).	('mutations', 'Var', (49, 58))	('PALB2', 'Gene', '79728', (43, 48))	('PALB2', 'Gene', (43, 48))	('FPC', 'cellular_component', 'GO:1990900', ('70', '73'))	('FPC', 'Disease', (70, 73))	('FPC', 'Disease', 'MESH:D011125', (70, 73))
16040	24624093	Nonsense and frameshift mutations, particularly in exon 11 of the PALB2 gene, result in a variety of premature stop codons and ultimately a truncated PALB2 protein, which is exceedingly rare in the general population and those without cancer (Slater et al.,).	('Nonsense', 'Var', (0, 8))	('cancer', 'Disease', (235, 241))	('result in', 'Reg', (78, 87))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('PALB2', 'Gene', '79728', (150, 155))	('truncated', 'MPA', (140, 149))	('PALB2', 'Gene', (150, 155))	('protein', 'Protein', (156, 163))	('PALB2', 'Gene', '79728', (66, 71))	('frameshift mutations', 'Var', (13, 33))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('premature stop codons', 'MPA', (101, 122))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('PALB2', 'Gene', (66, 71))
16041	24624093	Additionally, while some studies have suggested an earlier age of onset of pancreatic or breast cancer in those with PALB2 mutations in the setting of FPC, recent studies have not observed similar findings (Slater et al.,).	('pancreatic or breast cancer', 'Disease', 'MESH:D010190', (75, 102))	('FPC', 'cellular_component', 'GO:1990900', ('151', '154'))	('FPC', 'Disease', (151, 154))	('FPC', 'Disease', 'MESH:D011125', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('pancreatic or breast cancer', 'Disease', (75, 102))	('PALB2', 'Gene', (117, 122))	('PALB2', 'Gene', '79728', (117, 122))	('mutations', 'Var', (123, 132))
16044	24624093	Whereas initiation of PDAC tumorigenesis has been found to be driven by oncogenic KRAS mutations, disease progression has been associated with frequent loss of tumor suppressors within tumor cells, such as the PI3K/PTEN pathway.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('PI3K', 'molecular_function', 'GO:0016303', ('210', '214'))	('tumor', 'Disease', (27, 32))	('loss', 'NegReg', (152, 156))	('PDAC', 'Phenotype', 'HP:0006725', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('PTEN', 'Gene', (215, 219))	('PTEN', 'Gene', '5728', (215, 219))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('KRAS', 'Gene', (82, 86))	('tumor', 'Disease', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('PDAC', 'Chemical', '-', (22, 26))	('mutations', 'Var', (87, 96))
16045	24624093	Possibly due to promoter hypermethylation, aberrant expression and deletion of the PTEN gene has been frequently noted in primary tumor tissue (Asano et al.,).	('PTEN', 'Gene', '5728', (83, 87))	('deletion', 'Var', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('expression', 'MPA', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('aberrant', 'Var', (43, 51))	('PTEN', 'Gene', (83, 87))
16046	24624093	Furthermore, the PI3K/PTEN pathway has been reported to be activated in PDAC precursor lesions via activating mutations of PIK3CA, which is the gene that encodes PI3K (Schonleben et al.,; Koorstra et al.,).	('activating', 'PosReg', (99, 109))	('mutations', 'Var', (110, 119))	('PIK3CA', 'Gene', (123, 129))	('PIK3CA', 'Gene', '5290', (123, 129))	('PDAC', 'Chemical', '-', (72, 76))	('PI3K', 'molecular_function', 'GO:0016303', ('162', '166'))	('PTEN', 'Gene', (22, 26))	('activated', 'PosReg', (59, 68))	('PTEN', 'Gene', '5728', (22, 26))	('PI3K', 'molecular_function', 'GO:0016303', ('17', '21'))	('PDAC', 'Disease', (72, 76))	('PDAC', 'Phenotype', 'HP:0006725', (72, 76))
16047	24624093	Even in the absence of such mutations, it has been observed that the PI3K/AKT pathway is constitutively activated in the majority of pancreatic cancers, through aberrant expression of PTEN as well as amplification or activation of AKT2 kinase (Cheng et al.,; Ruggeri et al.,; Schlieman et al.,; Asano et al.,; Reichert et al.,; Koorstra et al.,).	('aberrant', 'Var', (161, 169))	('AKT', 'Gene', '207', (74, 77))	('activation', 'PosReg', (217, 227))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (133, 151))	('PI3K', 'molecular_function', 'GO:0016303', ('69', '73'))	('AKT', 'Gene', '207', (231, 234))	('AKT2', 'Gene', '208', (231, 235))	('pancreatic cancers', 'Disease', (133, 151))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('amplification', 'Var', (200, 213))	('PTEN', 'Gene', (184, 188))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (133, 150))	('AKT2', 'Gene', (231, 235))	('pancreatic cancers', 'Disease', 'MESH:D010190', (133, 151))	('AKT', 'Gene', (74, 77))	('activated', 'PosReg', (104, 113))	('PTEN', 'Gene', '5728', (184, 188))	('AKT', 'Gene', (231, 234))
16048	24624093	In mouse models, PDAC is driven by combined oncogenic KRAS mutation and haploinsufficient PTEN deficiency, which together promote marked NF-kB activation, its cytokine network (CCL20, CXCL1, IL-6, and IL-23), stromal activation, and immune cell infiltration; these processes shape the pancreatic cancer tumor microenvironment, stimulate the development of peritumoral stroma, and promote local and metastatic progression (Ying et al.,).	('CCL20', 'Gene', (177, 182))	('IL-6', 'Gene', '16193', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('peritumoral stroma', 'Disease', (356, 374))	('mutation', 'Var', (59, 67))	('peritumoral stroma', 'Disease', 'None', (356, 374))	('CCL20', 'Gene', '20297', (177, 182))	('pancreatic cancer tumor', 'Disease', 'MESH:D010190', (285, 308))	('promote', 'PosReg', (380, 387))	('haploinsufficient PTEN deficiency', 'Disease', 'MESH:D006223', (72, 105))	('PDAC', 'Chemical', '-', (17, 21))	('NF-kB', 'Gene', (137, 142))	('shape', 'Reg', (275, 280))	('IL-23', 'Gene', (201, 206))	('CCL', 'molecular_function', 'GO:0044101', ('177', '180'))	('pancreatic cancer tumor', 'Disease', (285, 308))	('men', 'Species', '9606', (348, 351))	('PDAC', 'Phenotype', 'HP:0006725', (17, 21))	('IL-23', 'Gene', '83430', (201, 206))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (285, 302))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('CXCL1', 'Gene', (184, 189))	('IL-6', 'Gene', (191, 195))	('mouse', 'Species', '10090', (3, 8))	('IL-23', 'molecular_function', 'GO:0045519', ('201', '206'))	('haploinsufficient PTEN deficiency', 'Disease', (72, 105))	('men', 'Species', '9606', (321, 324))	('CXCL1', 'Gene', '14825', (184, 189))	('stimulate', 'PosReg', (327, 336))	('IL-6', 'molecular_function', 'GO:0005138', ('191', '195'))
16054	24624093	The genetic progression model for PDAC, comparable to that of the adenoma-carcinoma sequence seen in colorectal cancer, results from sequential acquisition of mutations in the proto-oncogene KRAS followed by mutations in tumor suppressor genes such as p16/CDKN2A/INK4A, TP53, and SMAD4 that lead to disturbance in cell cycle regulation, and promote the PanIN-to-PDAC progression (Hruban et al.,; Schneider and Schmid,).	('tumor suppressor', 'molecular_function', 'GO:0008181', ('221', '237'))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('mutations', 'Var', (208, 217))	('TP53', 'Gene', '7157', (270, 274))	('PDAC', 'Chemical', '-', (362, 366))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('PDAC', 'Phenotype', 'HP:0006725', (362, 366))	('SMAD4', 'Gene', '4089', (280, 285))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('314', '335'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('221', '237'))	('INK4A', 'Gene', '1029', (263, 268))	('mutations', 'Var', (159, 168))	('CDKN2A', 'Gene', (256, 262))	('PanIN-to-PDAC progression', 'CPA', (353, 378))	('promote', 'PosReg', (341, 348))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('PDAC', 'Chemical', '-', (34, 38))	('KRAS', 'Gene', (191, 195))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (66, 83))	('INK4A', 'Gene', (263, 268))	('tumor', 'Disease', (221, 226))	('CDKN2A', 'Gene', '1029', (256, 262))	('PDAC', 'Phenotype', 'HP:0006725', (34, 38))	('TP53', 'Gene', (270, 274))	('p16', 'Gene', (252, 255))	('colorectal cancer', 'Disease', (101, 118))	('adenoma-carcinoma', 'Disease', (66, 83))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('rectal cancer', 'Phenotype', 'HP:0100743', (105, 118))	('p16', 'Gene', '1029', (252, 255))	('SMAD4', 'Gene', (280, 285))	('disturbance', 'Reg', (299, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('cell cycle', 'CPA', (314, 324))
16055	24624093	The noninvasive pancreatic intraepithelial neoplasia (PanIN) lesion may harbor many of the same mutations found in invasive PDAC, although there are likely to be an increasing number of mutations associated with increasing degrees of dysplasia within the PanIN (Hruban et al.,).	('mutations', 'Var', (186, 195))	('pancreatic intraepithelial neoplasia (PanIN) lesion', 'Disease', 'MESH:D018290', (16, 67))	('associated', 'Reg', (196, 206))	('dysplasia within the PanIN', 'Disease', (234, 260))	('PDAC', 'Chemical', '-', (124, 128))	('dysplasia within the PanIN', 'Disease', 'MESH:D001929', (234, 260))	('neoplasia', 'Phenotype', 'HP:0002664', (43, 52))	('noninvasive', 'Disease', (4, 15))	('PDAC', 'Phenotype', 'HP:0006725', (124, 128))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (27, 52))	('mutations', 'Var', (96, 105))
16056	24624093	The major genetic alterations leading to sporadic pancreatic cancer are thought to be mutations in the proto-oncogene, KRAS, as well as the p16/CDKN2A/INK4A, TP53, and DPC4/SMAD4 tumor suppressor genes, while mutations in BRCA2, the mismatch repair genes (hMLH1, hMSH2, and hMSH6), and the AKT2 and STK11/LKB1 genes are noted to be rare (Schneider and Schmid,; Hezel et al.,).	('TP53', 'Gene', (158, 162))	('INK4A', 'Gene', (151, 156))	('LKB1', 'Gene', '6794', (305, 309))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 67))	('sporadic pancreatic cancer', 'Disease', 'MESH:D010190', (41, 67))	('p16', 'Gene', (140, 143))	('STK11', 'molecular_function', 'GO:0033868', ('299', '304'))	('AKT2', 'Gene', (290, 294))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('hMSH6', 'Gene', (274, 279))	('STK11', 'Gene', '6794', (299, 304))	('sporadic pancreatic cancer', 'Disease', (41, 67))	('p16', 'Gene', '1029', (140, 143))	('SMAD4', 'Gene', (173, 178))	('hMSH2', 'Gene', (263, 268))	('mismatch repair', 'biological_process', 'GO:0006298', ('233', '248'))	('DPC4', 'Gene', (168, 172))	('BRCA2', 'Gene', (222, 227))	('CDKN2A', 'Gene', (144, 150))	('hMSH6', 'Gene', '2956', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('LKB1', 'Gene', (305, 309))	('TP53', 'Gene', '7157', (158, 162))	('DPC4', 'Gene', '4089', (168, 172))	('leading to', 'Reg', (30, 40))	('CDKN2A', 'Gene', '1029', (144, 150))	('SMAD4', 'Gene', '4089', (173, 178))	('BRCA2', 'Gene', '675', (222, 227))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('hMSH', 'molecular_function', 'GO:0018775', ('263', '267'))	('hMSH', 'molecular_function', 'GO:0018775', ('274', '278'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('179', '195'))	('INK4A', 'Gene', '1029', (151, 156))	('hMLH1', 'Gene', (256, 261))	('hMLH1', 'Gene', '4292', (256, 261))	('STK11', 'Gene', (299, 304))	('mutations', 'Var', (209, 218))	('AKT2', 'Gene', '208', (290, 294))	('tumor suppressor', 'biological_process', 'GO:0051726', ('179', '195'))	('hMSH2', 'Gene', '4436', (263, 268))	('tumor', 'Disease', (179, 184))
16057	24624093	Since p16/CDKN2A and BRCA2 mutations are not detected in the earliest sporadic premalignant pancreatic lesions and are more commonly found in later intermediate and advanced PanIN lesions, supports the hypothesis that these changes likely accumulate and impact the malignant progression of precursor lesions into PDAC rather than participate in cancer initiation (Hezel et al.,).	('mutations', 'Var', (27, 36))	('BRCA2', 'Gene', '675', (21, 26))	('malignant progression', 'CPA', (265, 286))	('PanIN lesions', 'Disease', 'MESH:D051437', (174, 187))	('PDAC', 'Chemical', '-', (313, 317))	('impact', 'Reg', (254, 260))	('PDAC', 'Phenotype', 'HP:0006725', (313, 317))	('PanIN lesions', 'Disease', (174, 187))	('CDKN2A', 'Gene', (10, 16))	('cancer initiation', 'Disease', (345, 362))	('pancreatic lesions', 'Disease', (92, 110))	('BRCA2', 'Gene', (21, 26))	('cancer initiation', 'Disease', 'MESH:D009369', (345, 362))	('CDKN2A', 'Gene', '1029', (10, 16))	('p16', 'Gene', (6, 9))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('pancreatic lesions', 'Disease', 'MESH:D010182', (92, 110))	('p16', 'Gene', '1029', (6, 9))	('accumulate', 'PosReg', (239, 249))
16058	24624093	It is likely that the relative late event of biallelic loss of BRCA2 in PDAC tumorigenesis is similar and shared between PDAC in those with germline and somatic mutations in the BRCA2 gene (Goggins et al.,; Hezel et al.,).	('loss', 'NegReg', (55, 59))	('BRCA2', 'Gene', '675', (63, 68))	('PDAC', 'Chemical', '-', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('PDAC', 'Chemical', '-', (72, 76))	('PDAC', 'Phenotype', 'HP:0006725', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('BRCA2', 'Gene', (178, 183))	('mutations', 'Var', (161, 170))	('BRCA2', 'Gene', (63, 68))	('tumor', 'Disease', (77, 82))	('PDAC', 'Disease', (72, 76))	('PDAC', 'Phenotype', 'HP:0006725', (72, 76))	('BRCA2', 'Gene', '675', (178, 183))
16059	24624093	KRAS gene mutations occur first in the lowest grade of intraductal lesions, known as PanIN-1 and are subsequently followed by p16/CDKN2A gene mutations, which are noted in PanIN-2 (moderately advanced/intermediate grade) lesions; the TP53, SMAD4, and sporadic BRCA2 inactivating mutations are not identified until further progression to a PanIN-3 (high grade) lesion (Hruban et al.,; Hezel et al.,).	('mutations', 'Var', (142, 151))	('TP53', 'Gene', '7157', (234, 238))	('TP53', 'Gene', (234, 238))	('p16', 'Gene', '1029', (126, 129))	('SMAD4', 'Gene', '4089', (240, 245))	('PanIN-2', 'Disease', 'MESH:D014923', (172, 179))	('CDKN2A', 'Gene', (130, 136))	('p16', 'Gene', (126, 129))	('CDKN2A', 'Gene', '1029', (130, 136))	('BRCA2', 'Gene', (260, 265))	('PanIN-2', 'Disease', (172, 179))	('SMAD4', 'Gene', (240, 245))	('mutations', 'Var', (10, 19))	('KRAS', 'Gene', (0, 4))	('BRCA2', 'Gene', '675', (260, 265))
16061	24624093	Mutated, constitutively activated oncogenes contribute to oncogenesis in PDAC, and include KRAS, BRAF, AKT2, and AIB I (Table 1) (Maitra et al.,).	('AKT2', 'Gene', (103, 107))	('AKT2', 'Gene', '208', (103, 107))	('contribute', 'Reg', (44, 54))	('oncogenesis', 'CPA', (58, 69))	('PDAC', 'Chemical', '-', (73, 77))	('oncogenesis', 'biological_process', 'GO:0007048', ('58', '69'))	('KRAS', 'Gene', (91, 95))	('AIB', 'Gene', '116833', (113, 116))	('AIB', 'Gene', (113, 116))	('BRAF', 'Gene', '673', (97, 101))	('PDAC', 'Disease', (73, 77))	('PDAC', 'Phenotype', 'HP:0006725', (73, 77))	('Mutated', 'Var', (0, 7))	('BRAF', 'Gene', (97, 101))
16062	24624093	PDAC harbors the highest incidence of mutations in RAS proteins, which are known to mediate pleiotropic effects, including cell proliferation, differentiation, survival, and migration via GTP-binding cytoplasmic protein activity (Schneider and Schmid,; Hezel et al.,).	('survival', 'CPA', (160, 168))	('GTP', 'Chemical', 'MESH:D006160', (188, 191))	('PDAC', 'Chemical', '-', (0, 4))	('cell proliferation', 'CPA', (123, 141))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('RAS proteins', 'Protein', (51, 63))	('cell proliferation', 'biological_process', 'GO:0008283', ('123', '141'))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('mutations', 'Var', (38, 47))	('migration', 'CPA', (174, 183))	('differentiation', 'CPA', (143, 158))	('GTP-binding', 'molecular_function', 'GO:0005525', ('188', '199'))
16063	24624093	Oncogenic KRAS, located on chromosome 12p, is one of the most frequently mutated genes in PDAC with over 90% of tumors harboring a KRAS gene mutation (Hruban et al.,; Maitra et al.,).	('PDAC', 'Phenotype', 'HP:0006725', (90, 94))	('chromosome', 'cellular_component', 'GO:0005694', ('27', '37'))	('KRAS', 'Gene', (131, 135))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PDAC', 'Chemical', '-', (90, 94))	('mutation', 'Var', (141, 149))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
16064	24624093	The vast majority of the KRAS activating point mutations occur at codon 12 and less frequently at codons 13 and 61, thereby resulting in a constitutively activated protein product and downstream stimulatory signals to RAS effector pathways, such as RAF-mitogen-activated protein (MAP) kinase, PI3K, and RalGDS pathways independent of growth factor stimulation (Hruban et al.,; Hezel et al.,; Maitra et al.,; Koorstra et al.,).	('RAS effector pathways', 'Pathway', (218, 239))	('protein', 'Protein', (164, 171))	('PI3K', 'Pathway', (293, 297))	('activating', 'PosReg', (30, 40))	('protein', 'cellular_component', 'GO:0003675', ('271', '278'))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('MAP', 'molecular_function', 'GO:0004239', ('280', '283'))	('point mutations', 'Var', (41, 56))	('constitutively', 'MPA', (139, 153))	('activated', 'PosReg', (154, 163))	('RalGDS', 'Gene', (303, 309))	('RAF', 'Gene', (249, 252))	('stimulatory signals', 'MPA', (195, 214))	('KRAS', 'Gene', (25, 29))	('PI3K', 'molecular_function', 'GO:0016303', ('293', '297'))	('RalGDS', 'Gene', '5900', (303, 309))	('RAF', 'Gene', '22882', (249, 252))
16065	24624093	These mutations appear to occur very early in the development of pancreatic neoplasia, as evidenced by the presence of KRAS mutations in noninvasive precursor lesions, including intraductal papillary mucinous neoplasms (IPMN) and PanINs (Hezel et al.,; Maitra et al.,).	('pancreatic neoplasia', 'Disease', (65, 85))	('neoplasm', 'Phenotype', 'HP:0002664', (209, 217))	('mutations', 'Var', (124, 133))	('pancreatic neoplasia', 'Disease', 'MESH:D009369', (65, 85))	('mucinous neoplasms', 'Phenotype', 'HP:0031495', (200, 218))	('pancreatic neoplasia', 'Phenotype', 'HP:0002894', (65, 85))	('neoplasia', 'Phenotype', 'HP:0002664', (76, 85))	('presence', 'Reg', (107, 115))	('neoplasms', 'Phenotype', 'HP:0002664', (209, 218))	('KRAS', 'Gene', (119, 123))	('intraductal papillary mucinous neoplasms', 'Disease', 'MESH:D000077779', (178, 218))	('intraductal papillary mucinous neoplasms', 'Disease', (178, 218))	('men', 'Species', '9606', (57, 60))
16066	24624093	KRAS mutations are the first known genetic alterations known to occur sporadically in normal pancreatic tissue, chronic pancreatitis, and smokers; moreover, they are detected in approximately 30% of early pancreatic neoplasms and close to 100% of advanced PDAC lesions.	('neoplasm', 'Phenotype', 'HP:0002664', (216, 224))	('pancreatic', 'Disease', 'MESH:D010195', (93, 103))	('pancreatic', 'Disease', 'MESH:D010195', (205, 215))	('pancreatic', 'Disease', (93, 103))	('pancreatic neoplasms', 'Phenotype', 'HP:0002894', (205, 225))	('detected', 'Reg', (166, 174))	('PDAC', 'Phenotype', 'HP:0006725', (256, 260))	('pancreatic', 'Disease', (205, 215))	('pancreatic neoplasms', 'Disease', (205, 225))	('mutations', 'Var', (5, 14))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (112, 132))	('neoplasms', 'Phenotype', 'HP:0002664', (216, 225))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (112, 132))	('pancreatic neoplasms', 'Disease', 'MESH:D010190', (205, 225))	('pancreatitis', 'Phenotype', 'HP:0001733', (120, 132))	('KRAS', 'Gene', (0, 4))	('PDAC', 'Chemical', '-', (256, 260))	('chronic pancreatitis', 'Disease', (112, 132))
16068	24624093	Biomarker studies have suggested KRAS activation alone is unlikely to single-handedly promote carcinogenesis given the finding of oncogenic KRAS in normal tissues, such as lung, pancreas and colon (Lu et al.,).	('carcinogenesis', 'Disease', 'MESH:D063646', (94, 108))	('pancreas and colon', 'Disease', 'MESH:D010190', (178, 196))	('KRAS', 'Var', (140, 144))	('carcinogenesis', 'Disease', (94, 108))
16070	24624093	Oncogenic mutations in KRAS result in a decreased intrinsic rate of GTP hydrolysis and make the molecule insensitive to GTPase activating proteins (GAPs) (Hezel et al.,).	('GTP', 'Chemical', 'MESH:D006160', (68, 71))	('GTP', 'Chemical', 'MESH:D006160', (120, 123))	('GTP hydrolysis', 'MPA', (68, 82))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('68', '82'))	('KRAS', 'Gene', (23, 27))	('intrinsic rate', 'MPA', (50, 64))	('mutations', 'Var', (10, 19))	('decreased', 'NegReg', (40, 49))
16071	24624093	These oncogenic mutations inhibit the protein's enzymatic activity; thus, an effective KRAS inhibitor would increase the GTPase activity or make the KRAS protein more susceptible to GAPs (Hezel et al.,).	('susceptible', 'MPA', (167, 178))	('enzymatic activity', 'MPA', (48, 66))	('increase', 'PosReg', (108, 116))	('protein', 'Protein', (38, 45))	('activity', 'MPA', (128, 136))	('mutations', 'Var', (16, 25))	('inhibit', 'NegReg', (26, 33))	('GAPs', 'MPA', (182, 186))	('GTPase activity', 'molecular_function', 'GO:0003924', ('121', '136'))	('make', 'Reg', (140, 144))	('GTP', 'Chemical', 'MESH:D006160', (121, 124))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('GTPase', 'Protein', (121, 127))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))
16073	24624093	Activating mutations in Hedgehog proteins have been associated with a variety of cancers.	('Activating mutations', 'Var', (0, 20))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('Hedgehog', 'Gene', (24, 32))	('associated', 'Reg', (52, 62))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
16076	24624093	Furthermore, it has been confirmed that the Hedgehog pathway also plays a role in metastases, with inhibition of Hedgehog signaling shown to reduce the incidence of systemic metastasis seen in PDAC xenografts (Berman et al.,; Maitra et al.,; Koorstra et al.,).	('PDAC', 'Phenotype', 'HP:0006725', (193, 197))	('Hedgehog signaling', 'Gene', (113, 131))	('systemic metastasis', 'CPA', (165, 184))	('inhibition', 'Var', (99, 109))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('PDAC', 'Chemical', '-', (193, 197))	('reduce', 'NegReg', (141, 147))	('metastases', 'Disease', (82, 92))	('metastases', 'Disease', 'MESH:D009362', (82, 92))
16079	24624093	It is mutated in 1/3 of pancreatic cancers with known wild-type KRAS (Calhoun et al.,; Maitra et al.,; Koorstra et al.,).	('pancreatic cancers', 'Phenotype', 'HP:0002894', (24, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('pancreatic cancers', 'Disease', 'MESH:D010190', (24, 42))	('pancreatic cancers', 'Disease', (24, 42))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (24, 41))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('mutated', 'Var', (6, 13))
16080	24624093	Thus, KRAS and BRAF oncogenes may function in a mutually exclusive manner in the transformation and carcinogenesis of pancreatic cancers; indeed, some studies suggest that a mutation in one of these two genes invariably results in retention of wild-type copies of the other (Maitra et al.,; Koorstra et al.,).	('BRAF', 'Gene', '673', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('carcinogenesis of pancreatic cancers', 'Disease', (100, 136))	('BRAF', 'Gene', (15, 19))	('mutation', 'Var', (174, 182))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (118, 135))	('retention', 'biological_process', 'GO:0051235', ('231', '240'))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (118, 136))	('carcinogenesis of pancreatic cancers', 'Disease', 'MESH:D010190', (100, 136))	('results in', 'Reg', (220, 230))
16095	24624093	Although germline and sporadic mutations have been identified with carriers of the germline p16-Leiden mutation, having an estimated 17% risk of developing pancreatic cancer by the age of 75, CDKN2A has been identified as one of the most frequently inactivated somatic tumor suppressors in PDAC (Koorstra et al.,).	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (156, 173))	('p16', 'Gene', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('PDAC', 'Phenotype', 'HP:0006725', (290, 294))	('pancreatic cancer', 'Disease', (156, 173))	('tumor', 'Disease', (269, 274))	('pancreatic cancer', 'Disease', 'MESH:D010190', (156, 173))	('CDKN2A', 'Gene', (192, 198))	('p16', 'Gene', '1029', (92, 95))	('PDAC', 'Chemical', '-', (290, 294))	('CDKN2A', 'Gene', '1029', (192, 198))	('mutation', 'Var', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
16096	24624093	p16INK4A/CDKN2A mutations cooperate with KRAS mutations in the development of PDAC, and are known to accelerate tumor progression in the setting of concurrent p53 mutations (Hezel et al.,).	('mutations', 'Var', (163, 172))	('CDKN2A', 'Gene', '1029', (9, 15))	('p53', 'Gene', (159, 162))	('p53', 'Gene', '7157', (159, 162))	('PDAC', 'Phenotype', 'HP:0006725', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('men', 'Species', '9606', (70, 73))	('mutations', 'Var', (16, 25))	('p16INK4A', 'Gene', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PDAC', 'Chemical', '-', (78, 82))	('tumor', 'Disease', (112, 117))	('KRAS', 'Gene', (41, 45))	('p16INK4A', 'Gene', '1029', (0, 8))	('accelerate', 'PosReg', (101, 111))	('CDKN2A', 'Gene', (9, 15))
16097	24624093	Germline mutations in exon 1alpha of the p16INK4A/CDKN2A gene are associated with FAMMM syndrome (Gruis et al.,; Schneider and Schmid,).	('Germline mutations in', 'Var', (0, 21))	('CDKN2A', 'Gene', (50, 56))	('FAMMM syndrome', 'Disease', 'OMIM:155600', (82, 96))	('CDKN2A', 'Gene', '1029', (50, 56))	('p16INK4A', 'Gene', (41, 49))	('associated', 'Reg', (66, 76))	('p16INK4A', 'Gene', '1029', (41, 49))	('FAMMM syndrome', 'Disease', (82, 96))
16099	24624093	Homozygous deletions resulting in inactivation of the p16INK4A/CDKN2A gene also frequently inactivate an adjacent gene on chromosome 9p, MTAP (methylthioadenosine phosphorylase), which is located 100 kilobases telomeric and plays an important role in the synthesis of adenosine.	('CDKN2A', 'Gene', '1029', (63, 69))	('p16INK4A', 'Gene', (54, 62))	('methylthioadenosine phosphorylase', 'Gene', (143, 176))	('adenosine', 'Chemical', 'MESH:D000241', (268, 277))	('methylthioadenosine phosphorylase', 'Gene', '4507', (143, 176))	('adenosine', 'Chemical', 'MESH:D000241', (153, 162))	('inactivate', 'NegReg', (91, 101))	('chromosome', 'cellular_component', 'GO:0005694', ('122', '132'))	('MTAP', 'Gene', (137, 141))	('deletions', 'Var', (11, 20))	('p16INK4A', 'Gene', '1029', (54, 62))	('synthesis', 'biological_process', 'GO:0009058', ('255', '264'))	('MTAP', 'Gene', '4507', (137, 141))	('CDKN2A', 'Gene', (63, 69))	('inactivation', 'MPA', (34, 46))
16100	24624093	As a result of this coincident inactivation, MTAP function is completely lost in approximately 30% of PDAC and is also under active investigation as a potential therapeutic target using purine biosynthesis inhibitors, such as L-alanosine (Hustinx et al.,; Maitra et al.,; Koorstra et al.,).	('PDAC', 'Chemical', '-', (102, 106))	('purine', 'Chemical', 'MESH:C030985', (186, 192))	('inactivation', 'Var', (31, 43))	('biosynthesis', 'biological_process', 'GO:0009058', ('193', '205'))	('PDAC', 'Disease', (102, 106))	('PDAC', 'Phenotype', 'HP:0006725', (102, 106))	('lost', 'NegReg', (73, 77))	('MTAP', 'Gene', (45, 49))	('L-alanosine', 'Chemical', 'MESH:C000082', (226, 237))	('MTAP', 'Gene', '4507', (45, 49))
16101	24624093	It has been suggested that use of such a targeted agent may be effective against the 1/3 of PDACs that harbor the deletion of this adjacent gene (Hustinx et al.,; Maitra et al.,; Koorstra et al.,).	('PDAC', 'Chemical', '-', (92, 96))	('PDAC', 'Phenotype', 'HP:0006725', (92, 96))	('PDACs', 'Disease', (92, 97))	('deletion', 'Var', (114, 122))
16103	24624093	Specifically, p53 is responsible for regulation of the G1/S cell cycle checkpoint, maintenance of G2/M arrest, induction of apoptosis, and protection against genomic rearrangement and accumulation of mutations.	('induction of apoptosis', 'biological_process', 'GO:0006915', ('111', '133'))	('regulation', 'biological_process', 'GO:0065007', ('37', '47'))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (14, 17))	('mutations', 'Var', (200, 209))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('60', '81'))	('G2/M arrest', 'CPA', (98, 109))	('men', 'Species', '9606', (175, 178))
16104	24624093	It also suppresses cellular transformation caused by oncogenic activation or loss of tumor suppressor pathways; thus, deletion or inactivation of TP53 is associated with aneuploidy, as well as the growth and survival of cells harboring chromosomal aberrations and genetic instability with potential for carcinogenic transformation (Schneider and Schmid,; Hezel et al.,; Maitra et al.,; Koorstra et al.,).	('tumor', 'Disease', (85, 90))	('inactivation', 'NegReg', (130, 142))	('suppresses', 'NegReg', (8, 18))	('TP53', 'Gene', '7157', (146, 150))	('tumor suppressor', 'biological_process', 'GO:0051726', ('85', '101'))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cellular transformation', 'CPA', (19, 42))	('TP53', 'Gene', (146, 150))	('aneuploidy', 'Disease', 'MESH:D000782', (170, 180))	('carcinogenic transformation', 'Disease', 'MESH:D020518', (303, 330))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('85', '101'))	('aneuploidy', 'Disease', (170, 180))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('carcinogenic transformation', 'Disease', (303, 330))	('deletion', 'Var', (118, 126))	('associated', 'Reg', (154, 164))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (236, 259))
16107	24624093	Additionally, p53-induced growth arrest is achieved by transactivation of p21.	('p53', 'Gene', (14, 17))	('growth arrest', 'Disease', 'MESH:D006323', (26, 39))	('growth arrest', 'Disease', (26, 39))	('p53', 'Gene', '7157', (14, 17))	('transactivation', 'Var', (55, 70))	('p21', 'Gene', (74, 77))	('growth arrest', 'Phenotype', 'HP:0001510', (26, 39))	('transactivation', 'biological_process', 'GO:2000144', ('55', '70'))	('p21', 'Gene', '644914', (74, 77))
16109	24624093	However, mutated p53 is unable to bind DNA, p21 is not available, and abnormal and deregulated growth occurs as a result.	('abnormal and deregulated growth', 'Phenotype', 'HP:0001507', (70, 101))	('p21', 'Gene', '644914', (44, 47))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('mutated', 'Var', (9, 16))	('p21', 'Gene', (44, 47))	('p53', 'Gene', (17, 20))	('growth', 'CPA', (95, 101))	('unable', 'NegReg', (24, 30))	('p53', 'Gene', '7157', (17, 20))
16115	24624093	Loss of SMAD4 interferes with the intracellular signaling cascades downstream from TGF-beta, resulting in decreased growth inhibition via loss of pro-apoptotic signaling or via inappropriate G1/S transition (Koorstra et al.,).	('decreased', 'NegReg', (106, 115))	('intracellular', 'cellular_component', 'GO:0005622', ('34', '47'))	('loss', 'NegReg', (138, 142))	('TGF-beta', 'Gene', (83, 91))	('SMAD4', 'Gene', (8, 13))	('interferes', 'NegReg', (14, 24))	('G1/S transition', 'CPA', (191, 206))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('growth inhibition', 'CPA', (116, 133))	('decreased growth', 'Phenotype', 'HP:0001510', (106, 122))	('signaling', 'biological_process', 'GO:0023052', ('160', '169'))	('SMAD4', 'Gene', '4089', (8, 13))	('TGF-beta', 'Gene', '7040', (83, 91))	('Loss', 'Var', (0, 4))	('pro-apoptotic signaling', 'MPA', (146, 169))
16121	24624093	This is particularly useful since PDAC with loss of Smad4 reportedly demonstrate an increased propensity for distant metastases and thus have a generally poorer prognosis, although SMAD4 gene status is not yet utilized for prognostic stratification (Schneider and Schmid,; Blackford et al.,).	('SMAD4', 'Gene', '4089', (181, 186))	('PDAC', 'Chemical', '-', (34, 38))	('Smad4', 'Gene', (52, 57))	('Smad4', 'Gene', '4089', (52, 57))	('metastases', 'Disease', 'MESH:D009362', (117, 127))	('PDAC', 'Phenotype', 'HP:0006725', (34, 38))	('SMAD4', 'Gene', (181, 186))	('loss', 'Var', (44, 48))	('metastases', 'Disease', (117, 127))
16125	24624093	Inactivation of the STK11 gene appears to play a role in both hereditary and sporadic PDAC (Schneider and Schmid,; Hezel et al.,).	('role', 'Reg', (49, 53))	('STK11', 'Gene', (20, 25))	('STK11', 'molecular_function', 'GO:0033868', ('20', '25'))	('PDAC', 'Chemical', '-', (86, 90))	('STK11', 'Gene', '6794', (20, 25))	('sporadic PDAC', 'Disease', (77, 90))	('play', 'Reg', (42, 46))	('Inactivation', 'Var', (0, 12))	('PDAC', 'Phenotype', 'HP:0006725', (86, 90))
16126	24624093	Germline mutations in this gene are associated with PJS and are identified in approximately 50% of PJS families who typically present with hamartomatous polyps of the GI tract, pigmented macules of the lips and buccal mucosa, as well as a 36% lifetime risk for the development of pancreatic cancer (>40-fold increased RR) (Giardiello et al.,; Sato et al.,; Hahn et al.,; Hezel et al.,).	('hamartomatous polyps of the GI tract', 'Disease', (139, 175))	('Germline mutations', 'Var', (0, 18))	('men', 'Species', '9606', (272, 275))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (280, 297))	('macules', 'Phenotype', 'HP:0012733', (187, 194))	('polyps of the GI tract', 'Phenotype', 'HP:0200008', (153, 175))	('men', 'Species', '9606', (180, 183))	('hamartomatous polyps of the GI tract', 'Disease', 'MESH:D011127', (139, 175))	('pancreatic cancer', 'Disease', (280, 297))	('hamartomatous polyps', 'Phenotype', 'HP:0004390', (139, 159))	('pancreatic cancer', 'Disease', 'MESH:D010190', (280, 297))	('associated', 'Reg', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))
16127	24624093	Somatic STK11 mutations have been observed in approximately 5% of sporadic PDAC, particularly those that arise in association within an IPMN, whereas loss of heterozygosity is seen in approximately 25% of patients with IPMN who lack PJS features (Sato et al.,; Hezel et al.,).	('patients', 'Species', '9606', (205, 213))	('STK11', 'Gene', '6794', (8, 13))	('PDAC', 'Disease', (75, 79))	('PDAC', 'Phenotype', 'HP:0006725', (75, 79))	('PDAC', 'Chemical', '-', (75, 79))	('STK11', 'molecular_function', 'GO:0033868', ('8', '13'))	('observed', 'Reg', (34, 42))	('mutations', 'Var', (14, 23))	('STK11', 'Gene', (8, 13))
16128	24624093	In a smaller percentage of PDAC, intragenic mutations and homozygous deletions of the MKK4 gene are noted.	('PDAC', 'Chemical', '-', (27, 31))	('MKK4', 'molecular_function', 'GO:0004708', ('86', '90'))	('deletions', 'Var', (69, 78))	('PDAC', 'Phenotype', 'HP:0006725', (27, 31))	('MKK4', 'Gene', (86, 90))	('PDAC', 'Disease', (27, 31))	('MKK4', 'Gene', '6416', (86, 90))
16140	24624093	In a retrospective analysis by Brunner et al, the combination of 5-fluorouracil and mitomycin C-based chemoradiotherapy demonstrated worse median overall survival (9.7 vs. 12.7 months) and 1 year overall survival (53 vs. 40%) compared to gemcitabine and cisplatin-based chemoradiotherapy in patients with locally advanced PDAC with similar toxicities.	('mitomycin C', 'Chemical', 'MESH:D016685', (84, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (254, 263))	('overall survival', 'MPA', (146, 162))	('mitomycin', 'Var', (84, 93))	('PDAC', 'Phenotype', 'HP:0006725', (322, 326))	('toxicities', 'Disease', 'MESH:D064420', (340, 350))	('patients', 'Species', '9606', (291, 299))	('gemcitabine', 'Chemical', 'MESH:C056507', (238, 249))	('worse', 'NegReg', (133, 138))	('PDAC', 'Chemical', '-', (322, 326))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (65, 79))	('overall', 'MPA', (196, 203))	('toxicities', 'Disease', (340, 350))
16143	24624093	Poly (ADP-ribose) polymerase-1/2 (PARP-1/2) activity and poly (ADP-ribose) polymerization are essential for the repair of single stranded (SS)-DNA breaks through the base excision repair (BER) pathways (Bryant et al.,).	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('Poly (ADP-ribose) polymerase-1/2', 'Gene', '64761;142;10038', (0, 32))	('BER', 'biological_process', 'GO:0006284', ('188', '191'))	('single stranded', 'Var', (122, 137))	('PARP-1/2', 'Gene', '64761;142;10038', (34, 42))	('PARP-1/2', 'Gene', (34, 42))	('base excision repair', 'biological_process', 'GO:0006284', ('166', '186'))
16146	24624093	Inhibition of PARP is therefore known to sensitize tumor cells to cytotoxic agents, such as topoisomerase-I inhibitors and alkylators, which induce DNA damage normally repaired by BER.	('sensitize', 'Reg', (41, 50))	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('PARP', 'Gene', (14, 18))	('topoisomerase', 'molecular_function', 'GO:0003917', ('92', '105'))	('Inhibition', 'Var', (0, 10))	('BER', 'biological_process', 'GO:0006284', ('180', '183'))	('topoisomerase', 'molecular_function', 'GO:0003918', ('92', '105'))	('PARP', 'Gene', '142', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('DNA', 'MPA', (148, 151))
16147	24624093	The resulting increase in HR repair that occurs in PARP-1 deficient mice is felt to represent an error-free mechanism, which likely explains why the genetic instability in PARP-1 deficient cells is not associated with accumulation of mutations or cancers (Bryant et al.,).	('mice', 'Species', '10090', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('HR repair', 'MPA', (26, 35))	('deficient', 'Var', (179, 188))	('deficient', 'Var', (58, 67))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancers', 'Disease', (247, 254))	('PARP-1', 'Gene', (172, 178))	('increase', 'PosReg', (14, 22))
16148	24624093	BRCA2 and other Fanconi Anemia-pathway defective cells are felt to be sensitive to single-agent PARP inhibition and restoring functional BRCA abrogates this activity.	('BRCA2', 'Gene', '675', (0, 5))	('BRCA', 'Gene', (137, 141))	('abrogates', 'NegReg', (142, 151))	('BRCA', 'Gene', (0, 4))	('Anemia', 'Phenotype', 'HP:0001903', (24, 30))	('PARP', 'Gene', (96, 100))	('Fanconi Anemia', 'Phenotype', 'HP:0001994', (16, 30))	('PARP', 'Gene', '142', (96, 100))	('BRCA2', 'Gene', (0, 5))	('restoring', 'Var', (116, 125))	('Fanconi Anemia', 'Disease', (16, 30))	('Fanconi Anemia', 'Disease', 'MESH:D005199', (16, 30))	('BRCA', 'Gene', '672', (137, 141))	('Fanconi Anemia-', 'Phenotype', 'HP:0001994', (16, 31))	('BRCA', 'Gene', '672', (0, 4))
16149	24624093	Bryant et al demonstrated that PARP inhibitors were profoundly cytotoxic to a BRCA2-deficient cell line at low concentrations relative to BRCA2-competent cells and normal cells, thus suggesting potential for a wide therapeutic index (Bryant et al.,).	('BRCA2-deficient', 'Disease', 'MESH:C564499', (78, 93))	('PARP', 'Gene', '142', (31, 35))	('BRCA2', 'Gene', '675', (138, 143))	('inhibitors', 'Var', (36, 46))	('cytotoxic', 'NegReg', (63, 72))	('BRCA2', 'Gene', (78, 83))	('PARP', 'Gene', (31, 35))	('BRCA2-deficient', 'Disease', (78, 93))	('BRCA2', 'Gene', (138, 143))	('BRCA2', 'Gene', '675', (78, 83))
16150	24624093	Whereas clonogenic survival was significantly reduced following PARP-1 and BRCA2 protein co-depletion in human cells using siRNA, depletion of PARP-2 with BRCA2 had no effect on clonogenic survival following treatment with PARP inhibitors.	('BRCA2', 'Gene', '675', (155, 160))	('human', 'Species', '9606', (105, 110))	('BRCA2', 'Gene', '675', (75, 80))	('depletion', 'Var', (130, 139))	('clonogenic survival', 'CPA', (8, 27))	('men', 'Species', '9606', (213, 216))	('PARP', 'Gene', '142', (64, 68))	('PARP', 'Gene', '142', (143, 147))	('reduced', 'NegReg', (46, 53))	('PARP', 'Gene', '142', (223, 227))	('BRCA2', 'Gene', (155, 160))	('PARP', 'Gene', (64, 68))	('PARP', 'Gene', (143, 147))	('PARP-2', 'Gene', '10038', (143, 149))	('BRCA2', 'Gene', (75, 80))	('PARP', 'Gene', (223, 227))	('co-depletion', 'Var', (89, 101))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('PARP-2', 'Gene', (143, 149))	('protein', 'Protein', (81, 88))
16154	24624093	Preclinical studies have demonstrated the potential effectiveness of PARP inhibitors in targeting pancreatic cancers demonstrating biallelic inactivation of the ATM gene and clinical trials are underway investigating the role of PARP-inhibition with DNA damaging agents in patients with or without BRCA-mutations (NCT01908478, NCT01585805) (Williamson et al.,).	('BRCA', 'Gene', (298, 302))	('NCT01908478', 'Var', (314, 325))	('PARP', 'Gene', '142', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('patients', 'Species', '9606', (273, 281))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (98, 115))	('pancreatic cancers', 'Disease', (98, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('PARP', 'Gene', '142', (229, 233))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (98, 116))	('pancreatic cancers', 'Disease', 'MESH:D010190', (98, 116))	('ATM', 'Gene', (161, 164))	('ATM', 'Gene', '472', (161, 164))	('PARP', 'Gene', (69, 73))	('BRCA', 'Gene', '672', (298, 302))	('DNA', 'cellular_component', 'GO:0005574', ('250', '253'))	('PARP', 'Gene', (229, 233))
16167	24624093	As noted previously, tumors with oncogenic KRAS are often associated with relative drug resistance and poor prognosis (Hezel et al.,; Barbie et al.,).	('oncogenic KRAS', 'Var', (33, 47))	('drug resistance', 'Phenotype', 'HP:0020174', (83, 98))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Disease', (21, 27))	('drug resistance', 'biological_process', 'GO:0009315', ('83', '98'))	('relative drug resistance', 'MPA', (74, 98))	('drug resistance', 'biological_process', 'GO:0042493', ('83', '98'))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
16168	24624093	Thus, the combination of oncogenic KRAS mutation with PTEN-deficiency seen in PDAC promote NF-kB activation and sustained activity of the NF-kB downstream cytokine pathway.	('mutation', 'Var', (40, 48))	('KRAS', 'Gene', (35, 39))	('activation', 'PosReg', (97, 107))	('PTEN-deficiency', 'Disease', (54, 69))	('PDAC', 'Phenotype', 'HP:0006725', (78, 82))	('NF-kB', 'Protein', (91, 96))	('PTEN-deficiency', 'Disease', 'MESH:D006223', (54, 69))	('PDAC', 'Chemical', '-', (78, 82))	('promote', 'PosReg', (83, 90))	('NF-kB downstream cytokine pathway', 'Pathway', (138, 171))	('activity', 'MPA', (122, 130))
16190	24624093	Furthermore, the effect of erlotinib may also potentially be due to inhibition of proangiogenic factors (VEGF, IL-8) by EGFR inhibitors, given that activation of the EGF receptor on tumor cells is known to induce the production of VEGF (Bruns et al.,; Li et al.,; Ducreux et al.,).	('IL-8', 'Gene', (111, 115))	('VEGF', 'MPA', (231, 235))	('EGFR', 'molecular_function', 'GO:0005006', ('120', '124'))	('IL-8', 'molecular_function', 'GO:0005153', ('111', '115'))	('tumor', 'Disease', (182, 187))	('EGF', 'molecular_function', 'GO:0005154', ('166', '169'))	('IL-8', 'Gene', '3576', (111, 115))	('inhibition', 'NegReg', (68, 78))	('EGFR', 'Gene', '1956', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('inhibitors', 'Var', (125, 135))	('erlotinib', 'Chemical', 'MESH:D000069347', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('EGFR', 'Gene', (120, 124))
16193	24624093	A phase III study investigated the addition of cetuximab to gemcitabine in an unselected patient population (not selected for presence of EGFR mutations) and found no significant improvement in overall or progression-free survival observed relative to gemcitabine alone (Ducreux et al.,; Philip et al.,).	('gemcitabine', 'Chemical', 'MESH:C056507', (60, 71))	('patient', 'Species', '9606', (89, 96))	('EGFR', 'Gene', '1956', (138, 142))	('EGFR', 'molecular_function', 'GO:0005006', ('138', '142'))	('EGFR', 'Gene', (138, 142))	('men', 'Species', '9606', (186, 189))	('cetuximab', 'Chemical', 'MESH:D000068818', (47, 56))	('gemcitabine', 'Chemical', 'MESH:C056507', (252, 263))	('mutations', 'Var', (143, 152))
16209	24624093	Furthermore, in a particular PDAC cell line, aberrant expression and activation of IGF-IR via paracrine and autocrine IGF-I signaling was noted to promote cell proliferation and growth-factor-independent survival (Nair et al.,).	('PDAC', 'Phenotype', 'HP:0006725', (29, 33))	('IGF-I', 'Gene', (118, 123))	('promote', 'PosReg', (147, 154))	('signaling', 'biological_process', 'GO:0023052', ('124', '133'))	('aberrant expression', 'Var', (45, 64))	('cell proliferation', 'CPA', (155, 173))	('IGF-I', 'Gene', '3479', (83, 88))	('IGF-IR', 'Gene', '3480', (83, 89))	('PDAC', 'Chemical', '-', (29, 33))	('IGF-IR', 'Gene', (83, 89))	('growth-factor-independent survival', 'CPA', (178, 212))	('IGF-I', 'Gene', '3479', (118, 123))	('IGF-I', 'Gene', (83, 88))	('cell proliferation', 'biological_process', 'GO:0008283', ('155', '173'))	('activation', 'PosReg', (69, 79))
16216	24624093	This would include patients with FPC or carriers of a mutation in an established high-penetrance PDAC susceptibility gene (e.g., BRCA2 or PALB2) with at least one case of pancreatic cancer in a first-degree relative (Brand et al.,; Bartsch et al.,; Klein,; Canto et al.,).	('FPC', 'Disease', 'MESH:D011125', (33, 36))	('mutation', 'Var', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('patients', 'Species', '9606', (19, 27))	('PDAC', 'Phenotype', 'HP:0006725', (97, 101))	('BRCA2', 'Gene', (129, 134))	('PDAC', 'Chemical', '-', (97, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (171, 188))	('FPC', 'cellular_component', 'GO:1990900', ('33', '36'))	('BRCA2', 'Gene', '675', (129, 134))	('PALB2', 'Gene', '79728', (138, 143))	('pancreatic cancer', 'Disease', (171, 188))	('PALB2', 'Gene', (138, 143))	('pancreatic cancer', 'Disease', 'MESH:D010190', (171, 188))	('FPC', 'Disease', (33, 36))
16220	24624093	These high-risk candidates for screening include first degree relatives of patients with PDAC from familial kindred with at least two affected first-degree relatives, patients with PJS, and carriers of p16, BRCA2, or HNPCC mutations with at least one affected first-degree relative.	('HNPCC', 'Disease', 'None', (217, 222))	('HNPCC', 'Disease', (217, 222))	('PDAC', 'Chemical', '-', (89, 93))	('BRCA2', 'Gene', (207, 212))	('patients', 'Species', '9606', (75, 83))	('patients', 'Species', '9606', (167, 175))	('p16', 'Gene', (202, 205))	('PDAC', 'Phenotype', 'HP:0006725', (89, 93))	('BRCA2', 'Gene', '675', (207, 212))	('HNPCC', 'Phenotype', 'HP:0006716', (217, 222))	('mutations', 'Var', (223, 232))	('p16', 'Gene', '1029', (202, 205))
16227	24130864	Mutations of the KRAS oncogene occur frequently in pancreatic cancer and represent an attractive target.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('pancreatic cancer', 'Disease', (51, 68))	('pancreatic cancer', 'Disease', 'MESH:D010190', (51, 68))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (17, 21))	('KRAS', 'Gene', '3845', (17, 21))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (51, 68))
16230	24130864	We investigated the combined effect of the PI3K inhibitor, GDC0941, and the MEK inhibitor, AZD6244, on cell viability, apoptosis and cell signaling in a panel of pancreatic cancer cell lines.	('GDC0941', 'Var', (59, 66))	('PI3', 'Gene', '5266', (43, 46))	('GDC0941', 'Chemical', 'MESH:C532162', (59, 66))	('pancreatic cancer', 'Disease', (162, 179))	('signaling', 'biological_process', 'GO:0023052', ('138', '147'))	('apoptosis', 'biological_process', 'GO:0097194', ('119', '128'))	('PI3K', 'molecular_function', 'GO:0016303', ('43', '47'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (162, 179))	('MEK', 'Gene', (76, 79))	('AZD6244', 'Chemical', 'MESH:C517975', (91, 98))	('PI3', 'Gene', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('apoptosis', 'biological_process', 'GO:0006915', ('119', '128'))	('MEK', 'Gene', '5609', (76, 79))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (162, 179))
16232	24130864	While BxPC-3 (KRAS wild type) and MIA PaCa-2 (KRAS mutated) cell lines were sensitive to GDC0941 and AZD6244 as single agents, synergistic inhibition of tumor cell growth and induction of apoptosis were observed in both cell lines when the two drugs were combined.	('cell growth', 'biological_process', 'GO:0016049', ('159', '170'))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (34, 44))	('KRAS', 'Gene', '3845', (14, 18))	('AZD6244', 'Chemical', 'MESH:C517975', (101, 108))	('KRAS', 'Gene', (46, 50))	('apoptosis', 'CPA', (188, 197))	('KRAS', 'Gene', '3845', (46, 50))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('GDC0941', 'Var', (89, 96))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('175', '197'))	('KRAS', 'Gene', (14, 18))	('GDC0941', 'Chemical', 'MESH:C532162', (89, 96))	('BxPC-3', 'CellLine', 'CVCL:0186', (6, 12))
16233	24130864	Interestingly, phosphorylation of the cap-dependent translational components, 4E-binding protein (p-4E-BP1) and S6 was found to be closely associated with sensitivity to GDC0941 and AZD6244.	('phosphorylation', 'MPA', (15, 30))	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('cap', 'Chemical', '-', (38, 41))	('sensitivity', 'MPA', (155, 166))	('GDC0941', 'Var', (170, 177))	('4E-BP1', 'Gene', '1978', (100, 106))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('associated', 'Reg', (139, 149))	('GDC0941', 'Chemical', 'MESH:C532162', (170, 177))	('AZD6244', 'Var', (182, 189))	('AZD6244', 'Chemical', 'MESH:C517975', (182, 189))	('phosphorylation', 'biological_process', 'GO:0016310', ('15', '30'))	('4E-BP1', 'Gene', (100, 106))
16234	24130864	In BxPC-3 cell xenografts, survival differences were observed between the control and the AZD6244, GDC0941, and combination groups.	('AZD6244', 'Chemical', 'MESH:C517975', (90, 97))	('survival differences', 'CPA', (27, 47))	('BxPC-3', 'CellLine', 'CVCL:0186', (3, 9))	('GDC0941', 'Chemical', 'MESH:C532162', (99, 106))	('AZD6244', 'Var', (90, 97))
16235	24130864	Our study provides the rationale for concurrent targeting of the PI3K and MEK pathways, regardless of KRAS status, and suggests that phosphorylation of 4E-BP1and S6 can serve as a predictive biomarker for response to treatment.	('MEK', 'Gene', '5609', (74, 77))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('4E-BP1', 'Gene', (152, 158))	('PI3', 'Gene', '5266', (65, 68))	('phosphorylation', 'Var', (133, 148))	('phosphorylation', 'biological_process', 'GO:0016310', ('133', '148'))	('men', 'Species', '9606', (222, 225))	('KRAS', 'Gene', (102, 106))	('4E-BP1', 'Gene', '1978', (152, 158))	('KRAS', 'Gene', '3845', (102, 106))	('PI3', 'Gene', (65, 68))	('MEK', 'Gene', (74, 77))
16241	24130864	The presence of a KRAS mutation is seen in 30% of premalignant lesions and in up to 90% of pancreatic cancer tumor specimens, suggesting that the KRAS mutation is the predominant known feature of pancreatic cancer molecular pathogenesis.	('pancreatic cancer', 'Disease', (196, 213))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('KRAS', 'Gene', (146, 150))	('KRAS', 'Gene', (18, 22))	('pancreatic cancer', 'Disease', 'MESH:D010190', (196, 213))	('mutation', 'Var', (23, 31))	('KRAS', 'Gene', '3845', (146, 150))	('KRAS', 'Gene', '3845', (18, 22))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('pancreatic cancer tumor', 'Disease', 'MESH:D010190', (91, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (196, 213))	('men', 'Species', '9606', (120, 123))	('pathogenesis', 'biological_process', 'GO:0009405', ('224', '236'))	('pancreatic cancer tumor', 'Disease', (91, 114))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))
16243	24130864	Mutated KRAS results in constant activation of the RAS pathway by locking RAS into the active GTP-binding state and further triggering multiple downstream signaling pathways including cell proliferation, apoptosis, differentiation, and survival.	('survival', 'CPA', (236, 244))	('GTP-binding', 'molecular_function', 'GO:0005525', ('94', '105'))	('activation', 'PosReg', (33, 43))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('KRAS', 'Gene', (8, 12))	('apoptosis', 'biological_process', 'GO:0097194', ('204', '213'))	('GTP', 'Chemical', 'MESH:D006160', (94, 97))	('apoptosis', 'biological_process', 'GO:0006915', ('204', '213'))	('KRAS', 'Gene', '3845', (8, 12))	('cell proliferation', 'CPA', (184, 202))	('differentiation', 'CPA', (215, 230))	('RAS pathway', 'Pathway', (51, 62))	('triggering', 'Reg', (124, 134))	('Mutated', 'Var', (0, 7))	('cell proliferation', 'biological_process', 'GO:0008283', ('184', '202'))	('apoptosis', 'CPA', (204, 213))
16245	24130864	This is hardly the case in KRAS downstream pathways, illustrated by the exceedingly low incidence of PIK3CA or BRAF mutations in pancreatic tumors.	('PIK3CA', 'Gene', '5290', (101, 107))	('KRAS', 'Gene', '3845', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('mutations', 'Var', (116, 125))	('pancreatic tumors', 'Disease', 'MESH:D010190', (129, 146))	('BRAF', 'Gene', '673', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('pancreatic tumors', 'Disease', (129, 146))	('KRAS', 'Gene', (27, 31))	('BRAF', 'Gene', (111, 115))	('PIK3CA', 'Gene', (101, 107))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (129, 146))
16250	24130864	GDC0941 has shown promising anti-tumor activity in the preclinical setting, and it is currently being tested in early phase clinical trials.	('GDC0941', 'Var', (0, 7))	('GDC0941', 'Chemical', 'MESH:C532162', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))
16251	24130864	AZD6244 is a potent, selective secondary generation MEK1/2 inhibitor, which inhibits MAPK/ERK in an ATP-uncompetitive fashion.	('ERK', 'Gene', (90, 93))	('MEK1/2', 'Gene', '5604;5605', (52, 58))	('MEK1/2', 'Gene', (52, 58))	('MAPK', 'molecular_function', 'GO:0004707', ('85', '89'))	('inhibits', 'NegReg', (76, 84))	('ATP', 'Chemical', 'MESH:D000255', (100, 103))	('ERK', 'molecular_function', 'GO:0004707', ('90', '93'))	('AZD6244', 'Chemical', 'MESH:C517975', (0, 7))	('MEK1', 'molecular_function', 'GO:0004708', ('52', '56'))	('AZD6244', 'Var', (0, 7))	('ERK', 'Gene', '5594', (90, 93))
16252	24130864	Along with other MEK inhibitors, AZD6422 is currently in early phase clinical trials.	('MEK', 'Gene', (17, 20))	('MEK', 'Gene', '5609', (17, 20))	('AZD6422', 'Chemical', '-', (33, 40))	('AZD6422', 'Var', (33, 40))
16261	24130864	Cell lines were treated with GDC0941, AZD6244 or a combination of GDC0941 and AZD6244, and the number of viable cells was used to calculate the CI values using CalcuSyn software (Biosoft, Cambridge, United Kingdom).	('GDC0941', 'Chemical', 'MESH:C532162', (66, 73))	('AZD6244', 'Var', (78, 85))	('GDC0941', 'Var', (29, 36))	('GDC0941', 'Chemical', 'MESH:C532162', (29, 36))	('AZD6244', 'Chemical', 'MESH:C517975', (78, 85))	('AZD6244', 'Var', (38, 45))	('AZD6244', 'Chemical', 'MESH:C517975', (38, 45))	('GDC0941', 'Var', (66, 73))
16262	24130864	Cells were then treated with various concentrations of GDC0941, AZD6244 or a combination of GDC0941 and AZD6244 for 72 hours.	('AZD6244', 'Chemical', 'MESH:C517975', (104, 111))	('GDC0941', 'Var', (55, 62))	('GDC0941', 'Chemical', 'MESH:C532162', (55, 62))	('AZD6244', 'Var', (64, 71))	('AZD6244', 'Chemical', 'MESH:C517975', (64, 71))	('GDC0941', 'Var', (92, 99))	('GDC0941', 'Chemical', 'MESH:C532162', (92, 99))
16266	24130864	When cells became 70-80% confluent, they were incubated with GDC0941, AZD6244 or both GDC0941 and AZD6244 for 24 hours.	('GDC0941', 'Var', (86, 93))	('AZD6244', 'Chemical', 'MESH:C517975', (70, 77))	('GDC0941', 'Chemical', 'MESH:C532162', (86, 93))	('AZD6244', 'Var', (98, 105))	('AZD6244', 'Chemical', 'MESH:C517975', (98, 105))	('AZD6244', 'Var', (70, 77))	('GDC0941', 'Var', (61, 68))	('GDC0941', 'Chemical', 'MESH:C532162', (61, 68))
16271	24130864	Primary antibodies included anti-phospho-AKT (Ser473), anti-Akt, anti-phospho-ERK (T202/Y204), anti-ERK, anti-phospho-S6 (S240/244), anti-S6, anti-phospho-4E-BP1(S65) and anti-4E-BP1 (Cell Signaling Technology, Beverly, MA, USA).	('4E-BP1', 'Gene', (176, 182))	('anti-phospho-S6 (S240/244', 'Var', (105, 130))	('AKT', 'Gene', '207', (41, 44))	('Ser', 'cellular_component', 'GO:0005790', ('46', '49'))	('ERK', 'molecular_function', 'GO:0004707', ('78', '81'))	('Akt', 'Gene', (60, 63))	('T202/Y204', 'Var', (83, 92))	('4E-BP1', 'Gene', '1978', (155, 161))	('Signaling', 'biological_process', 'GO:0023052', ('189', '198'))	('Akt', 'Gene', '207', (60, 63))	('ERK', 'Gene', '5594', (78, 81))	('4E-BP1', 'Gene', '1978', (176, 182))	('ERK', 'Gene', '5594', (100, 103))	('ERK', 'molecular_function', 'GO:0004707', ('100', '103'))	('AKT', 'Gene', (41, 44))	('4E-BP1', 'Gene', (155, 161))	('Ser473', 'Var', (46, 52))	('Ser473', 'Chemical', '-', (46, 52))	('ERK', 'Gene', (78, 81))	('anti-S6', 'Var', (133, 140))	('ERK', 'Gene', (100, 103))
16277	24130864	Mice that developed tumors reaching 100-150 mm3 in size were randomized into the following four groups with 8 mice in each group: vehicle, GDC0941, AZD6244, or the combination treatment.	('tumors', 'Disease', (20, 26))	('AZD6244', 'Var', (148, 155))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('AZD6244', 'Chemical', 'MESH:C517975', (148, 155))	('mice', 'Species', '10090', (110, 114))	('GDC0941', 'Var', (139, 146))	('GDC0941', 'Chemical', 'MESH:C532162', (139, 146))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('men', 'Species', '9606', (181, 184))
16285	24130864	BxPC-3 is a KRAS wild type pancreatic cancer cell line, while the other three cell lines harbor the KRAS mutation.	('KRAS', 'Gene', (100, 104))	('mutation', 'Var', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('KRAS', 'Gene', '3845', (100, 104))	('pancreatic cancer', 'Disease', (27, 44))	('pancreatic cancer', 'Disease', 'MESH:D010190', (27, 44))	('KRAS', 'Gene', (12, 16))	('KRAS', 'Gene', '3845', (12, 16))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (27, 44))	('BxPC-3', 'CellLine', 'CVCL:0186', (0, 6))
16289	24130864	The concentrations of GDC0941 resulting in 50% inhibition of cell viability (IC50) after 72 hours exposure were 376.4 nM in BxPC-3 cells and 754.6 nM in MIA PaCa-2 cells (Figure 1A).	('754.6 nM', 'Var', (141, 149))	('BxPC-3', 'CellLine', 'CVCL:0186', (124, 130))	('inhibition', 'NegReg', (47, 57))	('GDC0941', 'Gene', (22, 29))	('GDC0941', 'Chemical', 'MESH:C532162', (22, 29))	('cell viability', 'CPA', (61, 75))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (153, 163))	('376.4 nM', 'Var', (112, 120))
16290	24130864	AZD6244 alone also suppressed cell growth with an IC50 value of 599 nM and 375 nM in BxPC-3 and MIA PaCa-2 cells, respectively (Figure 1B).	('cell growth', 'biological_process', 'GO:0016049', ('30', '41'))	('suppressed', 'NegReg', (19, 29))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (96, 106))	('cell growth', 'CPA', (30, 41))	('BxPC-3', 'CellLine', 'CVCL:0186', (85, 91))	('AZD6244', 'Var', (0, 7))	('AZD6244', 'Chemical', 'MESH:C517975', (0, 7))
16292	24130864	We did observe a slight increase in PANC-1 cell growth with GDC0941at 1nM, 10nM, and 100nM, but changes were not statistically significant (control vs 1 nM, p=0.32, control vs 10 nM, p=0.17, control vs 100 nM, p=0.22).	('increase', 'PosReg', (24, 32))	('GDC0941at', 'Chemical', '-', (60, 69))	('PANC-1', 'CellLine', 'CVCL:0480', (36, 42))	('PANC-1 cell growth', 'CPA', (36, 54))	('GDC0941at', 'Var', (60, 69))	('cell growth', 'biological_process', 'GO:0016049', ('43', '54'))
16293	24130864	In addition, we compared control vs 1 nM AZD6244 in PANC-1 and MIA PaCa-2 cells, and no significant differences were observed (p=0.20, p=0.64, respectively) The anti-proliferative effect of combining a PI3K and MEK inhibitor was measured in BxPC-3 and MIA PaCa-2 cells by calculating the combination index (CI) according to the Chou-Talalay method (20) using a fixed dose ratio.	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (252, 262))	('BxPC-3', 'CellLine', 'CVCL:0186', (241, 247))	('AZD6244', 'Var', (41, 48))	('anti-proliferative effect', 'CPA', (161, 186))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (63, 73))	('PI3', 'Gene', '5266', (202, 205))	('PI3K', 'molecular_function', 'GO:0016303', ('202', '206'))	('PI3', 'Gene', (202, 205))	('MEK', 'Gene', (211, 214))	('PANC-1', 'CellLine', 'CVCL:0480', (52, 58))	('MEK', 'Gene', '5609', (211, 214))	('AZD6244', 'Chemical', 'MESH:C517975', (41, 48))
16294	24130864	Both GDC0941and AZD6244 were introduced to cell cultures at 0.25x, 0.5x, 1x, 2x and 4x their respective IC50s in the BxPC-3 and MIA PaCa-2 cell lines.	('GDC0941and', 'Chemical', '-', (5, 15))	('AZD6244', 'Var', (16, 23))	('AZD6244', 'Chemical', 'MESH:C517975', (16, 23))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (128, 138))	('GDC0941and', 'Var', (5, 15))	('50s', 'Species', '1214577', (106, 109))	('BxPC-3', 'CellLine', 'CVCL:0186', (117, 123))
16297	24130864	For the BxPC-3 cell line the following CI values were obtained: 0.4101 (ED50), 0.0112 (ED75) and 0.0003 (ED90).	('0.0112', 'Var', (79, 85))	('BxPC-3', 'CellLine', 'CVCL:0186', (8, 14))	('0.4101', 'Var', (64, 70))	('0.0003', 'Var', (97, 103))
16298	24130864	For the MIA PaCa-2 cell line the CI values were 0.02052 (ED50), 0.0295 (ED75) and 0.0440 (ED95).	('0.0295', 'Var', (64, 70))	('0.0440', 'Var', (82, 88))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (8, 18))	('0.02052', 'Var', (48, 55))
16299	24130864	The CI results suggested that GDC0941 and AZD6244 worked synergistically to produce an anti-proliferative effect in the BxPC-3 and MIA PaCa-2 cell lines (Figure 2A-B).	('AZD6244', 'Chemical', 'MESH:C517975', (42, 49))	('AZD6244', 'Var', (42, 49))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (131, 141))	('GDC0941', 'Var', (30, 37))	('BxPC-3', 'CellLine', 'CVCL:0186', (120, 126))	('GDC0941', 'Chemical', 'MESH:C532162', (30, 37))	('anti-proliferative effect', 'MPA', (87, 112))
16300	24130864	Interestingly, while GDC0941 or AZD6244 alone did not impact PANC-1 and Capan-2 cell growth, administration of these two drugs in combination mildly inhibited cell growth.	('GDC0941', 'Chemical', 'MESH:C532162', (21, 28))	('cell growth', 'CPA', (159, 170))	('cell growth', 'biological_process', 'GO:0016049', ('159', '170'))	('AZD6244', 'Chemical', 'MESH:C517975', (32, 39))	('cell growth', 'biological_process', 'GO:0016049', ('80', '91'))	('PANC-1', 'CellLine', 'CVCL:0480', (61, 67))	('Capan-2', 'CellLine', 'CVCL:0026', (72, 79))	('inhibited', 'NegReg', (149, 158))	('GDC0941', 'Var', (21, 28))
16304	24130864	AZD6244 alone at 600 nM and 2,400 nM increased the apoptosis rate of BxPC-3 cells to 26.5% and 27.2%, respectively (p<0.05, AZD6244 alone vs untreated group).	('BxPC-3', 'CellLine', 'CVCL:0186', (69, 75))	('AZD6244', 'Chemical', 'MESH:C517975', (124, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('AZD6244', 'Var', (0, 7))	('AZD6244', 'Chemical', 'MESH:C517975', (0, 7))	('apoptosis rate', 'CPA', (51, 65))
16305	24130864	A combination of GDC0941 and AZD6244 resulted in a much higher rate of apoptosis in BxPC-3 cells compared with the control group or inhibitor alone.	('GDC0941', 'Chemical', 'MESH:C532162', (17, 24))	('apoptosis', 'CPA', (71, 80))	('BxPC-3', 'CellLine', 'CVCL:0186', (84, 90))	('AZD6244', 'Var', (29, 36))	('AZD6244', 'Chemical', 'MESH:C517975', (29, 36))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('GDC0941', 'Var', (17, 24))
16306	24130864	The combination of GDC0941 at 380 nM and AZD6244 at 600 nM or the combination of GDC0941 at 1,520 nM and AZD6244 at 2,400 nM increased the BxPC-3 cell apoptosis rate to 63.3% and 82.8% respectively (p<0.05, combination vs. untreated group or single agent alone) (Figure 3A).	('increased', 'PosReg', (125, 134))	('apoptosis', 'biological_process', 'GO:0097194', ('151', '160'))	('BxPC-3', 'CellLine', 'CVCL:0186', (139, 145))	('apoptosis', 'biological_process', 'GO:0006915', ('151', '160'))	('BxPC-3 cell apoptosis rate', 'CPA', (139, 165))	('AZD6244', 'Var', (105, 112))	('AZD6244', 'Chemical', 'MESH:C517975', (105, 112))	('GDC0941', 'Var', (19, 26))	('GDC0941', 'Var', (81, 88))	('GDC0941', 'Chemical', 'MESH:C532162', (81, 88))	('AZD6244', 'Var', (41, 48))	('GDC0941', 'Chemical', 'MESH:C532162', (19, 26))	('AZD6244', 'Chemical', 'MESH:C517975', (41, 48))
16309	24130864	The combination of GDC0941 at 400 nM and AZD6244 at 200 nM or the combination of GDC0941 at 1,600 nM and AZD6244 at 800 nM increased the MIA PaCa-2 apoptosis rate to 49.5% and 55.6%, respectively, and this was a statistically significant difference compared to the untreated group or single agent alone (p<0.05) (Figure 3B).	('increased', 'PosReg', (123, 132))	('apoptosis', 'biological_process', 'GO:0097194', ('148', '157'))	('apoptosis', 'biological_process', 'GO:0006915', ('148', '157'))	('MIA PaCa-2 apoptosis rate', 'CPA', (137, 162))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (137, 147))	('AZD6244', 'Var', (105, 112))	('AZD6244', 'Chemical', 'MESH:C517975', (105, 112))	('GDC0941', 'Var', (19, 26))	('GDC0941', 'Var', (81, 88))	('GDC0941', 'Chemical', 'MESH:C532162', (81, 88))	('AZD6244', 'Var', (41, 48))	('GDC0941', 'Chemical', 'MESH:C532162', (19, 26))	('AZD6244', 'Chemical', 'MESH:C517975', (41, 48))
16311	24130864	Combining GDC0941 and AZD6244 also significantly increased the apoptosis rate in Capan-2 cells to 41.3%, compared to 12.2% without treatment or with single agent alone (p <0.05) (Figure 3D).	('apoptosis rate', 'CPA', (63, 77))	('GDC0941', 'Var', (10, 17))	('Capan-2', 'CellLine', 'CVCL:0026', (81, 88))	('AZD6244', 'Var', (22, 29))	('GDC0941', 'Chemical', 'MESH:C532162', (10, 17))	('increased', 'PosReg', (49, 58))	('AZD6244', 'Chemical', 'MESH:C517975', (22, 29))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('men', 'Species', '9606', (136, 139))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))
16313	24130864	The total protein levels of ERK, S6 and 4E-BP1 remained unchanged after treatment with GDC0941 and AZD6244 in each cell lines (Figure 4).	('ERK', 'Gene', (28, 31))	('protein levels', 'MPA', (10, 24))	('GDC0941', 'Var', (87, 94))	('GDC0941', 'Chemical', 'MESH:C532162', (87, 94))	('AZD6244', 'Var', (99, 106))	('men', 'Species', '9606', (77, 80))	('AZD6244', 'Chemical', 'MESH:C517975', (99, 106))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('ERK', 'Gene', '5594', (28, 31))	('ERK', 'molecular_function', 'GO:0004707', ('28', '31'))	('S6 and 4E-BP1', 'Gene', '6194;1978', (33, 46))
16314	24130864	p-ERK, p-S6 and p-4E-BP1 appeared to be suppressed by GDC0941 and AZD6244 combination treatment.	('p-ERK', 'Gene', (0, 5))	('4E-BP1', 'Gene', (18, 24))	('suppressed', 'NegReg', (40, 50))	('ERK', 'molecular_function', 'GO:0004707', ('2', '5'))	('men', 'Species', '9606', (91, 94))	('GDC0941', 'Var', (54, 61))	('4E-BP1', 'Gene', '1978', (18, 24))	('p-S6', 'Gene', '338413', (7, 11))	('p-ERK', 'Gene', '9451', (0, 5))	('GDC0941', 'Chemical', 'MESH:C532162', (54, 61))	('AZD6244', 'Var', (66, 73))	('AZD6244', 'Chemical', 'MESH:C517975', (66, 73))	('p-S6', 'Gene', (7, 11))
16318	24130864	The combination of both drugs reduced p-ERK (T202/Y204), p-AKT (S473), p-S6 (S240/244) and p-4E-BP1 (S65) expression compared with baseline in all cell lines tested.	('ERK', 'molecular_function', 'GO:0004707', ('40', '43'))	('p-ERK', 'Gene', (38, 43))	('AKT', 'Gene', (59, 62))	('4E-BP1', 'Gene', (93, 99))	('p-S6', 'Gene', '338413', (71, 75))	('expression', 'MPA', (106, 116))	('p-S6', 'Gene', (71, 75))	('reduced', 'NegReg', (30, 37))	('S473', 'Var', (64, 68))	('AKT', 'Gene', '207', (59, 62))	('4E-BP1', 'Gene', '1978', (93, 99))	('p-ERK', 'Gene', '9451', (38, 43))
16320	24130864	To understand the phenotypic differences seen in the MIA PaCa-2 (sensitive to GDC0491 and AZD6244) and PANC-1 (resistant to GDC0491 and AZD6244) cell lines, both of which harbor the KRAS mutation, we examined the differences in their downstream effectors following GDC0941 and AZD6244 administration (Figure 5).	('GDC0941', 'Var', (265, 272))	('AZD6244', 'Chemical', 'MESH:C517975', (90, 97))	('KRAS', 'Gene', '3845', (182, 186))	('GDC0941', 'Chemical', 'MESH:C532162', (265, 272))	('PANC-1', 'CellLine', 'CVCL:0480', (103, 109))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (53, 63))	('AZD6244', 'Var', (277, 284))	('AZD6244', 'Chemical', 'MESH:C517975', (136, 143))	('AZD6244', 'Chemical', 'MESH:C517975', (277, 284))	('KRAS', 'Gene', (182, 186))
16321	24130864	In both cell lines, GDC0941 suppressed phosphorylation of AKT, AZD6244 decreased p-ERK levels, and the combination of the two drugs suppressed both p-AKT and p-ERK levels.	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('p-ERK', 'Gene', '9451', (81, 86))	('p-ERK', 'Gene', (81, 86))	('ERK', 'molecular_function', 'GO:0004707', ('83', '86'))	('GDC0941', 'Chemical', 'MESH:C532162', (20, 27))	('AKT', 'Gene', '207', (150, 153))	('AZD6244', 'Var', (63, 70))	('decreased', 'NegReg', (71, 80))	('p-ERK', 'Gene', '9451', (158, 163))	('p-ERK', 'Gene', (158, 163))	('AKT', 'Gene', (58, 61))	('phosphorylation', 'MPA', (39, 54))	('AZD6244', 'Chemical', 'MESH:C517975', (63, 70))	('suppressed', 'NegReg', (28, 38))	('suppressed', 'NegReg', (132, 142))	('ERK', 'molecular_function', 'GO:0004707', ('160', '163'))	('GDC0941', 'Var', (20, 27))	('AKT', 'Gene', '207', (58, 61))	('AKT', 'Gene', (150, 153))
16322	24130864	GDC0941 and AZD6244 had a similar effect on AKT and ERK in the two cell lines.	('ERK', 'molecular_function', 'GO:0004707', ('52', '55'))	('GDC0941', 'Var', (0, 7))	('ERK', 'Gene', '5594', (52, 55))	('GDC0941', 'Chemical', 'MESH:C532162', (0, 7))	('AZD6244', 'Var', (12, 19))	('ERK', 'Gene', (52, 55))	('AZD6244', 'Chemical', 'MESH:C517975', (12, 19))	('AKT', 'Gene', '207', (44, 47))	('AKT', 'Gene', (44, 47))
16324	24130864	For example, GDC0941 and AZD6244 alone and in combination markedly inhibited p-S6 and p-4E-BP1expression levels in MIA PaCa-2 cells, compared with the minimal suppression observed in PANC-1 cells (Figure 5).	('AZD6244', 'Chemical', 'MESH:C517975', (25, 32))	('GDC0941', 'Chemical', 'MESH:C532162', (13, 20))	('inhibited', 'NegReg', (67, 76))	('PANC-1', 'CellLine', 'CVCL:0480', (183, 189))	('4E-BP1', 'Gene', (88, 94))	('p-S6', 'Gene', '338413', (77, 81))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (115, 125))	('p-S6', 'Gene', (77, 81))	('AZD6244', 'Var', (25, 32))	('4E-BP1', 'Gene', '1978', (88, 94))	('GDC0941', 'Var', (13, 20))
16325	24130864	Neither GDC0941 nor AZD6244 alone suppressed p-S6 and p-4E-BP1 in PANC-1 cells, suggesting that both effectors may serve as biomarkers associated with treatment response.	('4E-BP1', 'Gene', (56, 62))	('AZD6244', 'Chemical', 'MESH:C517975', (20, 27))	('PANC-1', 'CellLine', 'CVCL:0480', (66, 72))	('suppressed', 'NegReg', (34, 44))	('men', 'Species', '9606', (156, 159))	('GDC0941', 'Var', (8, 15))	('GDC0941', 'Chemical', 'MESH:C532162', (8, 15))	('4E-BP1', 'Gene', '1978', (56, 62))	('p-S6', 'Gene', '338413', (45, 49))	('p-S6', 'Gene', (45, 49))
16327	24130864	To detect the effect of GDC0941 and AZD6244 on tumor growth in vivo, we used GDC0941, AZD6244, and a combination of GDC0941and AZD6244 to treat BxPC-3 xenograft mice for 18 days.	('GDC0941', 'Chemical', 'MESH:C532162', (116, 123))	('mice', 'Species', '10090', (161, 165))	('tumor', 'Disease', (47, 52))	('GDC0941and', 'Chemical', '-', (116, 126))	('GDC0941', 'Chemical', 'MESH:C532162', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('GDC0941', 'Var', (77, 84))	('AZD6244', 'Chemical', 'MESH:C517975', (36, 43))	('GDC0941', 'Chemical', 'MESH:C532162', (77, 84))	('BxPC-3', 'CellLine', 'CVCL:0186', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('AZD6244', 'Chemical', 'MESH:C517975', (127, 134))	('GDC0941and', 'Var', (116, 126))	('AZD6244', 'Chemical', 'MESH:C517975', (86, 93))
16328	24130864	Compared to the control (vehicle) group, tumor volumes decreased significantly in the AZD6244 and combination groups (p=0.037 and p=0.032, respectively) but not in the GDC0941group as compared to control (Figure 6A).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('GDC0941', 'Chemical', 'MESH:C532162', (168, 175))	('tumor', 'Disease', (41, 46))	('decreased', 'NegReg', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('AZD6244', 'Var', (86, 93))	('AZD6244', 'Chemical', 'MESH:C517975', (86, 93))
16330	24130864	Because of the high frequency of KRAS mutations in pancreatic cancer, KRAS has been directly targeted in pre-clinical and clinical trials, but results have been disappointing.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('KRAS', 'Gene', (70, 74))	('pancreatic cancer', 'Disease', (51, 68))	('KRAS', 'Gene', (33, 37))	('KRAS', 'Gene', '3845', (70, 74))	('pre', 'molecular_function', 'GO:0003904', ('105', '108'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (51, 68))	('KRAS', 'Gene', '3845', (33, 37))	('mutations', 'Var', (38, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (51, 68))
16339	24130864	Secondly, our study showed that PI3K and MEK inhibition either alone or in combination can induce apoptosis.	('PI3K', 'molecular_function', 'GO:0016303', ('32', '36'))	('apoptosis', 'CPA', (98, 107))	('MEK', 'Gene', (41, 44))	('MEK', 'Gene', '5609', (41, 44))	('PI3', 'Gene', (32, 35))	('inhibition', 'Var', (45, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('PI3', 'Gene', '5266', (32, 35))	('induce', 'Reg', (91, 97))
16343	24130864	Our study supports a similar preclinical study in pancreatic cancer which showed that the treatment benefit of a MEK inhibitor was enhanced by an AKT inhibitor.	('MEK', 'Gene', '5609', (113, 116))	('AKT', 'Gene', '207', (146, 149))	('treatment benefit', 'CPA', (90, 107))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 67))	('inhibitor', 'Var', (117, 126))	('pancreatic cancer', 'Disease', (50, 67))	('AKT', 'Gene', (146, 149))	('men', 'Species', '9606', (95, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('enhanced', 'PosReg', (131, 139))	('MEK', 'Gene', (113, 116))
16345	24130864	PI3K pathway alterations including HER2 amplification, PI3KCA mutations or PTEN loss have been found to be associated with sensitivity to GDC0941 in breast cancer cell lines in vitro and in vivo; however, the above genetic alternations are rarely present in pancreatic tumors.	('sensitivity', 'MPA', (123, 134))	('pancreatic tumors', 'Disease', 'MESH:D010190', (258, 275))	('pancreatic tumors', 'Disease', (258, 275))	('HER2', 'Gene', '2064', (35, 39))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('PI3', 'Gene', '5266', (0, 3))	('GDC0941', 'Chemical', 'MESH:C532162', (138, 145))	('PI3', 'Gene', '5266', (55, 58))	('PTEN', 'Gene', (75, 79))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Disease', (149, 162))	('mutations', 'Var', (62, 71))	('HER2', 'Gene', (35, 39))	('associated', 'Reg', (107, 117))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (258, 275))	('PTEN', 'Gene', '5728', (75, 79))	('PI3', 'Gene', (0, 3))	('PI3', 'Gene', (55, 58))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('loss', 'NegReg', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('amplification', 'Var', (40, 53))
16346	24130864	Our study suggests that downstream p-AKT suppressed by GDC0941 does not predict cell sensitivity, nor does downregulated p-ERK predict sensitivity to AZD6244.	('GDC0941', 'Var', (55, 62))	('p-ERK', 'Gene', '9451', (121, 126))	('AKT', 'Gene', '207', (37, 40))	('p-ERK', 'Gene', (121, 126))	('cell sensitivity', 'CPA', (80, 96))	('suppressed', 'NegReg', (41, 51))	('GDC0941', 'Chemical', 'MESH:C532162', (55, 62))	('AZD6244', 'Chemical', 'MESH:C517975', (150, 157))	('AKT', 'Gene', (37, 40))	('ERK', 'molecular_function', 'GO:0004707', ('123', '126'))
16349	24130864	Both cell lines are reported to contain KRAS mutations, p53 mutations, wild type P16 and wild type DPC-4.	('DPC-4', 'Gene', '4089', (99, 104))	('DPC-4', 'Gene', (99, 104))	('mutations', 'Var', (45, 54))	('p53', 'Gene', (56, 59))	('P16', 'Gene', '1029', (81, 84))	('KRAS', 'Gene', (40, 44))	('p53', 'Gene', '7157', (56, 59))	('KRAS', 'Gene', '3845', (40, 44))	('contain', 'Reg', (32, 39))	('mutations', 'Var', (60, 69))	('P16', 'Gene', (81, 84))
16376	24086571	Previous epidemiological investigations have identified some possible risk factors of pancreatic cancer, such as smoking, chronic pancreatitis, long-standing diabetes, mutations of various genes and so on.	('smoking', 'Disease', (113, 120))	('diabetes', 'Disease', (158, 166))	('long-standing', 'Phenotype', 'HP:0003698', (144, 157))	('pancreatitis', 'Disease', (130, 142))	('pancreatic cancer', 'Disease', (86, 103))	('diabetes', 'Disease', 'MESH:D003920', (158, 166))	('long-standing', 'Disease', (144, 157))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('pancreatitis', 'Phenotype', 'HP:0001733', (130, 142))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (122, 142))	('pancreatitis', 'Disease', 'MESH:D010195', (130, 142))	('mutations', 'Var', (168, 177))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
16407	24086571	Three studies reported CagA+ H. pylori strains served as a risk factor of pancreatic cancer compared with CagA- strains, whereas the other three did not.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('CagA', 'Gene', (23, 27))	('CagA', 'Gene', '6279', (23, 27))	('strains', 'Var', (39, 46))	('CagA', 'Gene', (106, 110))	('CagA', 'Gene', '6279', (106, 110))	('pancreatic cancer', 'Disease', (74, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('H. pylori', 'Species', '210', (29, 38))
16429	24086571	One is the hypothetical pathway involving gastric antral colonization of H. pylori, hyperchlorhydria, enhanced release of secretin, proportional elevation in basal pancreatic bicarbonate output and pancreatic hyperplasia with accelerated metabolism and DNA synthesis, probably associated with a greater susceptibility to carcinogens.	('secretin', 'molecular_function', 'GO:0008565', ('122', '130'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('253', '266'))	('pancreatic', 'Disease', (164, 174))	('DNA synthesis', 'MPA', (253, 266))	('bicarbonate', 'Chemical', 'MESH:D001639', (175, 186))	('release of secretin', 'MPA', (111, 130))	('pancreatic hyperplasia', 'Phenotype', 'HP:0006277', (198, 220))	('elevation', 'PosReg', (145, 154))	('hyperchlorhydria', 'Disease', (84, 100))	('enhanced', 'PosReg', (102, 110))	('pancreatic hyperplasia', 'Disease', (198, 220))	('pancreatic', 'Disease', 'MESH:D010195', (198, 208))	('metabolism', 'MPA', (238, 248))	('pancreatic hyperplasia', 'Disease', 'MESH:D010195', (198, 220))	('DNA', 'cellular_component', 'GO:0005574', ('253', '256'))	('hyperchlorhydria', 'Disease', 'None', (84, 100))	('accelerated', 'PosReg', (226, 237))	('secretin', 'molecular_function', 'GO:0046659', ('122', '130'))	('pancreatic', 'Disease', (198, 208))	('H. pylori', 'Species', '210', (73, 82))	('pancreatic', 'Disease', 'MESH:D010195', (164, 174))	('metabolism', 'biological_process', 'GO:0008152', ('238', '248'))	('H. pylori', 'Var', (73, 82))
16433	24086571	Finally, it has been suggested that dietary intake of certain food, such as red and high-temperature cooked meat, and genetic variations in inflammation-related genes (such as COX-2) and susceptibility loci at chromosomes (such as 13q22.1, 21q21.3, 5p13.1) might be positively linked with pancreatic cancer, however, none of the eligible studies adjusted for these dietary or genetic factors.	('variations', 'Var', (126, 136))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (289, 306))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('pancreatic cancer', 'Disease', (289, 306))	('pancreatic cancer', 'Disease', 'MESH:D010190', (289, 306))	('linked', 'Reg', (277, 283))	('inflammation', 'Disease', 'MESH:D007249', (140, 152))	('inflammation', 'Disease', (140, 152))	('inflammation', 'biological_process', 'GO:0006954', ('140', '152'))
16438	23486238	Known cellular PEDF responses have expanded from the initial discovery that PEDF induces retinoblastoma cell differentiation to its anti-angiogenic, antitumorigenic and antimetastatic properties.	('PEDF', 'Var', (76, 80))	('anti-angiogenic', 'CPA', (132, 147))	('retinoblastoma', 'Phenotype', 'HP:0009919', (89, 103))	('cell differentiation', 'biological_process', 'GO:0030154', ('104', '124'))	('antimetastatic', 'CPA', (169, 183))	('antitumorigenic', 'CPA', (149, 164))	('retinoblastoma', 'Disease', (89, 103))	('retinoblastoma', 'Disease', 'MESH:D012175', (89, 103))	('induces', 'Reg', (81, 88))
16456	23486238	The amino acids that are crucial for these interactions have been mapped on human PEDF; these are basic amino acids for heparin binding (Lys146, Lys147 and Arg149) and for hyaluronan binding (Lys189, Lys191, Arg194 and Lys197), and acidic amino acids for collagen binding (Asp256, Asp258 and Asp300).	('hyaluronan', 'Chemical', 'MESH:D006820', (172, 182))	('Arg149', 'Chemical', '-', (156, 162))	('heparin binding', 'molecular_function', 'GO:0008201', ('120', '135'))	('Lys189', 'Var', (192, 198))	('Arg194', 'Chemical', '-', (208, 214))	('basic amino acids', 'Chemical', 'MESH:D024361', (98, 115))	('Arg194', 'Var', (208, 214))	('Lys189', 'Chemical', '-', (192, 198))	('Lys146', 'Chemical', '-', (137, 143))	('Lys191', 'Var', (200, 206))	('heparin', 'Chemical', 'MESH:D006493', (120, 127))	('Lys147', 'Var', (145, 151))	('Lys197', 'Var', (219, 225))	('Asp258', 'Chemical', '-', (281, 287))	('Asp258', 'Var', (281, 287))	('collagen binding', 'molecular_function', 'GO:0005518', ('255', '271'))	('Lys147', 'Chemical', '-', (145, 151))	('Arg149', 'Var', (156, 162))	('Asp256', 'Var', (273, 279))	('Asp300', 'Var', (292, 298))	('Lys146', 'Var', (137, 143))	('heparin', 'Protein', (120, 127))	('Asp300', 'Chemical', '-', (292, 298))	('Lys191', 'Chemical', '-', (200, 206))	('human', 'Species', '9606', (76, 81))	('Asp256', 'Chemical', '-', (273, 279))	('Lys197', 'Chemical', '-', (219, 225))	('hyaluronan binding', 'molecular_function', 'GO:0005540', ('172', '190'))
16466	23486238	In this regard, PEDF-treated retinoblastoma cells are less tumorigenic than untreated controls, as shown by their delayed formation of tumours in rat retinas.	('tumorigenic', 'MPA', (59, 70))	('rat', 'Species', '10116', (146, 149))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))	('less', 'NegReg', (54, 58))	('retinoblastoma', 'Disease', 'MESH:D012175', (29, 43))	('retinoblastoma', 'Disease', (29, 43))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('tumours', 'Disease', (135, 142))	('formation', 'biological_process', 'GO:0009058', ('122', '131'))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('retinoblastoma', 'Phenotype', 'HP:0009919', (29, 43))	('PEDF-treated', 'Var', (16, 28))
16468	23486238	PEDF also causes neuroendocrine differentiation in prostate cancer cells, in addition to inhibiting tumour angiogenesis.	('prostate cancer', 'Disease', 'MESH:D011471', (51, 66))	('angiogenesis', 'biological_process', 'GO:0001525', ('107', '119'))	('inhibiting', 'NegReg', (89, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (51, 66))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('causes', 'Reg', (10, 16))	('neuroendocrine', 'Disease', (17, 31))	('PEDF', 'Var', (0, 4))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('prostate cancer', 'Disease', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('tumour', 'Disease', (100, 106))
16469	23486238	More recently, it was demonstrated that PEDF inhibits the number and proliferation of brain metastases of breast cancer cells and concomitantly protects neurons close to the metastases from cell death, thus highlighting its role as a double agent in limiting brain metastases and their local consequences.	('protects', 'NegReg', (144, 152))	('metastases', 'Disease', (265, 275))	('rat', 'Species', '10116', (76, 79))	('cell death', 'biological_process', 'GO:0008219', ('190', '200'))	('inhibits', 'NegReg', (45, 53))	('metastases', 'Disease', 'MESH:D009362', (265, 275))	('metastases of breast cancer', 'Disease', 'MESH:D009362', (92, 119))	('PEDF', 'Var', (40, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('rat', 'Species', '10116', (29, 32))	('metastases', 'Disease', (92, 102))	('metastases', 'Disease', 'MESH:D009362', (92, 102))	('metastases', 'Disease', (174, 184))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('metastases', 'Disease', 'MESH:D009362', (174, 184))	('metastases of breast cancer', 'Disease', (92, 119))
16484	23486238	Furthermore, in vitro, PEDF inhibits melanoma cell growth by inducing apoptotic cell death.	('inhibits', 'NegReg', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('PEDF', 'Var', (23, 27))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('70', '90'))	('cell growth', 'biological_process', 'GO:0016049', ('46', '57'))	('inducing', 'Reg', (61, 69))	('apoptotic cell death', 'CPA', (70, 90))
16489	23486238	In another report, PEDF suppressed angiogenesis and the growth of gastric carcinoma in a xenograft model by downregulating hypoxia-inducible factor 1alpha (HIF1alpha) and VEGF.	('VEGF', 'CPA', (171, 175))	('HIF1alpha', 'Gene', '3091', (156, 165))	('hypoxia-inducible factor 1alpha', 'Gene', '3091', (123, 154))	('PEDF', 'Var', (19, 23))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (66, 83))	('growth', 'CPA', (56, 62))	('suppressed', 'NegReg', (24, 34))	('hypoxia-inducible factor 1alpha', 'Gene', (123, 154))	('downregulating', 'NegReg', (108, 122))	('gastric carcinoma', 'Disease', 'MESH:D013274', (66, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('HIF1alpha', 'Gene', (156, 165))	('angiogenesis', 'biological_process', 'GO:0001525', ('35', '47'))	('gastric carcinoma', 'Disease', (66, 83))	('angiogenesis', 'CPA', (35, 47))
16494	23486238	Interestingly, PEDF selectively induces endothelial cell apoptosis in actively remodelling vessels rather than mature, existing ones.	('endothelial cell apoptosis', 'CPA', (40, 66))	('PEDF', 'Var', (15, 19))	('rat', 'Species', '10116', (99, 102))	('induces', 'Reg', (32, 39))	('endothelial cell apoptosis', 'biological_process', 'GO:0072577', ('40', '66'))
16512	23486238	For example, it has been shown that PEDF can reduce the invasiveness of UMR 106-01 and SaOS-2 osteosarcoma cells, and can suppress the development of macroscopic pulmonary metastasis in an orthotopic human osteosarcoma model.	('osteosarcoma', 'Phenotype', 'HP:0002669', (206, 218))	('PEDF', 'Var', (36, 40))	('osteosarcoma', 'Disease', (206, 218))	('invasiveness', 'CPA', (56, 68))	('osteosarcoma', 'Disease', 'MESH:D012516', (206, 218))	('SaOS-2', 'CellLine', 'CVCL:0548', (87, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('development of macroscopic pulmonary metastasis', 'CPA', (135, 182))	('osteosarcoma', 'Disease', (94, 106))	('reduce', 'NegReg', (45, 51))	('human', 'Species', '9606', (200, 205))	('osteosarcoma', 'Phenotype', 'HP:0002669', (94, 106))	('suppress', 'NegReg', (122, 130))	('osteosarcoma', 'Disease', 'MESH:D012516', (94, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))
16523	23486238	Consistently, silencing of PEDF expression in normal melanocytes and poorly aggressive melanoma cell lines increased their migration and invasiveness, which translated into an increased proliferative and in vivo metastatic potential.	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('silencing', 'Var', (14, 23))	('rat', 'Species', '10116', (193, 196))	('aggressive melanoma', 'Disease', (76, 95))	('increased', 'PosReg', (176, 185))	('increased', 'PosReg', (107, 116))	('invasiveness', 'CPA', (137, 149))	('rat', 'Species', '10116', (126, 129))	('aggressive melanoma', 'Disease', 'MESH:D008545', (76, 95))	('migration', 'CPA', (123, 132))	('PEDF', 'Gene', (27, 31))
16525	23486238	Interestingly, Ladhani and co-workers reported that PEDF suppresses the rounded morphology of melanoma cells and inhibits the surface localization of MMP14 (also known as MT1-MMP).	('MMP', 'molecular_function', 'GO:0004235', ('150', '153'))	('MT1-MMP', 'Gene', '4323', (171, 178))	('MT1', 'molecular_function', 'GO:0043834', ('171', '174'))	('suppresses', 'NegReg', (57, 67))	('MT1-MMP', 'Gene', (171, 178))	('MMP14', 'Gene', '4323', (150, 155))	('surface localization', 'MPA', (126, 146))	('MMP14', 'Gene', (150, 155))	('melanoma', 'Disease', (94, 102))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('MMP', 'molecular_function', 'GO:0004235', ('175', '178'))	('MT1', 'molecular_function', 'GO:0043791', ('171', '174'))	('localization', 'biological_process', 'GO:0051179', ('134', '146'))	('MT1', 'molecular_function', 'GO:0047152', ('171', '174'))	('inhibits', 'NegReg', (113, 121))	('PEDF', 'Var', (52, 56))
16531	23486238	In the elastase (EL)-KrasG12D mouse model of non-invasive cystic papillary neoplasms, loss of Serpinf1 results in the development of pancreatic ductal adenocarcinoma.	('cystic papillary neoplasms', 'Disease', 'MESH:D002291', (58, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('Serpinf1', 'Gene', (94, 102))	('loss', 'Var', (86, 90))	('neoplasms', 'Phenotype', 'HP:0002664', (75, 84))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (133, 165))	('pancreatic ductal adenocarcinoma', 'Disease', (133, 165))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (133, 165))	('mouse', 'Species', '10090', (30, 35))	('cystic papillary neoplasms', 'Disease', (58, 84))
16537	23486238	The proposed mechanism for PEDF-mediated anti-angiogenesis involves cleavage at Val767 of the VEGFR1 transmem-brane domain and the intracellular translocation of the carboxy-terminal fragment of VEGFR1 (FIG.	('VEGFR1', 'Gene', (195, 201))	('cleavage', 'MPA', (68, 76))	('VEGFR1', 'Gene', '2321', (94, 100))	('anti-angiogenesis', 'CPA', (41, 58))	('VEGFR1', 'Gene', (94, 100))	('Val767', 'Var', (80, 86))	('angiogenesis', 'biological_process', 'GO:0001525', ('46', '58'))	('intracellular', 'cellular_component', 'GO:0005622', ('131', '144'))	('VEGFR1', 'Gene', '2321', (195, 201))
16547	23486238	Conversely, PEDF triggers JNK-mediated phosphorylation of NFATc2 and sequesters it in the cytoplasm, which prevents the NFATc2-mediated block of FLIP expression (FIG.	('NFATc2', 'Gene', (58, 64))	('NFATc2', 'Gene', '4773', (120, 126))	('block', 'MPA', (136, 141))	('PEDF', 'Var', (12, 16))	('JNK', 'Gene', (26, 29))	('NFATc2', 'Gene', '4773', (58, 64))	('JNK', 'Gene', '5599', (26, 29))	('NFATc2', 'Gene', (120, 126))	('prevents', 'NegReg', (107, 115))	('FLIP expression', 'MPA', (145, 160))
16554	23486238	DHA can reduce the invasive phenotype of human melanoma, breast and renal carcinoma cells in vitro, which implies that DHA might modify the tumour cell metastatic potential and be a lipid mediator of PEDF signalling.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('DHA', 'Var', (0, 3))	('DHA', 'Chemical', 'MESH:D004281', (0, 3))	('lipid', 'Chemical', 'MESH:D008055', (182, 187))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('human', 'Species', '9606', (41, 46))	('modify', 'Reg', (129, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('DHA', 'Chemical', 'MESH:D004281', (119, 122))	('tumour', 'Disease', (140, 146))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('breast and renal carcinoma', 'Disease', 'MESH:C538614', (57, 83))	('renal carcinoma', 'Phenotype', 'HP:0005584', (68, 83))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('signalling', 'biological_process', 'GO:0023052', ('205', '215'))	('DHA', 'Var', (119, 122))	('reduce', 'NegReg', (8, 14))
16562	23486238	Interestingly, a number of reports have shown that exogenous DHA induces cytotoxicity in a wide range of cancer cell types, which has led to the investigation of DHA in several clinical cancer trials.	('exogenous', 'Var', (51, 60))	('cytotoxicity', 'Disease', 'MESH:D064420', (73, 85))	('DHA', 'Chemical', 'MESH:D004281', (61, 64))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('DHA', 'Protein', (61, 64))	('cytotoxicity', 'Disease', (73, 85))	('DHA', 'Chemical', 'MESH:D004281', (162, 165))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
16565	23486238	PEDF binding to PEDFR upregulates PPARgamma, which leads to the suppression of nuclear factor-kappaB (NF-kappaB)-mediated transcriptional activation, reduced production of interleukin 8 (IL-8) and limited proliferation of prostate cancer cells (FIG.	('interleukin 8', 'Gene', (172, 185))	('IL-8', 'molecular_function', 'GO:0005153', ('187', '191'))	('nuclear factor-kappaB', 'Gene', (79, 100))	('binding', 'Var', (5, 12))	('proliferation', 'CPA', (205, 218))	('PPARgamma', 'Gene', (34, 43))	('IL-8', 'Gene', '3576', (187, 191))	('suppression', 'NegReg', (64, 75))	('reduced', 'NegReg', (150, 157))	('rat', 'Species', '10116', (212, 215))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('upregulates', 'PosReg', (22, 33))	('PPARgamma', 'Gene', '5468', (34, 43))	('PEDFR', 'Gene', (16, 21))	('prostate cancer', 'Disease', 'MESH:D011471', (222, 237))	('prostate cancer', 'Phenotype', 'HP:0012125', (222, 237))	('IL-8', 'Gene', (187, 191))	('interleukin 8', 'Gene', '3576', (172, 185))	('PEDFR', 'Chemical', '-', (16, 21))	('prostate cancer', 'Disease', (222, 237))	('binding', 'molecular_function', 'GO:0005488', ('5', '12'))	('nuclear factor-kappaB', 'Gene', '4790', (79, 100))
16567	23486238	PEDF binds laminin receptor through the Asp44-Asn77 region of PEDF (the 34-mer), and this interaction is linked to the anti-angiogenic functions of PEDF.	('Asp44-Asn77', 'Var', (40, 51))	('Asp44', 'Chemical', '-', (40, 45))	('binds', 'Interaction', (5, 10))	('linked', 'Reg', (105, 111))	('anti-angiogenic functions', 'CPA', (119, 144))	('laminin receptor', 'Protein', (11, 27))	('Asn77', 'Chemical', '-', (46, 51))
16570	23486238	More recently, Park and co-workers reported that PEDF binds to LRP6, which is a WNT co-receptor, and blocks the signalling that is induced by WNT ligands in retinal pigment epithelial cells.	('blocks', 'NegReg', (101, 107))	('signalling', 'biological_process', 'GO:0023052', ('112', '122'))	('LRP6', 'Gene', (63, 67))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('LRP6', 'Gene', '4040', (63, 67))	('signalling', 'MPA', (112, 122))	('N', 'Chemical', 'MESH:D009584', (143, 144))	('binds', 'Interaction', (54, 59))	('PEDF', 'Var', (49, 53))
16579	23486238	The involvement of the collagen-binding motif in the anti-angiogenic activity of PEDF was studied by Hosomichi and co-workers, who showed that a recombinant PEDF variant that is unable to bind collagen I does not inhibit tumour growth unlike wild-type PEDF and a PEDF variant with an altered heparin-binding site.	('variant', 'Var', (162, 169))	('collagen-binding', 'molecular_function', 'GO:0005518', ('23', '39'))	('tumour growth', 'Disease', (221, 234))	('tumour', 'Phenotype', 'HP:0002664', (221, 227))	('inhibit', 'NegReg', (213, 220))	('collagen', 'molecular_function', 'GO:0005202', ('193', '201'))	('heparin', 'Chemical', 'MESH:D006493', (292, 299))	('heparin-binding', 'molecular_function', 'GO:0008201', ('292', '307'))	('tumour growth', 'Disease', 'MESH:D006130', (221, 234))	('PEDF', 'Gene', (157, 161))
16593	23486238	Studying the transition from proliferation to differentiation in intestinal epithelial cells, they showed that silencing of NCOR1 in proliferating crypt cells results in a rapid growth arrest.	('NCOR1', 'Gene', (124, 129))	('silencing', 'Var', (111, 120))	('rat', 'Species', '10116', (36, 39))	('growth arrest', 'Disease', 'MESH:D006323', (178, 191))	('growth arrest', 'Disease', (178, 191))	('rat', 'Species', '10116', (140, 143))	('NCOR1', 'Gene', '9611', (124, 129))	('growth arrest', 'Phenotype', 'HP:0001510', (178, 191))
16612	23486238	They prepared phosphomimetic PEDF variants with increased anti-angiogenic activities that are much more efficient than wild-type PEDF at inhibiting growth and angiogenesis in breast cancer, colon cancer and glioblastoma xenograft models.	('glioblastoma', 'Disease', 'MESH:D005909', (207, 219))	('colon cancer', 'Disease', 'MESH:D015179', (190, 202))	('colon cancer', 'Phenotype', 'HP:0003003', (190, 202))	('variants', 'Var', (34, 42))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('anti-angiogenic activities', 'MPA', (58, 84))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Disease', (175, 188))	('inhibiting', 'NegReg', (137, 147))	('glioblastoma', 'Phenotype', 'HP:0012174', (207, 219))	('colon cancer', 'Disease', (190, 202))	('glioblastoma', 'Disease', (207, 219))	('angiogenesis', 'biological_process', 'GO:0001525', ('159', '171'))
16613	23486238	Remarkably, the antitumour activity of the phosphomimetic variants is comparable to that of the established anti-angiogenic agent bevacizumab, but they act in a VEGF-independent manner, without affecting the levels of VEGFA mRNA or VEGF receptor 2 phosphorylation.	('VEGFA', 'Gene', '7422', (218, 223))	('VEGF receptor', 'Gene', (232, 245))	('N', 'Chemical', 'MESH:D009584', (226, 227))	('variants', 'Var', (58, 66))	('bevacizumab', 'Chemical', 'MESH:D000068258', (130, 141))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('tumour', 'Disease', (20, 26))	('VEGFA', 'Gene', (218, 223))	('VEGF receptor', 'Gene', '3791', (232, 245))	('phosphorylation', 'biological_process', 'GO:0016310', ('248', '263'))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
16614	23486238	PEDF and its variants act on intratumoural endothelial apoptosis, but in contrast to results from other groups, the Seger group reported that the variant forms do not affect the survival of cancer cells in vitro, hence they concluded that the anti-angiogenic activity of these agents is the main property of the observed antitumour effect.	('tumoural', 'Disease', (34, 42))	('cancer', 'Disease', (190, 196))	('variants', 'Var', (13, 21))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('variant', 'Var', (146, 153))	('rat', 'Species', '10116', (32, 35))	('tumour', 'Disease', 'MESH:D009369', (325, 331))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', (325, 331))	('anti-angiogenic activity', 'CPA', (243, 267))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('tumour', 'Disease', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumour', 'Phenotype', 'HP:0002664', (325, 331))	('tumoural', 'Disease', 'MESH:D009369', (34, 42))
16617	23486238	Interestingly, we have identified a natural PEDF protein variant with enhanced tumour cell antimigratory and cell-death-inducing activities that was separated from the canonical wild-type form by ion-exchange chromatography.	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('rat', 'Species', '10116', (153, 156))	('cell-death', 'biological_process', 'GO:0008219', ('109', '119'))	('cell-death-inducing activities', 'CPA', (109, 139))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('rat', 'Species', '10116', (98, 101))	('variant', 'Var', (57, 64))	('enhanced', 'PosReg', (70, 78))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))
16620	23486238	In recent years it has become apparent that, in addition to the established antitumour activity of exogenously added PEDF, changes in the endogenous expression of PEDF are associated with the malignant progression of diverse tumour types.	('tumour', 'Disease', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('endogenous expression', 'MPA', (138, 159))	('tumour', 'Disease', (225, 231))	('associated with', 'Reg', (172, 187))	('malignant progression', 'CPA', (192, 213))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('changes', 'Var', (123, 130))	('PEDF', 'Gene', (163, 167))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))
16626	23486238	The fact that these studies were also correlated with in vitro experiments showing that modulating the levels of PEDF expression is sufficient to alter the sensitivity of breast cancer cells to endocrine therapy provides strong evidence supporting the prognostic value of PEDF for disease progression and patient outcome.	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Disease', (171, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('modulating', 'Var', (88, 98))	('sensitivity', 'MPA', (156, 167))	('PEDF', 'Gene', (113, 117))	('alter', 'Reg', (146, 151))	('patient', 'Species', '9606', (305, 312))
16636	23486238	These strategies are primarily focused in two areas: the development of protein or peptide therapeutics with enhanced antitumorigenic activity, such as PEDF phosphomimetics, PEDF variant forms or discrete PEDF-derived peptides that recapitulate the anticancer activity of full-length PEDF; and the establishment of efficient methods for PEDF administration that take advantage of delivery systems using either viral vectors directly, virally infected human mesenchymal stem cells, microparticles or nanoparticles of various compositions or implanted micro-osmotic pumps.	('rat', 'Species', '10116', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('cancer', 'Disease', (253, 259))	('antitumorigenic activity', 'CPA', (118, 142))	('rat', 'Species', '10116', (350, 353))	('human', 'Species', '9606', (451, 456))	('variant', 'Var', (179, 186))	('enhanced', 'PosReg', (109, 117))	('peptides', 'Chemical', 'MESH:D010455', (218, 226))
16657	23486238	Support for its anticancer role also comes from the findings that PEDF exhibits strong antimetastatic activity by suppressing tumour cell invasion and migration; these effects have been described in vitro and in several metastasis models in vivo.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('antimetastatic', 'CPA', (87, 101))	('rat', 'Species', '10116', (154, 157))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('tumour', 'Disease', (126, 132))	('cancer', 'Disease', (20, 26))	('suppressing', 'NegReg', (114, 125))	('PEDF', 'Var', (66, 70))
16672	12189555	Differential diagnosis between chronic pancreatitis and pancreatic cancer: value of the detection of KRAS2 mutations in circulating DNA KRAS2 mutations in codon 12 have been detected in about 80% of pancreatic cancers.	('mutations in', 'Var', (142, 154))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('pancreatic cancer', 'Disease', (56, 73))	('KRAS2', 'Gene', '3845', (136, 141))	('pancreatitis', 'Phenotype', 'HP:0001733', (39, 51))	('pancreatic cancers', 'Disease', 'MESH:D010190', (199, 217))	('pancreatitis', 'Disease', 'MESH:D010195', (39, 51))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (56, 73))	('pancreatitis', 'Disease', (39, 51))	('KRAS2', 'Gene', '3845', (101, 106))	('KRAS2', 'Gene', (136, 141))	('detected', 'Reg', (174, 182))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (31, 51))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (199, 217))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('mutations', 'Var', (107, 116))	('pancreatic cancer', 'Disease', 'MESH:D010190', (56, 73))	('pancreatic cancers', 'Disease', (199, 217))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('KRAS2', 'Gene', (101, 106))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))
16673	12189555	The aim of this study was to evaluate the value of KRAS2 mutations detection in circulating deoxyribo nucleic acid to differentiate pancreatic cancer from chronic pancreatitis.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('nucleic acid', 'cellular_component', 'GO:0005561', ('102', '114'))	('chronic pancreatitis', 'Disease', (155, 175))	('pancreatitis', 'Phenotype', 'HP:0001733', (163, 175))	('pancreatic cancer', 'Disease', (132, 149))	('pancreatic cancer', 'Disease', 'MESH:D010190', (132, 149))	('mutations', 'Var', (57, 66))	('KRAS2', 'Gene', (51, 56))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (155, 175))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (155, 175))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 149))	('KRAS2', 'Gene', '3845', (51, 56))
16675	12189555	Mutations at codon 12 of KRAS2 gene were searched for using polymerase chain reaction and allele specific amplification.	('KRAS2', 'Gene', '3845', (25, 30))	('Mutations', 'Var', (0, 9))	('KRAS2', 'Gene', (25, 30))
16677	12189555	KRAS2 mutations were found in 22 patients (47%) with pancreatic cancer and in four controls with chronic pancreatitis (13%) (P<0.002).	('chronic pancreatitis', 'Disease', 'MESH:D050500', (97, 117))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (97, 117))	('patients', 'Species', '9606', (33, 41))	('pancreatitis', 'Phenotype', 'HP:0001733', (105, 117))	('KRAS2', 'Gene', (0, 5))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (53, 70))	('chronic pancreatitis', 'Disease', (97, 117))	('KRAS2', 'Gene', '3845', (0, 5))	('pancreatic cancer', 'Disease', (53, 70))	('found', 'Reg', (21, 26))	('pancreatic cancer', 'Disease', 'MESH:D010190', (53, 70))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
16679	12189555	The sensitivity, specificity, positive and negative predictive values of serum serum KRAS2 mutations for the diagnosis of pancreatic cancer were 47, 87, 85 and 52%, respectively.	('pancreatic cancer', 'Disease', 'MESH:D010190', (122, 139))	('KRAS2', 'Gene', (85, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (122, 139))	('mutations', 'Var', (91, 100))	('KRAS2', 'Gene', '3845', (85, 90))	('pancreatic cancer', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
16680	12189555	KRAS2 mutations were not related to age, gender, smoking habit, tumour stage, or survival.	('KRAS2', 'Gene', (0, 5))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('KRAS2', 'Gene', '3845', (0, 5))	('mutations', 'Var', (6, 15))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
16681	12189555	Among the 26 patients with normal or non-contributive (due to cholestasis) serum carbohydrate antigen 19.9 levels, 14 (54%) had KRAS2 mutations.	('cholestasis', 'Disease', 'MESH:D002779', (62, 73))	('KRAS2', 'Gene', '3845', (128, 133))	('patients', 'Species', '9606', (13, 21))	('serum carbohydrate antigen 19.9 levels', 'MPA', (75, 113))	('mutations', 'Var', (134, 143))	('cholestasis', 'Disease', (62, 73))	('KRAS2', 'Gene', (128, 133))	('carbohydrate', 'Chemical', 'MESH:D002241', (81, 93))	('cholestasis', 'Phenotype', 'HP:0001396', (62, 73))
16683	12189555	Detection of KRAS2 mutations in circulating deoxyribo nucleic acid has a low sensitivity but a specificity about 90% for the diagnosis of pancreatic cancer.	('pancreatic cancer', 'Disease', (138, 155))	('KRAS2', 'Gene', (13, 18))	('pancreatic cancer', 'Disease', 'MESH:D010190', (138, 155))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('nucleic acid', 'cellular_component', 'GO:0005561', ('54', '66'))	('KRAS2', 'Gene', '3845', (13, 18))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))
16685	12189555	A combined normal serum carbohydrate antigen 19.9 and absence of circulating KRAS2 mutations makes the diagnosis of pancreatic cancer extremely unlikely.	('absence', 'NegReg', (54, 61))	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('KRAS2', 'Gene', (77, 82))	('carbohydrate', 'Chemical', 'MESH:D002241', (24, 36))	('KRAS2', 'Gene', '3845', (77, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('pancreatic cancer', 'Disease', (116, 133))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))
16691	12189555	Previous studies have reported KRAS2 gene mutations (almost always confined to codon 12) in 75 to 95% of exocrine pancreatic cancer (Caldas and Kern, 1995).	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('exocrine pancreatic cancer', 'Disease', (105, 131))	('KRAS2', 'Gene', (31, 36))	('mutations', 'Var', (42, 51))	('KRAS2', 'Gene', '3845', (31, 36))	('exocrine pancreatic cancer', 'Disease', 'MESH:D010190', (105, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))
16692	12189555	KRAS2 mutations provoke activation of nuclear transcriptor factors, resulting in cellular proliferation and also in tumour angiogenesis as reported recently (Banerjee et al, 2000; Ikeda et al, 2001).	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('KRAS2', 'Gene', (0, 5))	('tumour', 'Disease', (116, 122))	('cellular proliferation', 'CPA', (81, 103))	('KRAS2', 'Gene', '3845', (0, 5))	('activation', 'PosReg', (24, 34))	('angiogenesis', 'biological_process', 'GO:0001525', ('123', '135'))	('nuclear transcriptor factors', 'MPA', (38, 66))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('mutations', 'Var', (6, 15))
16693	12189555	Detection of KRAS2 mutations were first reported in surgically removed pancreatic tumoural tissue or at autopsy (Almoguera et al, 1988; Tada et al, 1991).	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('KRAS2', 'Gene', (13, 18))	('mutations', 'Var', (19, 28))	('KRAS2', 'Gene', '3845', (13, 18))	('pancreatic tumoural', 'Disease', (71, 90))	('pancreatic tumoural', 'Disease', 'MESH:D010190', (71, 90))	('pancreatic tumour', 'Phenotype', 'HP:0002894', (71, 88))
16694	12189555	Thereafter mutations were discovered in 63 to 83% of samples of pure pancreatic juice or main pancreatic duct brushing obtained during endoscopic retrograde pancreatography (Iguchi et al, 1996; Kondo et al, 1997; Tada et al, 1998; van Laethem et al, 1998; Okai et al, 1999; Watanabe et al, 1999; Ha et al, 2001; Pugliese et al, 2001; Seki et al, 2001) or at fine-needle tumour aspiration (Pabst et al, 1999; Puig et al, 2000), and in 20 to 54% of stools (Caldas et al, 1994; Wenger et al, 1999) from patients with pancreatic cancer.	('pancreatic', 'Disease', (69, 79))	('mutations', 'Var', (11, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (514, 531))	('pancreatic cancer', 'Disease', 'MESH:D010190', (514, 531))	('pure', 'molecular_function', 'GO:0034023', ('64', '68'))	('pancreatic', 'Disease', (94, 104))	('tumour', 'Disease', 'MESH:D009369', (370, 376))	('patients', 'Species', '9606', (500, 508))	('pancreatic', 'Disease', 'MESH:D010195', (514, 524))	('tumour', 'Disease', (370, 376))	('pancreatic', 'Disease', (514, 524))	('pancreatic cancer', 'Disease', (514, 531))	('aspiration', 'Phenotype', 'HP:0002835', (377, 387))	('pancreatic', 'Disease', 'MESH:D010195', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (525, 531))	('tumour', 'Phenotype', 'HP:0002664', (370, 376))	('pancreatic', 'Disease', 'MESH:D010195', (94, 104))
16695	12189555	Since then, mutations in the KRAS2 gene have been detected in the plasma of patients with colorectal, lung and haematological cancers (Anker et al, 1997).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('patients', 'Species', '9606', (76, 84))	('KRAS2', 'Gene', '3845', (29, 34))	('mutations', 'Var', (12, 21))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('detected', 'Reg', (50, 58))	('colorectal, lung and haematological cancers', 'Disease', 'MESH:D015179', (90, 133))	('KRAS2', 'Gene', (29, 34))
16696	12189555	To date, few studies have reported KRAS2 mutations in circulating DNA in patients with pancreatic cancer with a wide spectrum of sensitivity (27 to 81%) (Sorenson et al, 1994; Mulcahy et al, 1998; Yamada et al, 1998; Castells et al, 1999; Porta et al, 1999; Theodor et al, 2000).	('mutations', 'Var', (41, 50))	('KRAS2', 'Gene', '3845', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('pancreatic cancer', 'Disease', (87, 104))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('KRAS2', 'Gene', (35, 40))	('patients', 'Species', '9606', (73, 81))
16697	12189555	The aim of our study was to evaluate the value of KRAS2 mutation detection in circulating DNA in a large series of patients to differentiate pancreatic adenocarcinoma from chronic pancreatitis.	('KRAS2', 'Gene', (50, 55))	('patients', 'Species', '9606', (115, 123))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('pancreatitis', 'Phenotype', 'HP:0001733', (180, 192))	('chronic pancreatitis', 'Disease', (172, 192))	('KRAS2', 'Gene', '3845', (50, 55))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (141, 166))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (141, 166))	('pancreatic adenocarcinoma', 'Disease', (141, 166))	('mutation', 'Var', (56, 64))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (172, 192))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (172, 192))
16710	12189555	Only G12D mutations in codon 12 of the KRAS2 gene were searched for using allele-specific amplification, with the following primers: 5'-CTTGTGGTAGTTGGAGCTAA-3', 5'-AATGGTCCTGCACCAGTAATATG-3'.	('KRAS2', 'Gene', '3845', (39, 44))	('KRAS2', 'Gene', (39, 44))	('G12D', 'Mutation', 'rs121913529', (5, 9))	('G12D', 'Var', (5, 9))
16721	12189555	KRAS2 mutations were identified in the serum of 22 patients (47%) with pancreatic adenocarcinoma and in four patients (13%) with chronic pancreatitis (P<0.002).	('KRAS2', 'Gene', (0, 5))	('patients', 'Species', '9606', (109, 117))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (71, 96))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (129, 149))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (129, 149))	('pancreatitis', 'Phenotype', 'HP:0001733', (137, 149))	('patients', 'Species', '9606', (51, 59))	('KRAS2', 'Gene', '3845', (0, 5))	('chronic pancreatitis', 'Disease', (129, 149))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (71, 96))	('mutations', 'Var', (6, 15))	('pancreatic adenocarcinoma', 'Disease', (71, 96))
16722	12189555	The sensitivity, specificity, positive and negative predictive values of serum KRAS2 mutations for the diagnosis of pancreatic cancer were 47, 87, 85 and 52%, respectively.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('KRAS2', 'Gene', (79, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('mutations', 'Var', (85, 94))	('KRAS2', 'Gene', '3845', (79, 84))	('pancreatic cancer', 'Disease', (116, 133))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))
16723	12189555	There were no statistically significant differences in age, gender, smoking, tumour stage and survival, according to presence or absence of plasma KRAS2 mutations.	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('mutations', 'Var', (153, 162))	('KRAS2', 'Gene', (147, 152))	('tumour', 'Disease', (77, 83))	('KRAS2', 'Gene', '3845', (147, 152))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
16724	12189555	Among patients with chronic pancreatitis, no cancer occurred after a mean follow-up of 36 months (range 13-64), even in those with positive KRAS2 mutations (with follow-up of 40 months, range 20-61), assessed by clinical observation and abdominal computed tomography scan.	('KRAS2', 'Gene', (140, 145))	('chronic pancreatitis', 'Disease', (20, 40))	('mutations', 'Var', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('KRAS2', 'Gene', '3845', (140, 145))	('patients', 'Species', '9606', (6, 14))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (20, 40))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (20, 40))	('cancer', 'Disease', (45, 51))	('pancreatitis', 'Phenotype', 'HP:0001733', (28, 40))
16725	12189555	The sensitivity, specificity, positive and negative predictive values of abnormal Ca 19.9 levels for the diagnosis of pancreatic cancer were 91, 87, 91 and 87%, respectively (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (118, 135))	('abnormal', 'Var', (73, 81))	('pancreatic cancer', 'Disease', (118, 135))	('pancreatic cancer', 'Disease', 'MESH:D010190', (118, 135))
16729	12189555	In the present study, only the most frequent KRAS2 gene mutation G12D (aspartic acid) observed in pancreatic cancer (Iguchi et al, 1996; Tada et al, 1998; Castells et al, 1999; Watanabe et al, 1999) was analysed in the serum of patients and controls, in order to limit the cost of such test and to validate it in clinical practice.	('G12D', 'Mutation', 'rs121913529', (65, 69))	('aspartic acid', 'Chemical', 'MESH:D001224', (71, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (98, 115))	('patients', 'Species', '9606', (228, 236))	('G12D', 'Var', (65, 69))	('KRAS2', 'Gene', (45, 50))	('pancreatic cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('pancreatic cancer', 'Disease', 'MESH:D010190', (98, 115))	('KRAS2', 'Gene', '3845', (45, 50))
16730	12189555	Our study underlines the high feasibility of KRAS2 mutations analysis, as circulating DNA was obtained in sufficient quantities in all patients.	('patients', 'Species', '9606', (135, 143))	('mutations', 'Var', (51, 60))	('KRAS2', 'Gene', (45, 50))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('KRAS2', 'Gene', '3845', (45, 50))
16732	12189555	In the present study, detection of KRAS2 mutations in circulating DNA had a low sensitivity but a high specificity for the diagnosis of pancreatic cancer.	('mutations', 'Var', (41, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('KRAS2', 'Gene', '3845', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('KRAS2', 'Gene', (35, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('pancreatic cancer', 'Disease', (136, 153))
16734	12189555	Higher KRAS2 mutation prevalences have been reported in pancreatic or duodenal juice (63 to 87%), due probably to higher DNA tumour content in pancreatic juice as compared to plasma (Wilentz et al, 1998; van Laethem et al, 1998; Watanabe et al, 1999).	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('pancreatic', 'Disease', (56, 66))	('mutation', 'Var', (13, 21))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('KRAS2', 'Gene', (7, 12))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('pancreatic', 'Disease', 'MESH:D010195', (143, 153))	('pancreatic', 'Disease', (143, 153))	('KRAS2', 'Gene', '3845', (7, 12))	('tumour', 'Disease', (125, 131))	('pancreatic', 'Disease', 'MESH:D010195', (56, 66))	('higher', 'PosReg', (114, 120))
16736	12189555	Three studies have reported a higher specificity of serum KRAS2 mutations compared to the current study (100 vs 87%), but their control groups included few patients and essentially healthy subjects (Mulcahy et al, 1998; Porta et al, 1999; Theodor et al, 2000).	('patients', 'Species', '9606', (156, 164))	('specificity', 'MPA', (37, 48))	('KRAS2', 'Gene', (58, 63))	('mutations', 'Var', (64, 73))	('KRAS2', 'Gene', '3845', (58, 63))
16737	12189555	Since KRAS2 mutations have been reported in pancreatic tissue or juice from 6-42% of patients with chronic pancreatitis (Furuya et al, 1997; Mulligan et al, 1999; Luttges et al, 2000; Ha et al, 2001), and knowing that a part of this mutated DNA can be released into circulation (Yamada et al, 1998), the control group should include patients with chronic pancreatitis.	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (347, 367))	('pancreatitis', 'Phenotype', 'HP:0001733', (355, 367))	('KRAS2', 'Gene', (6, 11))	('mutations', 'Var', (12, 21))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (99, 119))	('chronic pancreatitis', 'Disease', (347, 367))	('pancreatic', 'Disease', 'MESH:D010195', (44, 54))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (99, 119))	('patients', 'Species', '9606', (333, 341))	('patients', 'Species', '9606', (85, 93))	('reported', 'Reg', (32, 40))	('pancreatic', 'Disease', (44, 54))	('KRAS2', 'Gene', '3845', (6, 11))	('chronic pancreatitis', 'Disease', (99, 119))	('pancreatitis', 'Phenotype', 'HP:0001733', (107, 119))	('DNA', 'cellular_component', 'GO:0005574', ('241', '244'))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (347, 367))
16739	12189555	The accuracy of serum KRAS2 mutation detection in the differential diagnosis between pancreatic cancer and chronic pancreatitis may be improved by performing quantitative PCR measurement of mutated DNA, in order to discriminate patients with unspecific low levels of mutated DNA (as supposed in chronic pancreatitis) from patients with high levels (pancreatic cancer), as suggested in pancreatic juice analysis by Tada et al (1998).	('KRAS2', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('pancreatic cancer', 'Disease', 'MESH:D010190', (349, 366))	('chronic pancreatitis', 'Disease', (107, 127))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (295, 315))	('mutation', 'Var', (28, 36))	('pancreatic', 'Disease', (85, 95))	('pancreatic', 'Disease', 'MESH:D010195', (385, 395))	('pancreatic cancer', 'Disease', (349, 366))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (107, 127))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('patients', 'Species', '9606', (322, 330))	('patients', 'Species', '9606', (228, 236))	('men', 'Species', '9606', (182, 185))	('chronic pancreatitis', 'Disease', (295, 315))	('pancreatic', 'Disease', (385, 395))	('pancreatic cancer', 'Disease', (85, 102))	('pancreatitis', 'Phenotype', 'HP:0001733', (115, 127))	('KRAS2', 'Gene', '3845', (22, 27))	('DNA', 'cellular_component', 'GO:0005574', ('198', '201'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (349, 366))	('pancreatic', 'Disease', 'MESH:D010195', (349, 359))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (295, 315))	('DNA', 'cellular_component', 'GO:0005574', ('275', '278'))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (107, 127))	('pancreatitis', 'Phenotype', 'HP:0001733', (303, 315))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('pancreatic', 'Disease', 'MESH:D010195', (85, 95))	('pancreatic', 'Disease', (349, 359))
16744	12189555	In the present study, the presence of KRAS2 mutations in serum was not correlated to age, gender and smoking habit.	('KRAS2', 'Gene', '3845', (38, 43))	('KRAS2', 'Gene', (38, 43))	('mutations', 'Var', (44, 53))
16745	12189555	It was neither correlated to tumour stage since mutations were detected in plasma of patients with non metastatic tumours, which supports the hypothesis that KRAS2 mutations are early events in pancreatic carcinogenesis (Jimenez et al, 1999).	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('tumour', 'Disease', (114, 120))	('tumours', 'Disease', (114, 121))	('tumour', 'Disease', (29, 35))	('men', 'Species', '9606', (223, 226))	('KRAS2', 'Gene', (158, 163))	('patients', 'Species', '9606', (85, 93))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('KRAS2', 'Gene', '3845', (158, 163))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('pancreatic carcinogenesis', 'Disease', (194, 219))	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('mutations', 'Var', (164, 173))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (194, 219))
16746	12189555	Two studies in the literature are in agreement with this result (Yamada et al, 1998; Theodor et al, 2000), but another one found a statistically significant relation between circulating DNA KRAS2 mutations and poor prognosis (Castells et al, 1999).	('poor prognosis', 'CPA', (210, 224))	('KRAS2', 'Gene', '3845', (190, 195))	('men', 'Species', '9606', (42, 45))	('DNA', 'cellular_component', 'GO:0005574', ('186', '189'))	('KRAS2', 'Gene', (190, 195))	('mutations', 'Var', (196, 205))
16747	12189555	Yamada et al (1998) have reported disappearance of detectable mutation in plasma after tumoural resection or radio-chemotherapy in six of nine patients, suggesting KRAS2 mutations may be used as a tumour relapse marker.	('tumour', 'Disease', 'MESH:D009369', (197, 203))	('tumour', 'Disease', (87, 93))	('mutations', 'Var', (170, 179))	('KRAS2', 'Gene', (164, 169))	('tumour', 'Disease', (197, 203))	('patients', 'Species', '9606', (143, 151))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('KRAS2', 'Gene', '3845', (164, 169))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))
16750	12189555	Three studies have evaluated occurrence of pancreatic cancer in patients with chronic pancreatitis with respect to KRAS2 mutations in pancreatic juice: only one found an increase in pancreatic cancer in patients with KRAS2 mutations with methodological limitations (few cases, early diagnosis of cancer after inclusion) (Furuya et al, 1997; Lohr et al, 2001; Queneau et al, 2001).	('pancreatic cancer', 'Disease', 'MESH:D010190', (182, 199))	('pancreatic', 'Disease', 'MESH:D010195', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('KRAS2', 'Gene', (115, 120))	('mutations', 'Var', (223, 232))	('pancreatitis', 'Phenotype', 'HP:0001733', (86, 98))	('pancreatic cancer', 'Disease', (182, 199))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (78, 98))	('pancreatic', 'Disease', (43, 53))	('KRAS2', 'Gene', (217, 222))	('patients', 'Species', '9606', (203, 211))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('pancreatic cancer', 'Disease', 'MESH:D010190', (43, 60))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('pancreatic', 'Disease', 'MESH:D010195', (134, 144))	('cancer', 'Disease', (54, 60))	('pancreatic', 'Disease', 'MESH:D010195', (182, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (182, 199))	('chronic pancreatitis', 'Disease', (78, 98))	('pancreatic cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('KRAS2', 'Gene', '3845', (115, 120))	('patients', 'Species', '9606', (64, 72))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (78, 98))	('pancreatic', 'Disease', (134, 144))	('pancreatic', 'Disease', (182, 192))	('cancer', 'Disease', (296, 302))	('KRAS2', 'Gene', '3845', (217, 222))
16751	12189555	To our knowledge, no study focused on the incidence of pancreatic cancer in patients with chronic pancreatitis according to serum KRAS2 mutations.	('patients', 'Species', '9606', (76, 84))	('KRAS2', 'Gene', (130, 135))	('chronic pancreatitis', 'Disease', (90, 110))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('pancreatic cancer', 'Disease', 'MESH:D010190', (55, 72))	('KRAS2', 'Gene', '3845', (130, 135))	('pancreatic cancer', 'Disease', (55, 72))	('pancreatitis', 'Phenotype', 'HP:0001733', (98, 110))	('mutations', 'Var', (136, 145))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (90, 110))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (90, 110))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))
16752	12189555	In the present study, follow-up was too short to demonstrate an increased risk of cancer in patients with chronic pancreatitis and serum KRAS2 mutations.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('chronic pancreatitis', 'Disease', (106, 126))	('KRAS2', 'Gene', (137, 142))	('patients', 'Species', '9606', (92, 100))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (106, 126))	('KRAS2', 'Gene', '3845', (137, 142))	('pancreatitis', 'Phenotype', 'HP:0001733', (114, 126))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (106, 126))	('mutations', 'Var', (143, 152))
16753	12189555	In conclusion, although detection of plasma KRAS2 mutations in circulating DNA is not a definitive argument for malignancy, it could contribute to cancer diagnosis.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('KRAS2', 'Gene', (44, 49))	('mutations', 'Var', (50, 59))	('contribute', 'Reg', (133, 143))	('men', 'Species', '9606', (103, 106))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('KRAS2', 'Gene', '3845', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('malignancy', 'Disease', 'MESH:D009369', (112, 122))	('cancer', 'Disease', (147, 153))	('malignancy', 'Disease', (112, 122))
16755	12189555	In patients with normal serum Ca 19.9 levels and no KRAS2 mutation, the diagnosis of pancreatic cancer can be excluded with almost certainty.	('pancreatic cancer', 'Disease', (85, 102))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutation', 'Var', (58, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('KRAS2', 'Gene', (52, 57))	('patients', 'Species', '9606', (3, 11))	('KRAS2', 'Gene', '3845', (52, 57))
16759	31630919	Pancreatic atrophy, calcifications, PD dilation and PD irregularity were observed in 80%, 68%, 65%, 58% cases, respectively.	('PD', 'Disease', 'MESH:D010300', (36, 38))	('irregularity', 'Var', (55, 67))	('Pancreatic atrophy', 'Disease', (0, 18))	('PD dilation', 'Disease', (36, 47))	('PD', 'Disease', 'MESH:D010300', (52, 54))	('Pancreatic atrophy', 'Disease', 'MESH:D010195', (0, 18))	('calcifications', 'Disease', (20, 34))	('PD dilation', 'Disease', 'MESH:D010300', (36, 47))
16887	33550277	High methylation of tumor suppressor genes can significantly inhibit the expression of genes and prevent them from exerting their ability to suppress tumors.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('ability', 'MPA', (130, 137))	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('expression of genes', 'MPA', (73, 92))	('inhibit', 'NegReg', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('High methylation', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('prevent', 'NegReg', (97, 104))	('methylation', 'biological_process', 'GO:0032259', ('5', '16'))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (20, 25))
16888	33550277	Effect, leading to unlimited growth of tumors; hypomethylation of oncogenes can activate oncogenes and promote tumor growth.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('hypomethylation', 'Var', (47, 62))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (111, 116))	('activate', 'PosReg', (80, 88))	('tumor', 'Disease', (39, 44))	('promote', 'PosReg', (103, 110))	('oncogenes', 'Protein', (89, 98))	('tumors', 'Disease', (39, 45))	('oncogenes', 'Gene', (66, 75))
16889	33550277	Aberrant DNA hypomethylation is one of the main abnormalities of tumor DNA methylation.	('DNA methylation', 'biological_process', 'GO:0006306', ('71', '86'))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('tumor', 'Disease', (65, 70))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('9', '28'))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Aberrant DNA', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
16890	33550277	Studies have reported that hypomethylation of the MYC and RAS promoter regions can lead to the activation of proto-oncogenes; hypomethylation of the IGF2 promoter region can lead to the loss of genetic imprinting.	('genetic imprinting', 'CPA', (194, 212))	('IGF2', 'Gene', '3481', (149, 153))	('hypomethylation', 'Var', (126, 141))	('MYC', 'Gene', '4609', (50, 53))	('loss', 'NegReg', (186, 190))	('IGF2', 'Gene', (149, 153))	('genetic imprinting', 'biological_process', 'GO:0071514', ('194', '212'))	('activation', 'PosReg', (95, 105))	('MYC', 'Gene', (50, 53))	('lead to', 'Reg', (83, 90))
16892	33550277	The chemical modification of DNA by endogenous and exogenous methylating agents (such as S-adenosylmethionine and N-methyl-N-nitrosourea) will produce a variety of genotoxic damage, of which N7- Methyl-2'-deoxyguanosine (m7dG) accounts for approximately 70-80% of total methylated lesions.	('m7dG', 'Chemical', '-', (221, 225))	("N7- Methyl-2'-deoxyguanosine", 'Chemical', 'MESH:C048746', (191, 219))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('age', 'Gene', '5973', (73, 76))	('genotoxic damage', 'Disease', (164, 180))	('chemical modification', 'Var', (4, 25))	('S-adenosylmethionine', 'Var', (89, 109))	('age', 'Gene', '5973', (177, 180))	('genotoxic damage', 'Disease', 'MESH:D009422', (164, 180))	('N-methyl-N-nitrosourea', 'Chemical', 'MESH:D008770', (114, 136))	('S-adenosylmethionine', 'Chemical', 'MESH:D012436', (89, 109))	('age', 'Gene', (73, 76))	('N7-', 'Var', (191, 194))	('age', 'Gene', (177, 180))	('produce', 'Reg', (143, 150))	('N-methyl-N-nitrosourea', 'Var', (114, 136))	('DNA', 'Gene', (29, 32))
16893	33550277	The N7 methylation of dG does not promote mutant replication, and the polbeta catalytic reaction across m7dG is slow but highly accurate.	('m7dG', 'Chemical', '-', (104, 108))	('polbeta', 'Enzyme', (70, 77))	('m7dG', 'Var', (104, 108))	('methylation', 'biological_process', 'GO:0032259', ('7', '18'))
16907	33550277	The results showed that a total of 646 DNA methylation gene loci were significantly correlated with PDAC OS (P<0.05).	('DNA methylation', 'biological_process', 'GO:0006306', ('39', '54'))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('methylation', 'Var', (43, 54))	('PDAC', 'Chemical', '-', (100, 104))	('correlated', 'Reg', (84, 94))	('PDAC', 'Phenotype', 'HP:0006725', (100, 104))	('PDAC OS', 'Disease', (100, 107))
16920	33550277	This revealed that the mutation rate of TGFBR2 was 9% in the high-risk group and 1% in the low-risk group.	('TGFBR2', 'Gene', (40, 46))	('TGFBR2', 'Gene', '7048', (40, 46))	('mutation', 'Var', (23, 31))
16921	33550277	The mutation rate of SMAD4 was 32% in the high-risk group and 16% in the low-risk group.	('SMAD4', 'Gene', '4089', (21, 26))	('mutation', 'Var', (4, 12))	('SMAD4', 'Gene', (21, 26))
16922	33550277	In addition, the enrichment analysis of these mutated genes in high-risk populations and other populations shows that there are differences in TGFBR2 and SMAD4 gene mutations between these two groups of patients (Figure 8).	('TGFBR2', 'Gene', (143, 149))	('SMAD4', 'Gene', (154, 159))	('patients', 'Species', '9606', (203, 211))	('TGFBR2', 'Gene', '7048', (143, 149))	('mutations', 'Var', (165, 174))	('differences', 'Reg', (128, 139))	('SMAD4', 'Gene', '4089', (154, 159))
16924	33550277	For example, low-risk patients of SMAD4 gene mutation can be treated with transcription factor complex, histone modification, transcription factor binding, and high-risk patients can also use clinically actionable on this basis.	('patients', 'Species', '9606', (170, 178))	('SMAD4', 'Gene', '4089', (34, 39))	('binding', 'Interaction', (147, 154))	('transcription factor', 'molecular_function', 'GO:0000981', ('74', '94'))	('histone modification', 'biological_process', 'GO:0016570', ('104', '124'))	('transcription', 'biological_process', 'GO:0006351', ('126', '139'))	('patients', 'Species', '9606', (22, 30))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('126', '154'))	('transcription', 'biological_process', 'GO:0006351', ('74', '87'))	('transcription factor complex', 'cellular_component', 'GO:0005667', ('74', '102'))	('mutation', 'Var', (45, 53))	('SMAD4', 'Gene', (34, 39))
16925	33550277	By analyzing the abovementioned mutated genes and the survival time of patients, it can be concluded that the higher the mutation rate of KRAS, CDKN2A, and TP53, the shorter the survival time of patients, with statistical significance (Figure 10).	('KRAS', 'Gene', (138, 142))	('KRAS', 'Gene', '3845', (138, 142))	('patients', 'Species', '9606', (71, 79))	('survival time', 'CPA', (178, 191))	('CDKN2A', 'Gene', (144, 150))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('shorter', 'NegReg', (166, 173))	('mutation', 'Var', (121, 129))	('patients', 'Species', '9606', (195, 203))	('CDKN2A', 'Gene', '1029', (144, 150))
16928	33550277	For example, the combination of SRPX2 and RAB31 may be an important prognostic marker for pancreatic cancer, with a 3-year AUC value of 0.748.	('combination', 'Var', (17, 28))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('SRPX2', 'Gene', (32, 37))	('RAB31', 'Gene', (42, 47))	('pancreatic cancer', 'Disease', (90, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('SRPX2', 'Gene', '27286', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('RAB31', 'Gene', '11031', (42, 47))
16934	33550277	Recently, epigenetic regulation was also shown to have an indispensable role in PDAC.	('regulation', 'biological_process', 'GO:0065007', ('21', '31'))	('PDAC', 'Chemical', '-', (80, 84))	('epigenetic regulation', 'Var', (10, 31))	('PDAC', 'Disease', (80, 84))	('PDAC', 'Phenotype', 'HP:0006725', (80, 84))
16935	33550277	Increasing evidence demonstrated that DNA methylation is closely related to the biogenesis and prognosis of a variety of tumor types.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('methylation', 'Var', (42, 53))	('DNA methylation', 'biological_process', 'GO:0006306', ('38', '53'))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('related', 'Reg', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
16937	33550277	Hypermethylation of the RASSF1A and BRCA1 promoters in circulating acellular tumor DNA is a biomarker for ovarian cancer.	('BRCA1', 'Gene', (36, 41))	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('Hypermethylation', 'Var', (0, 16))	('RASSF1A', 'Gene', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('ovarian cancer', 'Disease', (106, 120))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('RASSF1A', 'Gene', '11186', (24, 31))	('BRCA1', 'Gene', '672', (36, 41))	('tumor', 'Disease', (77, 82))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))
16938	33550277	SARDH methylation is an important prognostic factor for relapse-free survival in patients with RCC and has nothing to do with clinical prognosis, grade, stage, and metastatic status.	('age', 'Gene', '5973', (155, 158))	('SARDH', 'Gene', (0, 5))	('SARDH', 'Gene', '1757', (0, 5))	('patients', 'Species', '9606', (81, 89))	('relapse-free', 'Disease', (56, 68))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('RCC', 'Disease', (95, 98))	('age', 'Gene', (155, 158))	('methylation', 'Var', (6, 17))
16940	33550277	Experimental evidence shows that the methylation status of PCDH10 can predict the prognosis of patients with PDAC and has a significant effect on progression-free survival.	('predict', 'Reg', (70, 77))	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('PDAC', 'Disease', (109, 113))	('PDAC', 'Phenotype', 'HP:0006725', (109, 113))	('patients', 'Species', '9606', (95, 103))	('PCDH10', 'Gene', (59, 65))	('methylation status', 'Var', (37, 55))	('PCDH10', 'Gene', '57575', (59, 65))	('PDAC', 'Chemical', '-', (109, 113))	('effect', 'Reg', (136, 142))
16942	33550277	Patients with hypomethylated MUC1 and MUC4 have lower OS and thus these are potential prognostic biomarkers of PDAC.	('hypomethylated', 'Var', (14, 28))	('MUC4', 'Gene', (38, 42))	('MUC1', 'Gene', (29, 33))	('MUC1', 'Gene', '4582', (29, 33))	('lower', 'NegReg', (48, 53))	('PDAC', 'Chemical', '-', (111, 115))	('Patients', 'Species', '9606', (0, 8))	('MUC4', 'Gene', '4585', (38, 42))	('PDAC', 'Phenotype', 'HP:0006725', (111, 115))
16943	33550277	Hypomethylation of the SERPINB5 promoter distinguishes PDAC from pancreatitis.	('SERPINB5', 'Gene', '5268', (23, 31))	('PDAC', 'Phenotype', 'HP:0006725', (55, 59))	('SERPINB5', 'Gene', (23, 31))	('PDAC', 'Chemical', '-', (55, 59))	('Hypomethylation', 'Var', (0, 15))	('pancreatitis', 'Disease', (65, 77))	('distinguishes', 'Reg', (41, 54))	('PDAC', 'Disease', (55, 59))	('pancreatitis', 'Phenotype', 'HP:0001733', (65, 77))	('pancreatitis', 'Disease', 'MESH:D010195', (65, 77))
16947	33550277	Single-factor and multi-factor Cox analysis was performed to further verify these methylation sites and their predictive value in the prognosis of PDAC.	('PDAC', 'Chemical', '-', (147, 151))	('methylation', 'Var', (82, 93))	('Cox', 'Gene', '1351', (31, 34))	('PDAC', 'Disease', (147, 151))	('Cox', 'Gene', (31, 34))	('PDAC', 'Phenotype', 'HP:0006725', (147, 151))	('methylation', 'biological_process', 'GO:0032259', ('82', '93'))
16952	33550277	Inhibition of ITGB3 expression can upregulate miR-124-3p and downregulate the expression of lncRNA-H19, thereby inhibiting the proliferation and invasion of ectopic endometrial cells and providing a new target for the treatment of endometriosis.	('endometriosis', 'Disease', (231, 244))	('lncRNA-H19', 'Gene', (92, 102))	('endometriosis', 'Phenotype', 'HP:0030127', (231, 244))	('expression', 'MPA', (78, 88))	('proliferation', 'CPA', (127, 140))	('downregulate', 'NegReg', (61, 73))	('miR-124-3p', 'Gene', '406909', (46, 56))	('ITGB3', 'Gene', '3690', (14, 19))	('ITGB3', 'Gene', (14, 19))	('miR-124-3p', 'Gene', (46, 56))	('Inhibition', 'Var', (0, 10))	('upregulate', 'PosReg', (35, 45))	('endometriosis', 'Disease', 'MESH:D004715', (231, 244))	('invasion', 'CPA', (145, 153))	('inhibiting', 'NegReg', (112, 122))
16953	33550277	Inhibiting the expression of ITGB3 can increase the expression of miR-124-3p and thus inhibit the migration and invasion of gastric cancer, suggesting that miR-124-3p and ITGB3 may also be promising therapeutic targets for gastric cancer.	('Inhibiting', 'Var', (0, 10))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('miR-124-3p', 'Gene', (156, 166))	('increase', 'PosReg', (39, 47))	('inhibit', 'NegReg', (86, 93))	('ITGB3', 'Gene', '3690', (29, 34))	('gastric cancer', 'Disease', 'MESH:D013274', (223, 237))	('ITGB3', 'Gene', (29, 34))	('ITGB3', 'Gene', '3690', (171, 176))	('miR-124-3p', 'Gene', (66, 76))	('ITGB3', 'Gene', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('gastric cancer', 'Disease', (124, 138))	('gastric cancer', 'Phenotype', 'HP:0012126', (223, 237))	('gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('miR-124-3p', 'Gene', '406909', (156, 166))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('expression', 'MPA', (52, 62))	('gastric cancer', 'Disease', (223, 237))	('miR-124-3p', 'Gene', '406909', (66, 76))
16955	33550277	The G-888C polymorphism of the SDS (also known as SDH) gene may be related to the occurrence of diabetic retinopathy and has nothing to do with its progress.	('SDS', 'Gene', (31, 34))	('related', 'Reg', (67, 74))	('G-888C', 'Mutation', 'rs3759890', (4, 10))	('SDH', 'Gene', '1757', (50, 53))	('diabetic retinopathy', 'Disease', 'MESH:D003920', (96, 116))	('diabetic retinopathy', 'Disease', (96, 116))	('G-888C', 'Var', (4, 10))	('SDS', 'Chemical', 'MESH:D012967', (31, 34))	('SDH', 'Gene', (50, 53))	('retinopathy', 'Phenotype', 'HP:0000488', (105, 116))
16956	33550277	Its effect may be enhanced by interactions with the C-1214G polymorphism, but this weak association requires further study.	('C-1214G', 'Mutation', 'rs2055858', (52, 59))	('interactions', 'Interaction', (30, 42))	('C-1214G', 'Var', (52, 59))	('enhanced', 'PosReg', (18, 26))
16957	33550277	Cancer is closely related to genetic mutations.	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('genetic mutations', 'Var', (29, 46))
16958	33550277	Although gene mutations are not enough to become a necessary condition for cancer development, the process of cancer is the common result of gene mutations, epigenetic regulation, and external factors.	('cancer', 'Disease', (110, 116))	('gene mutations', 'Var', (141, 155))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('epigenetic regulation', 'Var', (157, 178))	('regulation', 'biological_process', 'GO:0065007', ('168', '178'))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('result', 'Reg', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
16959	33550277	Next-generation sequencing analysis of 50 cancer-related gene mutations, including driver genes in PDAC, found that the combination of KRAS and SMAD4 mutations is an independent adverse prognostic factor in PDAC.	('PDAC', 'Disease', (207, 211))	('PDAC', 'Chemical', '-', (99, 103))	('SMAD4', 'Gene', '4089', (144, 149))	('PDAC', 'Phenotype', 'HP:0006725', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('KRAS', 'Gene', (135, 139))	('KRAS', 'Gene', '3845', (135, 139))	('PDAC', 'Phenotype', 'HP:0006725', (99, 103))	('SMAD4', 'Gene', (144, 149))	('cancer', 'Disease', (42, 48))	('mutations', 'Var', (150, 159))	('PDAC', 'Chemical', '-', (207, 211))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('mutations', 'Var', (62, 71))
16961	33550277	Identifying this previously unknown mutation may help researchers to routinely test individuals with a strong family history of pancreatic cancer to determine whether they carry a mutation in the relevant gene, RABL3.	('RABL3', 'Gene', (211, 216))	('pancreatic cancer', 'Disease', 'MESH:D010190', (128, 145))	('pancreatic cancer', 'Disease', (128, 145))	('RABL3', 'Gene', '285282', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (128, 145))	('mutation', 'Var', (180, 188))
16963	33550277	In PDAC, KRAS gene mutations are closely related to its development.	('PDAC', 'Chemical', '-', (3, 7))	('KRAS', 'Gene', (9, 13))	('mutations', 'Var', (19, 28))	('PDAC', 'Phenotype', 'HP:0006725', (3, 7))	('KRAS', 'Gene', '3845', (9, 13))	('related', 'Reg', (41, 48))
16966	33550277	Although the functional mechanism of these four genes requires further study, the degree of methylation has a significant correlation with the prognosis of patients with PDAC and can be used as a potential therapeutic target for PDAC, thereby optimizing the treatment plan and prolonging the survival time of patients.	('patients', 'Species', '9606', (156, 164))	('PDAC', 'Phenotype', 'HP:0006725', (229, 233))	('methylation', 'Var', (92, 103))	('survival time', 'CPA', (292, 305))	('correlation', 'Reg', (122, 133))	('PDAC', 'Chemical', '-', (170, 174))	('methylation', 'biological_process', 'GO:0032259', ('92', '103'))	('prolonging', 'PosReg', (277, 287))	('PDAC', 'Chemical', '-', (229, 233))	('patients', 'Species', '9606', (309, 317))	('PDAC', 'Disease', (170, 174))	('PDAC', 'Phenotype', 'HP:0006725', (170, 174))
16975	33550277	One-way Cox proportional hazard model analysis of the training dataset identified several significant methylation genes as candidate markers correlated with PDAC prognosis.	('methylation', 'biological_process', 'GO:0032259', ('102', '113'))	('correlated', 'Reg', (141, 151))	('PDAC', 'Disease', (157, 161))	('PDAC', 'Phenotype', 'HP:0006725', (157, 161))	('methylation genes', 'Var', (102, 119))	('Cox', 'Gene', '1351', (8, 11))	('Cox', 'Gene', (8, 11))	('PDAC', 'Chemical', '-', (157, 161))
16983	33099898	This randomized phase 2 trial evaluated nal-IRI+5-FU/LV tolerability (Part 1), safety, and efficacy (Part 2; outcomes reported here) in Japanese patients with mPAC that progressed on gemcitabine-based therapy.	('nal-IRI+5-FU/LV', 'Var', (40, 55))	('mPAC', 'Disease', (159, 163))	('patients', 'Species', '9606', (145, 153))	('nal-IRI', 'Chemical', '-', (40, 47))	('LV', 'Chemical', 'MESH:D058766', (53, 55))	('5-FU', 'Chemical', 'MESH:D005472', (48, 52))	('PAC', 'Phenotype', 'HP:0002894', (160, 163))	('gemcitabine', 'Chemical', 'MESH:C056507', (183, 194))	('PAC', 'Phenotype', 'HP:0006699', (160, 163))	('mPAC', 'Chemical', '-', (159, 163))
16984	33099898	Patients were randomized 1:1 and stratified by KPS (70 and 80 vs. >=90) and baseline albumin (>=4.0 g/dl vs. <4.0 g/dl).	('>=4.0', 'Var', (94, 99))	('albumin', 'Gene', '213', (85, 92))	('albumin', 'Gene', (85, 92))	('Patients', 'Species', '9606', (0, 8))
16988	33099898	Investigator-assessed mPFS increase with nal-IRI+5-FU/LV was clinically meaningful and statistically significant versus 5-FU/LV (2.7 vs. 1.5 months, HR = 0.60).	('LV', 'Chemical', 'MESH:D058766', (125, 127))	('5-FU', 'Chemical', 'MESH:D005472', (120, 124))	('nal-IRI+5-FU/LV', 'Var', (41, 56))	('mPFS', 'CPA', (22, 26))	('LV', 'Chemical', 'MESH:D058766', (54, 56))	('5-FU', 'Chemical', 'MESH:D005472', (49, 53))	('nal-IRI', 'Chemical', '-', (41, 48))	('increase', 'PosReg', (27, 35))
16989	33099898	mOS was 6.3 months with nal-IRI+5-FU/LV and not reached with 5-FU/LV.	('mOS', 'Gene', (0, 3))	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('LV', 'Chemical', 'MESH:D058766', (37, 39))	('mOS', 'Gene', '17451', (0, 3))	('nal-IRI+5-FU/LV', 'Var', (24, 39))	('nal-IRI', 'Chemical', '-', (24, 31))	('LV', 'Chemical', 'MESH:D058766', (66, 68))	('5-FU', 'Chemical', 'MESH:D005472', (32, 36))
16990	33099898	ORR increased significantly with nal-IRI+5-FU/LV versus 5-FU/LV (18% vs. 0, rate difference 17.5).	('5-FU', 'Chemical', 'MESH:D005472', (41, 45))	('ORR', 'MPA', (0, 3))	('LV', 'Chemical', 'MESH:D058766', (46, 48))	('LV', 'Chemical', 'MESH:D058766', (61, 63))	('5-FU', 'Chemical', 'MESH:D005472', (56, 60))	('nal-IRI+5-FU/LV', 'Var', (33, 48))	('nal-IRI', 'Chemical', '-', (33, 40))
16992	33099898	In conclusion, clinically meaningful and statistically significant gains in investigator-assessed PFS and ORR were observed with nal-IRI+5-FU/LV versus 5-FU/LV in Japanese patients, with no new or unexpected safety signals.	('nal-IRI', 'Chemical', '-', (129, 136))	('LV', 'Chemical', 'MESH:D058766', (142, 144))	('PFS', 'CPA', (98, 101))	('ORR', 'MPA', (106, 109))	('gains', 'PosReg', (67, 72))	('5-FU', 'Chemical', 'MESH:D005472', (152, 156))	('patients', 'Species', '9606', (172, 180))	('LV', 'Chemical', 'MESH:D058766', (157, 159))	('nal-IRI+5-FU/LV', 'Var', (129, 144))	('5-FU', 'Chemical', 'MESH:D005472', (137, 141))
16994	33099898	This randomized phase 2 trial demonstrated clinically meaningful and statistically significant gains in investigator-assessed progression-free survival and objective response rate with nal-IRI+5-FU/LV vs 5-FU/LV in Japanese patients.	('progression-free survival', 'CPA', (126, 151))	('nal-IRI+5-FU/LV', 'Var', (185, 200))	('nal-IRI', 'Chemical', '-', (185, 192))	('LV', 'Chemical', 'MESH:D058766', (209, 211))	('LV', 'Chemical', 'MESH:D058766', (198, 200))	('5-FU', 'Chemical', 'MESH:D005472', (193, 197))	('objective response', 'CPA', (156, 174))	('patients', 'Species', '9606', (224, 232))	('gains', 'PosReg', (95, 100))	('5-FU', 'Chemical', 'MESH:D005472', (204, 208))
17007	33099898	nal-IRI exhibits a lower maximum concentration of free irinotecan in plasma, a longer half-life and an increased area under the curve in plasma for SN-38 compared with non-liposomal irinotecan.	('nal-IRI', 'Var', (0, 7))	('maximum concentration', 'MPA', (25, 46))	('increased', 'PosReg', (103, 112))	('area', 'MPA', (113, 117))	('nal-IRI', 'Chemical', '-', (0, 7))	('irinotecan', 'Chemical', 'MESH:D000077146', (182, 192))	('half-life', 'MPA', (86, 95))	('longer', 'PosReg', (79, 85))	('irinotecan', 'Chemical', 'MESH:D000077146', (55, 65))	('lower', 'NegReg', (19, 24))	('SN-38', 'Chemical', 'MESH:D000077146', (148, 153))
17009	33099898	19 ,  21 ,  23   In the global NAPOLI-1 phase 3 trial, nal-IRI+5-FU/LV significantly increased median OS versus 5-FU/LV (median OS: 6.1 vs. 4.2 months; unstratified hazard ratio [HR] = 0.67; p = 0.012) in patients with metastatic pancreatic ductal adenocarcinoma that progressed after gemcitabine-based therapy.	('patients', 'Species', '9606', (205, 213))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (230, 262))	('OS', 'Gene', '17451', (128, 130))	('gemcitabine', 'Chemical', 'MESH:C056507', (285, 296))	('nal-IRI+5-FU/LV', 'Var', (55, 70))	('nal-IRI', 'Chemical', '-', (55, 62))	('5-FU', 'Chemical', 'MESH:D005472', (63, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('LV', 'Chemical', 'MESH:D058766', (68, 70))	('increased', 'PosReg', (85, 94))	('pancreatic ductal adenocarcinoma', 'Disease', (230, 262))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (230, 262))	('OS', 'Gene', '17451', (102, 104))	('LV', 'Chemical', 'MESH:D058766', (117, 119))	('5-FU', 'Chemical', 'MESH:D005472', (112, 116))
17019	33099898	In Part 2, patients were randomized 1:1 between the two treatment arms following stratification for Karnofsky Performance Status (KPS; 70 and 80 vs. >=90) and baseline albumin levels (>=4.0 g/dl vs. <4.0 g/dl).	('patients', 'Species', '9606', (11, 19))	('>=4.0', 'Var', (184, 189))	('albumin', 'Gene', (168, 175))	('albumin', 'Gene', '213', (168, 175))
17028	33099898	Additional inclusion criteria were KPS >=70, adequate bone marrow reserves, liver and renal function, and documented disease progression after prior gemcitabine or any gemcitabine-containing therapy (excluding conventional irinotecan) in a locally advanced or metastatic setting.	('bone marrow reserves', 'CPA', (54, 74))	('gemcitabine', 'Chemical', 'MESH:C056507', (168, 179))	('irinotecan', 'Chemical', 'MESH:D000077146', (223, 233))	('gemcitabine', 'Chemical', 'MESH:C056507', (149, 160))	('KPS >=70', 'Var', (35, 43))
17055	33099898	None of the patients in the nal-IRI+5-FU/LV arm presented with Gilbert syndrome or had clear suggestive symptoms of the disease in their medical history.	('patients', 'Species', '9606', (12, 20))	('symptoms of the disease', 'Disease', (104, 127))	('nal-IRI+5-FU/LV', 'Var', (28, 43))	('nal-IRI', 'Chemical', '-', (28, 35))	('Gilbert syndrome', 'Disease', (63, 79))	('5-FU', 'Chemical', 'MESH:D005472', (36, 40))	('LV', 'Chemical', 'MESH:D058766', (41, 43))	('symptoms of the disease', 'Disease', 'MESH:D009202', (104, 127))	('Gilbert syndrome', 'Disease', 'MESH:D005878', (63, 79))
17059	33099898	According to independent assessment, patients in the nal-IRI+5-FU/LV arm achieved a median PFS of 1.7 months (95% CI: 1.5-3.6) with nal-IRI+5-FU/LV and 1.6 months (1.4-1.6) with 5-FU/LV (HR = 0.79, p = 0.376; see Figure 2B and Table 2).	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('LV', 'Chemical', 'MESH:D058766', (145, 147))	('5-FU', 'Chemical', 'MESH:D005472', (140, 144))	('patients', 'Species', '9606', (37, 45))	('LV', 'Chemical', 'MESH:D058766', (183, 185))	('5-FU', 'Chemical', 'MESH:D005472', (178, 182))	('nal-IRI+5-FU/LV', 'Var', (132, 147))	('nal-IRI', 'Chemical', '-', (132, 139))	('PFS', 'MPA', (91, 94))	('LV', 'Chemical', 'MESH:D058766', (66, 68))	('nal-IRI', 'Chemical', '-', (53, 60))
17062	33099898	Results from a sensitivity analysis excluding the six patients who were heterozygous or homozygous for UGT1A1*6 or UGT1A1*28 mutations showed no significant change in independently assessed PFS outcomes in either study arm (nal-IRI+5-FU/LV vs. 5-FU/LV: 1.7 vs. 1.5 months, HR 0.68 [95% CI 0.40-1.19], p = 0.177).	('5-FU', 'Chemical', 'MESH:D005472', (232, 236))	('mutations', 'Var', (125, 134))	('5-FU', 'Chemical', 'MESH:D005472', (244, 248))	('UGT1A1', 'Gene', '54658', (103, 109))	('patients', 'Species', '9606', (54, 62))	('UGT1A1', 'Gene', '54658', (115, 121))	('LV', 'Chemical', 'MESH:D058766', (249, 251))	('nal-IRI', 'Chemical', '-', (224, 231))	('UGT1A1', 'Gene', (103, 109))	('PFS', 'Disease', (190, 193))	('UGT1A1', 'Gene', (115, 121))	('LV', 'Chemical', 'MESH:D058766', (237, 239))
17073	33099898	More patients treated with nal-IRI+5-FU/LV achieved a CA19-9 response compared with those receiving 5-FU/LV (18% vs. 4%; see Figure 3 and Table 2), although this difference was not statistically significant (p = 0.193).	('patients', 'Species', '9606', (5, 13))	('nal-IRI+5-FU/LV', 'Var', (27, 42))	('5-FU', 'Chemical', 'MESH:D005472', (100, 104))	('LV', 'Chemical', 'MESH:D058766', (40, 42))	('LV', 'Chemical', 'MESH:D058766', (105, 107))	('CA19-9 response', 'MPA', (54, 69))	('nal-IRI', 'Chemical', '-', (27, 34))	('5-FU', 'Chemical', 'MESH:D005472', (35, 39))
17077	33099898	However, the proportion of patients receiving treatment for >=12 or >=18 weeks in the nal-IRI+5-FU/LV arm was approximately twofold higher than in the 5-FU/LV arm.	('higher', 'PosReg', (132, 138))	('5-FU', 'Chemical', 'MESH:D005472', (151, 155))	('nal-IRI+5-FU/LV', 'Var', (86, 101))	('LV', 'Chemical', 'MESH:D058766', (156, 158))	('nal-IRI', 'Chemical', '-', (86, 93))	('patients', 'Species', '9606', (27, 35))	('LV', 'Chemical', 'MESH:D058766', (99, 101))	('5-FU', 'Chemical', 'MESH:D005472', (94, 98))
17078	33099898	Overall, TEAEs were in the "Blood and lymphatic system disorders" or "gastrointestinal disorders" system-organ classes and were more frequent in patients receiving nal-IRI+5-FU/LV than in those who were administered 5-FU/LV; grade >=3 TEAEs occurred more frequently in 78% versus 37% patients (Table 4).	('patients', 'Species', '9606', (145, 153))	('nal-IRI+5-FU/LV', 'Var', (164, 179))	('nal-IRI', 'Chemical', '-', (164, 171))	('patients', 'Species', '9606', (284, 292))	('LV', 'Chemical', 'MESH:D058766', (177, 179))	('5-FU', 'Chemical', 'MESH:D005472', (216, 220))	('LV', 'Chemical', 'MESH:D058766', (221, 223))	('TEAEs', 'Disease', (9, 14))	('5-FU', 'Chemical', 'MESH:D005472', (172, 176))	('system disorders', 'Disease', 'MESH:D034721', (48, 64))	('gastrointestinal disorders', 'Disease', (70, 96))	('lymphatic system disorders', 'Phenotype', 'HP:0100763', (38, 64))	('gastrointestinal disorders', 'Phenotype', 'HP:0011024', (70, 96))	('gastrointestinal disorders', 'Disease', 'MESH:D005767', (70, 96))	('system disorders', 'Disease', (48, 64))
17081	33099898	Neutropenia of any grade occurred in 11% of patients receiving nal-IRI+5-FU/LV and none receiving 5-FU/LV.	('5-FU', 'Chemical', 'MESH:D005472', (71, 75))	('Neutropenia', 'Disease', 'MESH:D009503', (0, 11))	('patients', 'Species', '9606', (44, 52))	('nal-IRI+5-FU/LV', 'Var', (63, 78))	('nal-IRI', 'Chemical', '-', (63, 70))	('LV', 'Chemical', 'MESH:D058766', (76, 78))	('Neutropenia', 'Phenotype', 'HP:0001875', (0, 11))	('LV', 'Chemical', 'MESH:D058766', (103, 105))	('Neutropenia', 'Disease', (0, 11))	('5-FU', 'Chemical', 'MESH:D005472', (98, 102))
17083	33099898	Grade 3 and grade 4 treatment-related TEAEs were recorded in patients with mutations in UGT1A1 (homozygous UGT1A1*28, homozygous UGTA1A1*6, or heterozygous UGT1A1*28/*6; n = 3 in each arm).	('UGT1A1', 'Gene', '54658', (107, 113))	('patients', 'Species', '9606', (61, 69))	('UGT1A1', 'Gene', (107, 113))	('UGT1A1', 'Gene', '54658', (88, 94))	('mutations', 'Var', (75, 84))	('UGT1A1', 'Gene', '54658', (156, 162))	('UGT1A1', 'Gene', (88, 94))	('UGT1A1', 'Gene', (156, 162))
17084	33099898	All three patients in the nal-IRI+5-FU/LV arm had grade >=3 neutrophil count decreased, with one patient developing grade >=3 neutropenia; none of the three patients developed grade >=3 diarrhea.	('nal-IRI+5-FU/LV', 'Var', (26, 41))	('nal-IRI', 'Chemical', '-', (26, 33))	('patient', 'Species', '9606', (157, 164))	('neutropenia', 'Disease', 'MESH:D009503', (126, 137))	('LV', 'Chemical', 'MESH:D058766', (39, 41))	('neutrophil count decreased', 'Phenotype', 'HP:0001875', (60, 86))	('5-FU', 'Chemical', 'MESH:D005472', (34, 38))	('neutropenia', 'Phenotype', 'HP:0001875', (126, 137))	('patient', 'Species', '9606', (10, 17))	('patients', 'Species', '9606', (157, 165))	('diarrhea', 'Phenotype', 'HP:0002014', (186, 194))	('diarrhea', 'Disease', 'MESH:D003967', (186, 194))	('patient', 'Species', '9606', (97, 104))	('patients', 'Species', '9606', (10, 18))	('diarrhea', 'Disease', (186, 194))	('neutropenia', 'Disease', (126, 137))	('decreased', 'NegReg', (77, 86))
17085	33099898	TEAEs of any grade leading to dose modifications were more frequent in patients in the nal-IRI+5-FU/LV arm than in those in the 5-FU/LV arm (76% vs. 32%; see Table S3).	('TEAEs', 'Disease', (0, 5))	('LV', 'Chemical', 'MESH:D058766', (100, 102))	('5-FU', 'Chemical', 'MESH:D005472', (95, 99))	('dose modifications', 'MPA', (30, 48))	('patients', 'Species', '9606', (71, 79))	('5-FU', 'Chemical', 'MESH:D005472', (128, 132))	('nal-IRI+5-FU/LV', 'Var', (87, 102))	('nal-IRI', 'Chemical', '-', (87, 94))	('LV', 'Chemical', 'MESH:D058766', (133, 135))
17087	33099898	In patients receiving nal-IRI+5-FU/LV, decreased white blood cell count (46%), decreased neutrophil count (44%), and diarrhea (11%) were the most frequent TEAEs leading to dose delay.	('LV', 'Chemical', 'MESH:D058766', (35, 37))	('5-FU', 'Chemical', 'MESH:D005472', (30, 34))	('decreased', 'NegReg', (79, 88))	('white blood cell count', 'MPA', (49, 71))	('decreased neutrophil count', 'Phenotype', 'HP:0001875', (79, 105))	('diarrhea', 'Phenotype', 'HP:0002014', (117, 125))	('neutrophil count', 'MPA', (89, 105))	('diarrhea', 'Disease', 'MESH:D003967', (117, 125))	('diarrhea', 'Disease', (117, 125))	('patients', 'Species', '9606', (3, 11))	('nal-IRI+5-FU/LV', 'Var', (22, 37))	('decreased', 'NegReg', (39, 48))	('decreased white blood cell count', 'Phenotype', 'HP:0001882', (39, 71))	('nal-IRI', 'Chemical', '-', (22, 29))
17091	33099898	In patients receiving nal-IRI+5-FU/LV, four (9%) TEAEs with fatal outcome were reported: one due to infection (2%) and three due to progression of pancreatic carcinoma (7%; see Table S3).	('LV', 'Chemical', 'MESH:D058766', (35, 37))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (147, 167))	('5-FU', 'Chemical', 'MESH:D005472', (30, 34))	('TEAEs', 'Disease', (49, 54))	('infection', 'Disease', (100, 109))	('patients', 'Species', '9606', (3, 11))	('infection', 'Disease', 'MESH:D007239', (100, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('nal-IRI+5-FU/LV', 'Var', (22, 37))	('pancreatic carcinoma', 'Disease', (147, 167))	('nal-IRI', 'Chemical', '-', (22, 29))
17093	33099898	As previously discussed, in the NAPOLI-1 phase 3 study, nal-IRI+5-FU/LV significantly increased PFS and OS compared with 5-FU/LV in patients with mPAC that progressed on prior gemcitabine-based therapy.	('PAC', 'Phenotype', 'HP:0006699', (147, 150))	('PAC', 'Phenotype', 'HP:0002894', (147, 150))	('LV', 'Chemical', 'MESH:D058766', (69, 71))	('increased', 'PosReg', (86, 95))	('OS', 'Gene', '17451', (104, 106))	('PFS', 'MPA', (96, 99))	('nal-IRI+5-FU/LV', 'Var', (56, 71))	('nal-IRI', 'Chemical', '-', (56, 63))	('LV', 'Chemical', 'MESH:D058766', (126, 128))	('5-FU', 'Chemical', 'MESH:D005472', (121, 125))	('gemcitabine', 'Chemical', 'MESH:C056507', (176, 187))	('mPAC', 'Chemical', '-', (146, 150))	('patients', 'Species', '9606', (132, 140))	('5-FU', 'Chemical', 'MESH:D005472', (64, 68))
17094	33099898	27  In the current study, independently assessed median PFS was slightly longer with nal-IRI+5-FU/LV versus 5-FU/LV (1.7 vs. 1.6 months).	('nal-IRI+5-FU/LV', 'Var', (85, 100))	('nal-IRI', 'Chemical', '-', (85, 92))	('5-FU', 'Chemical', 'MESH:D005472', (108, 112))	('LV', 'Chemical', 'MESH:D058766', (98, 100))	('LV', 'Chemical', 'MESH:D058766', (113, 115))	('5-FU', 'Chemical', 'MESH:D005472', (93, 97))	('PFS', 'MPA', (56, 59))	('longer', 'PosReg', (73, 79))
17095	33099898	Importantly, investigator-assessed median PFS was significantly increased with nal-IRI+5-FU/LV compared with 5-FU/LV.	('LV', 'Chemical', 'MESH:D058766', (114, 116))	('nal-IRI+5-FU/LV', 'Var', (79, 94))	('5-FU', 'Chemical', 'MESH:D005472', (87, 91))	('LV', 'Chemical', 'MESH:D058766', (92, 94))	('PFS', 'CPA', (42, 45))	('nal-IRI', 'Chemical', '-', (79, 86))	('increased', 'PosReg', (64, 73))	('5-FU', 'Chemical', 'MESH:D005472', (109, 113))
17097	33099898	nal-IRI+5-FU/LV increased ORR, DCR, TTF, and CA19-9 response versus 5-FU/LV, with ORR reaching statistical significance.	('DCR', 'MPA', (31, 34))	('5-FU', 'Chemical', 'MESH:D005472', (68, 72))	('LV', 'Chemical', 'MESH:D058766', (73, 75))	('nal-IRI+5-FU/LV', 'Var', (0, 15))	('nal-IRI', 'Chemical', '-', (0, 7))	('increased', 'PosReg', (16, 25))	('TTF', 'MPA', (36, 39))	('LV', 'Chemical', 'MESH:D058766', (13, 15))	('CA19-9 response', 'MPA', (45, 60))	('ORR', 'MPA', (26, 29))	('5-FU', 'Chemical', 'MESH:D005472', (8, 12))
17108	33099898	The proportion of patients with a minimum time on treatment of >=12 or >=18 weeks was markedly lower in the 5-FU/LV arm compared with the nal-IRI+5-FU/LV arm.	('lower', 'NegReg', (95, 100))	('nal-IRI', 'Chemical', '-', (138, 145))	('5-FU', 'Chemical', 'MESH:D005472', (108, 112))	('LV', 'Chemical', 'MESH:D058766', (113, 115))	('5-FU', 'Chemical', 'MESH:D005472', (146, 150))	('patients', 'Species', '9606', (18, 26))	('5-FU/LV', 'Var', (108, 115))	('LV', 'Chemical', 'MESH:D058766', (151, 153))
17109	33099898	We hypothesize that patients in the 5-FU/LV arm likely experienced earlier disease progression than those in the nal-IRI+5-FU/LV arm and proceeded to efficacious post-study anticancer therapy sooner, thereby increasing their survival time.	('nal-IRI', 'Chemical', '-', (113, 120))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('5-FU/LV', 'Var', (36, 43))	('LV', 'Chemical', 'MESH:D058766', (41, 43))	('disease progression', 'CPA', (75, 94))	('LV', 'Chemical', 'MESH:D058766', (126, 128))	('5-FU', 'Chemical', 'MESH:D005472', (121, 125))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('5-FU', 'Chemical', 'MESH:D005472', (36, 40))	('survival', 'CPA', (225, 233))	('increasing', 'PosReg', (208, 218))
17113	33099898	In terms of number of prior lines of therapy, a lower proportion of patients in the NAPOLI-1 trial had received 0-1 prior lines of metastatic therapy compared with the present study (66% vs. 85% for nal-IRI+5-FU/LV; 69% vs. 71.8% for 5-FU/LV).	('NAPOLI-1', 'Gene', (84, 92))	('5-FU', 'Chemical', 'MESH:D005472', (234, 238))	('nal-IRI+5-FU/LV', 'Var', (199, 214))	('nal-IRI', 'Chemical', '-', (199, 206))	('LV', 'Chemical', 'MESH:D058766', (239, 241))	('patients', 'Species', '9606', (68, 76))	('5-FU', 'Chemical', 'MESH:D005472', (207, 211))	('LV', 'Chemical', 'MESH:D058766', (212, 214))
17114	33099898	27  A subanalysis of the NAPOLI-1 trial indicated that patients who had received 0-1 prior lines of metastatic therapy had better PFS outcomes when receiving nal-IRI+5-FU/LV versus 5-FU/LV, suggesting that earlier use of nal-IRI+5-FU/LV provides better PFS outcomes for patients.	('nal-IRI+5-FU/LV', 'Var', (158, 173))	('nal-IRI', 'Chemical', '-', (158, 165))	('5-FU', 'Chemical', 'MESH:D005472', (181, 185))	('better', 'PosReg', (123, 129))	('patients', 'Species', '9606', (270, 278))	('PFS', 'MPA', (130, 133))	('LV', 'Chemical', 'MESH:D058766', (186, 188))	('5-FU', 'Chemical', 'MESH:D005472', (229, 233))	('5-FU', 'Chemical', 'MESH:D005472', (166, 170))	('patients', 'Species', '9606', (55, 63))	('LV', 'Chemical', 'MESH:D058766', (171, 173))	('nal-IRI', 'Chemical', '-', (221, 228))	('LV', 'Chemical', 'MESH:D058766', (234, 236))
17119	33099898	For example, patients in the nal-IRI+5-FU/LV arm had, on average, an increased incidence of presence of hepatic lesions, and a lower KPS.	('5-FU', 'Chemical', 'MESH:D005472', (37, 41))	('nal-IRI', 'Chemical', '-', (29, 36))	('patients', 'Species', '9606', (13, 21))	('KPS', 'MPA', (133, 136))	('lower', 'NegReg', (127, 132))	('hepatic lesions', 'Disease', 'MESH:D056486', (104, 119))	('nal-IRI+5-FU/LV', 'Var', (29, 44))	('LV', 'Chemical', 'MESH:D058766', (42, 44))	('hepatic lesions', 'Disease', (104, 119))
17125	33099898	The incidence of all-grade neutropenia with nal-IRI+5-FU/LV was 11% (8% grade >=3), with one case of febrile neutropenia; the incidence of diarrhea was comparable to that previously reported for patients receiving the regimen in the NAPOLI-1 trial.	('diarrhea', 'Disease', (139, 147))	('neutropenia', 'Disease', 'MESH:D009503', (109, 120))	('diarrhea', 'Disease', 'MESH:D003967', (139, 147))	('neutropenia', 'Phenotype', 'HP:0001875', (109, 120))	('neutropenia', 'Disease', 'MESH:D009503', (27, 38))	('LV', 'Chemical', 'MESH:D058766', (57, 59))	('neutropenia', 'Disease', (109, 120))	('5-FU', 'Chemical', 'MESH:D005472', (52, 56))	('neutropenia', 'Phenotype', 'HP:0001875', (27, 38))	('patients', 'Species', '9606', (195, 203))	('febrile neutropenia', 'Disease', (101, 120))	('febrile neutropenia', 'Disease', 'MESH:D009503', (101, 120))	('diarrhea', 'Phenotype', 'HP:0002014', (139, 147))	('nal-IRI+5-FU/LV', 'Var', (44, 59))	('nal-IRI', 'Chemical', '-', (44, 51))	('neutropenia', 'Disease', (27, 38))
17127	33099898	There was a higher instance of neutropenia in patients receiving nal-IRI+5-FU/LV who had mutations in UGT1A1 (homozygous for UGT1A1*6 [n =2] or heterozygous for UGT1A1*6 and UGT1A1*28 [n =1]).	('UGT1A1', 'Gene', '54658', (102, 108))	('UGT1A1', 'Gene', '54658', (161, 167))	('neutropenia', 'Disease', (31, 42))	('patients', 'Species', '9606', (46, 54))	('UGT1A1', 'Gene', (174, 180))	('UGT1A1', 'Gene', (102, 108))	('UGT1A1', 'Gene', '54658', (125, 131))	('5-FU', 'Chemical', 'MESH:D005472', (73, 77))	('nal-IRI', 'Chemical', '-', (65, 72))	('neutropenia', 'Disease', 'MESH:D009503', (31, 42))	('UGT1A1', 'Gene', (125, 131))	('UGT1A1', 'Gene', (161, 167))	('LV', 'Chemical', 'MESH:D058766', (78, 80))	('neutropenia', 'Phenotype', 'HP:0001875', (31, 42))	('mutations', 'Var', (89, 98))	('UGT1A1', 'Gene', '54658', (174, 180))
17128	33099898	Although no firm conclusions can be drawn regarding safety in this small patient population, it is important to monitor patients with known UGT1A1 mutations for neutropenia.	('mutations', 'Var', (147, 156))	('UGT1A1', 'Gene', (140, 146))	('neutropenia', 'Phenotype', 'HP:0001875', (161, 172))	('patient', 'Species', '9606', (120, 127))	('neutropenia', 'Disease', 'MESH:D009503', (161, 172))	('patient', 'Species', '9606', (73, 80))	('patients', 'Species', '9606', (120, 128))	('neutropenia', 'Disease', (161, 172))	('UGT1A1', 'Gene', '54658', (140, 146))
17131	33099898	19 ,  23 ,  27 ,  32  Additionally, clinically meaningful and statistically significant gains in investigator-assessed PFS and ORR were observed with nal-IRI+5-FU/LV versus 5-FU/LV.	('ORR', 'CPA', (127, 130))	('LV', 'Chemical', 'MESH:D058766', (163, 165))	('PFS', 'CPA', (119, 122))	('5-FU', 'Chemical', 'MESH:D005472', (158, 162))	('gains', 'PosReg', (88, 93))	('LV', 'Chemical', 'MESH:D058766', (178, 180))	('nal-IRI+5-FU/LV', 'Var', (150, 165))	('nal-IRI', 'Chemical', '-', (150, 157))	('5-FU', 'Chemical', 'MESH:D005472', (173, 177))
17154	33035197	Furthermore, the body weight and tumor size of orthotopic PDAC mice were evaluated following the treatment of free GEM, LP (GEM) or GPC1-LP (GEM).	('GEM', 'Chemical', 'MESH:C056507', (141, 144))	('body weight', 'CPA', (17, 28))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('GEM', 'Chemical', 'MESH:C056507', (124, 127))	('GEM', 'Chemical', 'MESH:C056507', (115, 118))	('mice', 'Species', '10090', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('GPC1-LP', 'Var', (132, 139))
17156	33035197	These findings provided more insights into the anti-tumor potential for the biomedical application of GPC1-LP (GEM) in PDAC.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('PDAC', 'Disease', (119, 123))	('GEM', 'Chemical', 'MESH:C056507', (111, 114))	('GPC1-LP', 'Var', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
17170	33035197	Cumulative drug release profiles revealed that both LP (GEM) and GPC1-LP (GEM) exhibited a burst release of GEM within 5 h and a slow release from 5 h to 24 h at pH 7.4 (blood plasma) and pH 5.0 (tumor endocytic compartment) (Figure 1B).	('burst release', 'MPA', (91, 104))	('tumor', 'Disease', (196, 201))	('GEM', 'Chemical', 'MESH:C056507', (108, 111))	('GEM', 'Chemical', 'MESH:C056507', (56, 59))	('GEM', 'Chemical', 'MESH:C056507', (74, 77))	('GPC1-LP', 'Var', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
17171	33035197	Notably, almost 80 % of GEM was released from both LP (GEM) and GPC1-LP (GEM) within 24 h at pH 5.0, which was significantly higher than that at pH 7.4 (30%) (Figure 1B), indicating more GEM releasing into the tumor environment.	('GEM', 'Chemical', 'MESH:C056507', (24, 27))	('GEM', 'Chemical', 'MESH:C056507', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('GEM', 'Chemical', 'MESH:C056507', (73, 76))	('GPC1-LP', 'Var', (64, 71))	('GEM', 'Chemical', 'MESH:C056507', (187, 190))	('tumor', 'Disease', (210, 215))	('released', 'MPA', (32, 40))	('higher', 'PosReg', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
17177	33035197	Cell proliferation and apoptosis were used to evaluate the anti-tumor effect of GPC1-LP (GEM).	('GPC1-LP', 'Var', (80, 87))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('tumor', 'Disease', (64, 69))	('apoptosis', 'biological_process', 'GO:0097194', ('23', '32'))	('apoptosis', 'biological_process', 'GO:0006915', ('23', '32'))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('GEM', 'Chemical', 'MESH:C056507', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
17178	33035197	MTT assay showed that 293T cells treated with LP (GEM) exhibited similar cell viability with 293T cells treated with GPC1-LP (GEM) at 24 h and 48 h, while both were reduced compared with cells treated with free GEM (Figure 3A).	('GEM', 'Chemical', 'MESH:C056507', (126, 129))	('cell viability', 'CPA', (73, 87))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('293T', 'CellLine', 'CVCL:0063', (93, 97))	('GEM', 'Chemical', 'MESH:C056507', (211, 214))	('GEM', 'Chemical', 'MESH:C056507', (50, 53))	('GPC1-LP', 'Var', (117, 124))	('293T', 'CellLine', 'CVCL:0063', (22, 26))	('reduced', 'NegReg', (165, 172))
17181	33035197	The clone number was similar between 293T cells treated with LP (GEM) and GPC1-LP (GEM), while which were decreased compared to 293T cells treated with free GEM (P < 0.05, Figure 3B).	('decreased', 'NegReg', (106, 115))	('GEM', 'Chemical', 'MESH:C056507', (65, 68))	('293T', 'CellLine', 'CVCL:0063', (128, 132))	('GEM', 'Chemical', 'MESH:C056507', (83, 86))	('GPC1-LP', 'Var', (74, 81))	('293T', 'CellLine', 'CVCL:0063', (37, 41))	('GEM', 'Chemical', 'MESH:C056507', (157, 160))
17182	33035197	In PANC-1 and SW1990 cells, the clone number in cells treated with GPC1-LP (GEM) was the lowest, followed by cells treated with LP (GEM), cells treated with LP (GEM), cells treated with free GEM, and control cells (P < 0.05, Figure 3B).	('GPC1-LP', 'Var', (67, 74))	('clone number', 'CPA', (32, 44))	('lowest', 'NegReg', (89, 95))	('GEM', 'Chemical', 'MESH:C056507', (76, 79))	('GEM', 'Chemical', 'MESH:C056507', (132, 135))	('GEM', 'Chemical', 'MESH:C056507', (191, 194))	('SW1990', 'CellLine', 'CVCL:1723', (14, 20))	('PANC-1', 'CellLine', 'CVCL:0480', (3, 9))	('GEM', 'Chemical', 'MESH:C056507', (161, 164))
17183	33035197	These data indicated that GPC1-LP (GEM) had superior anti-proliferation effect than LP (GEM) and free GEM in PANC-1 and SW1990 cells.	('anti-proliferation effect', 'CPA', (53, 78))	('GEM', 'Chemical', 'MESH:C056507', (35, 38))	('GPC1-LP', 'Var', (26, 33))	('SW1990', 'CellLine', 'CVCL:1723', (120, 126))	('PANC-1', 'CellLine', 'CVCL:0480', (109, 115))	('GEM', 'Chemical', 'MESH:C056507', (88, 91))	('GEM', 'Chemical', 'MESH:C056507', (102, 105))
17184	33035197	Flow cytometry analysis found similar cell apoptosis in control cells, cells treated with LP, and cells treated with GPC1-LP, while the rate of apoptotic cells was increased in cells with free GEM compared with control cells, cells with LP, and cells with GPC1-LP; meanwhile, compared with cells with free GEM, cells with LP (GEM) showed the increased rate of apoptotic cells, and then GPC1-LP (GEM) treatment further increased the rate of apoptotic cells (Figure 4A).	('GEM', 'Chemical', 'MESH:C056507', (395, 398))	('apoptotic cells', 'CPA', (360, 375))	('GEM', 'Chemical', 'MESH:C056507', (306, 309))	('GEM', 'Chemical', 'MESH:C056507', (193, 196))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('GEM', 'Chemical', 'MESH:C056507', (326, 329))	('GPC1-LP', 'Var', (386, 393))
17185	33035197	Consistently, western blotting showed that compared with control cells, free GEM treatment distinctly inhibited Bcl-2 level as well as promoted the expression of Bax, cleaved-caspase-3 and cleaved-caspase-9 (P < 0.01), and both LP (GEM) and GPC1-LP (GEM) further inhibited Bcl-2 level as well as promoted the expression of Bax cleaved-caspase-3 and cleaved-caspase-9, especially GPC1-LP (GEM) (P < 0.05, Figure 4B).	('Bax', 'Gene', (162, 165))	('caspase-3', 'Gene', '836', (175, 184))	('caspase-3', 'Gene', '836', (335, 344))	('GEM', 'Chemical', 'MESH:C056507', (250, 253))	('caspase-3', 'Gene', (335, 344))	('Bax', 'Gene', '581', (162, 165))	('caspase-3', 'Gene', (175, 184))	('Bcl-2', 'molecular_function', 'GO:0015283', ('112', '117'))	('caspase-9', 'Gene', (357, 366))	('promoted', 'PosReg', (135, 143))	('caspase-9', 'Gene', (197, 206))	('expression', 'MPA', (309, 319))	('GEM', 'Chemical', 'MESH:C056507', (232, 235))	('Bcl-2', 'Gene', (273, 278))	('inhibited', 'NegReg', (263, 272))	('Bcl-2', 'Gene', (112, 117))	('Bcl-2', 'Gene', '596', (273, 278))	('GEM', 'Chemical', 'MESH:C056507', (388, 391))	('Bax', 'Gene', (323, 326))	('caspase-9', 'Gene', '842', (357, 366))	('inhibited', 'NegReg', (102, 111))	('Bax', 'Gene', '581', (323, 326))	('GEM', 'Chemical', 'MESH:C056507', (77, 80))	('Bcl-2', 'Gene', '596', (112, 117))	('Bcl-2', 'molecular_function', 'GO:0015283', ('273', '278'))	('expression', 'MPA', (148, 158))	('promoted', 'PosReg', (296, 304))	('GPC1-LP', 'Var', (379, 386))	('caspase-9', 'Gene', '842', (197, 206))
17186	33035197	These findings suggested that superior pro-apoptosis effect of GPC1-LP (GEM) than LP (GEM) and free GEM in PANC-1 and SW1990 cells.	('PANC-1', 'CellLine', 'CVCL:0480', (107, 113))	('GEM', 'Chemical', 'MESH:C056507', (100, 103))	('GEM', 'Chemical', 'MESH:C056507', (86, 89))	('pro-apoptosis effect', 'CPA', (39, 59))	('GEM', 'Chemical', 'MESH:C056507', (72, 75))	('pro-apoptosis', 'biological_process', 'GO:0043065', ('39', '52'))	('superior', 'PosReg', (30, 38))	('SW1990', 'CellLine', 'CVCL:1723', (118, 124))	('GPC1-LP', 'Var', (63, 70))
17187	33035197	In vivo experiments showed that the bodyweight of mice with different treatments, including LP, GPC1-LP, GEM, LP (GEM) and GPC1-LP (GEM), was in comparison to that of the orthotopic PDAC mice (Figure 5A).	('GEM', 'Chemical', 'MESH:C056507', (114, 117))	('GEM', 'Chemical', 'MESH:C056507', (132, 135))	('GEM', 'Chemical', 'MESH:C056507', (105, 108))	('GPC1-LP', 'Var', (123, 130))	('GPC1-LP', 'Var', (96, 103))	('mice', 'Species', '10090', (187, 191))	('mice', 'Species', '10090', (50, 54))	('bodyweight', 'CPA', (36, 46))
17188	33035197	Notably, the tumor weight was similar in control cells, cells with LP, and cells with GPC1-LP, while the tumor weight was lowest in cells with GPC1-LP (GEM), followed by cells with LP (GEM) and free GEM (Figure 5B), which suggested a better anti-tumor effect of GPC1-LP (GEM) on orthotopic PDAC mice.	('GEM', 'Chemical', 'MESH:C056507', (271, 274))	('tumor', 'Disease', (13, 18))	('GEM', 'Chemical', 'MESH:C056507', (185, 188))	('mice', 'Species', '10090', (295, 299))	('lowest', 'NegReg', (122, 128))	('GEM', 'Chemical', 'MESH:C056507', (199, 202))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('GEM', 'Chemical', 'MESH:C056507', (152, 155))	('better', 'PosReg', (234, 240))	('GPC1-LP', 'Var', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
17190	33035197	Moreover, we detected the mRNA expression of the hypoxic-related genes in tumor tissues through qRT-PCR, and found that GPC1-LP (GEM) could significantly inhibit the expression of the hypoxic-related genes (Figure 5D).	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('inhibit', 'NegReg', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('GPC1-LP', 'Var', (120, 127))	('GEM', 'Chemical', 'MESH:C056507', (129, 132))	('tumor', 'Disease', (74, 79))	('expression', 'MPA', (166, 176))
17192	33035197	Furthermore, both LP (GEM) and GPC1-LP (GEM) had no effects on body weight of orthotopic PDAC mice, while obviously reduced the tumor size.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('GEM', 'Chemical', 'MESH:C056507', (22, 25))	('GEM', 'Chemical', 'MESH:C056507', (40, 43))	('mice', 'Species', '10090', (94, 98))	('GPC1-LP', 'Var', (31, 38))	('tumor', 'Disease', (128, 133))	('reduced', 'NegReg', (116, 123))
17193	33035197	GPC1-LP (GEM) especially showed improved anti-cancer effect compared with LP (GEM) in vitro and in vivo.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('GEM', 'Chemical', 'MESH:C056507', (9, 12))	('GPC1-LP', 'Var', (0, 7))	('improved', 'PosReg', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('GEM', 'Chemical', 'MESH:C056507', (78, 81))
17210	33035197	Interestingly, our study found that higher dose of GEM released from both LP (GEM) and GPC1-LP (GEM) within 24 h at pH 5.0 (tumor endocytic compartment) than that at pH 7.4 (blood plasma), which indicated that more GEM was released under the tumor environment.	('GEM', 'Chemical', 'MESH:C056507', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('GEM', 'Chemical', 'MESH:C056507', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('GEM', 'Chemical', 'MESH:C056507', (215, 218))	('tumor', 'Disease', (242, 247))	('GEM', 'Chemical', 'MESH:C056507', (78, 81))	('GPC1-LP', 'Var', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
17216	33035197	Thus, this study prepared GPC1-LP (GEM), and GPC1-LP (GEM) treatment further inhibited cell proliferation and promoted cell apoptosis in PANC-1 cells, as well as suppressed the tumor size of orthotopic PDAC mice, compared with LP (GEM).	('tumor', 'Disease', (177, 182))	('GEM', 'Chemical', 'MESH:C056507', (35, 38))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('cell proliferation', 'biological_process', 'GO:0008283', ('87', '105'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('cell apoptosis', 'CPA', (119, 133))	('inhibited', 'NegReg', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('cell proliferation', 'CPA', (87, 105))	('GEM', 'Chemical', 'MESH:C056507', (231, 234))	('mice', 'Species', '10090', (207, 211))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('GEM', 'Chemical', 'MESH:C056507', (54, 57))	('GPC1-LP', 'Var', (45, 52))	('suppressed', 'NegReg', (162, 172))	('PANC-1', 'CellLine', 'CVCL:0480', (137, 143))	('promoted', 'PosReg', (110, 118))
17218	33035197	It's definitely worth that our study demonstrates the enhanced anti-tumor activity of GPC1-LP (GEM) in PDAC both in vitro and in vivo.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('GEM', 'Chemical', 'MESH:C056507', (95, 98))	('GPC1-LP', 'Var', (86, 93))	('PDAC', 'Disease', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('enhanced', 'PosReg', (54, 62))
17222	33035197	In conclusion, this study successfully developed GPC1-LP (GEM), and GPC1-LP (GEM) had a superior anti-tumor activity than LP (GEM) in PDAC in vitro and in vivo.	('GEM', 'Chemical', 'MESH:C056507', (126, 129))	('GPC1-LP', 'Var', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('GEM', 'Chemical', 'MESH:C056507', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('GEM', 'Chemical', 'MESH:C056507', (58, 61))
17223	33035197	Overall, GPC1-LP (GEM) might be a promising therapeutic nanomedicine in PDAC.	('GEM', 'Chemical', 'MESH:C056507', (18, 21))	('GPC1-LP', 'Var', (9, 16))	('PDAC', 'Disease', (72, 76))
17257	33035197	A total of 48 BALB/c nude mice with orthotopic PDAC were randomly and equally divided into 6 groups, and treated, respectively, with saline (control), LP, GPC1-LP, GEM, LP (GEM) and GPC1-LP (GEM) by intravenous injection twice a week for 2 weeks.	('nude mice', 'Species', '10090', (21, 30))	('GEM', 'Chemical', 'MESH:C056507', (173, 176))	('GEM', 'Chemical', 'MESH:C056507', (191, 194))	('GPC1-LP', 'Var', (182, 189))	('GPC1-LP', 'Var', (155, 162))	('GEM', 'Chemical', 'MESH:C056507', (164, 167))
17263	32916872	Deregulation of HSPGs resulting in malignancy may be due to either their abnormal expression levels or changes in their structure and functions as a result of the altered activity of their biosynthetic or remodeling enzymes.	('resulting in', 'Reg', (22, 34))	('functions', 'MPA', (134, 143))	('HSPG', 'Gene', '960', (16, 20))	('Deregulation', 'Var', (0, 12))	('HSPG', 'Gene', (16, 20))	('malignancy', 'Disease', 'MESH:D009369', (35, 45))	('altered', 'Reg', (163, 170))	('malignancy', 'Disease', (35, 45))	('changes', 'Reg', (103, 110))	('expression levels', 'MPA', (82, 99))	('activity', 'MPA', (171, 179))	('structure', 'MPA', (120, 129))
17282	32916872	Differential expression and structure/activity modifications of HSPGs have been found in several cancers and may correlate with either inhibitory or tumor-promoting activity.	('found', 'Reg', (80, 85))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('HSPG', 'Gene', '960', (64, 68))	('cancers', 'Disease', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('expression', 'MPA', (13, 23))	('HSPG', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('structure/activity', 'MPA', (28, 46))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (149, 154))	('modifications', 'Var', (47, 60))
17294	32916872	Then, the HS backbone undergoes modifications involving N-deacetylation and N-sulfation of glucosamine, C-5 epimerization of glucuronic acid to iduronic acid, 2-O-sulfation and 3-O-sulfation of uronic acid and glucosamine, respectively, and 6-O-sulfation of N-acetylated or N-sulfated glucosamine residues.	('glucuronic acid', 'Chemical', 'MESH:D020723', (125, 140))	('sulfation', 'biological_process', 'GO:0051923', ('245', '254'))	('uronic acid', 'Chemical', 'MESH:D014574', (129, 140))	('glucosamine', 'Chemical', 'MESH:D005944', (210, 221))	('iduronic acid', 'Chemical', 'MESH:D007067', (144, 157))	('glucosamine', 'Chemical', 'MESH:D005944', (91, 102))	('sulfate', 'Chemical', 'MESH:D013431', (276, 283))	('uronic acid', 'Chemical', 'MESH:D014574', (146, 157))	('sulfation', 'biological_process', 'GO:0051923', ('78', '87'))	('HS', 'Chemical', 'MESH:D006497', (10, 12))	('N-deacetylation', 'MPA', (56, 71))	('sulfation', 'biological_process', 'GO:0051923', ('163', '172'))	('uronic acid', 'Chemical', 'MESH:D014574', (194, 205))	('N-sulfation', 'MPA', (76, 87))	('modifications', 'Var', (32, 45))	('glucosamine', 'Chemical', 'MESH:D005944', (285, 296))	('C-5', 'Var', (104, 107))	('sulfation', 'biological_process', 'GO:0051923', ('181', '190'))
17299	32916872	The genetic loss of NDST4, a member of the N-deacetylase/N-sulfotransferase (NDST) family, correlates with an advanced pathological stage and poor survival in colorectal carcinomas.	('colorectal carcinomas', 'Disease', (159, 180))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (159, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('NDST4', 'Gene', '64579', (20, 25))	('NDST4', 'Gene', (20, 25))	('genetic loss', 'Var', (4, 16))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))
17301	32916872	Defective HS-3-O-sulfation due to methylation-associated repression of HS glucosamine 3-O-sulfotransferase gene (3-OST) results in being associated with chondrosarcoma progression, whereas hypermethylation of the 3-OST gene is associated with poor survival in non-small cell lung cancer.	('methylation-associated', 'Var', (34, 56))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (153, 167))	('3-OST', 'Gene', (213, 218))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (260, 286))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (264, 286))	('3-OST', 'Gene', '9957', (113, 118))	('associated with', 'Reg', (137, 152))	('lung cancer', 'Disease', (275, 286))	('HS', 'Chemical', 'MESH:D006497', (10, 12))	('HS', 'Chemical', 'MESH:D006497', (71, 73))	('HS-3-O-sulfation', 'MPA', (10, 26))	('repression', 'NegReg', (57, 67))	('3-OST', 'Gene', '9957', (213, 218))	('glucosamine', 'Chemical', 'MESH:D005944', (74, 85))	('lung cancer', 'Disease', 'MESH:D008175', (275, 286))	('sulfation', 'biological_process', 'GO:0051923', ('17', '26'))	('chondrosarcoma', 'Disease', 'MESH:D002813', (153, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (275, 286))	('chondrosarcoma', 'Disease', (153, 167))	('3-OST', 'Gene', (113, 118))
17304	32916872	Mutations in EXT1 or EXT2, members of the EXT family of glycosyltransferases are responsible for hereditary multiple osteochondromas that may degenerate into chondro- or osteo-sarcomas.	('hereditary multiple osteochondromas', 'Disease', 'MESH:D005097', (97, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('EXT', 'Gene', (21, 24))	('EXT', 'Gene', (13, 16))	('EXT2', 'Gene', '2132', (21, 25))	('EXT2', 'Gene', (21, 25))	('Mutations', 'Var', (0, 9))	('hereditary multiple osteochondromas', 'Disease', (97, 132))	('EXT1', 'Gene', '2131', (13, 17))	('EXT', 'Gene', '2131', (42, 45))	('osteo-sarcomas', 'Disease', (170, 184))	('responsible', 'Reg', (81, 92))	('osteo-sarcomas', 'Phenotype', 'HP:0002669', (170, 184))	('osteochondromas', 'Phenotype', 'HP:0030431', (117, 132))	('EXT', 'Gene', (42, 45))	('osteo-sarcomas', 'Disease', 'MESH:D012509', (170, 184))	('EXT1', 'Gene', (13, 17))	('sarcomas', 'Phenotype', 'HP:0100242', (176, 184))	('EXT', 'Gene', '2131', (13, 16))	('EXT', 'Gene', '2131', (21, 24))
17305	32916872	Furthermore, mutations in EXT2 have been detected in breast tumor patients, and thyroid cancer.	('thyroid cancer', 'Disease', (80, 94))	('thyroid cancer', 'Phenotype', 'HP:0002890', (80, 94))	('breast tumor', 'Disease', 'MESH:D001943', (53, 65))	('EXT2', 'Gene', (26, 30))	('thyroid cancer', 'Disease', 'MESH:D013964', (80, 94))	('EXT2', 'Gene', '2132', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('breast tumor', 'Disease', (53, 65))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (13, 22))	('detected', 'Reg', (41, 49))	('patients', 'Species', '9606', (66, 74))	('breast tumor', 'Phenotype', 'HP:0100013', (53, 65))
17306	32916872	Epigenetic inactivation of EXT1 by promoter hyper-methylation preventing HS chain synthesis is observed in leukemia and non-melanoma skin cancer.	('promoter hyper-methylation', 'Var', (35, 61))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (120, 144))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('skin cancer', 'Phenotype', 'HP:0008069', (133, 144))	('methylation', 'biological_process', 'GO:0032259', ('50', '61'))	('non-melanoma skin cancer', 'Disease', (120, 144))	('HS chain synthesis', 'MPA', (73, 91))	('synthesis', 'biological_process', 'GO:0009058', ('82', '91'))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('leukemia', 'Disease', 'MESH:D007938', (107, 115))	('EXT1', 'Gene', (27, 31))	('leukemia', 'Disease', (107, 115))	('HS', 'Chemical', 'MESH:D006497', (73, 75))	('Epigenetic inactivation', 'Var', (0, 23))	('EXT1', 'Gene', '2131', (27, 31))
17315	32916872	Overexpression of SDC1 correlates with tumor aggressiveness and poor survival in triple-negative breast carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (39, 59))	('breast carcinoma', 'Phenotype', 'HP:0003002', (97, 113))	('poor', 'NegReg', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('SDC1', 'Gene', (18, 22))	('SDC1', 'Gene', '6382', (18, 22))	('breast carcinoma', 'Disease', (97, 113))	('Overexpression', 'Var', (0, 14))	('tumor aggressiveness', 'Disease', (39, 59))	('breast carcinoma', 'Disease', 'MESH:D001943', (97, 113))	('aggressiveness', 'Phenotype', 'HP:0000718', (45, 59))
17321	32916872	Overexpression of GPC1 is a hallmark of breast cancer, esophageal squamous cell carcinoma, and gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (55, 89))	('GPC1', 'Gene', '2817', (18, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('hallmark of breast cancer', 'Disease', 'MESH:D001943', (28, 53))	('hallmark of breast cancer', 'Disease', (28, 53))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (95, 102))	('esophageal squamous cell carcinoma', 'Disease', (55, 89))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('GPC1', 'Gene', (18, 22))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
17327	32916872	Overexpression of GPC6 is associated with gastric adenocarcinoma and metastatic progression of cutaneous melanoma.	('GPC6', 'Gene', '10082', (18, 22))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('metastatic progression', 'CPA', (69, 91))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (42, 64))	('gastric adenocarcinoma', 'Disease', (42, 64))	('Overexpression', 'Var', (0, 14))	('GPC6', 'Gene', (18, 22))	('cutaneous melanoma', 'Disease', (95, 113))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (95, 113))	('associated with', 'Reg', (26, 41))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (95, 113))
17334	32916872	The aberrant expression of specific HSPGs in the various types of cancers significantly affects HSPG-ligand binding and subsequent signaling, thus determining the malignancy of the tumor phenotype.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('binding', 'Interaction', (108, 115))	('signaling', 'MPA', (131, 140))	('HSPG', 'Gene', '960', (96, 100))	('HSPG', 'Gene', (96, 100))	('ligand', 'molecular_function', 'GO:0005488', ('101', '107'))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('malignancy of the tumor', 'Disease', 'MESH:D009369', (163, 186))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('binding', 'molecular_function', 'GO:0005488', ('108', '115'))	('HSPG', 'Gene', '960', (36, 40))	('HSPG', 'Gene', (36, 40))	('affects', 'Reg', (88, 95))	('determining', 'Reg', (147, 158))	('malignancy of the tumor', 'Disease', (163, 186))	('aberrant expression', 'Var', (4, 23))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))
17339	32916872	Soluble SDC1 promotes the growth of myeloma tumors in vivo, while shed SDC2 enhances colon, lung, and breast cancer progression.	('SDC1', 'Gene', (8, 12))	('SDC1', 'Gene', '6382', (8, 12))	('breast cancer', 'Disease', (102, 115))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('colon', 'Disease', (85, 90))	('growth', 'MPA', (26, 32))	('promotes', 'PosReg', (13, 21))	('myeloma tumors', 'Disease', 'MESH:D009101', (36, 50))	('Soluble', 'cellular_component', 'GO:0005625', ('0', '7'))	('myeloma tumors', 'Disease', (36, 50))	('SDC2', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('lung', 'Disease', (92, 96))	('shed', 'Var', (66, 70))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('enhances', 'PosReg', (76, 84))
17340	32916872	SDC-1 shedding is associated with increased mitogenic activity and invasive potential of pancreatic cancer cells, whereas shedding of SDC4 in human endothelial cells promotes wound healing, angiogenesis, and inflammation.	('mitogenic activity', 'CPA', (44, 62))	('mitogenic activity', 'biological_process', 'GO:0045840', ('44', '62'))	('inflammation', 'biological_process', 'GO:0006954', ('208', '220'))	('invasive potential', 'CPA', (67, 85))	('angiogenesis', 'biological_process', 'GO:0001525', ('190', '202'))	('human', 'Species', '9606', (142, 147))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('increased', 'PosReg', (34, 43))	('angiogenesis', 'CPA', (190, 202))	('SDC-1', 'Gene', '6382', (0, 5))	('SDC-1', 'Gene', (0, 5))	('inflammation', 'Disease', 'MESH:D007249', (208, 220))	('SDC4', 'Gene', '6385', (134, 138))	('SDC4', 'Gene', (134, 138))	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('shedding', 'Var', (6, 14))	('inflammation', 'Disease', (208, 220))	('wound healing', 'biological_process', 'GO:0042060', ('175', '188'))	('promotes', 'PosReg', (166, 174))	('wound healing', 'CPA', (175, 188))	('pancreatic cancer', 'Disease', (89, 106))
17341	32916872	Furthermore, SDC1 shedding has been shown to trigger a switch from a proliferative to an invasive phenotype of breast cancer cells.	('SDC1', 'Gene', (13, 17))	('SDC1', 'Gene', '6382', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('shedding', 'Var', (18, 26))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('switch', 'Reg', (55, 61))	('breast cancer', 'Disease', (111, 124))	('trigger', 'Reg', (45, 52))	('proliferative', 'CPA', (69, 82))
17355	32916872	Depending on the tumor type, HSPG-regulated FGF binding and receptor dimerization triggers the activation of four main signaling pathways, including mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), and protein kinase C (PKC) pathways.	('AKT', 'Gene', '207', (289, 292))	('PKC', 'Gene', '5578;5582', (393, 396))	('protein', 'cellular_component', 'GO:0003675', ('271', '278'))	('PKC', 'molecular_function', 'GO:0004697', ('393', '396'))	('PKC', 'Gene', (393, 396))	('extracellular signal-regulated kinase', 'Gene', (189, 226))	('FGF', 'Protein', (44, 47))	('ERK', 'molecular_function', 'GO:0004707', ('228', '231'))	('extracellular signal-regulated kinase', 'Gene', '5594', (189, 226))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('transcription', 'biological_process', 'GO:0006351', ('349', '362'))	('MAPK', 'molecular_function', 'GO:0004707', ('183', '187'))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))	('ERK', 'Gene', '5594', (228, 231))	('tumor', 'Disease', (17, 22))	('phosphatidylinositol 3-kinase', 'Gene', '5293', (234, 263))	('protein kinase B', 'Gene', '2185', (271, 287))	('AKT', 'Gene', (289, 292))	('activation', 'PosReg', (95, 105))	('extracellular', 'cellular_component', 'GO:0005576', ('189', '202'))	('STAT', 'Gene', '6774', (364, 368))	('PI3K', 'molecular_function', 'GO:0016303', ('265', '269'))	('protein', 'cellular_component', 'GO:0003675', ('375', '382'))	('STAT', 'Gene', (364, 368))	('phosphatidylinositol 3-kinase', 'Gene', (234, 263))	('activator of transcription', 'Pathway', (336, 362))	('HSPG', 'Gene', '960', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('protein kinase B', 'Gene', (271, 287))	('binding', 'Var', (48, 55))	('JAK', 'molecular_function', 'GO:0004713', ('309', '312'))	('FGF binding', 'molecular_function', 'GO:0017134', ('44', '55'))	('HSPG', 'Gene', (29, 33))	('ERK', 'Gene', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('dimerization', 'Var', (69, 81))
17367	32916872	For example, in myeloma, shed SDC1 promotes HGF paracrine signaling that involves MAPK and PI3K cascade activation resulting in enhanced cell proliferation and survival.	('survival', 'CPA', (160, 168))	('HGF', 'Gene', (44, 47))	('activation', 'PosReg', (104, 114))	('myeloma', 'Disease', (16, 23))	('cell proliferation', 'CPA', (137, 155))	('HGF', 'Gene', '3082', (44, 47))	('SDC1', 'Gene', (30, 34))	('shed', 'Var', (25, 29))	('promotes', 'PosReg', (35, 43))	('SDC1', 'Gene', '6382', (30, 34))	('PI3K cascade', 'biological_process', 'GO:0014065', ('91', '103'))	('enhanced', 'PosReg', (128, 136))	('paracrine signaling', 'biological_process', 'GO:0038001', ('48', '67'))	('cell proliferation', 'biological_process', 'GO:0008283', ('137', '155'))	('myeloma', 'Disease', 'MESH:D009101', (16, 23))	('PI3K', 'molecular_function', 'GO:0016303', ('91', '95'))	('MAPK', 'MPA', (82, 86))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))
17369	32916872	Dysregulation of HSPG-regulated HGF/c-MET signaling in tumor microenvironment plays a key role in hepatocarcinoma.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('HSPG', 'Gene', '960', (17, 21))	('c-MET', 'Gene', '4233', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Dysregulation', 'Var', (0, 13))	('HSPG', 'Gene', (17, 21))	('tumor', 'Disease', (55, 60))	('hepatocarcinoma', 'Disease', 'None', (98, 113))	('c-MET', 'Gene', (36, 41))	('hepatocarcinoma', 'Disease', (98, 113))	('HGF', 'Gene', (32, 35))	('HGF', 'Gene', '3082', (32, 35))
17370	32916872	Strong evidence demonstrates a role for loss of HB-EGF in the tumor microenvironment in neuroblastoma pathogenesis.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('pathogenesis', 'biological_process', 'GO:0009405', ('102', '114'))	('neuroblastoma', 'Disease', 'MESH:D009447', (88, 101))	('HB-EGF', 'Gene', (48, 54))	('tumor', 'Disease', (62, 67))	('neuroblastoma', 'Disease', (88, 101))	('neuroblastoma', 'Phenotype', 'HP:0003006', (88, 101))	('loss', 'Var', (40, 44))	('HB-EGF', 'Gene', '1839', (48, 54))	('EGF', 'molecular_function', 'GO:0005154', ('51', '54'))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
17441	32916872	The HS mimetics OTR4120 and OTR4131 exhibit anti-tumoral effects in human hepatocellular carcinoma by interfering with HSPGs-mediated RANTES signaling.	('human', 'Species', '9606', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('OTR4120', 'Chemical', 'MESH:C533322', (16, 23))	('HS', 'Chemical', 'MESH:D006497', (4, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('HSPG', 'Gene', '960', (119, 123))	('interfering', 'NegReg', (102, 113))	('HSPG', 'Gene', (119, 123))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (74, 98))	('RANTES', 'Gene', (134, 140))	('RANTES', 'Gene', '6352', (134, 140))	('HS', 'Chemical', 'MESH:D006497', (119, 121))	('tumor', 'Disease', (49, 54))	('OTR4131', 'Var', (28, 35))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (74, 98))	('OTR4120', 'Var', (16, 23))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('OTR4131', 'Chemical', 'MESH:C542264', (28, 35))	('hepatocellular carcinoma', 'Disease', (74, 98))
17450	32916872	Indeed, the HS mimetics PI-88, PG545, and M402 have been shown to exert anti-angiogenic and antimetastatic effects by inhibiting heparanase in several types of cancers.	('PI-88', 'Var', (24, 29))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('PI-88', 'Chemical', 'MESH:C120158', (24, 29))	('cancers', 'Disease', (160, 167))	('M402', 'Var', (42, 46))	('anti-angiogenic', 'CPA', (72, 87))	('M402', 'Chemical', '-', (42, 46))	('heparanase', 'Gene', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('PG545', 'Var', (31, 36))	('antimetastatic effects', 'CPA', (92, 114))	('inhibiting', 'NegReg', (118, 128))	('heparanase', 'Gene', '10855', (129, 139))	('HS', 'Chemical', 'MESH:D006497', (12, 14))	('PG545', 'Chemical', 'MESH:C557899', (31, 36))
17456	32916872	Inhibition of human sulfatase 1 (SULF1) inhibits the malignant phenotype of gallbladder carcinoma cells by hindering the cell response to growth factors.	('human', 'Species', '9606', (14, 19))	('hindering', 'NegReg', (107, 116))	('sulfatase 1', 'Gene', '23213', (20, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('SULF1', 'Gene', '23213', (33, 38))	('SULF1', 'Gene', (33, 38))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (76, 97))	('Inhibition', 'Var', (0, 10))	('inhibits', 'NegReg', (40, 48))	('sulfatase 1', 'Gene', (20, 31))	('cell response', 'CPA', (121, 134))	('gallbladder carcinoma', 'Disease', (76, 97))	('malignant phenotype of', 'CPA', (53, 75))
17457	32916872	Thus, the modulation of tumor microenvironment by affecting the structure and/or activity of HSPGs represents an effective therapeutic strategy for preventing tumor growth and progression.	('HSPG', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('structure', 'MPA', (64, 73))	('modulation', 'Var', (10, 20))	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('preventing', 'NegReg', (148, 158))	('tumor', 'Disease', (159, 164))	('HSPG', 'Gene', '960', (93, 97))	('activity', 'MPA', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('affecting', 'Reg', (50, 59))
17479	32658872	Lynch syndrome is caused by mutations of DNA mismatch repair (MMR) genes.	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('Lynch syndrome', 'Disease', (0, 14))	('caused by', 'Reg', (18, 27))	('MMR', 'Gene', (62, 65))	('mutations', 'Var', (28, 37))	('MMR', 'biological_process', 'GO:0006298', ('62', '65'))	('mismatch repair', 'biological_process', 'GO:0006298', ('45', '60'))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))
17487	32658872	However, it is now recognized that in about 37% of sporadic colorectal cancer and 45% of noncolorectal cancer, MSI occurs in the absence of germline MMR mutations.	('MMR', 'Gene', (149, 152))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (153, 162))	('noncolorectal cancer', 'Disease', (89, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('MMR', 'biological_process', 'GO:0006298', ('149', '152'))	('noncolorectal cancer', 'Disease', 'MESH:D009369', (89, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('colorectal cancer', 'Disease', (60, 77))
17490	32658872	showed dMMR occurred in 0.8% of pancreatic ductal adenocarcinoma cases (7 out of 833 cases) and it was associated with high mutational load.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (32, 64))	('associated', 'Reg', (103, 113))	('high mutational load', 'Var', (119, 139))	('pancreatic ductal adenocarcinoma', 'Disease', (32, 64))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (32, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('dMMR', 'Chemical', '-', (7, 11))	('dMMR', 'Disease', (7, 11))
17493	32658872	evaluated the genetic features of 13 sporadic PDA patients with MSI and showed epigenetic and genetic inactivation of the hMLH1 gene.	('hMLH1', 'Gene', (122, 127))	('patients', 'Species', '9606', (50, 58))	('hMLH1', 'Gene', '4292', (122, 127))	('genetic inactivation', 'Var', (94, 114))	('PDA', 'Phenotype', 'HP:0006725', (46, 49))	('epigenetic', 'Var', (79, 89))
17533	32658872	Given his personal history of colon cancer and now pancreatic cancer and the history of family members with colon cancer, the patient proceeded with genetic testing, which came back positive for MLH1 mutation.	('colon cancer', 'Disease', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('colon cancer', 'Phenotype', 'HP:0003003', (30, 42))	('pancreatic cancer', 'Disease', (51, 68))	('colon cancer', 'Disease', 'MESH:D015179', (30, 42))	('MLH1', 'Gene', '4292', (195, 199))	('positive', 'Reg', (182, 190))	('MLH1', 'Gene', (195, 199))	('pancreatic cancer', 'Disease', 'MESH:D010190', (51, 68))	('patient', 'Species', '9606', (126, 133))	('colon cancer', 'Phenotype', 'HP:0003003', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('colon cancer', 'Disease', (30, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('colon cancer', 'Disease', 'MESH:D015179', (108, 120))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (51, 68))	('mutation', 'Var', (200, 208))
17534	32658872	The 17-gene panel from Ambry Genetics (Aliso Viejo, CA, USA) identified an MLH1 mutation, c.350C>T (p.T117M).	('c.350C>T', 'Var', (90, 98))	('MLH1', 'Gene', '4292', (75, 79))	('MLH1', 'Gene', (75, 79))	('p.T117M', 'Mutation', 'rs63750781', (100, 107))	('Aliso', 'Species', '111540', (39, 44))	('c.350C>T', 'Mutation', 'rs63750781', (90, 98))
17541	32658872	Thus, tumor tissue demonstrated MSI-H genotype.	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('MSI-H', 'Var', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
17559	32658872	Prothrombin G20210A, Factor V Leiden were ordered, but not performed due to insurance issues.	('Factor V Leiden', 'Gene', (21, 36))	('G20210A', 'Var', (12, 19))	('Prothrombin', 'Gene', (0, 11))	('G20210A', 'Mutation', 'rs1799963', (12, 19))	('Factor V Leiden', 'Gene', '2153', (21, 36))	('Prothrombin', 'Gene', '2147', (0, 11))
17668	32024640	Inhibition of STAT3 signaling in tumor-educated CD8+ T cells improved PDA growth control upon adoptive transfer to tumor-bearing mice.	('improved', 'PosReg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))	('CD8', 'Gene', (48, 51))	('STAT3 signaling', 'MPA', (14, 29))	('Inhibition', 'Var', (0, 10))	('PDA growth control', 'CPA', (70, 88))	('tumor', 'Disease', (33, 38))	('mice', 'Species', '10090', (129, 133))	('CD8', 'Gene', '925', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
17670	32024640	We also demonstrated that B cell-specific deletion of IL35 facilitated CD8+ T-cell activation independently of effector or regulatory CD4+ T cells and was sufficient to phenocopy therapeutic anti-IL35 blockade in overcoming resistance to anti-PD-1 immunotherapy.	('CD8', 'Gene', '925', (71, 74))	('IL35', 'Gene', (54, 58))	('IL35', 'molecular_function', 'GO:0070748', ('196', '200'))	('IL35', 'molecular_function', 'GO:0070748', ('54', '58'))	('facilitated', 'PosReg', (59, 70))	('T-cell activation', 'biological_process', 'GO:0042110', ('76', '93'))	('deletion', 'Var', (42, 50))	('CD8', 'Gene', (71, 74))
17671	32024640	Finally, we identified a circulating IL35+ B-cell subset in patients with PDA and demonstrated that presence of IL35+ cells predicted increased occurrence of phosphorylated (p)Stat3+CXCR3-CD8+ T cells in tumors and inversely correlated with a cytotoxic T-cell signature in patients.	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('Stat3', 'Gene', (176, 181))	('Stat3', 'Gene', '6774', (176, 181))	('CD8', 'Gene', (188, 191))	('PDA', 'Disease', (74, 77))	('patients', 'Species', '9606', (273, 281))	('phos', 'Chemical', '-', (158, 162))	('CD8', 'Gene', '925', (188, 191))	('patients', 'Species', '9606', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('IL35', 'molecular_function', 'GO:0070748', ('112', '116'))	('IL35', 'molecular_function', 'GO:0070748', ('37', '41'))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('increased', 'PosReg', (134, 143))	('presence', 'Var', (100, 108))	('IL35+ cells', 'Var', (112, 123))
17678	32024640	These studies suggest that reversing immune suppression in pancreatic cancer could improve endogenous T-cell activity.	('pancreatic cancer', 'Disease', 'MESH:D010190', (59, 76))	('pancreatic cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('reversing', 'Var', (27, 36))	('improve', 'PosReg', (83, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (59, 76))	('endogenous', 'MPA', (91, 101))
17696	32024640	To validate that the deletion of p35 or Ebi3 genes was specific to the B-cell lineage, splenic CD19+ B cells, CD11b+ myeloid cells, and CD4+ T cells were isolated by FACS from Bp35-/-, BWT, BEbi3+/- and BEbi3-/- mice (please see "Lymphocyte isolation" section).	('Bp35', 'Gene', (176, 180))	('mice', 'Species', '10090', (212, 216))	('CD11b', 'Gene', (110, 115))	('FACS', 'Gene', (166, 170))	('CD11b', 'Gene', '3684', (110, 115))	('deletion', 'Var', (21, 29))	('FACS', 'Gene', '14081', (166, 170))	('p35', 'cellular_component', 'GO:0070745', ('33', '36'))	('Bp35', 'Gene', '474187', (176, 180))	('p35', 'cellular_component', 'GO:0043514', ('33', '36'))	('p35', 'Gene', (33, 36))	('Ebi3', 'Gene', (40, 44))	('Ebi3', 'cellular_component', 'GO:0070744', ('40', '44'))	('Ebi3', 'cellular_component', 'GO:0070745', ('40', '44'))
17697	32024640	To verify specific deletion of Ebi3 gene from Tregs, Foxp3+ (YFP+) Tregs, Foxp3- (YFP-) conventional T cells (Tcon), and CD19+ B cells were purified from TregEbi3+/- and TregEbi3-/- mice by FACS.	('Tregs', 'Chemical', '-', (67, 72))	('FACS', 'Gene', (190, 194))	('deletion', 'Var', (19, 27))	('mice', 'Species', '10090', (182, 186))	('Foxp3', 'Gene', '20371', (74, 79))	('Ebi3', 'Gene', (31, 35))	('FACS', 'Gene', '14081', (190, 194))	('Foxp3', 'Gene', '20371', (53, 58))	('Ebi3', 'cellular_component', 'GO:0070744', ('31', '35'))	('Foxp3', 'Gene', (74, 79))	('Foxp3', 'Gene', (53, 58))	('Tregs', 'Chemical', '-', (46, 51))	('Ebi3', 'cellular_component', 'GO:0070745', ('31', '35'))
17701	32024640	Cells were confirmed to contain Kras, Cre, and p53 mutant alleles/transgene by genotyping.	('Kras', 'Gene', (32, 36))	('Kras', 'Gene', '16653', (32, 36))	('mutant', 'Var', (51, 57))	('p53', 'Gene', '22059', (47, 50))	('p53', 'Gene', (47, 50))
17706	32024640	For therapeutic experiments, mice received antibody treatment using anti-IL35 (V1.4C4.22) at 200 mug/week for 3 weeks, anti-IL27 (MM27-7B1) at 200 mug/week for 3 weeks, and/or anti-PD-1 (RMP1-14, BioXcell) at 200 mug/injection on days 7, 9, and 11, or their respective IgG isotype controls once an orthotopic tumor reached 4-5 mm (day 7)(Supplementary Table S2).	('antibody', 'molecular_function', 'GO:0003823', ('43', '51'))	('mice', 'Species', '10090', (29, 33))	('antibody', 'cellular_component', 'GO:0042571', ('43', '51'))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('RMP1-14', 'Gene', '104168;104225;109970;109961', (187, 194))	('IL27', 'cellular_component', 'GO:0070744', ('124', '128'))	('anti-PD-1', 'Var', (176, 185))	('RMP1-14', 'Gene', (187, 194))	('mug', 'molecular_function', 'GO:0043739', ('147', '150'))	('antibody', 'cellular_component', 'GO:0019815', ('43', '51'))	('tumor', 'Disease', (309, 314))	('IL27', 'Gene', '246779', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('mug', 'molecular_function', 'GO:0043739', ('97', '100'))	('anti-IL35', 'Var', (68, 77))	('antibody', 'cellular_component', 'GO:0019814', ('43', '51'))	('IL27', 'Gene', (124, 128))	('IL35', 'molecular_function', 'GO:0070748', ('73', '77'))	('mug', 'molecular_function', 'GO:0043739', ('213', '216'))	('IL27', 'molecular_function', 'GO:0045523', ('124', '128'))
17714	32024640	For CD4+ and CD8+ T-cell depletion studies, 200 mug of anti-CD4 (Bio X cell, BP0003-1, clone GK1.4) and 200 mug of anti-CD8 (Bio X Cell, BP0004-1, clone 53-6.7) or an IgG isotype control rat IgG2b, kappa and rat IgG2a, kappa (Bio X Cell), respectively, were administered intraperitoneally daily starting 3 days prior to tumor cell injection and twice a week after tumor cell injection.	('mug', 'molecular_function', 'GO:0043739', ('48', '51'))	('IgG2b', 'Gene', (191, 196))	('CD8', 'Gene', '925', (120, 123))	('IgG2b', 'Gene', '16016', (191, 196))	('IgG2a', 'Gene', '668478', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('GK1.4', 'Gene', (93, 98))	('IgG2a', 'Gene', (212, 217))	('IgG2a', 'cellular_component', 'GO:0071735', ('212', '217'))	('CD8', 'Gene', '925', (13, 16))	('tumor', 'Disease', (320, 325))	('GK1.4', 'Gene', '317653', (93, 98))	('IgG2b', 'cellular_component', 'GO:0071735', ('191', '196'))	('mug', 'molecular_function', 'GO:0043739', ('108', '111'))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('CD8', 'Gene', (120, 123))	('tumor', 'Disease', (364, 369))	('CD8', 'Gene', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('tumor', 'Disease', 'MESH:D009369', (364, 369))	('anti-CD4', 'Var', (55, 63))
17724	32024640	For isolation of tumor-infiltrating lymphocytes, tumor tissue was minced into 1-2 mm pieces and digested with collagenase IV (1.25 mg/mL; #LS004188, Worthington), 0.1% soybean trypsin inhibitor (#T9128, Sigma), hyaluronidase (1 mg/mL; #LS002592, Worthington), and DNase I (100 mg/mL; #LS002007, Worthington) in complete DMEM for 30 minutes at 37 C. Cell suspensions were passed through a 70-mum cell strainer (Falcon) and resuspended in RPMI media (Gibco).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('100 mg/mL', 'Var', (273, 282))	('#T9128', 'Var', (195, 201))	('DMEM', 'Chemical', '-', (320, 324))	('tumor', 'Disease', (49, 54))	('collagenase IV', 'molecular_function', 'GO:0004228', ('110', '124'))	('collagenase IV', 'molecular_function', 'GO:0004229', ('110', '124'))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('DNase I', 'molecular_function', 'GO:0004530', ('264', '271'))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('soybean', 'Species', '3847', (168, 175))	('RPMI media', 'Chemical', '-', (437, 447))
17751	32024640	The isolated PBMCs were then stained with anti-human CD19 (HIB19; Biolegend), CD24 (ML5; Biolegend), and CD38 (HB-7; Biolegend) in FACS buffer for 20 minutes on ice.	('CD24', 'Var', (78, 82))	('FACS', 'Gene', (131, 135))	('FACS', 'Gene', '14081', (131, 135))	('CD38', 'Gene', (105, 109))	('human', 'Species', '9606', (47, 52))	('CD38', 'Gene', '952', (105, 109))
17768	32024640	Anti-mouse antibodies included phospho-Histone 3 (Millipore, 06-570) and CK8 (DSHB, Troma-I).	('phos', 'Chemical', '-', (31, 35))	('CK8', 'Gene', '16691', (73, 76))	('CK8', 'Gene', (73, 76))	('mouse', 'Species', '10090', (5, 10))	('phospho-Histone', 'Var', (31, 46))
17776	32024640	Stained slides were counterstained with Hoechst 33258 (# H3569) and mounted with ProLong  Diamond Antifade Mountant (#P36961; Life Technologies (Carlsbad, CA).	('Hoechst 33258', 'Chemical', 'MESH:D006690', (40, 53))	('#P36961;', 'Var', (117, 125))	('# H3569', 'Var', (55, 62))
17801	32024640	In CD4+ T cells, IL35 mediates function via receptor chains IL12Rbeta2 and gp130, which signal to activate STAT1 and STAT4 but not STAT3.	('IL12', 'molecular_function', 'GO:0005143', ('60', '64'))	('gp130', 'molecular_function', 'GO:0004915', ('75', '80'))	('STAT1', 'Gene', '20846', (107, 112))	('IL35', 'molecular_function', 'GO:0070748', ('17', '21'))	('gp130', 'molecular_function', 'GO:0004921', ('75', '80'))	('STAT1', 'Gene', (107, 112))	('activate', 'PosReg', (98, 106))	('STAT4', 'Gene', '20849', (117, 122))	('gp130', 'molecular_function', 'GO:0004898', ('75', '80'))	('gp130', 'Gene', (75, 80))	('gp130', 'molecular_function', 'GO:0004897', ('75', '80'))	('IL12Rbeta2', 'Var', (60, 70))	('gp130', 'Gene', '16157', (75, 80))	('STAT4', 'Gene', (117, 122))
17802	32024640	To understand how IL35R contributes to STAT3 activation in CD8+ T cells, we sorted T cells based on singular expression of either IL12Rbeta2 or gp130 (Supplementary Fig.	('gp130', 'molecular_function', 'GO:0004897', ('144', '149'))	('STAT3', 'MPA', (39, 44))	('gp130', 'Gene', '16157', (144, 149))	('gp130', 'molecular_function', 'GO:0004915', ('144', '149'))	('CD8', 'Gene', (59, 62))	('gp130', 'molecular_function', 'GO:0004921', ('144', '149'))	('CD8', 'Gene', '925', (59, 62))	('gp130', 'molecular_function', 'GO:0004898', ('144', '149'))	('IL12', 'molecular_function', 'GO:0005143', ('130', '134'))	('IL35R', 'molecular_function', 'GO:0070747', ('18', '23'))	('IL12Rbeta2', 'Var', (130, 140))	('gp130', 'Gene', (144, 149))
17813	32024640	We reasoned that if IL35-driven activation of STAT3 in CD8+ T cells was an important factor driving CD8+ T cell exclusion and inactivity in PDA, then inhibition of STAT3 activation in tumor-educated immunosuppressed CD8+ T cells could confer antitumor responses.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('inhibition', 'Var', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('CD8', 'Gene', (216, 219))	('CD8', 'Gene', (100, 103))	('CD8', 'Gene', '925', (216, 219))	('tumor', 'Disease', (184, 189))	('CD8', 'Gene', '925', (100, 103))	('confer', 'Reg', (235, 241))	('CD8', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('CD8', 'Gene', '925', (55, 58))	('IL35', 'molecular_function', 'GO:0070748', ('20', '24'))	('tumor', 'Disease', (246, 251))
17822	32024640	To determine whether Treg-derived IL35 confers immunosuppression in PDA, we used mice with Treg-specific Foxp3Cre-YFP-driven deficiency in Ebi3 (TregEbi3-/-)(Supplementary Fig.	('Treg', 'Chemical', '-', (145, 149))	('mice', 'Species', '10090', (81, 85))	('Treg', 'Chemical', '-', (91, 95))	('Treg', 'Chemical', '-', (21, 25))	('deficiency', 'Var', (125, 135))	('Ebi3', 'cellular_component', 'GO:0070745', ('139', '143'))	('Ebi3', 'cellular_component', 'GO:0070744', ('139', '143'))	('Foxp3', 'Gene', '20371', (105, 110))	('IL35', 'molecular_function', 'GO:0070748', ('34', '38'))	('Foxp3', 'Gene', (105, 110))	('Ebi3', 'Protein', (139, 143))
17823	32024640	We found that Treg-specific deficiency in IL35 did not alter orthotropic tumor growth, as KPC cells injected into either TregEbi3+/- or TregEbi3-/- littermates grew to a comparable tumor size, even though Ebi3 expression in CD4+ T cells was reduced to background levels (Supplementary Fig.	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Treg', 'Chemical', '-', (136, 140))	('deficiency', 'Var', (28, 38))	('tumor', 'Disease', (73, 78))	('Treg', 'Chemical', '-', (14, 18))	('Ebi3', 'cellular_component', 'GO:0070745', ('205', '209'))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('KPC', 'Chemical', '-', (90, 93))	('Ebi3', 'cellular_component', 'GO:0070744', ('205', '209'))	('IL35', 'Gene', (42, 46))	('Treg', 'Chemical', '-', (121, 125))	('IL35', 'molecular_function', 'GO:0070748', ('42', '46'))
17824	32024640	Intratumoral and splenic frequency of total Foxp3+ Tregs, as well as cytokine production by B cells, was not altered in mice with Treg-specific deletion of Ebi3, suggesting that endogenous production of IL35 by Tregs in PDA does not control Treg or IL35+ B-cell expansion at the tumor site (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('Tregs', 'Chemical', '-', (211, 216))	('Treg', 'Chemical', '-', (130, 134))	('deletion', 'Var', (144, 152))	('IL35', 'molecular_function', 'GO:0070748', ('203', '207'))	('Treg', 'Chemical', '-', (241, 245))	('Tregs', 'Chemical', '-', (51, 56))	('Foxp3', 'Gene', (44, 49))	('cell expansion', 'biological_process', 'GO:0016049', ('257', '271'))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('Ebi3', 'cellular_component', 'GO:0070745', ('156', '160'))	('cytokine production', 'biological_process', 'GO:0001816', ('69', '88'))	('tumor', 'Disease', (279, 284))	('Foxp3', 'Gene', '20371', (44, 49))	('IL35', 'molecular_function', 'GO:0070748', ('249', '253'))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('mice', 'Species', '10090', (120, 124))	('Treg', 'Chemical', '-', (211, 215))	('Ebi3', 'cellular_component', 'GO:0070744', ('156', '160'))	('tumor', 'Disease', (5, 10))	('Ebi3', 'Gene', (156, 160))	('Treg', 'Chemical', '-', (51, 55))
17825	32024640	The frequency and activity of CD4+ and CD8+ T effector cells and frequencies of myeloid subsets were similar between TregEbi3+/- or TregEbi3-/- animals (Supplementary Fig.	('TregEbi3+/-', 'Var', (117, 128))	('CD8', 'Gene', (39, 42))	('CD8', 'Gene', '925', (39, 42))
17827	32024640	To determine whether B cell-derived IL35 confers immunosuppression in PDA, we first generated mice with B-cell specific deficiency in the p35 (Bp35-/-) subunit of IL35 using a mixed bone marrow chimera approach (Fig.	('Bp35', 'Gene', '474187', (143, 147))	('IL35', 'Gene', (163, 167))	('IL35', 'molecular_function', 'GO:0070748', ('163', '167'))	('deficiency', 'Var', (120, 130))	('p35', 'cellular_component', 'GO:0070745', ('138', '141'))	('Bp35', 'Gene', (143, 147))	('mice', 'Species', '10090', (94, 98))	('p35', 'cellular_component', 'GO:0043514', ('138', '141'))	('IL35', 'molecular_function', 'GO:0070748', ('36', '40'))
17831	32024640	These findings, together with our observations suggesting that IL35 affected antitumor immune responses, prompted investigation into the immune functionality following B cell-specific deletion of IL35.	('deletion', 'Var', (184, 192))	('IL35', 'molecular_function', 'GO:0070748', ('63', '67'))	('affected', 'Reg', (68, 76))	('IL35', 'molecular_function', 'GO:0070748', ('196', '200'))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('IL35', 'Gene', (196, 200))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
17833	32024640	Because it has been proposed that exogenous IL35 may promote expansion of suppressive Tregs by inducing its own expression in CD4+ T cells, we examined the ability of Tregs to produce IL35 in the context of B cell-specific deletion of this cytokine.	('expression', 'MPA', (112, 122))	('IL35', 'molecular_function', 'GO:0070748', ('44', '48'))	('Tregs', 'Chemical', '-', (167, 172))	('IL35', 'Gene', (44, 48))	('deletion', 'Var', (223, 231))	('IL35', 'molecular_function', 'GO:0070748', ('184', '188'))	('Tregs', 'Chemical', '-', (86, 91))	('inducing', 'Reg', (95, 103))	('exogenous', 'Var', (34, 43))	('promote', 'PosReg', (53, 60))
17836	32024640	The changes in the T-cell landscape were accompanied by increased infiltration and IFNgamma expression by effector CD8+ T cells, and overall, there was a significant increase in the ratio of CD4+ and CD8+ effector T cells to Tregs (Fig.	('CD8', 'Gene', '925', (115, 118))	('CD8', 'Gene', '925', (200, 203))	('increased', 'PosReg', (56, 65))	('increase', 'PosReg', (166, 174))	('IFNgamma', 'Gene', (83, 91))	('changes', 'Reg', (4, 11))	('CD4+', 'Var', (191, 195))	('infiltration', 'CPA', (66, 78))	('IFNgamma', 'Gene', '15978', (83, 91))	('T-cell landscape', 'CPA', (19, 35))	('CD8', 'Gene', (200, 203))	('Tregs', 'Chemical', '-', (225, 230))	('CD8', 'Gene', (115, 118))
17837	32024640	These results suggested that cancer-associated IL35 expression in B cells was sufficient to dampen productive T cell-mediated immune responses in PDA.	('cancer', 'Disease', (29, 35))	('IL35', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('dampen', 'NegReg', (92, 98))	('expression', 'Var', (52, 62))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('IL35', 'molecular_function', 'GO:0070748', ('47', '51'))	('PDA', 'Disease', (146, 149))
17841	32024640	To understand if B cell-specific deficiency in IL35 was sufficient to confer sensitivity to anti-PD-1, we treated BEbi3+/- and BEbi3-/- mice with anti-PD-1 or isotype control (Fig.	('deficiency', 'Var', (33, 43))	('mice', 'Species', '10090', (136, 140))	('IL35', 'molecular_function', 'GO:0070748', ('47', '51'))	('IL35', 'Gene', (47, 51))
17843	32024640	Combination of anti-PD-1 with B cell-specific loss of IL35 conferred additional significant reduction in tumor growth compared to BEbi3+/- mice treated with either isotype or anti-PD-1 or BEbi3-/- mice treated with isotype control (Fig.	('mice', 'Species', '10090', (197, 201))	('loss', 'NegReg', (46, 50))	('IL35', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('reduction', 'NegReg', (92, 101))	('IL35', 'molecular_function', 'GO:0070748', ('54', '58'))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('anti-PD-1', 'Var', (15, 24))	('mice', 'Species', '10090', (139, 143))	('tumor', 'Disease', (105, 110))
17846	32024640	Loss of B cell-derived Ebi3 increased CD4+ effector T cells and decreased intratumoral Treg frequency (Supplementary Fig.	('increased', 'PosReg', (28, 37))	('CD4+ effector T cells', 'CPA', (38, 59))	('Ebi3', 'cellular_component', 'GO:0070745', ('23', '27'))	('tumor', 'Disease', (79, 84))	('Ebi3', 'cellular_component', 'GO:0070744', ('23', '27'))	('Ebi3', 'Gene', (23, 27))	('Treg', 'Chemical', '-', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('decreased', 'NegReg', (64, 73))
17848	32024640	Anti-PD-1-treated BEbi3-/- mice exhibited slightly upward trending changes in effector CD4+ T cells, comparable with those in IgG-treated BEbi3-/- mice.	('mice', 'Species', '10090', (147, 151))	('changes', 'Reg', (67, 74))	('effector CD4+ T cells', 'MPA', (78, 99))	('mice', 'Species', '10090', (27, 31))	('Anti-PD-1-treated', 'Var', (0, 17))	('upward', 'PosReg', (51, 57))
17849	32024640	The ratio of CD4+ and CD8+ effector T cells to Tregs was significantly higher in BEbi3-/- mice treated with anti-PD-1 compared to the BEbi3-/- IgG cohort, and may contribute to better tumor control, but the frequency of myeloid cell subsets was not affected by B-cell loss of Ebi3 (Supplementary Fig.	('higher', 'PosReg', (71, 77))	('Ebi3', 'cellular_component', 'GO:0070744', ('276', '280'))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('Ebi3', 'cellular_component', 'GO:0070745', ('276', '280'))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('Tregs', 'Chemical', '-', (47, 52))	('tumor', 'Disease', (184, 189))	('anti-PD-1', 'Var', (108, 117))	('mice', 'Species', '10090', (90, 94))	('better', 'PosReg', (177, 183))	('CD8', 'Gene', (22, 25))	('CD8', 'Gene', '925', (22, 25))
17854	32024640	4E-F), B cell-specific deletion of IL35 correlated with increased expression of both CXCR3 and CCR5 and a concordant decrease of pSTAT1, pSTAT3, and pSTAT4 in CD8+ T cells (Fig.	('IL35', 'molecular_function', 'GO:0070748', ('35', '39'))	('CCR5', 'Gene', (95, 99))	('CCR', 'molecular_function', 'GO:0043880', ('95', '98'))	('IL35', 'Gene', (35, 39))	('increased', 'PosReg', (56, 65))	('deletion', 'Var', (23, 31))	('STAT4', 'Gene', '20849', (150, 155))	('expression', 'MPA', (66, 76))	('CD8', 'Gene', (159, 162))	('STAT4', 'Gene', (150, 155))	('STAT1', 'Gene', (130, 135))	('CD8', 'Gene', '925', (159, 162))	('CCR5', 'Gene', '12774', (95, 99))	('STAT1', 'Gene', '20846', (130, 135))	('decrease', 'NegReg', (117, 125))	('pSTAT3', 'MPA', (137, 143))	('CXCR3', 'MPA', (85, 90))
17864	32024640	Blockade of IL35 resulted in significant reduction of serum IL35 and a concordant reduction of tumor growth (Fig.	('IL35', 'molecular_function', 'GO:0070748', ('12', '16'))	('serum IL35', 'MPA', (54, 64))	('IL35', 'Gene', (12, 16))	('reduction', 'NegReg', (82, 91))	('Blockade', 'Var', (0, 8))	('IL35', 'molecular_function', 'GO:0070748', ('60', '64'))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))	('reduction', 'NegReg', (41, 50))
17867	32024640	Because anti-IL35 targets the Ebi3 subunit, which is also a subunit of IL27, we tested whether depletion of IL27 affected PDA growth.	('IL27', 'molecular_function', 'GO:0045523', ('71', '75'))	('IL27', 'Gene', (108, 112))	('IL27', 'molecular_function', 'GO:0045523', ('108', '112'))	('IL27', 'cellular_component', 'GO:0070744', ('71', '75'))	('IL27', 'Gene', '246779', (108, 112))	('IL27', 'cellular_component', 'GO:0070744', ('108', '112'))	('Ebi3', 'cellular_component', 'GO:0070745', ('30', '34'))	('IL27', 'Gene', (71, 75))	('Ebi3', 'cellular_component', 'GO:0070744', ('30', '34'))	('anti-IL35', 'Var', (8, 17))	('tested', 'Reg', (80, 86))	('IL35', 'molecular_function', 'GO:0070748', ('13', '17'))	('IL27', 'Gene', '246779', (71, 75))
17868	32024640	Anti-IL27 (against the p28 subunit) did not elicit reduced tumor growth, suggesting that the action of anti-IL35 was on target (Supplementary Fig.	('p28', 'cellular_component', 'GO:0070744', ('23', '26'))	('tumor', 'Disease', (59, 64))	('IL27', 'cellular_component', 'GO:0070744', ('5', '9'))	('p28', 'Gene', (23, 26))	('anti-IL35', 'Var', (103, 112))	('IL35', 'molecular_function', 'GO:0070748', ('108', '112'))	('IL27', 'Gene', (5, 9))	('IL27', 'molecular_function', 'GO:0045523', ('5', '9'))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('p28', 'Gene', '27061', (23, 26))	('IL27', 'Gene', '246779', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
17871	32024640	Survival of orthotopically injected mice treated with combination anti-IL35 and anti-PD-1 was also significantly improved (Fig.	('IL35', 'molecular_function', 'GO:0070748', ('71', '75'))	('Survival', 'CPA', (0, 8))	('anti-IL35', 'Var', (66, 75))	('anti-PD-1', 'Var', (80, 89))	('mice', 'Species', '10090', (36, 40))	('improved', 'PosReg', (113, 121))
17872	32024640	Treatment of animals bearing spontaneous KrasG12D;Trp53R172H;p48Cre/+ (KPC)-driven pancreatic cancer with either anti-IL35 alone or combination with anti-PD-1 also significantly reduced tumor growth (Fig.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('pancreatic cancer', 'Disease', (83, 100))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('tumor', 'Disease', (186, 191))	('p48', 'Gene', (61, 64))	('p48', 'Gene', '16391', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('IL35', 'molecular_function', 'GO:0070748', ('118', '122'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))	('anti-IL35', 'Var', (113, 122))	('reduced', 'NegReg', (178, 185))	('KPC', 'Chemical', '-', (71, 74))
17873	32024640	Reduced tumor growth in the orthotopic setting was accompanied by increased infiltration and activation of effector T cells, as well as a reduction in Treg frequency, corroborating our observations in models of complete or B cell-specific IL35 deficiency (Fig.	('Treg frequency', 'CPA', (151, 165))	('infiltration', 'CPA', (76, 88))	('IL35', 'molecular_function', 'GO:0070748', ('239', '243'))	('increased', 'PosReg', (66, 75))	('activation', 'CPA', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('Reduced', 'NegReg', (0, 7))	('IL35', 'Gene', (239, 243))	('Treg', 'Chemical', '-', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('deficiency', 'Var', (244, 254))	('reduction', 'NegReg', (138, 147))
17876	32024640	We also found that the frequency of PD-1+CD8+ T cells increased in treated animals, suggesting that anti-IL35 blockade in PDA resulted in increased effector function of CD8+ T cells (Supplementary Fig.	('IL35', 'molecular_function', 'GO:0070748', ('105', '109'))	('anti-IL35', 'Protein', (100, 109))	('increased', 'PosReg', (138, 147))	('CD8', 'Gene', (41, 44))	('CD8', 'Gene', '925', (41, 44))	('blockade', 'Var', (110, 118))	('effector function', 'CPA', (148, 165))	('CD8', 'Gene', (169, 172))	('CD8', 'Gene', '925', (169, 172))
17878	32024640	We confirmed that expression of CXCR3 and CCR5 was increased on CD8+ T cells derived from anti-IL35-treated animals, concordant with decreases in pSTAT3 and pSTAT4 activation, although no additional changes were observed upon addition of anti-PD-1 (Fig.	('CD8', 'Gene', (64, 67))	('IL35', 'molecular_function', 'GO:0070748', ('95', '99'))	('increased', 'PosReg', (51, 60))	('CD8', 'Gene', '925', (64, 67))	('CCR5', 'Gene', (42, 46))	('STAT4', 'Gene', '20849', (158, 163))	('expression', 'MPA', (18, 28))	('CXCR3', 'MPA', (32, 37))	('STAT4', 'Gene', (158, 163))	('CCR5', 'Gene', '12774', (42, 46))	('decreases', 'NegReg', (133, 142))	('CCR', 'molecular_function', 'GO:0043880', ('42', '45'))	('anti-IL35-treated', 'Var', (90, 107))
17882	32024640	QPCR revealed that the CD19+CD24hiCD27+ B10 subset produced IL10, whereas the CD19+CD24hiCD38hi immature B-cell subset was most similar to the murine Bregs and produced both IL10 and IL35 (Supplementary Fig.	('B10', 'Gene', '14940', (40, 43))	('CD24hiCD27', 'Gene', '12484;21940', (28, 38))	('IL10', 'MPA', (60, 64))	('IL35', 'MPA', (183, 187))	('IL35', 'molecular_function', 'GO:0070748', ('183', '187'))	('IL10', 'molecular_function', 'GO:0005141', ('174', '178'))	('B10', 'Gene', (40, 43))	('CD19+CD24hiCD38hi', 'Var', (78, 95))	('IL10', 'MPA', (174, 178))	('CD24hiCD27', 'Gene', (28, 38))	('murine', 'Species', '10090', (143, 149))	('IL10', 'molecular_function', 'GO:0005141', ('60', '64'))
17888	32024640	Overall, the frequency of CD19+CD24hiCD38hi immature B cells in the PB of PDA patients was significantly higher than in healthy controls (Fig.	('higher', 'PosReg', (105, 111))	('patients', 'Species', '9606', (78, 86))	('CD19+CD24hiCD38hi', 'Var', (26, 43))
17889	32024640	We found that CD19+CD24hiCD38hi peripheral B cells from PDA patients expressed significantly higher IL35 and IL10 compared to healthy controls and Bcon cells (Fig.	('higher', 'PosReg', (93, 99))	('CD19+CD24hiCD38hi', 'Var', (14, 31))	('IL10', 'molecular_function', 'GO:0005141', ('109', '113'))	('patients', 'Species', '9606', (60, 68))	('IL35', 'molecular_function', 'GO:0070748', ('100', '104'))	('PDA', 'Disease', (56, 59))
17903	32024640	Although the consequences of epithelial-specific IL35 expression in PDA on immune function are not yet clear, our initial analysis did not find a correlation between the frequency of IL35+ cancer cells and CD8+ T-cell infiltration into the tumor parenchyma (Supplementary Fig.	('tumor', 'Disease', (240, 245))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('IL35', 'molecular_function', 'GO:0070748', ('183', '187'))	('CD8', 'Gene', (206, 209))	('CD8', 'Gene', '925', (206, 209))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('IL35', 'molecular_function', 'GO:0070748', ('49', '53'))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('IL35', 'Gene', (49, 53))	('IL35+', 'Var', (183, 188))	('cancer', 'Disease', (189, 195))
17933	32024640	STAT inhibitor studies performed by us at this point were done ex vivo and are limited to proof-of-concept because all three inhibitors used (fludarabine, STA-21, and lysofylline) may have off-target effects.	('fludarabine', 'Chemical', 'MESH:C024352', (142, 153))	('lysofylline', 'Chemical', '-', (167, 178))	('lysofylline', 'Var', (167, 178))	('STA-21', 'Chemical', 'MESH:C500947', (155, 161))	('STAT', 'Gene', (0, 4))	('STAT', 'Gene', '20846;6774;20848;20849', (0, 4))
17944	32024640	Although our preliminary analysis did not indicate alterations in myeloid populations in either B cell- or Treg-specific deletion of IL35, it is still possible that IL35 may act on other immune cells apart from B cells and T cells.	('IL35', 'molecular_function', 'GO:0070748', ('165', '169'))	('deletion', 'Var', (121, 129))	('IL35', 'Gene', (133, 137))	('IL35', 'molecular_function', 'GO:0070748', ('133', '137'))	('act', 'Reg', (174, 177))	('Treg', 'Chemical', '-', (107, 111))
17947	32024640	We also demonstrated that presence of IL35+ B cells inversely correlated with antitumor cytotoxic T-cell activity and expansion of Bregs across distinct cancer types, suggesting that Bregs are major drivers of immunosuppression in a variety of cancers.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('IL35+ B cells', 'Var', (38, 51))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('IL35', 'molecular_function', 'GO:0070748', ('38', '42'))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancers', 'Disease', 'MESH:D009369', (244, 251))	('tumor', 'Disease', (82, 87))	('cancers', 'Disease', (244, 251))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))
17961	31903112	No additive effect was detected on cell viability when Met-inhibition was combined with MEK1/2 inhibition.	('MEK1/2', 'Gene', '5604;5605', (88, 94))	('Met-inhibition', 'Var', (55, 69))	('MEK1/2', 'Gene', (88, 94))	('Met', 'Chemical', 'MESH:C034758', (55, 58))	('MEK1', 'molecular_function', 'GO:0004708', ('88', '92'))
17964	31903112	Conclusions: Our findings demonstrate that while over-expression of Met is not predictive of Met-directed TKI response, immunoPET can detect Met over-expression in vivo and predicts for therapeutic response to Met-selective RLT.	('PET', 'Gene', '22095', (126, 129))	('predicts', 'Reg', (173, 181))	('over-expression', 'PosReg', (145, 160))	('Met', 'Chemical', 'MESH:C034758', (68, 71))	('PET', 'Gene', (126, 129))	('Met', 'Chemical', 'MESH:C034758', (210, 213))	('Met', 'Chemical', 'MESH:C034758', (141, 144))	('Met', 'Chemical', 'MESH:C034758', (93, 96))	('Met', 'Var', (141, 144))
17969	31903112	Activating mutations in the KRAS onocogene are present in >90% of pancreatic adenocarcinoma.	('KRAS', 'Gene', (28, 32))	('Activating mutations', 'Var', (0, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010195', (66, 91))	('pancreatic adenocarcinoma', 'Disease', (66, 91))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (66, 91))
17979	31903112	Furthermore, Met over-expression is associated with poor overall patient survival, and increased recurrence rates following surgery.	('increased', 'PosReg', (87, 96))	('over-expression', 'PosReg', (17, 32))	('Met', 'Chemical', 'MESH:C034758', (13, 16))	('Met', 'Var', (13, 16))	('patient', 'Species', '9606', (65, 72))	('recurrence rates', 'CPA', (97, 113))
17983	31903112	Because Met activates the KRAS pathway, we hypothesized that in cells that overexpress Met, combined blockade of the RAS pathway and Met would yield therapeutic synergy.	('overexpress', 'PosReg', (75, 86))	('Met', 'Var', (8, 11))	('activates', 'PosReg', (12, 21))	('Met', 'Chemical', 'MESH:C034758', (133, 136))	('yield', 'Reg', (143, 148))	('KRAS pathway', 'Pathway', (26, 38))	('RAS pathway', 'Pathway', (117, 128))	('Met', 'Chemical', 'MESH:C034758', (87, 90))	('Met', 'Var', (87, 90))	('Met', 'Chemical', 'MESH:C034758', (8, 11))
17984	31903112	This rationale was even specifically highlighted in previous reports on the interplay between Met signaling and KRAS mutant cancers.	('mutant', 'Var', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('KRAS', 'Gene', (112, 116))	('Met', 'Chemical', 'MESH:C034758', (94, 97))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
18006	31903112	Cells were incubated with 0.5 mg/mL of EZ-LINK Sulfo-Biotin (Thermo Fisher Scientific) for 30 min at 4  C with gentle rotation.	('gentle rotation', 'Disease', (111, 126))	('Sulfo-Biotin', 'Chemical', 'MESH:D001710', (47, 59))	('EZ-LINK', 'Var', (39, 46))	('gentle rotation', 'Disease', 'MESH:D009069', (111, 126))
18026	31903112	The immunoreactivity of the [89Zr]Zr-DFO-onartuzumab and [177Lu]Lu-DTPA-onartuzumab was determined using BxPC3, a human pancreatic cancer cell line which highly expresses Met, via a previously reported Lindmo method.	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('[177Lu]Lu-DTPA', 'Chemical', 'MESH:D008187', (57, 71))	('[89Zr]Zr-DFO', 'Chemical', 'MESH:D015040', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('Met', 'Chemical', 'MESH:C034758', (171, 174))	('[89Zr]Zr-DFO-onartuzumab', 'Var', (28, 52))	('human', 'Species', '9606', (114, 119))	('BxPC3', 'CellLine', 'CVCL:0186', (105, 110))	('pancreatic cancer', 'Disease', (120, 137))
18045	31903112	The mass of each organ was determined and the radioactivity of each sample was measured using a Wizard2 automatic gamma counter that was calibrated for the corresponding radioisotope, Zr-89 or Lu-177.	('Zr-89', 'Chemical', 'MESH:D015040', (184, 189))	('Zr-89', 'Var', (184, 189))	('Lu-177', 'Chemical', 'MESH:C575017', (193, 199))	('Lu-177', 'Var', (193, 199))
18058	31903112	Using the cancer microarray database Oncomine across matched tumor and normal gene expression datasets, we confirmed amplification of Met in several pancreatic cancer patient datasets (denoted by the first author of the relevant publication) (Figure 1A, top).	('tumor', 'Disease', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (149, 166))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', (10, 16))	('patient', 'Species', '9606', (167, 174))	('Met', 'Chemical', 'MESH:C034758', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('pancreatic cancer', 'Disease', 'MESH:D010190', (149, 166))	('gene expression', 'biological_process', 'GO:0010467', ('78', '93'))	('pancreatic cancer', 'Disease', (149, 166))	('Met', 'Var', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('amplification', 'Var', (117, 130))
18059	31903112	Analysis of pancreatic cancer data from The Cancer Genome Atlas (TCGA) demonstrates that Met expression is associated with unfavorable survival in patients with pancreatic adenocarcinoma (Figure 1A, bottom).	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010195', (161, 186))	('Cancer', 'Disease', (44, 50))	('Met expression', 'Var', (89, 103))	('pancreatic adenocarcinoma', 'Disease', (161, 186))	('unfavorable survival', 'MPA', (123, 143))	('Cancer', 'Disease', 'MESH:D009369', (44, 50))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (12, 29))	('Cancer', 'Phenotype', 'HP:0002664', (44, 50))	('Met', 'Chemical', 'MESH:C034758', (89, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (161, 186))	('pancreatic cancer', 'Disease', (12, 29))	('patients', 'Species', '9606', (147, 155))	('associated with', 'Reg', (107, 122))	('pancreatic cancer', 'Disease', 'MESH:D010190', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
18066	31903112	Notably, these four cell lines exhibit mutational status common in PDAC including KRAS, TP53, p16/CDKN2A, SMAD4 (Figure 1D).	('exhibit', 'Reg', (31, 38))	('p16', 'Gene', '1029', (94, 97))	('KRAS', 'Disease', (82, 86))	('mutational', 'Var', (39, 49))	('SMAD4', 'Gene', (106, 111))	('CDKN2A', 'Gene', (98, 104))	('TP53', 'Gene', '7157', (88, 92))	('p16', 'Gene', (94, 97))	('CDKN2A', 'Gene', '1029', (98, 104))	('TP53', 'Gene', (88, 92))	('SMAD4', 'Gene', '4089', (106, 111))
18067	31903112	While BxPC3 is KRAS wildtype, it harbors an activating BRAF mutation, making it functionally KRAS pathway-activated.	('mutation', 'Var', (60, 68))	('activating', 'PosReg', (44, 54))	('BRAF', 'Gene', '673', (55, 59))	('BRAF', 'Gene', (55, 59))	('BxPC3', 'CellLine', 'CVCL:0186', (6, 11))
18089	31903112	This hypothesis was supported by pilot in vivo therapy study in subcutaneous BxPC3 tumors performed with [177Lu]Lu-DTPA-onartuzumab RLT agent, which demonstrated a modest, but statistically significant decrease in tumor growth and overall survival benefit in the cohort of mice bearing BxPC3 tumors treated with three fractions (1.48 MBq(40muCi)/6.7mug x 3 administered at 3 day intervals) versus a single fraction (4.44 MBq(120muCi) /20mug x 1) (data not shown).	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('BxPC3', 'CellLine', 'CVCL:0186', (286, 291))	('tumor', 'Disease', (83, 88))	('[177Lu]Lu-DTPA', 'Chemical', 'MESH:D008187', (105, 119))	('[177Lu]Lu-DTPA-onartuzumab', 'Var', (105, 131))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('mug', 'molecular_function', 'GO:0043739', ('349', '352'))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('tumors', 'Disease', (292, 298))	('decrease', 'NegReg', (202, 210))	('BxPC3', 'CellLine', 'CVCL:0186', (77, 82))	('mice', 'Species', '10090', (273, 277))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('tumor', 'Disease', (214, 219))	('mug', 'molecular_function', 'GO:0043739', ('437', '440'))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', (292, 297))	('tumors', 'Disease', (83, 89))	('survival benefit', 'CPA', (239, 255))	('tumor', 'Disease', 'MESH:D009369', (292, 297))
18096	31903112	amplification) or activating mutations of Met are well-described predictors of response to Met-targeted kinase inhibitors, over-expression and epigenetic alterations might also be important in select cases.	('Met', 'Chemical', 'MESH:C034758', (91, 94))	('Met', 'Gene', (42, 45))	('over-expression', 'Var', (123, 138))	('activating', 'PosReg', (18, 28))	('epigenetic alterations', 'Var', (143, 165))	('Met', 'Chemical', 'MESH:C034758', (42, 45))
18097	31903112	Reports of a patient with KRAS mutant renal cell carcinoma showed a dramatic response to trametinib (MEK inhibitor) initially, and was found to have Met over-expression upon relapse, which was sensitive to treatment with crizotinib, an ALK and Met inhibitor.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (38, 58))	('mutant', 'Var', (31, 37))	('KRAS', 'Gene', (26, 30))	('patient', 'Species', '9606', (13, 20))	('trametinib', 'Chemical', 'MESH:C560077', (89, 99))	('over-expression', 'PosReg', (153, 168))	('response', 'MPA', (77, 85))	('ALK', 'Gene', '238', (236, 239))	('Met', 'Chemical', 'MESH:C034758', (149, 152))	('Met', 'Chemical', 'MESH:C034758', (244, 247))	('MEK', 'Gene', (101, 104))	('MEK', 'Gene', '5609', (101, 104))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (38, 58))	('crizotinib', 'Chemical', 'MESH:C551994', (221, 231))	('ALK', 'Gene', (236, 239))	('renal cell carcinoma', 'Disease', (38, 58))
18098	31903112	In KRAS-mutant non-small cell lung cancer (NSCLC) treated with trametinib, Manchado et al.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cell lung cancer', 'Disease', (25, 41))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (19, 41))	('trametinib', 'Chemical', 'MESH:C560077', (63, 73))	('cell lung cancer', 'Disease', 'MESH:D008175', (25, 41))	('KRAS-mutant', 'Var', (3, 14))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (15, 41))	('NSCLC', 'Disease', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
18100	31903112	Though not as extensively investigated as KRAS-mutant NSCLC models, promising results of combined trametinib/ponatinib therapy were reported in KRAS-mutant organoid-derived murine model of PDAC as well, suggesting a role for multidrug therapy.	('murine', 'Species', '10090', (173, 179))	('ponatinib', 'Chemical', 'MESH:C545373', (109, 118))	('KRAS-mutant', 'Var', (144, 155))	('trametinib', 'Chemical', 'MESH:C560077', (98, 108))	('NSCLC', 'Disease', (54, 59))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
18103	31903112	Others have demonstrated that abrogating KRAS activation via CRISPR/Cas9 has a limited effect on oncogenicity of PDAC lines due to compensatory signaling changes, further complicating therapeutic strategies for presumed KRAS driven tumors.	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('oncogenicity', 'MPA', (97, 109))	('abrogating', 'Var', (30, 40))	('KRAS', 'Gene', (41, 45))	('tumors', 'Disease', (232, 238))	('Cas', 'cellular_component', 'GO:0005650', ('68', '71'))	('tumors', 'Disease', 'MESH:D009369', (232, 238))
18105	31903112	These findings are in contrast to previous reports suggesting a therapeutic efficacy of Met inhibition in KRAS mutant tumors, albeit with TKIs that are more promiscuous than capmatinib.	('capmatinib', 'Chemical', 'None', (174, 184))	('mutant', 'Var', (111, 117))	('Met', 'Chemical', 'MESH:C034758', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('inhibition', 'NegReg', (92, 102))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('KRAS', 'Gene', (106, 110))	('tumors', 'Disease', (118, 124))	('Met', 'MPA', (88, 91))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
18113	31903112	Although Met is overexpressed in pancreatic cancer cells, the cell membrane presence of Met is highly dynamic, which contributes to its short membrane half-life.	('Met', 'Chemical', 'MESH:C034758', (9, 12))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (33, 50))	('Met', 'Chemical', 'MESH:C034758', (88, 91))	('Met', 'Var', (88, 91))	('cell membrane', 'cellular_component', 'GO:0005886', ('62', '75'))	('membrane', 'cellular_component', 'GO:0016020', ('142', '150'))	('pancreatic cancer', 'Disease', (33, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
18124	31903112	In fact, two open Phase I trials listed on clinicaltrials.gov aim to do just that using, HuMab5B1, a monoclonal antibody specific to CA19.9, a well-known serum and tissue biomarker for pancreatic cancer: NCT02687230 (Zr-89 labeled HuMab-5B1, a.k.a.	('pancreatic cancer', 'Disease', (185, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('NCT02687230', 'Var', (204, 215))	('pancreatic cancer', 'Disease', 'MESH:D010190', (185, 202))	('antibody', 'cellular_component', 'GO:0019814', ('112', '120'))	('Zr-89', 'Chemical', 'MESH:D015040', (217, 222))	('antibody', 'molecular_function', 'GO:0003823', ('112', '120'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (185, 202))	('antibody', 'cellular_component', 'GO:0042571', ('112', '120'))	('antibody', 'cellular_component', 'GO:0019815', ('112', '120'))
18158	30973678	The nuclear and cytosolic fractions were conducted using a PARIS Kit (Life Technologies, Carlsbad, CA, USA) as previously described.14  The LINC00511 and CCND2 3'-UTR sequences containing the wild-type or mutant miR-124-3p binding sites were synthesized.	('LINC00511', 'Gene', (140, 149))	('miR-124-3p', 'Gene', (212, 222))	('binding', 'molecular_function', 'GO:0005488', ('223', '230'))	('CCND2', 'Gene', (154, 159))	('mutant', 'Var', (205, 211))	('LINC00511', 'Gene', '400619', (140, 149))	('miR-124-3p', 'Gene', '406909', (212, 222))	('CCND2', 'Gene', '894', (154, 159))
18177	30973678	The survival analysis based on the TCGA database demonstrated that the high level of SP1 indicated the poor prognosis of glioma patients (Figure 2I).	('SP1', 'Gene', (85, 88))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('high level', 'Var', (71, 81))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('patients', 'Species', '9606', (128, 136))	('glioma', 'Disease', (121, 127))
18182	30973678	Transwell assay for the invasion was carried out and indicated the stimulative invaded cells of LINC00511 overexpression plasmid and the inhibition of LINC00511 silencing (Figure 3D).	('LINC00511', 'Gene', (151, 160))	('LINC00511', 'Gene', (96, 105))	('overexpression', 'PosReg', (106, 120))	('silencing', 'Var', (161, 170))	('LINC00511', 'Gene', '400619', (151, 160))	('LINC00511', 'Gene', '400619', (96, 105))
18183	30973678	In vivo, the LINC00511 silencing could repress the tumour growth of glioma cells (Figure 3E,F).	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('LINC00511', 'Gene', (13, 22))	('tumour growth of glioma', 'Disease', 'MESH:D005910', (51, 74))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('silencing', 'Var', (23, 32))	('tumour growth of glioma', 'Disease', (51, 74))	('LINC00511', 'Gene', '400619', (13, 22))	('glioma cells', 'Disease', (68, 80))	('repress', 'NegReg', (39, 46))	('glioma cells', 'Disease', 'MESH:D005910', (68, 80))
18186	30973678	Database lncLocator (http://www.csbio.sjtu.edu.cn/bioinf/lncLocator/) showed that lncRNA LINC00511 was mainly located in the cytosol and cytoplasm of glioma cells (Figure 4A).	('LINC00511', 'Gene', (89, 98))	('glioma cells', 'Disease', 'MESH:D005910', (150, 162))	('cytoplasm', 'cellular_component', 'GO:0005737', ('137', '146'))	('cytosol', 'cellular_component', 'GO:0005829', ('125', '132'))	('LINC00511', 'Gene', '400619', (89, 98))	('lncRNA', 'Var', (82, 88))	('glioma cells', 'Disease', (150, 162))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
18191	30973678	In the U251 cells, the transfection of LINC00511 siRNA up-regulated the miR-124-3p, while the transfection of LINC00511 plasmid reduced the miR-124-3p (Figure 4F).	('up-regulated', 'PosReg', (55, 67))	('transfection', 'Var', (23, 35))	('LINC00511', 'Gene', '400619', (39, 48))	('U251', 'CellLine', 'CVCL:0021', (7, 11))	('miR-124-3p', 'Gene', (72, 82))	('LINC00511', 'Gene', (110, 119))	('miR-124-3p', 'Gene', '406909', (140, 150))	('miR-124-3p', 'Gene', (140, 150))	('LINC00511', 'Gene', (39, 48))	('LINC00511', 'Gene', '400619', (110, 119))	('miR-124-3p', 'Gene', '406909', (72, 82))
18192	30973678	So, the data suggest that LINC00511 epigenetically sponges the miR-124-3p in the glioma cells.	('epigenetically', 'Var', (36, 50))	('glioma cells', 'Disease', 'MESH:D005910', (81, 93))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('miR-124-3p', 'Gene', '406909', (63, 73))	('miR-124-3p', 'Gene', (63, 73))	('sponges', 'NegReg', (51, 58))	('LINC00511', 'Gene', '400619', (26, 35))	('glioma cells', 'Disease', (81, 93))	('LINC00511', 'Gene', (26, 35))
18196	30973678	Western blot analysis revealed that the cyclin D2 protein, encoded by the CCND2 gene, was increased in the miR-124-3p inhibitor transfection (Figure 5C).	('CCND2', 'Gene', (74, 79))	('miR-124-3p', 'Gene', (107, 117))	('increased', 'PosReg', (90, 99))	('cyclin D2', 'Gene', '894', (40, 49))	('cyclin D2', 'Gene', (40, 49))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('CCND2', 'Gene', '894', (74, 79))	('transfection', 'Var', (128, 140))	('cyclin', 'molecular_function', 'GO:0016538', ('40', '46'))	('miR-124-3p', 'Gene', '406909', (107, 117))
18197	30973678	Moreover, the transfection of LINC00511 siRNA could reduce the CCND2 mRNA level, however, the LINC00511 plasmid activated it (Figure 5D).	('LINC00511', 'Gene', '400619', (94, 103))	('LINC00511', 'Gene', (30, 39))	('transfection', 'Var', (14, 26))	('reduce', 'NegReg', (52, 58))	('LINC00511', 'Gene', '400619', (30, 39))	('CCND2', 'Gene', (63, 68))	('LINC00511', 'Gene', (94, 103))	('CCND2', 'Gene', '894', (63, 68))
18210	30973678	miRNA-124-3p was found to be interacted with LINC00511 3'-UTR, which was confirmed by the luciferase reporter assay.	('interacted', 'Interaction', (29, 39))	('LINC00511', 'Gene', (45, 54))	('LINC00511', 'Gene', '400619', (45, 54))	('miRNA-124-3p', 'Var', (0, 12))
18319	30700038	An Integrative Data Mining and Omics-Based Translational Model for the Identification and Validation of Oncogenic Biomarkers of Pancreatic Cancer Substantial alterations at the multi-omics level of pancreatic cancer (PC) impede the possibility to diagnose and treat patients in early stages.	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (128, 145))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (128, 145))	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))	('patients', 'Species', '9606', (266, 274))	('impede', 'NegReg', (221, 227))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (198, 215))	('Pancreatic Cancer', 'Disease', (128, 145))	('PC', 'Phenotype', 'HP:0002894', (217, 219))	('alterations', 'Var', (158, 169))	('pancreatic cancer', 'Disease', (198, 215))	('pancreatic cancer', 'Disease', 'MESH:D010190', (198, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
18322	30700038	Survival analysis revealed that patients with high expression of ADAM9 (Hazard ratio (HR)OS = 2.2, p-value < 0.001), ANXA2 (HROS = 2.1, p-value < 0.001), and LAMC2 (HRDFS = 1.8, p-value = 0.012) exhibited poorer survival rates.	('LAMC2', 'Gene', '3918', (158, 163))	('ANXA2', 'Gene', '302', (117, 122))	('patients', 'Species', '9606', (32, 40))	('ADAM9', 'Gene', '8754', (65, 70))	('ADAM9', 'Gene', (65, 70))	('ANXA2', 'Gene', (117, 122))	('high expression', 'Var', (46, 61))	('poorer', 'NegReg', (205, 211))	('LAMC2', 'Gene', (158, 163))	('survival rates', 'CPA', (212, 226))
18351	30700038	Genetic alterations occur commonly in patients with curable pancreatic pre-malignant lesions, making the biomarker discovery at early stages indispensable.	('Genetic alterations', 'Var', (0, 19))	('pancreatic', 'Disease', 'MESH:D010195', (60, 70))	('pancreatic', 'Disease', (60, 70))	('patients', 'Species', '9606', (38, 46))	('pre', 'molecular_function', 'GO:0003904', ('71', '74'))
18356	30700038	The KM survival analysis revealed that PC patients with high expression levels of 17 of the candidate genes exhibited a poorer overall survival (OS) or disease-free survival (DFS).	('PC', 'Phenotype', 'HP:0002894', (39, 41))	('disease-free survival', 'CPA', (152, 173))	('high expression levels', 'Var', (56, 78))	('patients', 'Species', '9606', (42, 50))	('overall survival', 'CPA', (127, 143))	('poorer', 'NegReg', (120, 126))
18357	30700038	Particularly, patients overexpressing ADAM9, ANXA2, ITGA2, or MET, had both poorer OS and DFS rates than those with low gene expression.	('MET', 'Var', (62, 65))	('ANXA2', 'Gene', '302', (45, 50))	('ADAM9', 'Gene', (38, 43))	('ADAM9', 'Gene', '8754', (38, 43))	('poorer', 'NegReg', (76, 82))	('ITGA2', 'Gene', (52, 57))	('ITGA2', 'Gene', '3673', (52, 57))	('ANXA2', 'Gene', (45, 50))	('patients', 'Species', '9606', (14, 22))	('gene expression', 'biological_process', 'GO:0010467', ('120', '135'))	('DFS rates', 'CPA', (90, 99))
18362	30700038	The analysis revealed that LAMC2, ADAM9, ANXA2, CDH3, SERPINB5, EPHA2, GPRC5A, ITGA2, ITGB6, and MET were likely associated with the worse outcome of PC with FDR < 0.05.	('ADAM9', 'Gene', '8754', (34, 39))	('ADAM9', 'Gene', (34, 39))	('EPHA2', 'Gene', (64, 69))	('CDH3', 'Gene', (48, 52))	('SERPINB5', 'Gene', (54, 62))	('ANXA2', 'Gene', '302', (41, 46))	('LAMC2', 'Gene', (27, 32))	('associated with', 'Reg', (113, 128))	('ITGA2', 'Gene', '3673', (79, 84))	('MET', 'Var', (97, 100))	('PC', 'Phenotype', 'HP:0002894', (150, 152))	('EPHA2', 'Gene', '1969', (64, 69))	('ITGB6', 'Gene', '3694', (86, 91))	('ITGA2', 'Gene', (79, 84))	('LAMC2', 'Gene', '3918', (27, 32))	('ITGB6', 'Gene', (86, 91))	('SERPINB5', 'Gene', '5268', (54, 62))	('CDH3', 'Gene', '1001', (48, 52))	('GPRC5A', 'Gene', '9052', (71, 77))	('ANXA2', 'Gene', (41, 46))	('GPRC5A', 'Gene', (71, 77))
18395	30700038	Similarly, the high expression of stromal ANXA2 was significantly correlated with short disease-free survival and overall survival, while the high expression of ADAM9 was associated with poor tumor differentiation and short overall survival in PDAC patients.	('high', 'Var', (15, 19))	('poor', 'NegReg', (187, 191))	('disease-free survival', 'CPA', (88, 109))	('tumor', 'Disease', (192, 197))	('expression', 'MPA', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('PDAC', 'Chemical', '-', (244, 248))	('patients', 'Species', '9606', (249, 257))	('ANXA2', 'Gene', (42, 47))	('overall survival', 'CPA', (114, 130))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('PDAC', 'Phenotype', 'HP:0006725', (244, 248))	('ADAM9', 'Gene', '8754', (161, 166))	('ADAM9', 'Gene', (161, 166))	('ANXA2', 'Gene', '302', (42, 47))	('associated', 'Reg', (171, 181))	('short', 'NegReg', (82, 87))
18406	30700038	It was expected that miRNA would diminish drug resistance of tumors through various regulatory mechanisms.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('miRNA', 'Var', (21, 26))	('drug resistance', 'Phenotype', 'HP:0020174', (42, 57))	('drug', 'MPA', (42, 46))	('diminish', 'NegReg', (33, 41))	('drug resistance', 'biological_process', 'GO:0009315', ('42', '57'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('drug resistance', 'biological_process', 'GO:0042493', ('42', '57'))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
18419	30700038	All samples were formalin-fixed paraffin-embedded and stored at 4  C. The Affymetrix-based datasets GSE16515, GSE28735, GSE15471, GSE18670, and GSE41368, were included in the gene expression meta-analysis.	('GSE28735', 'Var', (110, 118))	('GSE15471', 'Var', (120, 128))	('gene expression', 'biological_process', 'GO:0010467', ('175', '190'))	('GSE41368', 'Var', (144, 152))	('formalin', 'Chemical', 'MESH:D005557', (17, 25))	('GSE18670', 'Var', (130, 138))	('paraffin', 'Chemical', 'MESH:D010232', (32, 40))	('GSE16515', 'Var', (100, 108))
18445	30700038	; writing:review and editing, all authors; visualization, N.P.L., K.H.J., N.H.A., H.H.Y., T.D.N.	('H.H.Y.', 'Var', (82, 88))	('H.H.Y', 'CellLine', 'CVCL:Y658', (82, 87))	('K.H.J.', 'Var', (66, 72))
18477	30429887	DNA methylation has also been found to be involved in the activation process, as the DNA methylation of SOCS1 in CAF activated the phosphorylation of STAT3 and increased the expression of insulin-like growth factor 1 (IGF-1) to promote pancreatic cancer cell (PCC) proliferation.	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('phosphorylation', 'biological_process', 'GO:0016310', ('131', '146'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (236, 253))	('SOCS1', 'Gene', '8651', (104, 109))	('insulin-like growth factor 1', 'Gene', (188, 216))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('IGF-1', 'Gene', (218, 223))	('DNA methylation', 'biological_process', 'GO:0006306', ('85', '100'))	('pancreatic cancer', 'Disease', (236, 253))	('promote', 'PosReg', (228, 235))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('188', '214'))	('expression', 'MPA', (174, 184))	('increased', 'PosReg', (160, 169))	('IGF-1', 'Gene', '3479', (218, 223))	('phosphorylation', 'MPA', (131, 146))	('insulin-like growth factor 1', 'Gene', '3479', (188, 216))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (236, 253))	('methylation', 'Var', (89, 100))	('SOCS1', 'Gene', (104, 109))	('DNA', 'Var', (85, 88))	('STAT3', 'Protein', (150, 155))	('PCC', 'cellular_component', 'GO:0120205', ('260', '263'))	('activated', 'PosReg', (117, 126))
18495	30429887	Genome instability and mutation, along with tumor-promoting inflammation are two underlying hallmarks that precede the emergence of the mentioned tumor biological capabilities.	('inflammation', 'biological_process', 'GO:0006954', ('60', '72'))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mutation', 'Var', (23, 31))	('inflammation', 'Disease', 'MESH:D007249', (60, 72))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('inflammation', 'Disease', (60, 72))	('Genome instability', 'CPA', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
18496	30429887	Subsequent to these changes, the reprogramming of energy metabolism and the evasion of immune destruction are also included in cancer hallmarks.	('reprogramming of', 'CPA', (33, 49))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer hallmarks', 'Disease', 'MESH:D009369', (127, 143))	('metabolism', 'biological_process', 'GO:0008152', ('57', '67'))	('changes', 'Var', (20, 27))	('immune destruction', 'CPA', (87, 105))	('cancer hallmarks', 'Disease', (127, 143))
18498	30429887	As critical players in the TME, CAFs in PDAC have been demonstrated by previous studies to promote tumor proliferation and growth, accelerate invasion and metastasis, induce angiogenesis, promote inflammation and immune destruction, regulate tumor metabolism, and induce chemoresistance, and these effects contribute to the acquisition of the major hallmarks of pancreatic cancer (Figure 2).	('metabolism', 'biological_process', 'GO:0008152', ('248', '258'))	('CAFs', 'Var', (32, 36))	('hallmarks of pancreatic cancer', 'Disease', 'MESH:D010190', (349, 379))	('tumor', 'Disease', (242, 247))	('contribute', 'Reg', (306, 316))	('induce', 'Reg', (167, 173))	('inflammation', 'Disease', (196, 208))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('angiogenesis', 'biological_process', 'GO:0001525', ('174', '186'))	('angiogenesis', 'CPA', (174, 186))	('induce', 'Reg', (264, 270))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('PDAC', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('promote', 'PosReg', (188, 195))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('immune destruction', 'CPA', (213, 231))	('PDAC', 'Chemical', '-', (40, 44))	('accelerate', 'PosReg', (131, 141))	('regulate', 'Reg', (233, 241))	('chemoresistance', 'CPA', (271, 286))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (362, 379))	('PDAC', 'Phenotype', 'HP:0006725', (40, 44))	('inflammation', 'biological_process', 'GO:0006954', ('196', '208'))	('promote', 'PosReg', (91, 98))	('inflammation', 'Disease', 'MESH:D007249', (196, 208))	('hallmarks of pancreatic cancer', 'Disease', (349, 379))	('growth', 'CPA', (123, 129))
18509	30429887	reported that genetic depletion of FAP in a mouse model promoted tumor progression and decreased murine survival.	('mouse', 'Species', '10090', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('decreased', 'NegReg', (87, 96))	('genetic depletion', 'Var', (14, 31))	('FAP', 'Gene', '2191', (35, 38))	('promoted', 'PosReg', (56, 64))	('FAP', 'Gene', (35, 38))	('murine survival', 'CPA', (97, 112))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('murine', 'Species', '10090', (97, 103))
18515	30429887	In an orthotopic model of PDAC, coinjection of PSCs increased the proportion of mice with distant metastasis.	('increased', 'PosReg', (52, 61))	('PSC', 'Gene', (47, 50))	('PDAC', 'Chemical', '-', (26, 30))	('PDAC', 'Phenotype', 'HP:0006725', (26, 30))	('mice', 'Species', '10090', (80, 84))	('coinjection', 'Var', (32, 43))	('PSC', 'Gene', '100653366', (47, 50))
18520	30429887	found that inhibitors of PSC autophagy decreased the tumor size in nude mice, as well as distant metastasis.	('autophagy', 'biological_process', 'GO:0016236', ('29', '38'))	('PSC autophagy decreased the tumor', 'Disease', 'MESH:D015209', (25, 58))	('PSC autophagy decreased the tumor', 'Disease', (25, 58))	('nude mice', 'Species', '10090', (67, 76))	('autophagy', 'biological_process', 'GO:0006914', ('29', '38'))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('distant metastasis', 'CPA', (89, 107))	('inhibitors', 'Var', (11, 21))
18521	30429887	In addition, although autophagy inhibition caused by Atg7 knockdown in PSCs did not affect PCC proliferation, it decreased cancer cell invasion, suggesting that the decreased metastasis was not only due to the reduced number of primary PCCs, but also due to the inhibition of PCC invasiveness.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('decreased', 'NegReg', (165, 174))	('reduced', 'NegReg', (210, 217))	('knockdown', 'Var', (58, 67))	('autophagy', 'biological_process', 'GO:0016236', ('22', '31'))	('PCC', 'cellular_component', 'GO:0120205', ('276', '279'))	('PCC', 'cellular_component', 'GO:0120205', ('91', '94'))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('Atg7', 'Gene', '10533', (53, 57))	('metastasis', 'CPA', (175, 185))	('PCC invasiveness', 'CPA', (276, 292))	('Atg7', 'Gene', (53, 57))	('cancer', 'Disease', (123, 129))	('autophagy', 'biological_process', 'GO:0006914', ('22', '31'))	('PSC', 'Gene', '100653366', (71, 74))	('inhibition', 'NegReg', (262, 272))	('decreased', 'NegReg', (113, 122))	('PSC', 'Gene', (71, 74))
18529	30429887	Inhibition of miR-210 reduced cell migration and CAF-induced EMT in PCCs, which suggests that miR-210 may play a role in CAF-induced EMT.	('miR-210', 'Gene', '406992', (94, 101))	('miR-210', 'Gene', '406992', (14, 21))	('cell migration', 'biological_process', 'GO:0016477', ('30', '44'))	('EMT', 'biological_process', 'GO:0001837', ('61', '64'))	('Inhibition', 'Var', (0, 10))	('reduced', 'NegReg', (22, 29))	('miR-210', 'Gene', (94, 101))	('cell migration', 'CPA', (30, 44))	('miR-210', 'Gene', (14, 21))	('EMT', 'biological_process', 'GO:0001837', ('133', '136'))	('CAF-induced EMT', 'CPA', (49, 64))
18551	30429887	Notably, although CAFs have been considered to facilitate tumor angiogenesis, depletion of the tumor-promoting function of CAFs may evoke a strong angiogenic response instead of an attenuated one.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('CAFs', 'Gene', (123, 127))	('evoke', 'Reg', (132, 137))	('depletion', 'Var', (78, 87))	('angiogenesis', 'biological_process', 'GO:0001525', ('64', '76'))	('angiogenic response', 'CPA', (147, 166))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
18553	30429887	demonstrated that genetic depletion of SHH resulted in increased vascularity in a mouse model of PDAC.	('vascularity', 'CPA', (65, 76))	('genetic depletion', 'Var', (18, 35))	('increased', 'PosReg', (55, 64))	('PDAC', 'Chemical', '-', (97, 101))	('SHH', 'Gene', (39, 42))	('mouse', 'Species', '10090', (82, 87))	('PDAC', 'Disease', (97, 101))	('PDAC', 'Phenotype', 'HP:0006725', (97, 101))
18562	30429887	3D coculture of monocytes with PCCs and fibroblasts was shown to increase the production of immunosuppressive cytokines, such as IL-6, IL-8, IL-10, GM-CSF and M-CSF, which are known to promote the polarization of M2-like macrophages and MDSCs.	('increase', 'PosReg', (65, 73))	('GM-CSF', 'Gene', '12981', (148, 154))	('production', 'MPA', (78, 88))	('M-CSF', 'Var', (159, 164))	('IL-6', 'molecular_function', 'GO:0005138', ('129', '133'))	('IL-8', 'molecular_function', 'GO:0005153', ('135', '139'))	('immunosuppressive cytokines', 'MPA', (92, 119))	('IL-10', 'Gene', '16153', (141, 146))	('IL-10', 'molecular_function', 'GO:0005141', ('141', '146'))	('GM-CSF', 'Gene', (148, 154))	('IL-10', 'Gene', (141, 146))
18584	30429887	Notably, in contrast to the macropinosome, during the medium of macrocinobytosis, which has been exclusively reported in PCCs with mutant Kras, CDE-mediated metabolic remodeling was described to be independent of Kras mutation.	('macrocinobytosis', 'Disease', (64, 80))	('mutant', 'Var', (131, 137))	('macropinosome', 'cellular_component', 'GO:0044354', ('28', '41'))	('Kras', 'Gene', (213, 217))	('macrocinobytosis', 'Disease', 'None', (64, 80))	('Kras', 'Gene', (138, 142))	('Kras', 'Gene', '3845', (213, 217))	('Kras', 'Gene', '3845', (138, 142))
18596	30429887	showed that STAT3 activation in PCCs induced by CAF-derived IL-6 could mediate chemoresistance in PDAC; thus, disrupting IL-6 signaling using anti-IL6R antibodies holds promise for improving chemotherapeutic efficacy in PDAC.	('PDAC', 'Chemical', '-', (220, 224))	('IL-6', 'molecular_function', 'GO:0005138', ('121', '125'))	('IL6R', 'molecular_function', 'GO:0004915', ('147', '151'))	('IL6R', 'Gene', (147, 151))	('PDAC', 'Disease', (98, 102))	('PDAC', 'Phenotype', 'HP:0006725', (98, 102))	('IL-6', 'molecular_function', 'GO:0005138', ('60', '64'))	('disrupting', 'Var', (110, 120))	('improving', 'PosReg', (181, 190))	('PDAC', 'Disease', (220, 224))	('PDAC', 'Phenotype', 'HP:0006725', (220, 224))	('signaling', 'biological_process', 'GO:0023052', ('126', '135'))	('IL6R', 'Gene', '3570', (147, 151))	('STAT3', 'MPA', (12, 17))	('mediate', 'Reg', (71, 78))	('PDAC', 'Chemical', '-', (98, 102))	('chemoresistance', 'CPA', (79, 94))
18599	30429887	A recent study found that CDEs could increase the chemoresistance-inducing factor Snail in recipient tumor cells and promote tumor proliferation and drug resistance.	('drug resistance', 'biological_process', 'GO:0009315', ('149', '164'))	('drug resistance', 'biological_process', 'GO:0042493', ('149', '164'))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('CDEs', 'Var', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('drug resistance', 'CPA', (149, 164))	('drug resistance', 'Phenotype', 'HP:0020174', (149, 164))	('tumor', 'Disease', (125, 130))	('increase', 'PosReg', (37, 45))	('CDEs', 'Chemical', '-', (26, 30))	('promote', 'PosReg', (117, 124))	('chemoresistance-inducing', 'MPA', (50, 74))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
18600	30429887	Treatment of gemcitabine-exposed CAFs with an inhibitor of exosome release, GW4869, significantly increased cancer cell apoptosis in coculture models.	('gemcitabine', 'Chemical', 'MESH:C056507', (13, 24))	('GW4869', 'Chemical', 'MESH:C468773', (76, 82))	('exosome', 'cellular_component', 'GO:0070062', ('59', '66'))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('apoptosis', 'biological_process', 'GO:0097194', ('120', '129'))	('GW4869', 'Var', (76, 82))	('increased', 'PosReg', (98, 107))	('apoptosis', 'biological_process', 'GO:0006915', ('120', '129'))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
18606	30429887	demonstrated that PDAC tumors exhibited enhanced malignant biological behaviors and increased vascularity through genetic abortion of SHH in mouse models, indicating that stromal components may to some extent restrain the development of PDAC.	('PDAC', 'Chemical', '-', (237, 241))	('vascularity', 'CPA', (94, 105))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('increased', 'PosReg', (84, 93))	('PDAC', 'Phenotype', 'HP:0006725', (237, 241))	('enhanced', 'PosReg', (40, 48))	('PDAC', 'Disease', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('restrain', 'NegReg', (209, 217))	('mouse', 'Species', '10090', (141, 146))	('genetic abortion', 'Var', (114, 130))	('malignant biological behaviors', 'CPA', (49, 79))	('tumors', 'Disease', (23, 29))	('development', 'CPA', (222, 233))	('PDAC', 'Chemical', '-', (18, 22))	('PDAC', 'Disease', (237, 241))	('PDAC', 'Phenotype', 'HP:0006725', (18, 22))	('SHH', 'Gene', (134, 137))	('tumors', 'Disease', 'MESH:D009369', (23, 29))
18632	30429887	In a recent Phase II study comparing PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) and nab-paclitaxel/gemcitabine (AG) in patients with metastatic PDAC.	('gemcitabine', 'Chemical', 'MESH:C056507', (102, 113))	('PDAC', 'Chemical', '-', (147, 151))	('PEGPH20', 'Var', (37, 44))	('gemcitabine', 'Chemical', 'MESH:C056507', (65, 76))	('PDAC', 'Phenotype', 'HP:0006725', (147, 151))	('patients', 'Species', '9606', (122, 130))	('paclitaxel', 'Chemical', 'MESH:D017239', (54, 64))	('PEGPH20', 'Chemical', '-', (37, 44))	('paclitaxel', 'Chemical', 'MESH:D017239', (91, 101))	('metastatic PDAC', 'Disease', (136, 151))	('PAG', 'Chemical', '-', (78, 81))
18633	30429887	Progression-free survival significantly increased (PAG v AG, hazard ratio [HR], P = .049) and in patients with high tissue HA (HR, 0.51; P = .048).	('HA', 'Chemical', 'MESH:D006820', (123, 125))	('high tissue', 'Var', (111, 122))	('PAG', 'Chemical', '-', (51, 54))	('increased', 'PosReg', (40, 49))	('Progression-free survival', 'CPA', (0, 25))	('patients', 'Species', '9606', (97, 105))
18634	30429887	Thus, these studies may indicate that gemcitabine plus PEGPH20 exhibits promising therapeutic benefits in patients with advanced PDAC, especially in the subgroup with high HA content.	('gemcitabine', 'Chemical', 'MESH:C056507', (38, 49))	('PEGPH20', 'Chemical', '-', (55, 62))	('HA', 'Chemical', 'MESH:D006820', (172, 174))	('PDAC', 'Disease', (129, 133))	('PDAC', 'Phenotype', 'HP:0006725', (129, 133))	('patients', 'Species', '9606', (106, 114))	('PDAC', 'Chemical', '-', (129, 133))	('PEGPH20', 'Var', (55, 62))
18636	30429887	It has been reported that compared to gemcitabine alone, nab-paclitaxel plus gemcitabine significantly improves the prognosis of metastatic PDAC.	('gemcitabine', 'Chemical', 'MESH:C056507', (38, 49))	('PDAC', 'Chemical', '-', (140, 144))	('nab-paclitaxel', 'Var', (57, 71))	('paclitaxel', 'Chemical', 'MESH:D017239', (61, 71))	('PDAC', 'Phenotype', 'HP:0006725', (140, 144))	('metastatic PDAC', 'Disease', (129, 144))	('gemcitabine', 'Chemical', 'MESH:C056507', (77, 88))	('improves', 'PosReg', (103, 111))
18637	30429887	Nab-paclitaxel is considered to deplete the dense stroma and accumulate chemotherapy drugs in the tumor compartment.	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('chemotherapy', 'MPA', (72, 84))	('Nab-paclitaxel', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('deplete', 'NegReg', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('accumulate', 'PosReg', (61, 71))	('tumor', 'Disease', (98, 103))
18643	30429887	Therefore, treatments that inactivate CAF may provide a novel strategy for the treatment of this lethal disease, and a Phase II trial of Minnelide in patients with refractory pancreatic cancer is underway (NCT03117920).	('pancreatic cancer', 'Disease', 'MESH:D010190', (175, 192))	('pancreatic cancer', 'Disease', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('Minnelide', 'Chemical', 'MESH:C579022', (137, 146))	('inactivate', 'Var', (27, 37))	('patients', 'Species', '9606', (150, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (175, 192))	('CAF', 'Gene', (38, 41))
18646	30429887	However, although IPI-926, an SHH pathway inhibitor, achieved promising results in a preclinical study, it showed no clinical benefit in clinical trials (NCT01130142 and NCT01383538).	('NCT01383538', 'Var', (170, 181))	('IPI-926', 'Chemical', 'MESH:C541444', (18, 25))	('NCT01130142', 'Var', (154, 165))	('IPI-926', 'Var', (18, 25))
18651	30429887	have shown that although high expression of serum amyloid A 1 (SAA1) in the stroma is associated with poorer survival, the ablation of germline Saa3 in PCCs did not inhibit tumor progression of PDAC in mice.	('serum amyloid A 1', 'Gene', '20208', (44, 61))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('PDAC', 'Phenotype', 'HP:0006725', (194, 198))	('SAA1', 'Gene', (63, 67))	('mice', 'Species', '10090', (202, 206))	('poorer', 'NegReg', (102, 108))	('ablation', 'Var', (123, 131))	('SAA1', 'Gene', '20208', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('serum amyloid A 1', 'Gene', (44, 61))	('tumor', 'Disease', (173, 178))	('PDAC', 'Chemical', '-', (194, 198))	('inhibit', 'NegReg', (165, 172))
18657	30429887	Another study showed that blockage of the STAT3 pathway, in combination with gemcitabine, could enhance the efficacy of drug delivery in a mouse model of pancreatic cancer, thus improving the treatment effect in human patients with pancreatic cancer through stroma modification and downregulation of cytidine deaminase instead of depletion of the tumor stromal compartment.	('tumor stroma', 'Disease', 'MESH:D009369', (347, 359))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (154, 171))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (232, 249))	('improving', 'PosReg', (178, 187))	('downregulation', 'NegReg', (282, 296))	('human', 'Species', '9606', (212, 217))	('pancreatic cancer', 'Disease', 'MESH:D010190', (154, 171))	('patients', 'Species', '9606', (218, 226))	('treatment effect', 'MPA', (192, 208))	('mouse', 'Species', '10090', (139, 144))	('pancreatic cancer', 'Disease', 'MESH:D010190', (232, 249))	('gemcitabine', 'Chemical', 'MESH:C056507', (77, 88))	('drug delivery', 'MPA', (120, 133))	('pancreatic cancer', 'Disease', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('enhance', 'PosReg', (96, 103))	('blockage', 'Var', (26, 34))	('tumor stroma', 'Disease', (347, 359))	('efficacy', 'MPA', (108, 116))	('pancreatic cancer', 'Disease', (232, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('STAT3 pathway', 'Pathway', (42, 55))
18660	30429887	A very recent study in murine models confirmed this possible strategy, as preclinical results demonstrated that the inhibition of the JAK activator IL-6 might increase the therapeutic response to anti-PD-L1 treatment in PDAC.	('PDAC', 'Chemical', '-', (220, 224))	('inhibition', 'Var', (116, 126))	('JAK', 'molecular_function', 'GO:0004713', ('134', '137'))	('therapeutic response', 'CPA', (172, 192))	('murine', 'Species', '10090', (23, 29))	('PDAC', 'Disease', (220, 224))	('PDAC', 'Phenotype', 'HP:0006725', (220, 224))	('IL-6', 'molecular_function', 'GO:0005138', ('148', '152'))	('increase', 'PosReg', (159, 167))
18668	28259593	Using an endoscopic distal cap to collectpancreatic fluid from the ampulla Duodenal collections of pancreatic fluid can be used as a source of mutations and other markers of pancreatic ductal neoplasia, but admixing pancreatic juice with duodenal contents lowers the concentrations of mutations.	('pancreatic', 'Disease', (216, 226))	('neoplasia', 'Phenotype', 'HP:0002664', (192, 201))	('pancreatic ductal neoplasia', 'Disease', 'MESH:D021441', (174, 201))	('pancreatic', 'Disease', 'MESH:D010195', (99, 109))	('concentrations', 'MPA', (267, 281))	('pancreatic', 'Disease', 'MESH:D010195', (174, 184))	('pancreatic', 'Disease', (99, 109))	('lowers', 'NegReg', (256, 262))	('pancreatic', 'Disease', 'MESH:D010195', (216, 226))	('pancreatic', 'Disease', 'MESH:D010195', (41, 51))	('pancreatic', 'Disease', (174, 184))	('pancreatic', 'Disease', (41, 51))	('admixing', 'Var', (207, 215))	('pancreatic ductal neoplasia', 'Disease', (174, 201))
18672	28259593	Among all subjects, mutation concentrations were higher in pancreatic juice samples collected using the endoscopic cap method (median 0.028%, interquartile range 0-0.077) compared to the non-cap-collected (0.019%, 0-0.044) (P = 0.055).	('pancreatic', 'Disease', 'MESH:D010195', (59, 69))	('higher', 'PosReg', (49, 55))	('mutation', 'Var', (20, 28))	('pancreatic', 'Disease', (59, 69))
18673	28259593	Among pancreatic juice samples with detectable mutations, mutation concentrations were higher in the cap-collected juice samples than in those collected without the cap (0.055%, interquartile range [IQR] 0.026-0.092 vs. 0.032%, IQR 0.020-0.066, P =0.031).	('mutation concentrations', 'MPA', (58, 81))	('mutations', 'Var', (47, 56))	('pancreatic', 'Disease', 'MESH:D010195', (6, 16))	('pancreatic', 'Disease', (6, 16))	('higher', 'PosReg', (87, 93))
18676	28259593	Pancreatic screening and surveillance is being performed in an attempt to identify precancerous lesions and early pancreatic cancer among asymptomatic subjects judged to be at sufficiently increased risk of developing pancreatic cancer based on either their pancreatic cancer family history, an inheritance of mutations in pancreatic cancer susceptibility genes or the presence of pancreatic cysts.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (218, 235))	('pancreatic cancer', 'Disease', 'MESH:D010190', (323, 340))	('Pancreatic', 'Disease', 'MESH:D010195', (0, 10))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))	('mutations', 'Var', (310, 319))	('pancreatic cancer', 'Disease', 'MESH:D010190', (258, 275))	('pancreatic cancer', 'Disease', (323, 340))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('pancreatic cysts', 'Disease', (381, 397))	('pancreatic cysts', 'Phenotype', 'HP:0001737', (381, 397))	('pancreatic cancer', 'Disease', 'MESH:D010190', (218, 235))	('precancerous lesions', 'Disease', 'MESH:D011230', (83, 103))	('Pancreatic', 'Disease', (0, 10))	('pancreatic cancer', 'Disease', (258, 275))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('pancreatic cancer', 'Disease', 'MESH:D010190', (114, 131))	('pancreatic cancer', 'Disease', (218, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (323, 340))	('presence of pancreatic cysts', 'Phenotype', 'HP:0001737', (369, 397))	('pancreatic cancer', 'Disease', (114, 131))	('pancreatic cyst', 'Phenotype', 'HP:0001737', (381, 396))	('pancreatic cysts', 'Disease', 'MESH:D010181', (381, 397))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (258, 275))	('precancerous lesions', 'Disease', (83, 103))
18680	28259593	PanIN and IPMN lesions can harbor the driver mutations of pancreatic ductal adenocarcinoma.	('pancreatic ductal adenocarcinoma', 'Disease', (58, 90))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (58, 90))	('mutations', 'Var', (45, 54))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (58, 90))
18684	28259593	Studies using these samples revealed that GNAS mutations detected in pancreatic fluid samples collected from the duodenum are highly correlated with the presence of IPMN, that KRAS mutations are commonly detected in pancreatic fluid samples of patients who are undergoing screening for their family history of pancreatic cancer and that mutation concentrations as well as mutations that are known to arise in high-grade dysplasia and invasive cancer such as in SMAD4 are helpful in distinguishing the presence of pancreatic ductal adenocarcinoma.	('GNAS', 'Gene', '2778', (42, 46))	('pancreatic cancer', 'Disease', (310, 327))	('detected', 'Reg', (204, 212))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('patients', 'Species', '9606', (244, 252))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (513, 545))	('pancreatic', 'Disease', (69, 79))	('pancreatic', 'Disease', (513, 523))	('SMAD4', 'Gene', '4089', (461, 466))	('mutations', 'Var', (47, 56))	('KRAS', 'Gene', '3845', (176, 180))	('mutations', 'Var', (181, 190))	('pancreatic', 'Disease', 'MESH:D010195', (216, 226))	('pancreatic', 'Disease', 'MESH:D010195', (310, 320))	('cancer', 'Phenotype', 'HP:0002664', (443, 449))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (310, 327))	('KRAS', 'Gene', (176, 180))	('dysplasia', 'Disease', (420, 429))	('dysplasia', 'Disease', 'MESH:D004476', (420, 429))	('invasive cancer', 'Disease', (434, 449))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (513, 545))	('invasive cancer', 'Disease', 'MESH:D009362', (434, 449))	('pancreatic', 'Disease', (216, 226))	('pancreatic', 'Disease', (310, 320))	('pancreatic cancer', 'Disease', 'MESH:D010190', (310, 327))	('GNAS', 'Gene', (42, 46))	('pancreatic', 'Disease', 'MESH:D010195', (69, 79))	('pancreatic ductal adenocarcinoma', 'Disease', (513, 545))	('pancreatic', 'Disease', 'MESH:D010195', (513, 523))	('SMAD4', 'Gene', (461, 466))
18705	28259593	Primers (Integrated DNA Technologies, Coralville, IA) and probes (Custom TaqMan  Probes, Thermo Fisher Scientific, Waltham, MA) were designed for KRAS (G12D, G12V and G12R) and GNAS (R201C and R201H) which cover the mutational status in KRAS and GNAS over 90% of total mutation in pancreatic neoplasms.	('KRAS', 'Gene', (237, 241))	('GNAS', 'Gene', (177, 181))	('KRAS', 'Gene', '3845', (146, 150))	('G12V', 'Var', (158, 162))	('GNAS', 'Gene', '2778', (177, 181))	('GNAS', 'Gene', (246, 250))	('KRAS', 'Gene', (146, 150))	('G12D', 'Var', (152, 156))	('pancreatic neoplasms', 'Disease', 'MESH:D010190', (281, 301))	('G12R', 'Mutation', 'rs121913530', (167, 171))	('G12D', 'Mutation', 'rs121913529', (152, 156))	('GNAS', 'Gene', '2778', (246, 250))	('pancreatic neoplasms', 'Disease', (281, 301))	('R201C', 'Var', (183, 188))	('G12R', 'Var', (167, 171))	('KRAS', 'Gene', '3845', (237, 241))	('R201H', 'Mutation', 'rs121913495', (193, 198))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))	('pancreatic neoplasms', 'Phenotype', 'HP:0002894', (281, 301))	('neoplasms', 'Phenotype', 'HP:0002664', (292, 301))	('G12V', 'Mutation', 'rs121913529', (158, 162))	('R201H', 'Var', (193, 198))
18710	28259593	The fluorescent value thresholds for FAM (mutant DNA) were as follows: KRAS G12D 4500, G12V 5000, G12R 5000 and GNAS R201C 4500 and R201H 5000 (Fig.	('R201H 5000', 'Var', (132, 142))	('G12D', 'Mutation', 'rs121913529', (76, 80))	('GNAS', 'Gene', (112, 116))	('G12R', 'Mutation', 'rs121913530', (98, 102))	('R201H', 'Mutation', 'rs121913495', (132, 137))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('KRAS', 'Gene', (71, 75))	('G12R 5000', 'Var', (98, 107))	('KRAS', 'Gene', '3845', (71, 75))	('G12V', 'Var', (87, 91))	('G12V', 'SUBSTITUTION', 'None', (87, 91))	('GNAS', 'Gene', '2778', (112, 116))
18711	28259593	To determine the precision of the ddPCR assays, we analyzed serial dilutions using cell line DNA samples from PANC-1, CFPAC-1 and HPNE cell lines (American Type Culture Collection, Manassas, VA) which harbored KRAS G12D, G12V and KRAS wild type codon 12, respectively.	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('HPNE', 'CellLine', 'CVCL:C466', (130, 134))	('KRAS', 'Gene', '3845', (210, 214))	('KRAS', 'Gene', '3845', (230, 234))	('G12V', 'Mutation', 'rs121913529', (221, 225))	('PANC-1', 'CellLine', 'CVCL:0480', (110, 116))	('G12D', 'Mutation', 'rs121913529', (215, 219))	('CFPAC-1', 'CellLine', 'CVCL:1119', (118, 125))	('KRAS', 'Gene', (230, 234))	('G12V', 'Var', (221, 225))	('KRAS', 'Gene', (210, 214))
18715	28259593	Thus, we determined the threshold for calling a sample as having a mutation was if the number of positive droplets was above one, zero, zero, one and one positive droplet for KRAS G12D, G12V and G12R and GNASR201C and R201H, respectively.	('G12V', 'Var', (186, 190))	('G12V', 'Mutation', 'rs121913529', (186, 190))	('G12D', 'Mutation', 'rs121913529', (180, 184))	('GNAS', 'Gene', (204, 208))	('R201H', 'Mutation', 'rs121913495', (218, 223))	('G12R', 'Mutation', 'rs121913530', (195, 199))	('GNAS', 'Gene', '2778', (204, 208))	('KRAS', 'Gene', (175, 179))	('G12R', 'Var', (195, 199))	('KRAS', 'Gene', '3845', (175, 179))	('R201H', 'Var', (218, 223))
18721	28259593	KRAS mutations were detected in 88 (55.7%) of the 156 pancreatic juice samples including G12D in 46 (29.1%), G12V in 44 (27.8%) and G12R in 45 (28.5%) samples, and GNAS mutations were detected in 48 (30.4%) juice samples (R201C in 30 [19.0%] and R201H in 26 [16.5%] patients).	('detected', 'Reg', (20, 28))	('KRAS', 'Gene', '3845', (0, 4))	('patients', 'Species', '9606', (266, 274))	('G12V', 'Var', (109, 113))	('G12V', 'Mutation', 'rs121913529', (109, 113))	('pancreatic', 'Disease', 'MESH:D010195', (54, 64))	('G12R', 'Var', (132, 136))	('GNAS', 'Gene', (164, 168))	('mutations', 'Var', (5, 14))	('R201H', 'Mutation', 'rs121913495', (246, 251))	('G12D', 'Var', (89, 93))	('R201C', 'Var', (222, 227))	('pancreatic', 'Disease', (54, 64))	('G12R', 'Mutation', 'rs121913530', (132, 136))	('G12D', 'Mutation', 'rs121913529', (89, 93))	('KRAS', 'Gene', (0, 4))	('GNAS', 'Gene', '2778', (164, 168))	('R201H', 'Var', (246, 251))
18723	28259593	Forty-eight (49.5%) of 97 high-risk patients had a detectable KRAS mutation in their pancreatic juice, including 34 (53.1%) of 64 with and 14 (42.4%) of 33 without cysts suspected to be IPMN, a prevalence very similar to what we reported previously in this population.	('KRAS', 'Gene', (62, 66))	('mutation', 'Var', (67, 75))	('detectable', 'Reg', (51, 61))	('IPMN', 'Disease', (186, 190))	('KRAS', 'Gene', '3845', (62, 66))	('patients', 'Species', '9606', (36, 44))	('pancreatic', 'Disease', 'MESH:D010195', (85, 95))	('pancreatic', 'Disease', (85, 95))
18724	28259593	Patients with KRAS mutations in their pancreatic juice were older on average than those without a KRAS mutation (P = 0.056).	('KRAS', 'Gene', '3845', (98, 102))	('KRAS', 'Gene', '3845', (14, 18))	('mutations', 'Var', (19, 28))	('pancreatic', 'Disease', 'MESH:D010195', (38, 48))	('Patients', 'Species', '9606', (0, 8))	('KRAS', 'Gene', (98, 102))	('pancreatic', 'Disease', (38, 48))	('KRAS', 'Gene', (14, 18))
18730	28259593	While duodenal collections of pancreatic juice can be easily collected during an endoscopic evaluation of the pancreas and these samples contain markers of pancreatic ductal neoplasia, marker concentrations in these samples are typically low (concentrations ~0.1%) and improvements in pancreatic juice sample collection would improve the detection of mutations and other markers of pancreatic neoplasia.	('mutations', 'Var', (351, 360))	('pancreatic', 'Disease', (285, 295))	('pancreatic', 'Disease', 'MESH:D010195', (156, 166))	('improve', 'PosReg', (326, 333))	('neoplasia', 'Phenotype', 'HP:0002664', (393, 402))	('pancreatic neoplasia', 'Disease', (382, 402))	('pancreatic', 'Disease', (30, 40))	('pancreatic neoplasia', 'Phenotype', 'HP:0002894', (382, 402))	('pancreatic ductal neoplasia', 'Disease', 'MESH:D021441', (156, 183))	('pancreas', 'Disease', 'MESH:D010190', (110, 118))	('pancreatic', 'Disease', (156, 166))	('pancreatic', 'Disease', 'MESH:D010195', (382, 392))	('pancreatic ductal neoplasia', 'Disease', (156, 183))	('pancreatic', 'Disease', 'MESH:D010195', (285, 295))	('neoplasia', 'Phenotype', 'HP:0002664', (174, 183))	('pancreatic', 'Disease', (382, 392))	('pancreatic', 'Disease', 'MESH:D010195', (30, 40))	('pancreatic neoplasia', 'Disease', 'MESH:D009369', (382, 402))	('pancreas', 'Disease', (110, 118))
18732	28259593	The results of this study support the hypothesis that improving how pancreatic fluid is collected can lead to a higher concentration of mutations in pancreatic juice samples collected from the duodenum.	('higher', 'PosReg', (112, 118))	('pancreatic', 'Disease', (149, 159))	('pancreatic', 'Disease', 'MESH:D010195', (149, 159))	('pancreatic', 'Disease', 'MESH:D010195', (68, 78))	('mutations', 'Var', (136, 145))	('pancreatic', 'Disease', (68, 78))	('concentration', 'MPA', (119, 132))
18735	28259593	In conclusion, we showed that our new method "cap" in collecting pancreatic fluid from the duodenal lumen improved rare mutation detection.	('improved', 'PosReg', (106, 114))	('pancreatic', 'Disease', 'MESH:D010195', (65, 75))	('pancreatic', 'Disease', (65, 75))	('rare mutation', 'Var', (115, 128))
18744	28556564	There was a statistically significant better survival (P = 0.04) for blood group O cases than non-O cases among unresected but not among resected patients.	('survival', 'MPA', (45, 53))	('patients', 'Species', '9606', (146, 154))	('blood group O', 'Var', (69, 82))	('better', 'PosReg', (38, 44))
18752	28556564	In addition, inherited susceptibility plays a role in the disease, both as high-risk gene variants in the context of familial cancer syndromes 7 and as the presence of variants with modest effect, usually discovered by genome-wide association studies (GWAS) 8.	('familial cancer syndromes', 'Disease', (117, 142))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('variants', 'Var', (90, 98))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (117, 142))
18753	28556564	In a landmark GWAS paper, the Pancreatic Cancer Cohort Consortium (PanScan) reported that the statistically most significant variants associating with pancreatic cancer risk belonged to the ABO locus on chromosome 9q34 9.	('pancreatic cancer', 'Disease', 'MESH:D010190', (151, 168))	('Pancreatic Cancer', 'Disease', (30, 47))	('chromosome', 'cellular_component', 'GO:0005694', ('203', '213'))	('variants', 'Var', (125, 133))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (30, 47))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('ABO', 'Gene', '28', (190, 193))	('ABO', 'Gene', (190, 193))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (30, 47))	('pancreatic cancer', 'Disease', (151, 168))
18756	28556564	A frequent ABO variant is a one-base pair deletion that inactivates the encoded enzyme, leaving the H antigen unaltered and corresponding to the O phenotype 10.	('ABO', 'Gene', (11, 14))	('corresponding', 'Reg', (124, 137))	('inactivates', 'NegReg', (56, 67))	('ABO', 'Gene', '28', (11, 14))	('variant', 'Var', (15, 22))	('H antigen unaltered', 'MPA', (100, 119))	('leaving', 'Reg', (88, 95))
18759	28556564	Data from PanScan demonstrated that, among all common ABO variants, the greatest risk of pancreatic cancer was conferred by the A 1 allele 13 which gives rise to the ABO protein with highest enzymatic activity 14.	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('A 1', 'Gene', '597', (128, 131))	('variants', 'Var', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('A 1', 'Gene', (128, 131))	('ABO', 'Gene', (166, 169))	('ABO', 'Gene', '28', (166, 169))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('ABO', 'Gene', '28', (54, 57))	('ABO', 'Gene', (54, 57))	('pancreatic cancer', 'Disease', (89, 106))
18780	28556564	Each sample was tested for three common SNPs at the ABO locus (Table S1): rs8176704 (intron 3) for the A2 allele (Assay ID: C_30336657_10), rs8176746 (exon 7) for the B allele (Assay ID: C_25610772_20), and rs505922 (intron 1) for the O allele (Assay ID: C_2253769_10).	('rs505922', 'Mutation', 'rs505922', (207, 215))	('rs8176704', 'Var', (74, 83))	('ABO', 'Gene', (52, 55))	('rs8176704', 'Mutation', 'rs8176704', (74, 83))	('ABO', 'Gene', '28', (52, 55))	('rs8176746', 'Mutation', 'rs8176746', (140, 149))	('rs505922', 'Var', (207, 215))
18781	28556564	The samples were also screened for the FUT2 variant rs601338 (Assay ID: C_2405292_10), which determines secretor status of ABH antigens.	('determines', 'Reg', (93, 103))	('ABH', 'Gene', (123, 126))	('ABH', 'Gene', '8846', (123, 126))	('FUT2', 'Gene', (39, 43))	('rs601338', 'Mutation', 'rs601338', (52, 60))	('FUT2', 'Gene', '2524', (39, 43))	('rs601338', 'Var', (52, 60))
18791	28556564	In both groups, the most common ABO genotypes were A1O and OO, and the least frequent were BB and A2A2.	('ABO', 'Gene', '28', (32, 35))	('ABO', 'Gene', (32, 35))	('A1O', 'Var', (51, 54))
18814	28556564	Because the secretion of soluble H antigen is associated with susceptibility to multiple pathogens through adherence to the gastrointestinal mucosa we looked at the secretor phenotype determined by the rs601338 FUT2 polymorphism (Tables S1, S2).	('gastrointestinal mucosa', 'Disease', 'MESH:D005767', (124, 147))	('gastrointestinal mucosa', 'Disease', (124, 147))	('FUT2', 'Gene', (211, 215))	('rs601338', 'Mutation', 'rs601338', (202, 210))	('rs601338', 'Var', (202, 210))	('FUT2', 'Gene', '2524', (211, 215))	('soluble', 'cellular_component', 'GO:0005625', ('25', '32'))	('secretion', 'biological_process', 'GO:0046903', ('12', '21'))	('secretion', 'MPA', (12, 21))
18821	28160547	Analysis of 641 patients revealed that genetic status of DPC4 was associated with overall survival and was highly correlated with recurrence patterns, as inactivation of the DPC4 gene was the strongest predictor of metastatic recurrence (odds ratio = 4.28).	('DPC4', 'Gene', '4089', (174, 178))	('DPC4', 'Gene', (174, 178))	('inactivation', 'Var', (154, 166))	('patients', 'Species', '9606', (16, 24))	('associated', 'Reg', (66, 76))	('metastatic recurrence', 'CPA', (215, 236))	('DPC4', 'Gene', (57, 61))	('DPC4', 'Gene', '4089', (57, 61))
18828	28160547	The development and growth of PDAC involves various genetic alterations in oncogenic activation, loss of tumor suppressor gene function, and the overexpression of receptor-ligand systems.	('PDAC', 'Chemical', '-', (30, 34))	('loss', 'NegReg', (97, 101))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('105', '121'))	('overexpression', 'PosReg', (145, 159))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('PDAC', 'Disease', (30, 34))	('PDAC', 'Phenotype', 'HP:0006725', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('alterations', 'Var', (60, 71))	('receptor-ligand', 'molecular_function', 'GO:0005102', ('163', '178'))	('oncogenic', 'CPA', (75, 84))	('tumor', 'Disease', (105, 110))	('men', 'Species', '9606', (11, 14))	('tumor suppressor', 'biological_process', 'GO:0051726', ('105', '121'))
18829	28160547	Among the several key genes known to contribute to pancreatic carcinogenesis, genetic alterations in K-ras and DPC4/SMAD4 are correlated with patient survival.	('SMAD4', 'Gene', '4089', (116, 121))	('K-ras', 'Gene', (101, 106))	('pancreatic carcinogenesis', 'Disease', (51, 76))	('K-ras', 'Gene', '3845', (101, 106))	('patient', 'Species', '9606', (142, 149))	('SMAD4', 'Gene', (116, 121))	('correlated with', 'Reg', (126, 141))	('DPC4', 'Gene', (111, 115))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (51, 76))	('DPC4', 'Gene', '4089', (111, 115))	('genetic alterations', 'Var', (78, 97))
18834	28160547	demonstrated that the genetic status of DPC4 was correlated with patterns of failure in patients with pancreatic cancer.	('correlated', 'Reg', (49, 59))	('patients', 'Species', '9606', (88, 96))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('genetic status', 'Var', (22, 36))	('DPC4', 'Gene', '4089', (40, 44))	('DPC4', 'Gene', (40, 44))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
18835	28160547	These investigators performed rapid autopsies on patients with documented pancreatic cancer and found that the histological features and patterns of failure were correlated with the genetic status of DPC4 (i.e., locally destructive tumors in patients with an expressed DPC4 gene vs. distant metastasis in patients with an inactivated DPC4 gene).	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('DPC4', 'Gene', (334, 338))	('DPC4', 'Gene', (200, 204))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('patients', 'Species', '9606', (242, 250))	('DPC4', 'Gene', '4089', (334, 338))	('DPC4', 'Gene', '4089', (200, 204))	('expressed', 'Var', (259, 268))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('patients', 'Species', '9606', (305, 313))	('DPC4', 'Gene', (269, 273))	('pancreatic cancer', 'Disease', (74, 91))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('patients', 'Species', '9606', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('men', 'Species', '9606', (67, 70))	('DPC4', 'Gene', '4089', (269, 273))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Disease', (232, 238))
18842	28160547	The results of this study indicate that the genetic status of DPC4 plays a key role in the recurrence patterns following pancreatectomy for PDAC and can be used in the establishment of therapeutic strategies for recurrent PDAC.	('used', 'Reg', (156, 160))	('PDAC', 'Chemical', '-', (140, 144))	('PDAC', 'Disease', (222, 226))	('DPC4', 'Gene', (62, 66))	('PDAC', 'Phenotype', 'HP:0006725', (222, 226))	('DPC4', 'Gene', '4089', (62, 66))	('men', 'Species', '9606', (177, 180))	('genetic status', 'Var', (44, 58))	('PDAC', 'Phenotype', 'HP:0006725', (140, 144))	('PDAC', 'Chemical', '-', (222, 226))
18855	28160547	The overall survival (OS) of patients was significantly associated with the following factors: CA19-9 level, cancer location, T stage, N stage, major vessel resection, resection margin status, tumor differentiation, presence of perineural invasion, presence of lymphovascular invasion, inactivation of the DPC4 gene, and adjuvant therapy.	('patients', 'Species', '9606', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('cancer', 'Disease', (109, 115))	('DPC4', 'Gene', (306, 310))	('associated', 'Reg', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('inactivation', 'Var', (286, 298))	('DPC4', 'Gene', '4089', (306, 310))	('tumor', 'Disease', (193, 198))	('lymphovascular invasion', 'CPA', (261, 284))
18856	28160547	Localization throughout the entire pancreas, inactivation of DPC4 gene function, and no adjuvant therapy were identified as independent factors that determined metastatic recurrence.	('DPC4', 'Gene', '4089', (61, 65))	('Localization', 'biological_process', 'GO:0051179', ('0', '12'))	('DPC4', 'Gene', (61, 65))	('inactivation', 'Var', (45, 57))	('metastatic recurrence', 'CPA', (160, 181))
18857	28160547	Among these factors, inactivation of the DPC4 gene was the most strongly correlated with metastatic recurrence (adjusted odds ratio, [aOR] = 4.28).	('DPC4', 'Gene', (41, 45))	('inactivation', 'Var', (21, 33))	('DPC4', 'Gene', '4089', (41, 45))	('correlated', 'Reg', (73, 83))	('aOR', 'molecular_function', 'GO:0033726', ('134', '137'))	('metastatic recurrence', 'CPA', (89, 110))
18896	28160547	In a clinical setting, Iacobuzio-Donahue et al reported that the initial DPC4 genetic status in PDAC was correlated with patterns of failure, which were locally destructive or metastatic tumors; however, these investigators concluded that further follow-up prospective studies were needed.	('PDAC', 'Chemical', '-', (96, 100))	('DPC4', 'Gene', '4089', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('DPC4', 'Gene', (73, 77))	('genetic status', 'Var', (78, 92))	('PDAC', 'Disease', (96, 100))	('PDAC', 'Phenotype', 'HP:0006725', (96, 100))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))
18897	28160547	Our present study also revealed that the genetic status of DPC4 highly reflected clinical features and initial recurrence patterns following pancreatectomy: an expressed DPC4 gene was associated with locoregional recurrence, and inactivation of DPC4 was correlated with metastatic recurrence.	('metastatic recurrence', 'CPA', (270, 291))	('DPC4', 'Gene', (59, 63))	('DPC4', 'Gene', '4089', (59, 63))	('DPC4', 'Gene', (170, 174))	('locoregional recurrence', 'CPA', (200, 223))	('DPC4', 'Gene', '4089', (170, 174))	('DPC4', 'Gene', (245, 249))	('correlated', 'Reg', (254, 264))	('DPC4', 'Gene', '4089', (245, 249))	('associated with', 'Reg', (184, 199))	('inactivation', 'Var', (229, 241))
18902	28160547	Therefore, diminishing the tumor burden may create a synergistic effect to improve survival in cooperation with systemic CTx.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('diminishing', 'Var', (11, 22))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('improve', 'PosReg', (75, 82))	('survival', 'MPA', (83, 91))
18916	28160547	Our findings suggest clinical relevance of the genetic status of DPC4 in terms of distinct features, including infiltrative features and recurrence patterns, as well as responses to treatment modalities.	('DPC4', 'Gene', '4089', (65, 69))	('DPC4', 'Gene', (65, 69))	('men', 'Species', '9606', (187, 190))	('genetic', 'Var', (47, 54))
18945	26908446	MicroRNA-323-3p inhibits cell invasion and metastasis in pancreatic ductal adenocarcinoma via direct suppression of SMAD2 and SMAD3 Pancreatic ductal adenocarcinoma (PDAC), which accounts for 96% of all pancreatic cancer cases, is characterized by rapid progression, invasion and metastasis.	('pancreatic cancer', 'Disease', (203, 220))	('Pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (132, 164))	('Pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (132, 164))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (203, 220))	('pancreatic cancer', 'Disease', 'MESH:D010190', (203, 220))	('PDAC', 'Phenotype', 'HP:0006725', (166, 170))	('SMAD3', 'Gene', (126, 131))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (57, 89))	('pancreatic ductal adenocarcinoma', 'Disease', (57, 89))	('suppression', 'NegReg', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (57, 89))	('PDAC', 'Chemical', '-', (166, 170))	('inhibits', 'NegReg', (16, 24))	('MicroRNA-323-3p', 'Var', (0, 15))	('Pancreatic ductal adenocarcinoma', 'Disease', (132, 164))	('SMAD2', 'Gene', '4087', (116, 121))	('SMAD2', 'Gene', (116, 121))
18948	26908446	The results of this study suggested that miR-323-3p expression in PDAC tissues and cell lines was significantly decreased compared to levels in normal pancreatic tissues and primary cultured pancreatic duct epithelial cells.	('PDAC', 'Chemical', '-', (66, 70))	('PDAC', 'Phenotype', 'HP:0006725', (66, 70))	('miR-323-3p', 'Var', (41, 51))	('decreased', 'NegReg', (112, 121))	('PDAC', 'Disease', (66, 70))
18949	26908446	Further investigation revealed that miR-323-3p directly targeted and suppressed SMAD2 and SMAD3, both key components in TGF-beta signaling.	('TGF-beta', 'Gene', (120, 128))	('miR-323-3p', 'Var', (36, 46))	('SMAD3', 'Gene', '4088', (90, 95))	('signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('SMAD2', 'Gene', (80, 85))	('SMAD2', 'Gene', '4087', (80, 85))	('suppressed', 'NegReg', (69, 79))	('TGF-beta', 'Gene', '7040', (120, 128))	('SMAD3', 'Gene', (90, 95))
18951	26908446	Ectopic overexpression of miR-323-3p significantly inhibited, while silencing of miR-323-3p increased the migration and invasion abilities of PDAC cells in vitro.	('migration', 'CPA', (106, 115))	('PDAC', 'Chemical', '-', (142, 146))	('increased', 'PosReg', (92, 101))	('silencing', 'Var', (68, 77))	('PDAC', 'Phenotype', 'HP:0006725', (142, 146))	('miR-323-3p', 'Gene', (81, 91))	('inhibited', 'NegReg', (51, 60))	('invasion abilities', 'CPA', (120, 138))
18952	26908446	Moreover, using an in vivo mouse model, we demonstrated that overexpressing of miR-323-3p significantly reduced, while knockdown of miR-323-3p enhanced lung metastatic colonization of PANC-1 cells.	('reduced', 'NegReg', (104, 111))	('enhanced', 'PosReg', (143, 151))	('miR-323-3p', 'Var', (132, 142))	('mouse', 'Species', '10090', (27, 32))	('lung metastatic colonization of', 'CPA', (152, 183))	('miR-323-3p', 'Var', (79, 89))
18953	26908446	Furthermore, miR-323-3p-induced TGF-b signaling inhibition and cell motility suppression were partially rescued by overexpressing of Smad2 and Smad3 in PDAC cells.	('signaling', 'biological_process', 'GO:0023052', ('38', '47'))	('TGF-b', 'Gene', (32, 37))	('Smad2', 'Gene', '4087', (133, 138))	('overexpressing', 'PosReg', (115, 129))	('PDAC', 'Phenotype', 'HP:0006725', (152, 156))	('cell motility suppression', 'CPA', (63, 88))	('Smad2', 'Gene', (133, 138))	('Smad3', 'Gene', '4088', (143, 148))	('TGF-b', 'Gene', '7040', (32, 37))	('PDAC', 'Chemical', '-', (152, 156))	('Smad3', 'Gene', (143, 148))	('miR-323-3p-induced', 'Var', (13, 31))	('inhibition', 'NegReg', (48, 58))	('cell motility', 'biological_process', 'GO:0048870', ('63', '76'))
18954	26908446	Our findings suggest that re-expression of miR-323-3p might offer a novel therapeutic target against metastasis in patients with PDAC.	('patients', 'Species', '9606', (115, 123))	('PDAC', 'Disease', (129, 133))	('PDAC', 'Phenotype', 'HP:0006725', (129, 133))	('miR-323-3p', 'Var', (43, 53))	('metastasis', 'CPA', (101, 111))	('PDAC', 'Chemical', '-', (129, 133))
18967	26908446	Increased expression of TGF-beta has been associated with vessel invasion, liver metastasis, advanced tumor stages and shorter survival times in patient with PDAC; conversely, targeting TGF-beta signaling in human PDAC cells is found to suppress metastasis and prolong survival in mouse model.	('liver metastasis', 'Disease', 'MESH:D009362', (75, 91))	('PDAC', 'Chemical', '-', (158, 162))	('PDAC', 'Phenotype', 'HP:0006725', (214, 218))	('TGF-beta', 'Gene', '7040', (186, 194))	('signaling', 'biological_process', 'GO:0023052', ('195', '204'))	('metastasis', 'CPA', (246, 256))	('PDAC', 'Phenotype', 'HP:0006725', (158, 162))	('targeting', 'Var', (176, 185))	('human', 'Species', '9606', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('TGF-beta', 'Gene', (186, 194))	('survival', 'CPA', (269, 277))	('TGF-beta', 'Gene', '7040', (24, 32))	('prolong', 'PosReg', (261, 268))	('liver metastasis', 'Disease', (75, 91))	('tumor', 'Disease', (102, 107))	('mouse', 'Species', '10090', (281, 286))	('suppress', 'NegReg', (237, 245))	('TGF-beta', 'Gene', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('patient', 'Species', '9606', (145, 152))	('PDAC', 'Chemical', '-', (214, 218))
18973	26908446	Furthermore, miR-323-3p directly suppressed expression of SMAD2 and SMAD3 leading to inactivation of TGF-beta signaling.	('inactivation', 'NegReg', (85, 97))	('SMAD3', 'Gene', '4088', (68, 73))	('expression', 'MPA', (44, 54))	('TGF-beta', 'Gene', '7040', (101, 109))	('SMAD2', 'Gene', (58, 63))	('SMAD2', 'Gene', '4087', (58, 63))	('SMAD3', 'Gene', (68, 73))	('TGF-beta', 'Gene', (101, 109))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))	('miR-323-3p', 'Var', (13, 23))	('suppressed', 'NegReg', (33, 43))
18974	26908446	Overall, our results have suggested that re-expression of miR-323-3p may provide a potential strategy for treating patients with metastatic PDAC.	('patients', 'Species', '9606', (115, 123))	('PDAC', 'Chemical', '-', (140, 144))	('PDAC', 'Phenotype', 'HP:0006725', (140, 144))	('metastatic PDAC', 'Disease', (129, 144))	('miR-323-3p', 'Var', (58, 68))
18976	26908446	The analyses showed that miR-323-3p was significantly downregulated in pancreatic tumor tissues compared to normal tissues (Figure 1A and Supplementary Figure S1).	('pancreatic tumor', 'Disease', (71, 87))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (71, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('miR-323-3p', 'Var', (25, 35))	('pancreatic tumor', 'Disease', 'MESH:D010190', (71, 87))	('downregulated', 'NegReg', (54, 67))
18978	26908446	Comparisons between the expression levels of miR-323-3p in archived PDAC tissue specimens and patients' clinicopathologic characteristics revealed that decreased expression of miR-323-3p was strongly correlated with clinical stage (P = 0.046) and TNM classification (T: P = 0.037; N: P = 0.004; M: P = 0.001; Supplementary Table S1 and S2).	('miR-323-3p', 'Var', (176, 186))	('TNM', 'Gene', '10178', (247, 250))	('patients', 'Species', '9606', (94, 102))	('clinical stage', 'CPA', (216, 230))	('PDAC', 'Phenotype', 'HP:0006725', (68, 72))	('TNM', 'Gene', (247, 250))	('decreased', 'NegReg', (152, 161))	('expression', 'MPA', (162, 172))	('PDAC', 'Chemical', '-', (68, 72))
18979	26908446	Furthermore, low expression levels of miR-323-3p predicted shorter overall survival (P < 0.001) and metastasis-free survival (P < 0.001) in patients with primary PDAC (Figure 1D).	('expression levels', 'MPA', (17, 34))	('low', 'NegReg', (13, 16))	('metastasis-free survival', 'CPA', (100, 124))	('shorter', 'NegReg', (59, 66))	('overall survival', 'CPA', (67, 83))	('PDAC', 'Chemical', '-', (162, 166))	('patients', 'Species', '9606', (140, 148))	('miR-323-3p', 'Var', (38, 48))	('primary PDAC', 'Disease', (154, 166))	('PDAC', 'Phenotype', 'HP:0006725', (162, 166))
18980	26908446	Collectively, these results demonstrated that miR-323-3p was downregulated in human PDAC and was associated with enhanced tumor progression and poorer prognosis in patients with PDAC.	('PDAC', 'Disease', (84, 88))	('downregulated', 'NegReg', (61, 74))	('PDAC', 'Phenotype', 'HP:0006725', (84, 88))	('miR-323-3p', 'Var', (46, 56))	('PDAC', 'Chemical', '-', (178, 182))	('enhanced', 'PosReg', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('PDAC', 'Chemical', '-', (84, 88))	('PDAC', 'Phenotype', 'HP:0006725', (178, 182))	('patients', 'Species', '9606', (164, 172))	('human', 'Species', '9606', (78, 83))	('tumor', 'Disease', (122, 127))
18981	26908446	The biological function of miR-323-3p in the progression of PDAC was investigated by stably transducing miR-323-3p into BxPc3 and PANC-1 PDAC cell lines (Supplementary Figure S2A).	('miR-323-3p', 'Var', (104, 114))	('transducing', 'Reg', (92, 103))	('PDAC', 'Disease', (60, 64))	('PDAC', 'Phenotype', 'HP:0006725', (60, 64))	('PDAC', 'Phenotype', 'HP:0006725', (137, 141))	('PDAC', 'Chemical', '-', (60, 64))	('PDAC', 'Chemical', '-', (137, 141))
18982	26908446	Western blotting showed that overexpression of miR-323-3p led to marked upregulation of epithelial markers E-cadherin and a-catenin with concurrent downregulation of mesenchymal markers vimentin and N-cadherin (Figure 2A).	('E-cadherin', 'Gene', '999', (107, 117))	('vimentin', 'cellular_component', 'GO:0045098', ('186', '194'))	('upregulation', 'PosReg', (72, 84))	('overexpression', 'PosReg', (29, 43))	('vimentin', 'Gene', '7431', (186, 194))	('N-cadherin', 'Gene', (199, 209))	('mesenchymal', 'CPA', (166, 177))	('miR-323-3p', 'Var', (47, 57))	('vimentin', 'Gene', (186, 194))	('epithelial', 'CPA', (88, 98))	('cadherin', 'molecular_function', 'GO:0008014', ('201', '209'))	('N-cadherin', 'Gene', '1000', (199, 209))	('cadherin', 'molecular_function', 'GO:0008014', ('109', '117'))	('a-catenin', 'Protein', (122, 131))	('E-cadherin', 'Gene', (107, 117))	('vimentin', 'cellular_component', 'GO:0045099', ('186', '194'))	('downregulation', 'NegReg', (148, 162))
18985	26908446	As shown in Figure 2D and 2E, the number of metastatic lung foci was significantly reduced in mice injected with PANC-1-miR-323-3p-transduced cells compared to those injected with vector control cells.	('reduced', 'NegReg', (83, 90))	('PANC-1-miR-323-3p-transduced', 'Var', (113, 141))	('mice', 'Species', '10090', (94, 98))
18986	26908446	This indicated that metastatic lung colonization could be inhibited by overexpression of miR-323-3p in PDAC cells.	('overexpression', 'PosReg', (71, 85))	('metastatic lung colonization', 'CPA', (20, 48))	('PDAC', 'Chemical', '-', (103, 107))	('miR-323-3p', 'Var', (89, 99))	('inhibited', 'NegReg', (58, 67))	('PDAC', 'Phenotype', 'HP:0006725', (103, 107))
18987	26908446	Collectively, these results demonstrated that overexpression of miR-323-3p could inhibit PDAC cell motility in vitro and abrogated the metastatic progression of PDAC in vivo.	('PDAC', 'Chemical', '-', (161, 165))	('PDAC', 'Chemical', '-', (89, 93))	('overexpression', 'PosReg', (46, 60))	('abrogated', 'NegReg', (121, 130))	('inhibit', 'NegReg', (81, 88))	('metastatic progression of', 'CPA', (135, 160))	('PDAC', 'Disease', (161, 165))	('PDAC', 'Disease', (89, 93))	('miR-323-3p', 'Var', (64, 74))	('PDAC', 'Phenotype', 'HP:0006725', (89, 93))	('PDAC', 'Phenotype', 'HP:0006725', (161, 165))	('cell motility', 'biological_process', 'GO:0048870', ('94', '107'))
18988	26908446	Having demonstrated that overexpression of miR-323-3p inhibited metastasis in PDAC in vitro and in vivo, the effect of inhibiting miR-323-3p expression on the invasive and metastatic behaviors of PDAC cells was examined.	('inhibited', 'NegReg', (54, 63))	('PDAC', 'Phenotype', 'HP:0006725', (78, 82))	('miR-323-3p', 'Var', (43, 53))	('PDAC', 'Phenotype', 'HP:0006725', (196, 200))	('PDAC', 'Chemical', '-', (78, 82))	('metastasis in PDAC', 'CPA', (64, 82))	('overexpression', 'PosReg', (25, 39))	('PDAC', 'Chemical', '-', (196, 200))
18989	26908446	The expression of miR-323-3p was inhibited by transfection with antago-miR323-3p in BxPc3 and PANC-1 cells (Supplementary Figure S3A).	('miR-323-3p', 'Var', (18, 28))	('expression', 'MPA', (4, 14))	('miR323', 'Gene', '442897', (71, 77))	('miR323', 'Gene', (71, 77))	('inhibited', 'NegReg', (33, 42))
18990	26908446	Western blotting confirmed that inhibition of miR-323-3p led to a marked decrease in the levels of epithelial markers E-cadherin and a-catenin with increased levels of mesenchymal markers vimentin and N-cadherin in BxPc3 and PANC-1 PDAC cells compared to their levels in vector control cells (Figure 3A).	('N-cadherin', 'Gene', '1000', (201, 211))	('a-catenin', 'MPA', (133, 142))	('vimentin', 'cellular_component', 'GO:0045099', ('188', '196'))	('E-cadherin', 'Gene', (118, 128))	('E-cadherin', 'Gene', '999', (118, 128))	('cadherin', 'molecular_function', 'GO:0008014', ('120', '128'))	('increased', 'PosReg', (148, 157))	('miR-323-3p', 'Var', (46, 56))	('PDAC', 'Phenotype', 'HP:0006725', (232, 236))	('vimentin', 'cellular_component', 'GO:0045098', ('188', '196'))	('vimentin', 'Gene', '7431', (188, 196))	('decrease', 'NegReg', (73, 81))	('levels', 'MPA', (158, 164))	('PDAC', 'Chemical', '-', (232, 236))	('N-cadherin', 'Gene', (201, 211))	('cadherin', 'molecular_function', 'GO:0008014', ('203', '211'))	('vimentin', 'Gene', (188, 196))
18991	26908446	These in vitro results were supported by observations in vivo: silencing of miR-323-3p in PANC-1 cells injected into a mouse model significantly increased metastatic lung colonization relatively to controls (Figure 3D and 3E; P < 0.05; Supplementary Figure S3C).	('mouse', 'Species', '10090', (119, 124))	('metastatic lung colonization', 'CPA', (155, 183))	('miR-323-3p', 'Gene', (76, 86))	('increased', 'PosReg', (145, 154))	('silencing', 'Var', (63, 72))
18992	26908446	Collectively, these results demonstrated that downregulation of miR-323-3p promoted invasion- and metastasis-related properties of PDAC cells in vitro and in vivo.	('downregulation', 'NegReg', (46, 60))	('promoted', 'PosReg', (75, 83))	('PDAC', 'Chemical', '-', (131, 135))	('miR-323-3p', 'Var', (64, 74))	('PDAC', 'Phenotype', 'HP:0006725', (131, 135))
18995	26908446	In order to explore the regulatory mechanisms by which miR-323-3p promoted PDAC progression, Western blotting and luciferase reporter assays were conducted.	('PDAC', 'Disease', (75, 79))	('PDAC', 'Phenotype', 'HP:0006725', (75, 79))	('PDAC', 'Chemical', '-', (75, 79))	('promoted', 'PosReg', (66, 74))	('miR-323-3p', 'Var', (55, 65))
18996	26908446	Western blotting revealed that expression of SMAD2 and SMAD3 proteins were markedly decreased in miR-323-3p-transduced PDAC cells, whereas inhibition of miR-323-3p had the opposite effect (Figure 4B).	('PDAC', 'Phenotype', 'HP:0006725', (119, 123))	('SMAD2', 'Gene', (45, 50))	('SMAD2', 'Gene', '4087', (45, 50))	('SMAD3', 'Gene', '4088', (55, 60))	('expression', 'MPA', (31, 41))	('SMAD3', 'Gene', (55, 60))	('miR-323-3p-transduced', 'Var', (97, 118))	('proteins', 'Protein', (61, 69))	('decreased', 'NegReg', (84, 93))	('PDAC', 'Chemical', '-', (119, 123))
18997	26908446	Luciferase assays showed that the reporter activities linked with the 3'UTRs of SMAD2 and SMAD3 transcripts were significantly reduced by overexpression of miR-323-3p; whereas, they were increased by inhibition of endogenous miR-323-3p (Figure 4C; P < 0.05).	('miR-323-3p', 'Var', (156, 166))	("3'UTRs", 'MPA', (70, 76))	('overexpression', 'PosReg', (138, 152))	('SMAD3', 'Gene', '4088', (90, 95))	('SMAD2', 'Gene', (80, 85))	('SMAD2', 'Gene', '4087', (80, 85))	('SMAD3', 'Gene', (90, 95))	('reduced', 'NegReg', (127, 134))	('reporter activities', 'MPA', (34, 53))
18998	26908446	Further investigation by immunoprecipitation of microribonucleoprotein (miRNP) revealed that miR-323-3p overexpression enriched the transcripts of SMAD2 and SMAD3, but not that of GAPDH or 5s rRNA controls (Figure 4D).	('miR-323-3p', 'Var', (93, 103))	('SMAD3', 'Gene', (157, 162))	('SMAD2', 'Gene', (147, 152))	('GAPDH', 'Gene', '2597', (180, 185))	('SMAD2', 'Gene', '4087', (147, 152))	('GAPDH', 'Gene', (180, 185))	('SMAD3', 'Gene', '4088', (157, 162))	('overexpression', 'PosReg', (104, 118))
18999	26908446	In addition, RIP assay was performed and showed that miR-323-3p did not bind to 3`UTR of Smad1 and Smad5 in the PDAC cell lines (Figure 4D).	('miR-323-3p', 'Var', (53, 63))	('Smad5', 'Gene', '4090', (99, 104))	('bind', 'Interaction', (72, 76))	('Smad1', 'Gene', (89, 94))	('RIP', 'Gene', '8737', (13, 16))	('PDAC', 'Phenotype', 'HP:0006725', (112, 116))	('RIP', 'Gene', (13, 16))	('Smad5', 'Gene', (99, 104))	('Smad1', 'Gene', '4086', (89, 94))	('not', 'NegReg', (68, 71))	('PDAC', 'Chemical', '-', (112, 116))
19000	26908446	Consistently, western blotting analysis revealed that overexpression or knockdown of miR-323-3p did not affect the protein expression of Smad1or Smad5 (Supplementary Figure S4), suggesting that Smad1 and Smad5 might not be the authentic targets of miR-323-3p in PDAC cells.	('Smad5', 'Gene', (145, 150))	('Smad5', 'Gene', (204, 209))	('Smad1', 'Gene', '4086', (194, 199))	('PDAC', 'Chemical', '-', (262, 266))	('Smad1', 'Gene', (137, 142))	('miR-323-3p', 'Var', (85, 95))	('Smad5', 'Gene', '4090', (145, 150))	('Smad5', 'Gene', '4090', (204, 209))	('Smad1', 'Gene', '4086', (137, 142))	('PDAC', 'Phenotype', 'HP:0006725', (262, 266))	('Smad1', 'Gene', (194, 199))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))
19004	26908446	The TGF-b-induced luciferase activity was significantly suppressed in PDAC cells following overexpression of miR-323-3p; whereas silencing of miR-323-3p elevated luciferase activity in these cells (Figure 5A; P < 0.05).	('miR-323-3p', 'Var', (142, 152))	('suppressed', 'NegReg', (56, 66))	('TGF-b', 'Gene', '7040', (4, 9))	('PDAC', 'Chemical', '-', (70, 74))	('miR-323-3p', 'Var', (109, 119))	('luciferase activity', 'molecular_function', 'GO:0047077', ('162', '181'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('18', '37'))	('PDAC', 'Phenotype', 'HP:0006725', (70, 74))	('luciferase activity', 'molecular_function', 'GO:0045289', ('162', '181'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('162', '181'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('18', '37'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('18', '37'))	('luciferase', 'Enzyme', (162, 172))	('luciferase activity', 'molecular_function', 'GO:0050248', ('162', '181'))	('TGF-b', 'Gene', (4, 9))	('elevated', 'PosReg', (153, 161))	('luciferase activity', 'molecular_function', 'GO:0050397', ('162', '181'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('18', '37'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('18', '37'))	('activity', 'MPA', (29, 37))	('silencing', 'Var', (129, 138))	('activity', 'MPA', (173, 181))	('luciferase', 'Enzyme', (18, 28))
19005	26908446	Western blotting revealed that the total expression, phosphorylation and nuclear accumulation of SMAD2 and SMAD3 were reduced by overexpression of miR-323-3p but increased when miR-323-3p expression was silenced (Figure 5B).	('increased', 'PosReg', (162, 171))	('expression', 'MPA', (41, 51))	('nuclear accumulation', 'MPA', (73, 93))	('SMAD3', 'Gene', '4088', (107, 112))	('reduced', 'NegReg', (118, 125))	('SMAD3', 'Gene', (107, 112))	('SMAD2', 'Gene', (97, 102))	('SMAD2', 'Gene', '4087', (97, 102))	('miR-323-3p', 'Var', (147, 157))	('phosphorylation', 'MPA', (53, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))
19006	26908446	Moreover, the binding affinity of Smad2 and Smad3 to the PAI-1 promoter was significantly decreased in miR-323-3p-transduced cells, while increased in miR-323-3p knockdown cells (Figure 5E).	('PAI-1', 'Gene', (57, 62))	('increased', 'PosReg', (138, 147))	('Smad3', 'Gene', (44, 49))	('decreased', 'NegReg', (90, 99))	('miR-323-3p-transduced', 'Var', (103, 124))	('Smad2', 'Gene', '4087', (34, 39))	('PAI-1', 'Gene', '5054', (57, 62))	('Smad2', 'Gene', (34, 39))	('binding', 'molecular_function', 'GO:0005488', ('14', '21'))	('binding affinity', 'Interaction', (14, 30))	('Smad3', 'Gene', '4088', (44, 49))
19007	26908446	Consistently, the mRNA expression levels of Smad2/3 target genes PAI-1 and COL7A1were decreased in miR-323-3p overexpressing cells but increased in miR-323-3p knockdown cells as determined by Real-time PCR (Figure 5F).	('COL7A1', 'Gene', '1294', (75, 81))	('Smad2/3', 'Gene', (44, 51))	('PAI-1', 'Gene', (65, 70))	('miR-323-3p', 'Var', (99, 109))	('increased', 'PosReg', (135, 144))	('PAI-1', 'Gene', '5054', (65, 70))	('decreased', 'NegReg', (86, 95))	('Smad2/3', 'Gene', '4087;4088', (44, 51))	('mRNA expression levels', 'MPA', (18, 40))	('COL7A1', 'Gene', (75, 81))
19008	26908446	In addition, we also showed that miR-323-3p did not significantly alter the activities of AKT, MAPK and nuclear factor of activated T-cells (NFAT) signalling pathways (Supplementary Figure S5A-S5D), which have been involved in the Smad-independent arm of TGF-bbeta signalling.	('signalling', 'biological_process', 'GO:0023052', ('147', '157'))	('MAPK', 'Gene', (95, 99))	('miR-323-3p', 'Var', (33, 43))	('AKT', 'Gene', (90, 93))	('activities', 'MPA', (76, 86))	('MAPK', 'molecular_function', 'GO:0004707', ('95', '99'))	('Smad', 'Gene', (231, 235))	('TGF-b', 'Gene', (255, 260))	('signalling', 'biological_process', 'GO:0023052', ('265', '275'))	('nuclear factor of activated T-cells', 'Pathway', (104, 139))	('Smad', 'Gene', '4089;4086;4089;4090', (231, 235))	('MAPK', 'Gene', '5594', (95, 99))	('AKT', 'Gene', '207', (90, 93))	('TGF-b', 'Gene', '7040', (255, 260))
19009	26908446	In combination, these findings demonstrated that downregulation of miR-323-3p promoted activation of the TGF-beta signaling pathway.	('activation', 'PosReg', (87, 97))	('miR-323-3p', 'Var', (67, 77))	('TGF-beta', 'Gene', '7040', (105, 113))	('TGF-beta', 'Gene', (105, 113))	('downregulation', 'NegReg', (49, 63))	('signaling pathway', 'biological_process', 'GO:0007165', ('114', '131'))
19010	26908446	The functional roles of SMAD2 and SMAD3 in miR-323-3p-induced TGF-beta signaling and the invasive properties of PDAC cells were investigated further in SMAD4-wild type PANC-1 and SMAD4-null BxPc3 PDAC cell lines.	('signaling', 'biological_process', 'GO:0023052', ('71', '80'))	('SMAD2', 'Gene', '4087', (24, 29))	('SMAD4', 'Gene', '4089', (179, 184))	('SMAD3', 'Gene', '4088', (34, 39))	('TGF-beta', 'Gene', (62, 70))	('SMAD3', 'Gene', (34, 39))	('PDAC', 'Chemical', '-', (112, 116))	('SMAD2', 'Gene', (24, 29))	('miR-323-3p-induced', 'Var', (43, 61))	('SMAD4', 'Gene', '4089', (152, 157))	('PDAC', 'Phenotype', 'HP:0006725', (112, 116))	('SMAD4', 'Gene', (179, 184))	('PDAC', 'Phenotype', 'HP:0006725', (196, 200))	('TGF-beta', 'Gene', '7040', (62, 70))	('SMAD4', 'Gene', (152, 157))	('PDAC', 'Chemical', '-', (196, 200))
19013	26908446	Conversely, silencing of miR-323-3p in BxPc3 and PANC-1 cells promoted the TGF- b-induced luciferase activities, EMT and cell migration/invasion abilities compared to the control cells, while silencing of SMAD2 or SMAD3 led to a significant reduction of these effects in antagomiR-323-3p transfected cells (Figures 6E-6H and Supplementary Figure S6B; P < 0.05).	('SMAD3', 'Gene', (214, 219))	('luciferase', 'Enzyme', (90, 100))	('TGF- b', 'Gene', '7040', (75, 81))	('EMT', 'biological_process', 'GO:0001837', ('113', '116'))	('cell migration/invasion abilities', 'CPA', (121, 154))	('silencing', 'Var', (12, 21))	('SMAD3', 'Gene', '4088', (214, 219))	('TGF- b', 'Gene', (75, 81))	('cell migration', 'biological_process', 'GO:0016477', ('121', '135'))	('activities', 'MPA', (101, 111))	('SMAD2', 'Gene', (205, 210))	('miR-323-3p', 'Var', (25, 35))	('promoted', 'PosReg', (62, 70))	('SMAD2', 'Gene', '4087', (205, 210))
19014	26908446	Taken together, these results demonstrated that miR-323-3p-mediated TGF-b signaling inhibition, EMT and cell motility suppression were at least partially caused by repressing of Smad2 and Smad3 in PDAC cells.	('Smad3', 'Gene', '4088', (188, 193))	('cell motility', 'biological_process', 'GO:0048870', ('104', '117'))	('inhibition', 'NegReg', (84, 94))	('TGF-b', 'Gene', (68, 73))	('suppression', 'NegReg', (118, 129))	('PDAC', 'Phenotype', 'HP:0006725', (197, 201))	('Smad2', 'Gene', '4087', (178, 183))	('Smad3', 'Gene', (188, 193))	('TGF-b', 'Gene', '7040', (68, 73))	('miR-323-3p-mediated', 'Var', (48, 67))	('cell motility', 'CPA', (104, 117))	('EMT', 'biological_process', 'GO:0001837', ('96', '99'))	('Smad2', 'Gene', (178, 183))	('PDAC', 'Chemical', '-', (197, 201))	('signaling', 'biological_process', 'GO:0023052', ('74', '83'))
19019	26908446	As such, miR-323-3p-mediated suppression of SMAD2 and SMAD3 could be clinically important in PDAC treatments.	('SMAD3', 'Gene', (54, 59))	('PDAC', 'Chemical', '-', (93, 97))	('suppression', 'NegReg', (29, 40))	('miR-323-3p-mediated', 'Var', (9, 28))	('SMAD2', 'Gene', '4087', (44, 49))	('SMAD3', 'Gene', '4088', (54, 59))	('PDAC', 'Disease', (93, 97))	('PDAC', 'Phenotype', 'HP:0006725', (93, 97))	('SMAD2', 'Gene', (44, 49))
19021	26908446	Several miRNAs have been found to be differentially expressed in tumoral and normal pancreatic tissues: decreased expression of miR96 promotes cell invasion and tumor growth in PDAC; low levels of mir-146a induces the metastatic phenotype; whereas high levels of miR-10a promotes invasiveness in PDAC cells.	('miR-10a', 'Gene', (263, 270))	('promotes', 'PosReg', (134, 142))	('induces', 'Reg', (206, 213))	('invasiveness', 'CPA', (280, 292))	('mir-146a', 'Gene', (197, 205))	('miR96', 'Gene', (128, 133))	('mir-146a', 'Gene', '406938', (197, 205))	('miR96', 'Gene', '407053', (128, 133))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('metastatic phenotype', 'CPA', (218, 238))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cell invasion', 'CPA', (143, 156))	('PDAC', 'Chemical', '-', (296, 300))	('miR-10a', 'Gene', '406902', (263, 270))	('decreased', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('PDAC', 'Chemical', '-', (177, 181))	('PDAC', 'Phenotype', 'HP:0006725', (296, 300))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('PDAC', 'Phenotype', 'HP:0006725', (177, 181))	('tumoral', 'Disease', (65, 72))	('tumoral', 'Disease', 'MESH:D009369', (65, 72))
19025	26908446	Mutation or deletion of SMAD4 gene has been reported in 60% of PDAC cases and has been associated with poor prognosis.	('deletion', 'Var', (12, 20))	('PDAC', 'Chemical', '-', (63, 67))	('SMAD4', 'Gene', '4089', (24, 29))	('Mutation', 'Var', (0, 8))	('PDAC', 'Disease', (63, 67))	('reported', 'Reg', (44, 52))	('PDAC', 'Phenotype', 'HP:0006725', (63, 67))	('SMAD4', 'Gene', (24, 29))
19112	27199515	The present study identified the association of high-grade parasympathetic neurogenesis with frequent occurrence of tumor budding and its role as an independent and highly unfavorable prognostic factor in PDAC, and deepens our understanding of the role of parasympathetic neurogenesis in PDAC in several aspects.	('high-grade', 'Var', (48, 58))	('PDAC', 'Disease', (205, 209))	('budding', 'biological_process', 'GO:0007114', ('122', '129'))	('PDAC', 'Phenotype', 'HP:0006725', (288, 292))	('PDAC', 'Chemical', '-', (205, 209))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('neurogenesis', 'biological_process', 'GO:0022008', ('272', '284'))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('neurogenesis', 'biological_process', 'GO:0022008', ('75', '87'))	('PDAC', 'Chemical', '-', (288, 292))	('tumor', 'Disease', (116, 121))	('PDAC', 'Phenotype', 'HP:0006725', (205, 209))	('association', 'Interaction', (33, 44))
19119	27199515	In the present study, high-grade parasympathetic neurogenesis was associated with aggressive clinicopathologic features of tumors such as the presence of tumor budding and early recurrence.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('high-grade', 'Var', (22, 32))	('neurogenesis', 'biological_process', 'GO:0022008', ('49', '61'))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('budding', 'biological_process', 'GO:0007114', ('160', '167'))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', (154, 159))
19136	26469831	In RNA-Seq data and in microarray expression data, high DSG3 expression correlated significantly with poor survival (P=0.000356 and P=0.00499).	('poor survival', 'CPA', (102, 115))	('RNA', 'cellular_component', 'GO:0005562', ('3', '6'))	('DSG3', 'Gene', '1830', (56, 60))	('high', 'Var', (51, 55))	('DSG3', 'Gene', (56, 60))	('expression', 'MPA', (61, 71))
19137	26469831	We identify DSG3 as a negative prognostic biomarker in resected PDAC, as high DSG3 expression is associated with poor overall survival and poor tumour-specific survival.	('DSG3', 'Gene', (12, 16))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('PDAC', 'Phenotype', 'HP:0006725', (64, 68))	('poor', 'NegReg', (139, 143))	('overall survival', 'CPA', (118, 134))	('DSG3', 'Gene', (78, 82))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('poor', 'NegReg', (113, 117))	('PDAC', 'Disease', (64, 68))	('tumour', 'Disease', (144, 150))	('expression', 'MPA', (83, 93))	('PDAC', 'Chemical', '-', (64, 68))	('DSG3', 'Gene', '1830', (12, 16))	('high', 'Var', (73, 77))	('DSG3', 'Gene', '1830', (78, 82))
19151	26469831	These findings indicate that a dysregulation of desmosomal proteins plays a role in carcinogenesis.	('carcinogenesis', 'Disease', (84, 98))	('carcinogenesis', 'Disease', 'MESH:D063646', (84, 98))	('dysregulation', 'Var', (31, 44))	('desmosomal proteins', 'Protein', (48, 67))
19176	26469831	SurvExpress was utilised to compare survival profiles for individuals segregated based on high and low DSG1, DSG2 and DSG3 expression with risk groups maximised and censored for survival in months ( GSE21501,).	('DSG3', 'Gene', (118, 122))	('DSG1', 'Gene', '1828', (103, 107))	('low', 'NegReg', (99, 102))	('DSG1', 'Gene', (103, 107))	('DSG3', 'Gene', '1830', (118, 122))	('DSG2', 'Gene', '1829', (109, 113))	('DSG2', 'Gene', (109, 113))	('high', 'Var', (90, 94))
19185	26469831	Of note, the majority of patients had high-grade tumours (n=106; 64.2%) with significantly shorter survival than patients with low-grade tumours (28 months vs 16 months, P=0.001, Table 1 and Figure 1B).	('tumours', 'Disease', (49, 56))	('low-grade tumours', 'Disease', (127, 144))	('tumours', 'Disease', (137, 144))	('low-grade tumours', 'Disease', 'MESH:D008228', (127, 144))	('patients', 'Species', '9606', (113, 121))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('tumours', 'Disease', 'MESH:D009369', (137, 144))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('patients', 'Species', '9606', (25, 33))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('survival', 'MPA', (99, 107))	('shorter', 'NegReg', (91, 98))	('high-grade', 'Var', (38, 48))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
19193	26469831	Interestingly, high DSG3 expression was associated with poor tumour differentiation (P<0.001), whereas no such association was detected for DSG1 and DSG2.	('high', 'Var', (15, 19))	('DSG1', 'Gene', '1828', (140, 144))	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('DSG3', 'Gene', '1830', (20, 24))	('DSG2', 'Gene', '1829', (149, 153))	('expression', 'MPA', (25, 35))	('DSG2', 'Gene', (149, 153))	('DSG3', 'Gene', (20, 24))	('tumour', 'Disease', (61, 67))	('DSG1', 'Gene', (140, 144))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
19197	26469831	Interestingly, high DSG3 expression within the tumour tissue significantly correlated with a shorter post-interventional survival time (23 months vs 15 months, P=0.011, Figure 3C and Table 2).	('high', 'Var', (15, 19))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('DSG3', 'Gene', '1830', (20, 24))	('expression', 'MPA', (25, 35))	('tumour', 'Disease', (47, 53))	('DSG3', 'Gene', (20, 24))	('shorter', 'NegReg', (93, 100))	('post-interventional survival time', 'CPA', (101, 134))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
19208	26469831	Surprisingly, we also detected a significantly shorter survival for patients with a high DSG2 expressing tumour (median survival time 19.7 months vs 22.5 months; P=0.029, Figure 4A).	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('shorter', 'NegReg', (47, 54))	('DSG2', 'Gene', (89, 93))	('high', 'Var', (84, 88))	('tumour', 'Disease', (105, 111))	('patients', 'Species', '9606', (68, 76))	('DSG2', 'Gene', '1829', (89, 93))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('survival', 'MPA', (55, 63))
19211	26469831	Again, high DSG3 expression was significantly associated with poor patient survival (median survival time 21 vs 15 months; P=0.00499, Supplementary Figure S7A), whereas no such association was detected for DSG1 (median survival time 17 vs 19 months; P=0.607, Supplementary Figure S7B) or DSG2 (median survival time 19 vs 17 months; P=0.592, Supplementary Figure S7C).	('DSG1', 'Gene', (206, 210))	('DSG3', 'Gene', (12, 16))	('DSG1', 'Gene', '1828', (206, 210))	('DSG2', 'Gene', '1829', (288, 292))	('expression', 'MPA', (17, 27))	('DSG2', 'Gene', (288, 292))	('patient survival', 'CPA', (67, 83))	('high', 'Var', (7, 11))	('DSG3', 'Gene', '1830', (12, 16))	('poor', 'NegReg', (62, 66))	('patient', 'Species', '9606', (67, 74))
19213	26469831	Using a well-defined collection of R0-resected PDAC specimens, we show that high DSG3 expression is significantly associated with shorter postoperative patient survival, whereas no such association was detected for DSG1 or DSG2 expression.	('DSG2', 'Gene', '1829', (223, 227))	('DSG2', 'Gene', (223, 227))	('DSG3', 'Gene', '1830', (81, 85))	('PDAC', 'Phenotype', 'HP:0006725', (47, 51))	('DSG3', 'Gene', (81, 85))	('DSG1', 'Gene', (215, 219))	('expression', 'MPA', (86, 96))	('patient', 'Species', '9606', (152, 159))	('DSG1', 'Gene', '1828', (215, 219))	('high', 'Var', (76, 80))	('shorter', 'NegReg', (130, 137))	('postoperative patient survival', 'CPA', (138, 168))	('PDAC', 'Chemical', '-', (47, 51))
19216	26469831	Surprisingly, in the TCGA data set also high DSG2 expression correlated with poor patient survival, although with a much lower statistical power.	('high', 'Var', (40, 44))	('patient', 'Species', '9606', (82, 89))	('poor', 'NegReg', (77, 81))	('DSG2', 'Gene', '1829', (45, 49))	('expression', 'MPA', (50, 60))	('patient survival', 'CPA', (82, 98))	('DSG2', 'Gene', (45, 49))
19224	26469831	In line with these findings, high DSG3 expression has been associated with increased metastasis formation.	('high', 'Var', (29, 33))	('formation', 'biological_process', 'GO:0009058', ('96', '105'))	('DSG3', 'Gene', '1830', (34, 38))	('metastasis formation', 'CPA', (85, 105))	('DSG3', 'Gene', (34, 38))	('expression', 'MPA', (39, 49))	('increased', 'PosReg', (75, 84))
19237	26416426	Further mechanistic studies demonstrated that aberrant expression and activation of TAZ in pancreatic cancer cells resulted from suppression of the expression of Merlin, a positive regulator upstream of the Hippo pathway, and that the oncogenic function of TAZ in pancreatic cancer cells was mediated by TEA/ATTS domain transcription factors.	('TAZ', 'Gene', (84, 87))	('Merlin', 'Gene', '4771', (162, 168))	('expression', 'MPA', (148, 158))	('oncogenic function', 'CPA', (235, 253))	('pancreatic cancer', 'Disease', (91, 108))	('Merlin', 'Gene', (162, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (264, 281))	('pancreatic cancer', 'Disease', (264, 281))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (264, 281))	('expression', 'MPA', (55, 65))	('transcription', 'biological_process', 'GO:0006351', ('320', '333'))	('aberrant', 'Var', (46, 54))	('activation', 'PosReg', (70, 80))	('suppression', 'NegReg', (129, 140))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))
19243	26416426	Recent studies revealed that pancreatic cancer is essentially a genetic disease, resulting from genetic and epigenetic alterations.	('epigenetic alterations', 'Var', (108, 130))	('genetic disease', 'Disease', (64, 79))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (29, 46))	('pancreatic cancer', 'Disease', (29, 46))	('pancreatic cancer', 'Disease', 'MESH:D010190', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('genetic disease', 'Disease', 'MESH:D030342', (64, 79))
19244	26416426	Therefore, identification of key genetic and epigenetic alterations that promote pancreatic cancer development and progression should help the generation of novel strategies for early detection and treatment of pancreatic cancer.	('progression', 'CPA', (115, 126))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('pancreatic cancer', 'Disease', (211, 228))	('pancreatic cancer', 'Disease', 'MESH:D010190', (211, 228))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('promote', 'PosReg', (73, 80))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('epigenetic alterations', 'Var', (45, 67))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (211, 228))	('pancreatic cancer', 'Disease', (81, 98))
19247	26416426	In contrast, inactivation of the Hippo pathway results in TAZ/YAP nuclear translocation, with interacting with TEA/ATTS domain (TEAD) transcription factors and transactivating their downstream targets, including connective tissue growth factor (CTGF) and survivin, and involving in cell proliferation, stem cell self-renewal, and tumorigenesis.	('connective tissue growth factor', 'Gene', '1490', (212, 243))	('inactivation', 'Var', (13, 25))	('connective tissue growth factor', 'Gene', (212, 243))	('tumor', 'Disease', (330, 335))	('transcription', 'biological_process', 'GO:0006351', ('134', '147'))	('Hippo', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('transactivating', 'PosReg', (160, 175))	('YAP', 'Gene', '10413', (62, 65))	('interacting', 'Interaction', (94, 105))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('nuclear translocation', 'MPA', (66, 87))	('cell proliferation', 'biological_process', 'GO:0008283', ('282', '300'))	('results in', 'Reg', (47, 57))	('survivin', 'Protein', (255, 263))	('stem cell self-renewal', 'CPA', (302, 324))	('cell proliferation', 'CPA', (282, 300))	('involving in', 'Reg', (269, 281))	('YAP', 'Gene', (62, 65))
19249	26416426	There are genetically engineered mouse strains of TAZ deletion, which show extensive abnormalities, particularly in the kidneys and lungs.	('deletion', 'Var', (54, 62))	('TAZ', 'Gene', (50, 53))	('mouse', 'Species', '10090', (33, 38))
19255	26416426	Furthermore, mutation of the NF2 gene and loss of Merlin protein occur in many different types of cancer, suggesting a general tumor-suppressive role for Merlin.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('Merlin', 'Gene', (50, 56))	('occur', 'Reg', (65, 70))	('NF2', 'Gene', '4771', (29, 32))	('Merlin', 'Gene', '4771', (50, 56))	('tumor', 'Disease', (127, 132))	('mutation', 'Var', (13, 21))	('Merlin', 'Gene', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Merlin', 'Gene', '4771', (154, 160))	('cancer', 'Disease', (98, 104))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('NF2', 'Gene', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('protein', 'Protein', (57, 64))	('loss', 'NegReg', (42, 46))
19293	26416426	The MST and LATS kinases in the Hippo pathway phosphorylate TAZ in four HXRXXS motifs, and four serine residues (S66, S89, S177, and S311) are located in the HXRXXS motifs.	('S311', 'Var', (133, 137))	('S89', 'Var', (118, 121))	('S177', 'Var', (123, 127))	('Hippo pathway', 'Pathway', (32, 45))	('serine', 'Chemical', 'MESH:D012694', (96, 102))	('S66', 'Var', (113, 116))
19298	26416426	To test this in pancreatic cancer cases, we first transfected BxPC-3 and AsPC-1 cells with a control vector, TAZ, 4SA, or 4SA-S51A, which had an additional point mutation of 4SA in the TEAD-binding domain and lacked TEAD binding.	('binding', 'molecular_function', 'GO:0005488', ('221', '228'))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('AsPC-1', 'CellLine', 'CVCL:0152', (73, 79))	('lacked', 'NegReg', (209, 215))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (16, 33))	('binding', 'molecular_function', 'GO:0005488', ('190', '197'))	('TEAD binding', 'Interaction', (216, 228))	('S51A', 'Mutation', 'p.S51A', (126, 130))	('pancreatic cancer', 'Disease', (16, 33))	('point mutation', 'Var', (156, 170))	('pancreatic cancer', 'Disease', 'MESH:D010190', (16, 33))	('BxPC-3', 'CellLine', 'CVCL:0186', (62, 68))
19299	26416426	However, the promoting effect of 4SA-S51A was lower than that of 4SA (Figure 6A).	('promoting effect', 'MPA', (13, 29))	('S51A', 'Mutation', 'p.S51A', (37, 41))	('lower', 'NegReg', (46, 51))	('4SA-S51A', 'Var', (33, 41))
19300	26416426	Furthermore, the function of 4SA-S51A in inducing cell proliferation, migration, invasion, and expression of EMT markers was much more attenuated than that of 4SA (Figure 6A, 6B, 6C).	('S51A', 'Mutation', 'p.S51A', (33, 37))	('migration', 'CPA', (70, 79))	('EMT', 'biological_process', 'GO:0001837', ('109', '112'))	('invasion', 'CPA', (81, 89))	('attenuated', 'NegReg', (135, 145))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('4SA-S51A', 'Var', (29, 37))	('inducing', 'PosReg', (41, 49))	('expression', 'MPA', (95, 105))	('cell proliferation', 'CPA', (50, 68))
19322	26416426	We further investigated the mechanism of aberrant expression and activation of TAZ in pancreatic cancer cases.	('aberrant', 'Var', (41, 49))	('pancreatic cancer', 'Disease', (86, 103))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('TAZ', 'Gene', (79, 82))	('activation', 'PosReg', (65, 75))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
19327	26416426	By using mutants of TAZ, we found that 4SA-S51A attenuated 4SA-induced pancreatic cancer cell proliferation, migration, invasion, and expression of EMT markers.	('4SA-S51A', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('EMT', 'biological_process', 'GO:0001837', ('148', '151'))	('expression', 'MPA', (134, 144))	('attenuated', 'NegReg', (48, 58))	('S51A', 'Mutation', 'p.S51A', (43, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('4SA-induced', 'Gene', (59, 70))	('invasion', 'CPA', (120, 128))	('migration', 'CPA', (109, 118))	('cell proliferation', 'biological_process', 'GO:0008283', ('89', '107'))	('pancreatic cancer', 'Disease', (71, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (71, 88))
19344	26416426	Full-length TAZ and its mutants TAZ-4SA and TAZ-4SA-S51A were cloned into pcDNA3.0-HA as HindIII-EcoRI fragments (HA-TAZ, HA-4SA, and HA-4SA-S51A).	('HA-4SA-S51A', 'Var', (134, 145))	('S51A', 'Mutation', 'p.S51A', (141, 145))	('S51A', 'Mutation', 'p.S51A', (52, 56))	('TAZ', 'Gene', (12, 15))	('HA-4SA', 'Var', (122, 128))
19363	26416426	BxPC-3 and FG cells were transfected for 6 h with different reagents respective to different groups (control vector and HA-TAZ or control and Sh-TAZ-1), and AsPC-1 cells were transfected for 6 h with a control, HA-TAZ, HA-4SA, or HA-4SA-S51A.	('TAZ-1', 'Gene', '6901', (145, 150))	('TAZ-1', 'Gene', (145, 150))	('HA-TAZ', 'Var', (211, 217))	('HA-4SA', 'Var', (219, 225))	('BxPC-3', 'CellLine', 'CVCL:0186', (0, 6))	('S51A', 'Mutation', 'p.S51A', (237, 241))	('AsPC-1', 'CellLine', 'CVCL:0152', (157, 163))	('HA-4SA-S51A', 'Var', (230, 241))
19373	26820738	In vitro analyses showed that silencing of PTGR2 expression enhanced ROS production, suppressed pancreatic cell proliferation, and promoted cell death through increasing 15-keto-PGE2.	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (170, 182))	('enhanced ROS production', 'Phenotype', 'HP:0025464', (60, 83))	('suppressed', 'NegReg', (85, 95))	('cell death', 'CPA', (140, 150))	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('PTGR2', 'Gene', '145482', (43, 48))	('ROS', 'Chemical', 'MESH:D017382', (69, 72))	('cell death', 'biological_process', 'GO:0008219', ('140', '150'))	('PTGR2', 'Gene', (43, 48))	('silencing', 'Var', (30, 39))	('ROS production', 'MPA', (69, 83))	('pancreatic', 'Disease', 'MESH:D010195', (96, 106))	('15-keto-PGE2', 'MPA', (170, 182))	('increasing', 'PosReg', (159, 169))	('enhanced', 'PosReg', (60, 68))	('promoted', 'PosReg', (131, 139))	('pancreatic', 'Disease', (96, 106))
19374	26820738	Mechanistically, silencing of PTGR2 or addition of 15-keto-PGE2 suppressed the expressions of solute carrier family 7 member 11 (xCT) and cystathionine gamma-lyase (CTH), two important providers of intracellular cysteine for the generation of glutathione (GSH), which is widely accepted as the first-line antioxidative defense.	('glutathione', 'Chemical', 'MESH:D005978', (243, 254))	('carrier', 'molecular_function', 'GO:0005215', ('101', '108'))	('cystathionine gamma-lyase', 'Gene', '1491', (138, 163))	('expressions', 'MPA', (79, 90))	('solute carrier family 7 member 11', 'Gene', (94, 127))	('suppressed', 'NegReg', (64, 74))	('PTGR2', 'Gene', '145482', (30, 35))	('cysteine', 'Chemical', 'MESH:D003545', (212, 220))	('cystathionine gamma-lyase', 'Gene', (138, 163))	('xCT', 'Gene', '23657', (129, 132))	('solute carrier family 7 member 11', 'Gene', '23657', (94, 127))	('GSH', 'Chemical', 'MESH:D005978', (256, 259))	('intracellular', 'cellular_component', 'GO:0005622', ('198', '211'))	('PTGR2', 'Gene', (30, 35))	('CTH', 'Gene', '1491', (165, 168))	('CTH', 'Gene', (165, 168))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (51, 63))	('silencing', 'Var', (17, 26))	('xCT', 'Gene', (129, 132))
19382	26820738	Over-expression of PTGR2 suppressed while inactivation of PTGR2 increased PPARgamma-mediated adipogenesis and lipid metabolism.	('adipogenesis', 'biological_process', 'GO:0060612', ('93', '105'))	('PTGR2', 'Gene', '145482', (19, 24))	('PPARgamma', 'Gene', (74, 83))	('PTGR2', 'Gene', (19, 24))	('inactivation', 'Var', (42, 54))	('PPARgamma', 'Gene', '5468', (74, 83))	('PTGR2', 'Gene', '145482', (58, 63))	('lipid metabolism', 'biological_process', 'GO:0006629', ('110', '126'))	('PTGR2', 'Gene', (58, 63))	('lipid metabolism', 'MPA', (110, 126))	('lipid', 'Chemical', 'MESH:D008055', (110, 115))	('increased', 'PosReg', (64, 73))	('adipogenesis', 'biological_process', 'GO:0045444', ('93', '105'))
19386	26820738	We showed both in vitro and in vivo that knockdown of PTGR2 suppressed tumor growth and induced apoptosis through ROS-mediated signaling involving ERK1/2 and caspase 3 activities.	('ERK1/2', 'Gene', '5595;5594', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('induced', 'Reg', (88, 95))	('PTGR2', 'Gene', '145482', (54, 59))	('caspase 3', 'Gene', (158, 167))	('caspase 3', 'Gene', '836', (158, 167))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('ERK1', 'molecular_function', 'GO:0004707', ('147', '151'))	('tumor', 'Disease', (71, 76))	('knockdown', 'Var', (41, 50))	('suppressed', 'NegReg', (60, 70))	('ROS', 'Chemical', 'MESH:D017382', (114, 117))	('PTGR2', 'Gene', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('apoptosis', 'CPA', (96, 105))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('ROS-mediated signaling', 'MPA', (114, 136))	('ERK1/2', 'Gene', (147, 153))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
19391	26820738	However, ROS can also promote pro-oncogenic signaling pathways and aids in cancer progression.	('promote', 'PosReg', (22, 29))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('aids', 'Reg', (67, 71))	('pro-oncogenic signaling pathways', 'Pathway', (30, 62))	('signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('ROS', 'Var', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
19402	26820738	Studies of xCT in these cancers all demonstrated that knocking down xCT or blocking its activity led to suppressed proliferation, induced ROS level and cell death, and tumor regression.	('activity', 'MPA', (88, 96))	('blocking', 'NegReg', (75, 83))	('suppressed', 'NegReg', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('xCT', 'Gene', '23657', (68, 71))	('xCT', 'Gene', '23657', (11, 14))	('knocking down', 'Var', (54, 67))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cell death', 'CPA', (152, 162))	('cancers', 'Disease', (24, 31))	('tumor', 'Disease', (168, 173))	('proliferation', 'CPA', (115, 128))	('ROS level', 'MPA', (138, 147))	('cell death', 'biological_process', 'GO:0008219', ('152', '162'))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('induced', 'PosReg', (130, 137))	('xCT', 'Gene', (68, 71))	('xCT', 'Gene', (11, 14))	('ROS', 'Chemical', 'MESH:D017382', (138, 141))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
19418	26820738	The sequences of the siRNAs are as follows: si-PTGR2, 5'-CGAAUGGAAGAAGUCUAUUUAUU-3'; and si-Cont, 5'-UGGUUUACAUGUCGACUAAUUA-3'.	('si-Cont', 'Var', (89, 96))	('PTGR2', 'Gene', (47, 52))	('PTGR2', 'Gene', '145482', (47, 52))
19456	26820738	Interestingly, silencing of PTGR2 significantly suppressed the growth rates of BxPC-3 and Capan-2 while the growth rates of PL45, PANC-1 and MIA PaCa-2 were unaffected (Fig 2E and 2F).	('BxPC-3', 'CellLine', 'CVCL:0186', (79, 85))	('PANC-1', 'CellLine', 'CVCL:0480', (130, 136))	('silencing', 'Var', (15, 24))	('suppressed', 'NegReg', (48, 58))	('PTGR2', 'Gene', '145482', (28, 33))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (141, 151))	('growth', 'MPA', (63, 69))	('Capan-2', 'CellLine', 'CVCL:0026', (90, 97))	('PTGR2', 'Gene', (28, 33))
19457	26820738	Since BxPC-3 and Capan-2 could self-generate highest level of prostaglandins, we suspected that the biological outcomes resulted from silencing of PTGR2 were related to the disturbance of prostaglandin metabolism.	('prostaglandin metabolism', 'biological_process', 'GO:0006693', ('188', '212'))	('prostaglandin', 'Chemical', 'MESH:D011453', (188, 201))	('prostaglandins', 'Chemical', 'MESH:D011453', (62, 76))	('prostaglandin', 'Chemical', 'MESH:D011453', (62, 75))	('Capan-2', 'CellLine', 'CVCL:0026', (17, 24))	('silencing', 'Var', (134, 143))	('PTGR2', 'Gene', (147, 152))	('PTGR2', 'Gene', '145482', (147, 152))	('BxPC-3', 'CellLine', 'CVCL:0186', (6, 12))
19460	26820738	We further found that silencing of PTGR2 also did not affect the protein levels of COX1, COX2 and 15-PGDH in both BxPC-3 (Fig 3C) and Capan-2 cells (S2A Fig).	('15-PGDH', 'Gene', '873', (98, 105))	('protein levels', 'MPA', (65, 79))	('Capan-2', 'CellLine', 'CVCL:0026', (134, 141))	('BxPC-3', 'CellLine', 'CVCL:0186', (114, 120))	('15-PGDH', 'Gene', (98, 105))	('COX1', 'Gene', (83, 87))	('COX2', 'Gene', (89, 93))	('silencing', 'Var', (22, 31))	('COX1', 'Gene', '4512', (83, 87))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('COX2', 'Gene', '4513', (89, 93))	('PTGR2', 'Gene', (35, 40))	('PTGR2', 'Gene', '145482', (35, 40))
19461	26820738	Thus we next examined the levels of PTGR2 substrate and product after PTGR2 silencing.	('silencing', 'Var', (76, 85))	('PTGR2', 'Gene', (36, 41))	('PTGR2', 'Gene', '145482', (36, 41))	('PTGR2', 'Gene', '145482', (70, 75))	('PTGR2', 'Gene', (70, 75))
19466	26820738	Silencing PTGR2 induced PPARgamma transcriptional activity in cell lines expressing either low (BxPC-3) or high (PANC-1) PPARgamma (Fig 4B and 4C).	('PPARgamma', 'Gene', '5468', (121, 130))	('BxPC-3', 'CellLine', 'CVCL:0186', (96, 102))	('PPARgamma', 'Gene', '5468', (24, 33))	('PANC-1', 'CellLine', 'CVCL:0480', (113, 119))	('PTGR2', 'Gene', (10, 15))	('PPARgamma', 'Gene', (24, 33))	('PTGR2', 'Gene', '145482', (10, 15))	('Silencing', 'Var', (0, 9))	('PPARgamma', 'Gene', (121, 130))
19467	26820738	To elucidate if the biological outcomes observed from silencing of PTGR2 were related to PPARgamma activity, we first treated BxPC-3 with synthetic PPARgamma agonist Brl and 15-keto-PGE2 alone or together with the irreversible PPARgamma antagonist GW9662 and performed PPRE reporter assay to ensure that the drugs we used worked properly to induce or to block PPARgamma transcriptional activity.	('PPARgamma', 'Gene', '5468', (227, 236))	('PPARgamma', 'Gene', '5468', (148, 157))	('Brl', 'Gene', '23774', (166, 169))	('silencing', 'Var', (54, 63))	('PTGR2', 'Gene', (67, 72))	('PPARgamma', 'Gene', (89, 98))	('PTGR2', 'Gene', '145482', (67, 72))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (174, 186))	('PPARgamma', 'Gene', (360, 369))	('PPARgamma', 'Gene', '5468', (360, 369))	('GW9662', 'Chemical', 'MESH:C457499', (248, 254))	('PPARgamma', 'Gene', '5468', (89, 98))	('PPARgamma', 'Gene', (148, 157))	('Brl', 'Gene', (166, 169))	('PPARgamma', 'Gene', (227, 236))	('BxPC-3', 'CellLine', 'CVCL:0186', (126, 132))
19468	26820738	PPRE reporter assay showed that both Brl, 15-keto-PGE2 and GW9662 worked properly, although they seemed to work better in PANC-1 cells (Fig 4D and 4F), possibly due to the fact that BxPC-3 already self-produce abundant 15-keto-PGE2 and thus the drugs were not as effective.	('GW9662', 'Var', (59, 65))	('GW9662', 'Chemical', 'MESH:C457499', (59, 65))	('PANC-1', 'CellLine', 'CVCL:0480', (122, 128))	('Brl', 'Gene', '23774', (37, 40))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (219, 231))	('BxPC-3', 'CellLine', 'CVCL:0186', (182, 188))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (42, 54))	('Brl', 'Gene', (37, 40))
19469	26820738	Consistently, treatment with Brl or 15-keto-PGE2 also suppressed cell viability in both BxPC-3 and PANC-1 cells.	('Brl', 'Gene', (29, 32))	('suppressed', 'NegReg', (54, 64))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (36, 48))	('Brl', 'Gene', '23774', (29, 32))	('cell viability', 'CPA', (65, 79))	('BxPC-3', 'CellLine', 'CVCL:0186', (88, 94))	('PANC-1', 'CellLine', 'CVCL:0480', (99, 105))	('15-keto-PGE2', 'Var', (36, 48))
19470	26820738	GW9662 seemed to be able to reverse the suppressive effect of 15-keto-PGE2 and Brl in BxPC-3 slightly, but was ineffective in PANC-1 cells (Fig 4E and 4G).	('Brl', 'Gene', '23774', (79, 82))	('BxPC-3', 'CellLine', 'CVCL:0186', (86, 92))	('GW9662', 'Var', (0, 6))	('GW9662', 'Chemical', 'MESH:C457499', (0, 6))	('PANC-1', 'CellLine', 'CVCL:0480', (126, 132))	('Brl', 'Gene', (79, 82))	('BxPC-3', 'MPA', (86, 92))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (62, 74))
19471	26820738	Our data suggested that the cell death-promoting effect of 15-keto-PGE2 is mediated partly but not entirely through PPARgamma activation.	('15-keto-PGE2', 'Var', (59, 71))	('cell death-promoting', 'CPA', (28, 48))	('PPARgamma', 'Gene', (116, 125))	('cell death', 'biological_process', 'GO:0008219', ('28', '38'))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (59, 71))	('PPARgamma', 'Gene', '5468', (116, 125))
19474	26820738	Thus, we next attempted to investigate why manipulating PTGR2 expression, which altered the concentration of its substrate 15-keto-PGE2, affected ROS and cell death.	('affected', 'Reg', (137, 145))	('cell death', 'CPA', (154, 164))	('ROS', 'MPA', (146, 149))	('manipulating', 'Var', (43, 55))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (123, 135))	('altered', 'Reg', (80, 87))	('ROS', 'Chemical', 'MESH:D017382', (146, 149))	('cell death', 'biological_process', 'GO:0008219', ('154', '164'))	('PTGR2', 'Gene', '145482', (56, 61))	('concentration of', 'MPA', (92, 108))	('PTGR2', 'Gene', (56, 61))
19477	26820738	Thus, we first examined if silencing of PTGR2 altered the expression levels of major genes regulating cellular oxidative stress.	('silencing', 'Var', (27, 36))	('expression levels of major genes', 'MPA', (58, 90))	('PTGR2', 'Gene', (40, 45))	('PTGR2', 'Gene', '145482', (40, 45))	('altered', 'Reg', (46, 53))	('oxidative stress', 'Phenotype', 'HP:0025464', (111, 127))
19479	26820738	We further confirmed the protein expressions of these three genes and found that only xCT and CTH expressions were suppressed after silencing of PTGR2.	('PTGR2', 'Gene', '145482', (145, 150))	('xCT', 'Gene', (86, 89))	('silencing', 'Var', (132, 141))	('xCT', 'Gene', '23657', (86, 89))	('CTH', 'Gene', '1491', (94, 97))	('CTH', 'Gene', (94, 97))	('suppressed', 'NegReg', (115, 125))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('PTGR2', 'Gene', (145, 150))
19484	26820738	Treatment of PANC-1 cells with 15-keto-PGE2 also resulted in significantly elevated ROS production (Fig 6A).	('15-keto-PGE2', 'Var', (31, 43))	('elevated ROS production', 'Phenotype', 'HP:0025464', (75, 98))	('elevated', 'PosReg', (75, 83))	('PANC-1', 'CellLine', 'CVCL:0480', (13, 19))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (31, 43))	('ROS production', 'MPA', (84, 98))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))
19487	26820738	Next, we thought to see if 15-keto-PGE2 could also induce cell death as did silencing PTGR2, and if so, whether the cell death induced is caused by excess ROS accumulated as a result of reduced GSH due to down-regulated xCT and CTH.	('CTH', 'Gene', '1491', (228, 231))	('cell death', 'biological_process', 'GO:0008219', ('116', '126'))	('xCT', 'Gene', (220, 223))	('silencing', 'Var', (76, 85))	('ROS', 'Chemical', 'MESH:D017382', (155, 158))	('ROS', 'Protein', (155, 158))	('reduced', 'NegReg', (186, 193))	('cell death', 'biological_process', 'GO:0008219', ('58', '68'))	('cell death', 'CPA', (58, 68))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (27, 39))	('GSH', 'Chemical', 'MESH:D005978', (194, 197))	('xCT', 'Gene', '23657', (220, 223))	('CTH', 'Gene', (228, 231))	('down-regulated', 'NegReg', (205, 219))	('PTGR2', 'Gene', (86, 91))	('GSH', 'MPA', (194, 197))	('PTGR2', 'Gene', '145482', (86, 91))
19498	26820738	Importantly, when comparing to cells treated with control siRNA, the reduced GSH level after silencing of PTGR2 was reversed when treating cells with NAC or 2-ME (Fig 7B).	('NAC', 'Gene', (150, 153))	('GSH level', 'MPA', (77, 86))	('silencing', 'Var', (93, 102))	('NAC', 'Gene', '7504', (150, 153))	('reduced', 'NegReg', (69, 76))	('PTGR2', 'Gene', '145482', (106, 111))	('NAC', 'cellular_component', 'GO:0005854', ('150', '153'))	('PTGR2', 'Gene', (106, 111))	('GSH', 'Chemical', 'MESH:D005978', (77, 80))	('2-ME', 'Chemical', '-', (157, 161))
19499	26820738	Moreover, induced apoptotic and necrotic cells after silencing of PTGR2 was rescued after treatment with NAC and 2-ME (Fig 7E and 7F).	('NAC', 'Gene', (105, 108))	('NAC', 'Gene', '7504', (105, 108))	('NAC', 'cellular_component', 'GO:0005854', ('105', '108'))	('2-ME', 'Chemical', '-', (113, 117))	('necrotic', 'Disease', (32, 40))	('apoptotic', 'CPA', (18, 27))	('silencing', 'Var', (53, 62))	('necrotic', 'Disease', 'MESH:D009336', (32, 40))	('PTGR2', 'Gene', (66, 71))	('PTGR2', 'Gene', '145482', (66, 71))
19500	26820738	Taken together, our data suggested that silencing PTGR2, which resulted in excess 15-keto-PGE2, induced ROS-dependent cell death by affecting cellular glutathione level through manipulating xCT and CTH expressions.	('xCT', 'Gene', '23657', (190, 193))	('cell death', 'biological_process', 'GO:0008219', ('118', '128'))	('CTH', 'Gene', '1491', (198, 201))	('CTH', 'Gene', (198, 201))	('cellular glutathione level', 'MPA', (142, 168))	('manipulating', 'Reg', (177, 189))	('glutathione', 'Chemical', 'MESH:D005978', (151, 162))	('PTGR2', 'Gene', (50, 55))	('excess', 'PosReg', (75, 81))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (82, 94))	('PTGR2', 'Gene', '145482', (50, 55))	('ROS', 'Chemical', 'MESH:D017382', (104, 107))	('ROS-dependent cell death', 'CPA', (104, 128))	('induced', 'Reg', (96, 103))	('xCT', 'Gene', (190, 193))	('silencing', 'Var', (40, 49))	('affecting', 'Reg', (132, 141))
19503	26820738	Silencing of PTGR2 suppressed pancreatic cancer cell growth and induced cancer cell death through increased 15-keto-PGE2 and ROS levels.	('suppressed', 'NegReg', (19, 29))	('cancer', 'Disease', (41, 47))	('cell growth', 'biological_process', 'GO:0016049', ('48', '59'))	('Silencing', 'Var', (0, 9))	('cancer', 'Disease', (72, 78))	('pancreatic cancer', 'Disease', 'MESH:D010190', (30, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('ROS levels', 'MPA', (125, 135))	('induced', 'Reg', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('15-keto-PGE2', 'MPA', (108, 120))	('PTGR2', 'Gene', '145482', (13, 18))	('increased', 'PosReg', (98, 107))	('pancreatic cancer', 'Disease', (30, 47))	('ROS', 'Chemical', 'MESH:D017382', (125, 128))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (108, 120))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (30, 47))	('cell death', 'biological_process', 'GO:0008219', ('79', '89'))	('PTGR2', 'Gene', (13, 18))
19506	26820738	In our study, silencing of PTGR2 only affected the proliferation rate of BxPC-3 and Capan-2, both of which can self-generate abundant prostaglandins due to the high expression levels of COX proteins.	('silencing', 'Var', (14, 23))	('BxPC-3', 'CellLine', 'CVCL:0186', (73, 79))	('COX', 'Gene', '1351', (186, 189))	('proliferation rate', 'CPA', (51, 69))	('Capan-2', 'CellLine', 'CVCL:0026', (84, 91))	('prostaglandins', 'Chemical', 'MESH:D011453', (134, 148))	('PTGR2', 'Gene', '145482', (27, 32))	('COX', 'Gene', (186, 189))	('PTGR2', 'Gene', (27, 32))	('expression levels', 'MPA', (165, 182))
19508	26820738	This heterogeneity of pancreatic cancer phenotypes also reflected in our study as silencing PTGR2, which in turn disturbed prostaglandin metabolism, did not show noticeable effect on cell lines that cannot self-generate prostaglandins, including PL45, PANC-1 and MIA PaCa-2.	('PTGR2', 'Gene', '145482', (92, 97))	('prostaglandin metabolism', 'MPA', (123, 147))	('PTGR2', 'Gene', (92, 97))	('prostaglandin', 'Chemical', 'MESH:D011453', (220, 233))	('PANC-1', 'CellLine', 'CVCL:0480', (252, 258))	('prostaglandin', 'Chemical', 'MESH:D011453', (123, 136))	('prostaglandins', 'Chemical', 'MESH:D011453', (220, 234))	('silencing', 'Var', (82, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (22, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (22, 39))	('pancreatic cancer', 'Disease', (22, 39))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (263, 273))	('disturbed', 'Reg', (113, 122))	('prostaglandin metabolism', 'biological_process', 'GO:0006693', ('123', '147'))
19510	26820738	Since there are abundant cancer-associated fibroblasts (CAFs) in the tumor stromal area under physiological condition, we speculate that under co-culture condition with CAFs, suppressed growth rate or induced cell death we observed in PTGR2-silenced pancreatic cancer cells (BxPC-3 and Capan-2) could be lost because the decrease in 15-keto-PGE2 after silencing of PTGR2 could be provided by the tumor microenvironment.	('PTGR2', 'Gene', '145482', (365, 370))	('15-keto-PGE2', 'MPA', (333, 345))	('tumor', 'Phenotype', 'HP:0002664', (396, 401))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (250, 267))	('cancer', 'Disease', (25, 31))	('decrease', 'NegReg', (321, 329))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('PTGR2', 'Gene', '145482', (235, 240))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (333, 345))	('cancer', 'Disease', (261, 267))	('Capan-2', 'CellLine', 'CVCL:0026', (286, 293))	('pancreatic cancer', 'Disease', 'MESH:D010190', (250, 267))	('cell death', 'biological_process', 'GO:0008219', ('209', '219'))	('BxPC-3', 'CellLine', 'CVCL:0186', (275, 281))	('PTGR2', 'Gene', (365, 370))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('tumor', 'Disease', (396, 401))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('pancreatic cancer', 'Disease', (250, 267))	('tumor', 'Disease', 'MESH:D009369', (396, 401))	('PTGR2', 'Gene', (235, 240))	('tumor', 'Disease', (69, 74))	('silencing', 'Var', (352, 361))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
19511	26820738	As the biological outcomes obtained from silencing of PTGR2 were related to the disturbance of prostaglandin metabolism, this also suggested the importance of PTGR2 enzymatic activity, which greatly affects the concentrations of its substrate and product.	('PTGR2', 'Gene', '145482', (159, 164))	('prostaglandin metabolism', 'MPA', (95, 119))	('silencing', 'Var', (41, 50))	('prostaglandin', 'Chemical', 'MESH:D011453', (95, 108))	('disturbance', 'MPA', (80, 91))	('PTGR2', 'Gene', (54, 59))	('PTGR2', 'Gene', '145482', (54, 59))	('prostaglandin metabolism', 'biological_process', 'GO:0006693', ('95', '119'))	('related', 'Reg', (65, 72))	('PTGR2', 'Gene', (159, 164))
19519	26820738	Because 15-keto-PGE2 is an endogenous PPARgamma ligand, we also attempted to investigate whether the biological outcomes observed from silencing of PTGR2 were related to PPARgamma activity.	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (8, 20))	('PTGR2', 'Gene', '145482', (148, 153))	('PPARgamma', 'Gene', '5468', (170, 179))	('silencing', 'Var', (135, 144))	('ligand', 'molecular_function', 'GO:0005488', ('48', '54'))	('PPARgamma', 'Gene', (38, 47))	('PPARgamma', 'Gene', (170, 179))	('PPARgamma', 'Gene', '5468', (38, 47))	('PTGR2', 'Gene', (148, 153))
19520	26820738	In our study, silencing PTGR2 or addition of 15-keto-PGE2 both induced PPARgamma transcriptional activity.	('silencing', 'Var', (14, 23))	('PPARgamma', 'Gene', (71, 80))	('PPARgamma', 'Gene', '5468', (71, 80))	('PTGR2', 'Gene', (24, 29))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (45, 57))	('PTGR2', 'Gene', '145482', (24, 29))	('induced', 'Reg', (63, 70))
19522	26820738	However, addition of the selective and irreversible PPARgamma antagonist GW9662 did not completely reverse the 15-keto-PGE2-induced cell death.	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (111, 123))	('PPARgamma', 'Gene', '5468', (52, 61))	('cell death', 'biological_process', 'GO:0008219', ('132', '142'))	('GW9662', 'Var', (73, 79))	('GW9662', 'Chemical', 'MESH:C457499', (73, 79))	('PPARgamma', 'Gene', (52, 61))
19531	26820738	Manipulating PTGR2 expression affects both the level of its substrate 15-keto-PGE2, as well as the level of its product 13,14-dihydro-15-keto-PGE2.	('level of', 'MPA', (99, 107))	('affects', 'Reg', (30, 37))	('Manipulating', 'Var', (0, 12))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (134, 146))	('PTGR2', 'Gene', '145482', (13, 18))	('PTGR2', 'Gene', (13, 18))	('15-keto-PGE2', 'Chemical', 'MESH:C026346', (70, 82))	('level of', 'MPA', (47, 55))
19551	22450368	For the 88 patients whose cancers had abnormal SLC5A8 expression, median survival was 1.4 years, as compared to 3.9 years in patients whose cancers both expressed high levels of SLC5A8 and lacked nuclear expression.	('expression', 'MPA', (54, 64))	('SLC5A8', 'Gene', (178, 184))	('SLC5A8', 'Gene', '160728', (47, 53))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('abnormal', 'Var', (38, 46))	('SLC5A8', 'Gene', '160728', (178, 184))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('nuclear expression', 'MPA', (196, 214))	('SLC5A8', 'Gene', (47, 53))	('lacked', 'NegReg', (189, 195))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('patients', 'Species', '9606', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('patients', 'Species', '9606', (125, 133))
19552	22450368	SLC5A8 nuclear translocation and loss of expression are associated with poor outcome in pancreatic ductal adenocarcinoma.	('SLC5A8', 'Gene', (0, 6))	('expression', 'MPA', (41, 51))	('pancreatic ductal adenocarcinoma', 'Disease', (88, 120))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (88, 120))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (88, 120))	('SLC5A8', 'Gene', '160728', (0, 6))	('nuclear translocation', 'Var', (7, 28))	('loss of', 'NegReg', (33, 40))
19557	22450368	Abnormal expression of the tumor suppressor gene SLC5A8 may be useful as a prognostic biomarker and is potentially of interest for the development of pancreatic cancer treatments.	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('men', 'Species', '9606', (142, 145))	('SLC5A8', 'Gene', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Disease', (27, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('men', 'Species', '9606', (173, 176))	('expression', 'MPA', (9, 19))	('SLC5A8', 'Gene', '160728', (49, 55))	('Abnormal', 'Var', (0, 8))	('tumor suppressor', 'biological_process', 'GO:0051726', ('27', '43'))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('pancreatic cancer', 'Disease', (150, 167))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('27', '43'))
19561	22450368	We and others have reported that loss of SLC5A8 expression resulting from DNA hypermethylation in the promoter region is associated with prognostic features in cancers of the brain, colon, thyroid, stomach, breast, lung, prostate, and head and neck, as well as acute myeloid leukemia.	('cancers of the brain', 'Disease', 'MESH:D001932', (160, 180))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('74', '94'))	('SLC5A8', 'Gene', '160728', (41, 47))	('lung', 'Disease', (215, 219))	('acute myeloid leukemia', 'Disease', (261, 283))	('prostate', 'Disease', (221, 229))	('neck', 'cellular_component', 'GO:0044326', ('244', '248'))	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('cancers of the brain', 'Disease', (160, 180))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('leukemia', 'Phenotype', 'HP:0001909', (275, 283))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('SLC5A8', 'Gene', (41, 47))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (261, 283))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (267, 283))	('thyroid', 'Disease', (189, 196))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (261, 283))	('colon', 'Disease', 'MESH:D015179', (182, 187))	('cancers of the brain', 'Phenotype', 'HP:0030692', (160, 180))	('associated', 'Reg', (121, 131))	('breast', 'Disease', (207, 213))	('colon', 'Disease', (182, 187))	('stomach', 'Disease', (198, 205))	('loss', 'Var', (33, 37))
19562	22450368	In a previous study, we showed by methylation-specific polymerase chain reaction that SLC5A8 CpG island methylation was infrequent in non-neoplastic pancreas (NNP) (11%) but common in pancreatic cancer (70%), a finding consistent with tumor-specific loss of SLC5A8 expression.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (184, 201))	('neoplastic pancreas', 'Phenotype', 'HP:0002894', (138, 157))	('non-neoplastic pancreas', 'Disease', 'MESH:D010190', (134, 157))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('SLC5A8', 'Gene', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('SLC5A8', 'Gene', '160728', (258, 264))	('SLC5A8', 'Gene', '160728', (86, 92))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('pancreatic cancer', 'Disease', (184, 201))	('tumor', 'Disease', (235, 240))	('methylation', 'Var', (104, 115))	('pancreatic cancer', 'Disease', 'MESH:D010190', (184, 201))	('common', 'Reg', (174, 180))	('non-neoplastic pancreas', 'Disease', (134, 157))	('methylation', 'biological_process', 'GO:0032259', ('104', '115'))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('SLC5A8', 'Gene', (258, 264))
19563	22450368	Using bisulfite sequencing analysis, we also observed that pancreatic cancer cell lines that did not express SLC5A8 were densely methylated in the promoter region.	('pancreatic cancer', 'Disease', 'MESH:D010190', (59, 76))	('methylated', 'Var', (129, 139))	('pancreatic cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('bisulfite', 'Chemical', 'MESH:C042345', (6, 15))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (59, 76))	('SLC5A8', 'Gene', (109, 115))	('SLC5A8', 'Gene', '160728', (109, 115))
19564	22450368	SLC5A8 expression in these cell lines was restored by treatment with the demethylating agent 5-aza-deoxycytidine, implying that SLC5A8 expression is suppressed by aberrant DNA methylation in pancreatic cancer.	('SLC5A8', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('aberrant DNA methylation', 'Var', (163, 187))	('DNA methylation', 'biological_process', 'GO:0006306', ('172', '187'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (191, 208))	('expression', 'MPA', (7, 17))	('SLC5A8', 'Gene', (128, 134))	('SLC5A8', 'Gene', '160728', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('expression', 'MPA', (135, 145))	('pancreatic cancer', 'Disease', (191, 208))	('SLC5A8', 'Gene', '160728', (128, 134))	('pancreatic cancer', 'Disease', 'MESH:D010190', (191, 208))	('suppressed', 'NegReg', (149, 159))	('5-aza-deoxycytidine', 'Chemical', 'MESH:D000077209', (93, 112))	('men', 'Species', '9606', (59, 62))
19565	22450368	In colon and thyroid cancer, hypermethylation in the promoter region of SLC5A8 has been found to be associated with disease progression features, including target tissue invasion, lymphangiogenesis, multifocality, and advanced stage.	('tissue invasion', 'biological_process', 'GO:0001404', ('163', '178'))	('multifocality', 'Disease', (199, 212))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('colon and thyroid cancer', 'Disease', 'MESH:D013964', (3, 27))	('lymphangiogenesis', 'CPA', (180, 197))	('SLC5A8', 'Gene', (72, 78))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('180', '197'))	('associated', 'Reg', (100, 110))	('SLC5A8', 'Gene', '160728', (72, 78))	('target tissue invasion', 'CPA', (156, 178))	('hypermethylation', 'Var', (29, 45))	('thyroid cancer', 'Phenotype', 'HP:0002890', (13, 27))
19611	22450368	Specifically, nuclear SLC5A8 expression was present in 54% (26/48) of cancers with an SLC5A8 score higher than 4, but in only 26% (16/62) of cancers with a low score of 4 or less (P < 0.01).	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SLC5A8', 'Gene', (86, 92))	('score', 'Var', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('SLC5A8', 'Gene', '160728', (86, 92))	('SLC5A8', 'Gene', (22, 28))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (70, 77))	('SLC5A8', 'Gene', '160728', (22, 28))	('cancers', 'Disease', (141, 148))
19623	22450368	For the 88 patients whose cancers had these abnormalities in SLC5A8 expression, median survival was 1.4 years, in contrast to a median survival of 3.9 years in the 22 patients whose cancers both expressed high levels of SLC5A8 and lacked nuclear expression.	('SLC5A8', 'Gene', (220, 226))	('lacked', 'NegReg', (231, 237))	('SLC5A8', 'Gene', '160728', (61, 67))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('patients', 'Species', '9606', (167, 175))	('cancers', 'Disease', (26, 33))	('SLC5A8', 'Gene', '160728', (220, 226))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('SLC5A8', 'Gene', (61, 67))	('cancers', 'Disease', (182, 189))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('patients', 'Species', '9606', (11, 19))	('abnormalities', 'Var', (44, 57))	('nuclear expression', 'MPA', (238, 256))
19624	22450368	In the probability of surviving 3 years in patients with abnormal PDA, SLC5A8 expression was 0.26 (95% CI, 0.15-0.40), as compared to 0.63 (95% CI, 0.34-0.82) in those patients whose cancers had patterns of SLC5A8 expression typical of NNP.	('PDA', 'Gene', (66, 69))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('cancers', 'Disease', (183, 190))	('expression', 'MPA', (78, 88))	('PDA', 'Phenotype', 'HP:0006725', (66, 69))	('patients', 'Species', '9606', (43, 51))	('SLC5A8', 'Gene', (207, 213))	('SLC5A8', 'Gene', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('patients', 'Species', '9606', (168, 176))	('SLC5A8', 'Gene', '160728', (207, 213))	('SLC5A8', 'Gene', '160728', (71, 77))	('abnormal', 'Var', (57, 65))	('expression', 'MPA', (214, 224))	('PDA', 'Chemical', '-', (66, 69))
19627	22450368	We first determined whether any of the 3 characteristics predicting poor survival were associated with abnormal SLC5A8 expression as characterized by loss of SLC5A8 expression alone, nuclear SLC5A8 expression alone, or both.	('SLC5A8', 'Gene', '160728', (158, 164))	('expression', 'MPA', (119, 129))	('abnormal', 'Var', (103, 111))	('SLC5A8', 'Gene', (191, 197))	('expression', 'MPA', (165, 175))	('SLC5A8', 'Gene', (112, 118))	('loss', 'NegReg', (150, 154))	('SLC5A8', 'Gene', '160728', (191, 197))	('SLC5A8', 'Gene', (158, 164))	('SLC5A8', 'Gene', '160728', (112, 118))
19628	22450368	No association was found between abnormal SLC5A8 expression and poor tumor differentiation (P = 0.76), local extrapancreatic extension (P = 1.00), or lymphatic invasion (P = 0.46).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('SLC5A8', 'Gene', (42, 48))	('tumor', 'Disease', (69, 74))	('SLC5A8', 'Gene', '160728', (42, 48))	('expression', 'MPA', (49, 59))	('local extrapancreatic extension', 'CPA', (103, 134))	('abnormal', 'Var', (33, 41))	('lymphatic invasion', 'CPA', (150, 168))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
19629	22450368	We next used a multivariable Cox proportional hazard model to determine whether adjusting for these 3 histopathologic characteristics would change the worse survival predicted by the Kaplan-Meier estimate for abnormal SLC5A8 expression in PDA (Fig.	('abnormal', 'Var', (209, 217))	('SLC5A8', 'Gene', (218, 224))	('PDA', 'Chemical', '-', (239, 242))	('PDA', 'Phenotype', 'HP:0006725', (239, 242))	('expression', 'MPA', (225, 235))	('SLC5A8', 'Gene', '160728', (218, 224))
19631	22450368	SLC5A8 is regarded as a tumor suppressor gene whose expression is silenced by epigenetic changes in a number of cancers, and in a previous study, we found evidence that this is the case in pancreatic adenocarcinoma as well.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('SLC5A8', 'Gene', (0, 6))	('silenced', 'NegReg', (66, 74))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('epigenetic changes', 'Var', (78, 96))	('pancreatic adenocarcinoma', 'Disease', (189, 214))	('tumor', 'Disease', (24, 29))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (189, 214))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('expression', 'MPA', (52, 62))	('SLC5A8', 'Gene', '160728', (0, 6))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (189, 214))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('cancers', 'Disease', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
19634	22450368	Survival in patients whose cancers had either or both abnormalities of SLC5A8 expression was decidedly worse than in patients whose cancers had neither abnormality.	('cancers', 'Disease', (132, 139))	('patients', 'Species', '9606', (12, 20))	('expression', 'MPA', (78, 88))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('worse', 'NegReg', (103, 108))	('Survival', 'MPA', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('abnormalities', 'Var', (54, 67))	('SLC5A8', 'Gene', (71, 77))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('SLC5A8', 'Gene', '160728', (71, 77))	('patients', 'Species', '9606', (117, 125))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (27, 34))
19637	22450368	Li et al suggested that nuclear ING4 may modulate the transactivation of target genes, promoting apoptosis and cell cycle arrest through interactions with p300 and p21.	('interactions', 'Interaction', (137, 149))	('p300', 'Gene', '2033', (155, 159))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (111, 128))	('p21', 'Gene', (164, 167))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('promoting', 'PosReg', (87, 96))	('p21', 'Gene', '644914', (164, 167))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('111', '128'))	('ING4', 'Gene', (32, 36))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('cell cycle arrest', 'CPA', (111, 128))	('transactivation', 'biological_process', 'GO:2000144', ('54', '69'))	('p300', 'Gene', (155, 159))	('ING4', 'Gene', '51147', (32, 36))	('nuclear', 'Var', (24, 31))	('transactivation', 'MPA', (54, 69))	('modulate', 'Reg', (41, 49))	('apoptosis', 'CPA', (97, 106))
19639	22450368	Our findings are consistent with other studies in colon, thyroid, lung, breast, prostate, and oral cancers reporting evidence for loss of SLC5A8 expression by epigenetic silencing and an association with tumor progression.	('colon', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('epigenetic silencing', 'Var', (159, 179))	('oral cancers', 'Disease', 'MESH:D009062', (94, 106))	('SLC5A8', 'Gene', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('oral cancers', 'Disease', (94, 106))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('expression', 'MPA', (145, 155))	('tumor', 'Disease', (204, 209))	('association', 'Interaction', (187, 198))	('colon', 'Disease', 'MESH:D015179', (50, 55))	('SLC5A8', 'Gene', '160728', (138, 144))	('loss', 'NegReg', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
19640	22450368	The proposed function of SLC5A8 as a tumor suppressor gene is based not only on reversible hypermethylation in the promoter region, but also on its association with tumor progression and survival in cancers of the colon and thyroid.	('SLC5A8', 'Gene', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancers of the colon', 'Disease', (199, 219))	('SLC5A8', 'Gene', '160728', (25, 31))	('cancers of the colon', 'Disease', 'MESH:D015179', (199, 219))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', (37, 42))	('association', 'Interaction', (148, 159))	('hypermethylation', 'Var', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))	('tumor', 'Disease', (165, 170))
19641	22450368	Li and colleagues reported that 60% of colon cancers were methylated in the promoter region of SLC5A8, whereas only 5% of normal epithelial specimens were methylated.	('men', 'Species', '9606', (145, 148))	('colon cancer', 'Phenotype', 'HP:0003003', (39, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('methylated', 'Var', (58, 68))	('colon cancers', 'Disease', (39, 52))	('SLC5A8', 'Gene', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('colon cancers', 'Disease', 'MESH:D015179', (39, 52))	('colon cancers', 'Phenotype', 'HP:0003003', (39, 52))	('SLC5A8', 'Gene', '160728', (95, 101))
19642	22450368	Moreover, DNA methylation seems to be an early event in carcinogenesis, as approximately 60% of precursor lesions were methylated in the SLC5A8 promoter region.	('SLC5A8', 'Gene', '160728', (137, 143))	('methylated', 'Var', (119, 129))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('carcinogenesis', 'Disease', 'MESH:D063646', (56, 70))	('carcinogenesis', 'Disease', (56, 70))	('SLC5A8', 'Gene', (137, 143))	('DNA methylation', 'biological_process', 'GO:0006306', ('10', '25'))
19645	22450368	In thyroid cancer, 26% to 50% of tumor tissues were methylated in the SLC5A8 promoter region.	('SLC5A8', 'Gene', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('thyroid cancer', 'Disease', 'MESH:D013964', (3, 17))	('methylated', 'Var', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('SLC5A8', 'Gene', '160728', (70, 76))	('tumor', 'Disease', (33, 38))	('thyroid cancer', 'Disease', (3, 17))	('thyroid cancer', 'Phenotype', 'HP:0002890', (3, 17))
19646	22450368	Porra and colleagues observed that SLC5A8 was methylated in 90% of papillary thyroid carcinomas.	('SLC5A8', 'Gene', (35, 41))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (77, 95))	('papillary thyroid carcinomas', 'Disease', (67, 95))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (67, 95))	('SLC5A8', 'Gene', '160728', (35, 41))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (67, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('methylated', 'Var', (46, 56))
19648	22450368	Hu and colleagues reported that aberrant methylation of SLC5A8 is associated with progression of thyroid cancer, although these results were not replicated in another study.	('aberrant methylation', 'Var', (32, 52))	('thyroid cancer', 'Phenotype', 'HP:0002890', (97, 111))	('SLC5A8', 'Gene', (56, 62))	('thyroid cancer', 'Disease', (97, 111))	('associated with', 'Reg', (66, 81))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('SLC5A8', 'Gene', '160728', (56, 62))	('thyroid cancer', 'Disease', 'MESH:D013964', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
19650	22450368	Ueno and colleagues reported that 30% (23/71) of gastric tumor tissues were methylated in the SLC5A8 promoter, whereas 83% (10/12) of gastric cancer cell lines were found to be methylated.	('gastric tumor', 'Disease', 'MESH:D013274', (49, 62))	('gastric tumor', 'Phenotype', 'HP:0006753', (49, 62))	('gastric cancer', 'Disease', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('SLC5A8', 'Gene', (94, 100))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('methylated', 'Var', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('SLC5A8', 'Gene', '160728', (94, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('gastric tumor', 'Disease', (49, 62))
19656	22450368	For example, loss of heterozygosity at 18q, the locus of Smad4, is a common mechanism for inactivation of Smad4 in pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('loss of heterozygosity', 'Var', (13, 35))	('pancreatic cancer', 'Disease', (115, 132))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('inactivation', 'NegReg', (90, 102))	('Smad4', 'Gene', (57, 62))	('Smad4', 'Gene', '4089', (57, 62))	('Smad4', 'Gene', (106, 111))	('Smad4', 'Gene', '4089', (106, 111))
19658	22450368	In another study, nuclear expression of maspin, a member of the serine protease inhibitors family, has been associated with tumor status and a better prognosis in pancreatic cancer.	('maspin', 'Gene', (40, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (163, 180))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('maspin', 'Gene', '5268', (40, 46))	('tumor', 'Disease', (124, 129))	('pancreatic cancer', 'Disease', 'MESH:D010190', (163, 180))	('associated', 'Reg', (108, 118))	('pancreatic cancer', 'Disease', (163, 180))	('nuclear expression', 'Var', (18, 36))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
19673	22450368	The decidedly worse survival in patients whose cancers had SLC5A8 nuclear translocation, loss of expression or both suggests that abnormal of SLC5A8 expression may be a useful prognostic biomarker for survival after pancreatectomy for PDA.	('abnormal', 'Var', (130, 138))	('SLC5A8', 'Gene', (59, 65))	('patients', 'Species', '9606', (32, 40))	('SLC5A8', 'Gene', (142, 148))	('nuclear translocation', 'MPA', (66, 87))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('PDA', 'Phenotype', 'HP:0006725', (235, 238))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('PDA', 'Chemical', '-', (235, 238))	('SLC5A8', 'Gene', '160728', (59, 65))	('cancers', 'Disease', (47, 54))	('expression', 'MPA', (149, 159))	('SLC5A8', 'Gene', '160728', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('expression', 'MPA', (97, 107))	('loss', 'NegReg', (89, 93))
19679	25239611	By randomly splitting matched samples into a training (n=186) and validation (n=214) set we were able to develop and validate a biomarker panel consisting of CA19.9, CA125 and LAMC2 that significantly improved the performance of CA19.9 alone.	('CA125', 'Gene', (166, 171))	('LAMC2', 'Gene', (176, 181))	('LAMC2', 'Gene', '3918', (176, 181))	('improved', 'PosReg', (201, 209))	('CA19.9', 'Var', (158, 164))	('CA125', 'Gene', '94025', (166, 171))
19688	25239611	The current gold-standard serum biomarker CA19.9 is used in the clinic only for disease monitoring and prognosis, has limited sensitivity in PDAC detection due to its absence in Lewisa-b- individuals (5-10% of Caucasian population), is minimally elevated in early premalignant disease and is elevated in other benign conditions and multiple cancer types.	('premalignant disease', 'Disease', 'MESH:D004194', (264, 284))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('absence', 'NegReg', (167, 174))	('PDAC', 'Chemical', '-', (141, 145))	('CA19.9', 'Var', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('premalignant disease', 'Disease', (264, 284))	('cancer', 'Disease', (341, 347))
19713	25239611	The reduced coefficient models evaluated for diagnostic performance are: (1) CA19.9 + 1.11   CA125, (2) CA19.9 + 0.202   LAMC2, (3) CA19.9 + 1.13   CA125 + 0.143   LAMC2.	('CA125', 'Gene', (93, 98))	('LAMC2', 'Gene', '3918', (164, 169))	('LAMC2', 'Gene', (121, 126))	('LAMC2', 'Gene', '3918', (121, 126))	('CA19.9 + 0.202', 'Var', (104, 118))	('CA125', 'Gene', '94025', (148, 153))	('CA125', 'Gene', '94025', (93, 98))	('LAMC2', 'Gene', (164, 169))	('CA125', 'Gene', (148, 153))
19720	25239611	As shown in Table 2, the AUCs for CA19.9 and CA125 in discriminating all benign from all PDAC samples were comparable in the training (AUCCA19.9= 0.85, AUCCA125=0.77) and validation sets (AUCCA19.9= 0.80, AUCCA125=0.78).	('CA125', 'Gene', (155, 160))	('PDAC', 'Chemical', '-', (89, 93))	('CA125', 'Gene', (208, 213))	('CA19.9', 'Var', (34, 40))	('CA125', 'Gene', '94025', (45, 50))	('CA125', 'Gene', '94025', (155, 160))	('CA125', 'Gene', '94025', (208, 213))	('CA125', 'Gene', (45, 50))
19724	25239611	Based on the ROC analysis in the training set comparing all PDAC (n=111) versus all benign conditions (n=65), the optimum diagnostic cutoff for CA19.9 was 20.3 U/mL (sensitivity 77.5%, specificity 83.1%; Table 2).	('PDAC', 'Disease', (60, 64))	('PDAC', 'Chemical', '-', (60, 64))	('CA19.9', 'Var', (144, 150))
19728	25239611	Our proposed panel significantly improved the performance of CA19.9 in the primary measure (benign vs. all PDAC; Table 2 and Figure 3) as well as the secondary measures (Table 2 and Supplementary Figure 3).The power of distinguishing benign conditions from all PDAC cases increased from AUCCA19.9 = 0.85 to AUCCA19.9+CA125+LAMC2 = 0.93 in the training cohort and from AUCCA19.9=0.80 to AUCCA19.9+CA125+LAMC2= 0.87 in the validation cohort (p<0.005).	('LAMC2', 'Gene', (402, 407))	('increased', 'PosReg', (272, 281))	('LAMC2', 'Gene', (323, 328))	('LAMC2', 'Gene', '3918', (402, 407))	('AUCCA19.9 =', 'Var', (287, 298))	('LAMC2', 'Gene', '3918', (323, 328))	('PDAC', 'Chemical', '-', (107, 111))	('CA125', 'Gene', '94025', (317, 322))	('PDAC', 'Chemical', '-', (261, 265))	('AUCCA19.9=0.80', 'Var', (368, 382))	('CA125', 'Gene', '94025', (396, 401))	('benign conditions', 'Disease', (234, 251))	('CA125', 'Gene', (317, 322))	('CA125', 'Gene', (396, 401))
19735	25239611	In terms of disease detection, CA19.9 is neither very sensitive (it is elevated mainly in late cancer stages and up to 10% of the population genetically negative) nor specific (elevated in non-pancreatic cancers and several benign conditions).	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (193, 210))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('elevated', 'Reg', (177, 185))	('elevated', 'PosReg', (71, 79))	('non-pancreatic cancers', 'Disease', 'MESH:D010190', (189, 211))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (193, 211))	('CA19.9', 'Var', (31, 37))	('benign conditions', 'Disease', (224, 241))	('non-pancreatic cancers', 'Disease', (189, 211))
19751	25239611	In this study we identify and validate a biomarker panel consisting of CA19.9, CA125 and LAMC2 that is better at detecting PDAC patients than CA19.9 alone, most notably at early disease stages.	('CA19.9', 'Var', (71, 77))	('CA125', 'Gene', '94025', (79, 84))	('PDAC', 'Disease', (123, 127))	('LAMC2', 'Gene', (89, 94))	('patients', 'Species', '9606', (128, 136))	('CA125', 'Gene', (79, 84))	('LAMC2', 'Gene', '3918', (89, 94))	('PDAC', 'Chemical', '-', (123, 127))
19754	25239611	For pancreatic cancer, the most widely used marker, CA19.9, lacks the necessary sensitivity and specificity for early detection and is, therefore, only recommended for monitoring response to treatment in patients who had elevated levels prior to treatment.	('pancreatic cancer', 'Disease', (4, 21))	('lacks', 'NegReg', (60, 65))	('patients', 'Species', '9606', (204, 212))	('pancreatic cancer', 'Disease', 'MESH:D010190', (4, 21))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (4, 21))	('CA19.9', 'Var', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
19762	23992306	In addition, the levels of phospho-Akt and phospho-NF-kappaB in BxPC-3 and Panc-1 cells were reduced by both resveratrol and LY294002 (a PI3-K inhibitor).	('LY294002', 'Chemical', 'MESH:C085911', (125, 133))	('LY294002', 'Var', (125, 133))	('reduced', 'NegReg', (93, 100))	('NF-kappaB', 'Gene', '4790', (51, 60))	('Panc-1', 'CellLine', 'CVCL:0480', (75, 81))	('Akt', 'Gene', '207', (35, 38))	('BxPC-3', 'CellLine', 'CVCL:0186', (64, 70))	('levels', 'MPA', (17, 23))	('NF-kappaB', 'Gene', (51, 60))	('resveratrol', 'Chemical', 'MESH:D000077185', (109, 120))	('PI3-K', 'molecular_function', 'GO:0016303', ('137', '142'))	('Akt', 'Gene', (35, 38))
19790	23992306	The anti-Akt, anti-phospho-Akt (Ser473), anti-NF-kappaB, and anti-phospho-NF-kappaB (Ser468) antibodies were obtained from Cell Signaling Technology (Beverly, MA, USA).	('NF-kappaB', 'Gene', (46, 55))	('Akt', 'Gene', (9, 12))	('NF-kappaB', 'Gene', (74, 83))	('Ser473', 'Var', (32, 38))	('Ser473', 'Chemical', '-', (32, 38))	('Signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('Akt', 'Gene', '207', (27, 30))	('Ser468', 'Chemical', '-', (85, 91))	('Ser', 'cellular_component', 'GO:0005790', ('85', '88'))	('NF-kappaB', 'Gene', '4790', (46, 55))	('Akt', 'Gene', (27, 30))	('Ser', 'cellular_component', 'GO:0005790', ('32', '35'))	('NF-kappaB', 'Gene', '4790', (74, 83))	('Akt', 'Gene', '207', (9, 12))
19827	23992306	Moreover, a PI-3K inhibitor, LY294002, could also inhibit the expression of p-Akt and p-NF-kappaB, indicating that the NF-kappaB transcription factor is modulated by the PI-3K/Akt pathway (Fig.	('PI-3', 'Gene', (12, 16))	('NF-kappaB', 'Gene', (88, 97))	('Akt', 'Gene', (78, 81))	('NF-kappaB', 'Gene', '4790', (88, 97))	('LY294002', 'Chemical', 'MESH:C085911', (29, 37))	('modulated', 'Reg', (153, 162))	('PI-3', 'Gene', '5266', (170, 174))	('PI-3', 'Gene', '5266', (12, 16))	('Akt', 'Gene', '207', (78, 81))	('NF-kappaB', 'Gene', (119, 128))	('PI-3K', 'molecular_function', 'GO:0016303', ('12', '17'))	('transcription factor', 'molecular_function', 'GO:0000981', ('129', '149'))	('NF-kappaB', 'Gene', '4790', (119, 128))	('expression', 'MPA', (62, 72))	('PI-3', 'Gene', (170, 174))	('Akt', 'Gene', (176, 179))	('inhibit', 'NegReg', (50, 57))	('PI-3K', 'molecular_function', 'GO:0016303', ('170', '175'))	('LY294002', 'Var', (29, 37))	('transcription', 'biological_process', 'GO:0006351', ('129', '142'))	('Akt', 'Gene', '207', (176, 179))
19828	23992306	To assess whether the PI-3K/Akt signaling pathway plays an important role in pancreatic cancer metastasis, the effect of LY294002 on pancreatic cancer cell motility and invasion was determined by wound-healing and transwell invasion assays, respectively.	('pancreatic cancer metastasis', 'Disease', 'MESH:D009362', (77, 105))	('PI-3', 'Gene', '5266', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PI-3K', 'molecular_function', 'GO:0016303', ('22', '27'))	('cell motility', 'biological_process', 'GO:0048870', ('151', '164'))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('wound-healing', 'biological_process', 'GO:0042060', ('196', '209'))	('LY294002', 'Var', (121, 129))	('Akt signaling', 'biological_process', 'GO:0043491', ('28', '41'))	('Akt', 'Gene', (28, 31))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (133, 150))	('pancreatic cancer metastasis', 'Disease', (77, 105))	('pancreatic cancer cell motility', 'Disease', (133, 164))	('LY294002', 'Chemical', 'MESH:C085911', (121, 129))	('Akt', 'Gene', '207', (28, 31))	('signaling pathway', 'biological_process', 'GO:0007165', ('32', '49'))	('pancreatic cancer cell motility', 'Disease', 'MESH:D010190', (133, 164))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('PI-3', 'Gene', (22, 26))
19829	23992306	5A) ability was significantly inhibited 24 h after the addition of LY294002.	('LY294002', 'Chemical', 'MESH:C085911', (67, 75))	('inhibited', 'NegReg', (30, 39))	('LY294002', 'Var', (67, 75))
19830	23992306	Additionally, the average cell number that invaded into the lower chamber decreased with LY294002 treatment (Fig.	('LY294002', 'Var', (89, 97))	('decreased', 'NegReg', (74, 83))	('cell number that invaded into the lower chamber', 'CPA', (26, 73))	('LY294002', 'Chemical', 'MESH:C085911', (89, 97))
19864	23992306	showed that increased insulin-like growth factor I receptor expression induced by active Akt markedly enhances the invasiveness of human pancreatic cancer cells.	('expression', 'MPA', (60, 70))	('active', 'Var', (82, 88))	('Akt', 'Gene', '207', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('enhances', 'PosReg', (102, 110))	('increased', 'PosReg', (12, 21))	('human', 'Species', '9606', (131, 136))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (137, 154))	('factor I', 'molecular_function', 'GO:0003818', ('42', '50'))	('Akt', 'Gene', (89, 92))	('pancreatic cancer', 'Disease', (137, 154))	('pancreatic cancer', 'Disease', 'MESH:D010190', (137, 154))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('22', '48'))	('insulin-like growth factor I receptor', 'Protein', (22, 59))
19869	23992306	After suppressing the PI-3K/Akt signaling pathway by LY249002, the expression of p-Akt and p-NF-kappaB as well as the invasion and migration ability of both BxPC-3 and Panc-1 pancreatic cancer cells were decreased.	('pancreatic cancer', 'Disease', (175, 192))	('suppressing', 'NegReg', (6, 17))	('PI-3', 'Gene', '5266', (22, 26))	('PI-3K', 'molecular_function', 'GO:0016303', ('22', '27'))	('Akt signaling', 'biological_process', 'GO:0043491', ('28', '41'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (175, 192))	('BxPC-3', 'CellLine', 'CVCL:0186', (157, 163))	('NF-kappaB', 'Gene', (93, 102))	('Akt', 'Gene', (28, 31))	('LY249002', 'Var', (53, 61))	('Akt', 'Gene', (83, 86))	('LY249002', 'Chemical', '-', (53, 61))	('NF-kappaB', 'Gene', '4790', (93, 102))	('decreased', 'NegReg', (204, 213))	('Akt', 'Gene', '207', (83, 86))	('Akt', 'Gene', '207', (28, 31))	('pancreatic cancer', 'Disease', 'MESH:D010190', (175, 192))	('signaling pathway', 'biological_process', 'GO:0007165', ('32', '49'))	('Panc-1', 'CellLine', 'CVCL:0480', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('PI-3', 'Gene', (22, 26))	('expression', 'MPA', (67, 77))
19906	24267969	PTV90 and PTV80 were adjusted to avoid the jejunum, bowel, and stomach by 3 mm to generate the final volumes, PTV90-final and PTV80-final.	('PTV', 'Chemical', '-', (0, 3))	('PTV80-final', 'Var', (126, 137))	('PTV', 'Chemical', '-', (126, 129))	('PTV', 'cellular_component', 'GO:1990257', ('110', '113'))	('PTV', 'Chemical', '-', (10, 13))	('bowel', 'Disease', 'MESH:D015212', (52, 57))	('PTV90-final', 'Var', (110, 121))	('PTV', 'Chemical', '-', (110, 113))	('bowel', 'Disease', (52, 57))	('PTV', 'cellular_component', 'GO:1990257', ('126', '129'))	('PTV', 'cellular_component', 'GO:1990257', ('0', '3'))	('PTV', 'cellular_component', 'GO:1990257', ('10', '13'))
19919	24267969	The percentage of patients experiencing local recurrence was significantly greater in patients receiving CTA than in those receiving CRT (65% vs 38%, P = .007).	('CTA', 'Var', (105, 108))	('patients', 'Species', '9606', (18, 26))	('CTA', 'Chemical', '-', (105, 108))	('local recurrence', 'CPA', (40, 56))	('patients', 'Species', '9606', (86, 94))
19923	24267969	An institution-dependent expansion could be created, if necessary, on both CTV80 and CTV90 to generate PTV80 and PTV90.	('PTV90', 'Var', (113, 118))	('CTV90', 'Gene', (85, 90))	('CTV80', 'Gene', (75, 80))	('PTV80', 'Var', (103, 108))	('PTV', 'cellular_component', 'GO:1990257', ('113', '116'))	('PTV', 'Chemical', '-', (103, 106))	('PTV', 'Chemical', '-', (113, 116))	('PTV', 'cellular_component', 'GO:1990257', ('103', '106'))
19964	23425074	Research now indicates that CXCR2 and its ligands are intimately involved in tumor regulation and growth and that inhibition of its function shows promising results in multiple cancer types, including pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (201, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('regulation', 'biological_process', 'GO:0065007', ('83', '93'))	('pancreatic cancer', 'Disease', (201, 218))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('pancreatic cancer', 'Disease', 'MESH:D010190', (201, 218))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('inhibition', 'Var', (114, 124))	('tumor', 'Disease', (77, 82))	('results', 'Reg', (157, 164))
20040	23425074	CXCR2 is also thought to be important for wound healing in the periphery via neutrophil recruitment and there is evidence that CXCR2 may have differing functions depending on location as Cxcr2-/- mice can still localize neutrophils to the CNS in response to inflammatory demyelination similar to wild-type mice.	('inflammatory demyelination', 'Phenotype', 'HP:0011096', (258, 284))	('mice', 'Species', '10090', (196, 200))	('wound healing', 'biological_process', 'GO:0042060', ('42', '55'))	('demyelination', 'Disease', (271, 284))	('demyelination', 'Disease', 'MESH:D003711', (271, 284))	('mice', 'Species', '10090', (306, 310))	('localize', 'MPA', (211, 219))	('Cxcr2-/-', 'Var', (187, 195))
20044	23425074	In an animal model of COPD, inhibition of CXCR2 leads to decreased mucous secretion as well as decreased goblet cell hyperplasia.	('decreased', 'NegReg', (95, 104))	('goblet cell hyperplasia', 'Disease', 'MESH:D002276', (105, 128))	('CXCR2', 'MPA', (42, 47))	('goblet cell hyperplasia', 'Disease', (105, 128))	('COPD', 'Disease', (22, 26))	('inhibition', 'Var', (28, 38))	('mucous secretion', 'MPA', (67, 83))	('decreased', 'NegReg', (57, 66))	('COPD', 'Phenotype', 'HP:0006510', (22, 26))	('COPD', 'Disease', 'MESH:D029424', (22, 26))
20050	23425074	However, blocking CXCR2 in sepsis led to decreased liver injury and mortality in a mouse model, but did not affect bacterial clearance.	('decreased liver', 'Phenotype', 'HP:0001410', (41, 56))	('mouse', 'Species', '10090', (83, 88))	('sepsis', 'Phenotype', 'HP:0100806', (27, 33))	('sepsis', 'Disease', (27, 33))	('mortality', 'CPA', (68, 77))	('decreased liver injury', 'Disease', (41, 63))	('sepsis', 'Disease', 'MESH:D018805', (27, 33))	('blocking', 'Var', (9, 17))	('decreased liver injury', 'Disease', 'MESH:D056486', (41, 63))
20054	23425074	Inhibiting CXCR2 in a kidney transplant model reduces neutrophil accumulation and maintains function of the graft in ischemia/reperfusion models.	('ischemia', 'Disease', 'MESH:D007511', (117, 125))	('Inhibiting', 'Var', (0, 10))	('ischemia', 'Disease', (117, 125))	('reduces', 'NegReg', (46, 53))	('function', 'MPA', (92, 100))	('neutrophil accumulation', 'MPA', (54, 77))
20056	23425074	Multiple sclerosis, traumatic brain injury (TBI) and AD are all associated with presence of chemokines and chemokine receptors.	('traumatic brain injury', 'Disease', (20, 42))	('associated', 'Reg', (64, 74))	('TBI', 'Disease', (44, 47))	('traumatic brain injury', 'Disease', 'MESH:D000070642', (20, 42))	('AD', 'Phenotype', 'HP:0002511', (53, 55))	('AD', 'Disease', 'MESH:D000544', (53, 55))	('AD', 'Disease', (53, 55))	('Multiple sclerosis', 'Disease', 'MESH:D009103', (0, 18))	('Multiple sclerosis', 'Disease', (0, 18))	('presence', 'Var', (80, 88))	('chemokine receptor', 'Gene', '7852', (107, 125))	('TBI', 'Disease', 'MESH:D000070642', (44, 47))	('chemokine receptor', 'Gene', (107, 125))
20067	23425074	In addition, blockade of ELR+ CXC chemokines and CXCR2 reduces tumorigenesis/angiogenesis in lung, esophageal, renal cell, colon and pancreatic cancers.	('tumor', 'Disease', (63, 68))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (133, 151))	('esophageal', 'Disease', (99, 109))	('colon and pancreatic cancers', 'Disease', 'MESH:D010190', (123, 151))	('blockade', 'Var', (13, 21))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (133, 150))	('lung', 'Disease', (93, 97))	('reduces', 'NegReg', (55, 62))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('angiogenesis', 'biological_process', 'GO:0001525', ('77', '89'))	('renal cell', 'Disease', (111, 121))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
20071	23425074	Interestingly, these experiments bring up a fascinating issue that links CXCR2 and other chemokines and possibly chemokine receptors to the importance of the tumor environment and myeloid cells in the promotion of tumor development, as the dominant cell type of CXCR2 expression in the blood in these experiments were shown to be Ly6G+ neutrophils and that deficiency of CXCR2 attenuated neutrophil recruitment and decreased tumor-associated leukocytes.	('attenuated', 'NegReg', (377, 387))	('tumor', 'Disease', (425, 430))	('tumor', 'Disease', (158, 163))	('chemokine receptor', 'Gene', '7852', (113, 131))	('decreased', 'NegReg', (415, 424))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('chemokine receptor', 'Gene', (113, 131))	('deficiency', 'Var', (357, 367))	('neutrophil recruitment', 'CPA', (388, 410))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (425, 430))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (425, 430))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
20089	23425074	Using a pancreatic cancer model based on transgenic mice harboring a pancreas epithelium-specific knockout of transcription growth factor beta (TGFbeta) type II receptor in the context of active Kras expression (Kras+Tgfbr2-KO) Ijichi et al.	('Tgfbr2', 'Gene', '21813', (217, 223))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (8, 25))	('knockout', 'Var', (98, 106))	('transcription growth factor beta (TGFbeta) type II receptor', 'Gene', '21813', (110, 169))	('Tgfbr2', 'Gene', (217, 223))	('pancreatic cancer', 'Disease', (8, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('pancreatic cancer', 'Disease', 'MESH:D010190', (8, 25))	('transcription', 'biological_process', 'GO:0006351', ('110', '123'))	('transgenic mice', 'Species', '10090', (41, 56))
20097	23425074	Furthermore, inhibition of CXCR2 in addition to gemcitabine treatment also showed evidence of increase in overall survival with decreased tumor volume via inhibition of angiogenesis along with decreased macrophage and neutrophil migration into PDAC tissues, although with no advantage over CXCR inhibition or gemcitabine treatment alone.	('inhibition', 'NegReg', (155, 165))	('angiogenesis', 'CPA', (169, 181))	('tumor', 'Disease', (138, 143))	('increase', 'PosReg', (94, 102))	('PDAC', 'Chemical', '-', (244, 248))	('inhibition', 'Var', (13, 23))	('gemcitabine', 'Chemical', 'MESH:C056507', (309, 320))	('gemcitabine', 'Chemical', 'MESH:C056507', (48, 59))	('decreased', 'NegReg', (128, 137))	('PDAC', 'Phenotype', 'HP:0006725', (244, 248))	('overall survival', 'CPA', (106, 122))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('decreased', 'NegReg', (193, 202))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
20105	23425074	It is clear that CXCR2 and its chemokines are an intriguing target for preventing angiogenesis as blockade of CXCR2 with either broad spectrum GPCR antagonist or CXCR2 antibody blocks pancreatic cancer angiogenesis, but the mechanism by which this axis encourages angiogenesis and cancer progression remains unclear.	('antibody', 'cellular_component', 'GO:0019814', ('168', '176'))	('angiogenesis', 'biological_process', 'GO:0001525', ('264', '276'))	('antibody blocks pancreatic cancer', 'Disease', 'MESH:D010190', (168, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('angiogenesis', 'biological_process', 'GO:0001525', ('82', '94'))	('GPCR', 'Gene', '441931', (143, 147))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (184, 201))	('blockade', 'Var', (98, 106))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('antibody', 'molecular_function', 'GO:0003823', ('168', '176'))	('antibody', 'cellular_component', 'GO:0042571', ('168', '176'))	('cancer', 'Disease', (195, 201))	('antibody', 'cellular_component', 'GO:0019815', ('168', '176'))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('angiogenesis', 'biological_process', 'GO:0001525', ('202', '214'))	('cancer', 'Disease', (281, 287))	('antibody blocks pancreatic cancer', 'Disease', (168, 201))	('GPCR', 'Gene', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
20110	23425074	Some information related to this question may come from signaling downstream of the Kras oncogene as activated Kras mutations enhance production of angiogenic factors (including CXC chemokines and VEGF) in immortalized pancreatic epithelial cell systems, and blocking of MEK signaling inhibits production of chemokines.	('VEGF', 'Gene', '7422', (197, 201))	('pancreatic epithelial', 'Disease', (219, 240))	('MEK', 'Gene', (271, 274))	('enhance', 'PosReg', (126, 133))	('signaling', 'biological_process', 'GO:0023052', ('275', '284'))	('inhibits', 'NegReg', (285, 293))	('MEK', 'Gene', '5609', (271, 274))	('VEGF', 'Gene', (197, 201))	('pancreatic epithelial', 'Disease', 'MESH:D010195', (219, 240))	('production of chemokines', 'MPA', (294, 318))	('mutations', 'Var', (116, 125))	('Kras', 'Gene', (111, 115))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))
20117	23425074	showed that CXCL1/2 is hyperactivated in breast cancer cell lines by chemotherapy and that blocking CXCR2 in conjunction with chemotherapeutic agents could markedly reduce lung metastases in xenograft-implanted mice (using metastatic breast cancer cell lines).	('lung metastases', 'Disease', (172, 187))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('lung metastases', 'Disease', 'MESH:D009362', (172, 187))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('hyperactivated', 'PosReg', (23, 37))	('CXCR2', 'MPA', (100, 105))	('breast cancer', 'Disease', (234, 247))	('CXCL1/2', 'Gene', '20315;14825;20310', (12, 19))	('reduce', 'NegReg', (165, 171))	('CXCL1/2', 'Gene', (12, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('mice', 'Species', '10090', (211, 215))	('blocking', 'Var', (91, 99))
20122	23425074	However, although NSAIDs have been reported to be associated with a reduced risk for multiple malignancies, pancreatic cancer was not among them.	('NSAIDs', 'Var', (18, 24))	('pancreatic cancer', 'Disease', (108, 125))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('multiple malignancies', 'Disease', 'MESH:D009369', (85, 106))	('multiple malignancies', 'Disease', (85, 106))	('reduced', 'NegReg', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))
20132	23425074	Finally, in many studies, antibodies of IL-8/CXCL8 and Gro-alpha or CXCR2 have been shown to inhibit growth of Capan-1 cells or to inhibit tumor growth in other studies.	('inhibit', 'NegReg', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('inhibit', 'NegReg', (131, 138))	('antibodies', 'Var', (26, 36))	('Capan-1', 'CellLine', 'CVCL:0237', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('growth', 'CPA', (101, 107))	('IL-8', 'molecular_function', 'GO:0005153', ('40', '44'))	('IL-8/CXCL8', 'Gene', (40, 50))
20146	23425074	CXCR2 and its ligands induce cellular senescence during early tumorigenesis, such that further understanding of at which point of tumorigenesis CXCR2 and its ligands become cancer-promoting rather than cancer-inhibiting warrants investigation.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cancer', 'Disease', (173, 179))	('CXCR2', 'Var', (144, 149))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('cellular senescence', 'biological_process', 'GO:0090398', ('29', '48'))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Disease', (202, 208))	('cellular senescence', 'MPA', (29, 48))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
20150	23425074	It has also been proposed that single nucleotide polymorphisms (SNP) of CXCR2 may play a role in pancreatic cancer, and although none have been yet identified in pancreatic cancer patients, this possibility introduces the intriguing idea that some as yet unknown alteration of CXCR2 may also be implicated in its role in pancreatic cancer growth as SNP have been identified in CF patients that are correlated with lung dysfunction.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (321, 338))	('patients', 'Species', '9606', (380, 388))	('patients', 'Species', '9606', (180, 188))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (97, 114))	('implicated', 'Reg', (295, 305))	('pancreatic cancer', 'Disease', 'MESH:D010190', (162, 179))	('pancreatic cancer', 'Disease', 'MESH:D010190', (321, 338))	('pancreatic cancer', 'Disease', (162, 179))	('pancreatic cancer', 'Disease', 'MESH:D010190', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('CF', 'Disease', 'MESH:D003550', (377, 379))	('pancreatic cancer', 'Disease', (321, 338))	('lung dysfunction', 'Phenotype', 'HP:0005952', (414, 430))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('single nucleotide polymorphisms', 'Var', (31, 62))	('lung dysfunction', 'Disease', (414, 430))	('pancreatic cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (162, 179))	('lung dysfunction', 'Disease', 'MESH:D008171', (414, 430))
20159	23425074	Inhibition of the CXCR2 axis leads to decreased angiogenesis, attenuates pancreatic cancer progression and reduces tumor volume in mouse models.	('decreased', 'NegReg', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('pancreatic cancer', 'Disease', (73, 90))	('attenuates', 'NegReg', (62, 72))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('mouse', 'Species', '10090', (131, 136))	('tumor', 'Disease', (115, 120))	('reduces', 'NegReg', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Inhibition', 'Var', (0, 10))	('angiogenesis', 'biological_process', 'GO:0001525', ('48', '60'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))	('angiogenesis', 'CPA', (48, 60))
20160	23547054	GSK-3alpha Promotes Oncogenic KRAS Function in Pancreatic Cancer via TAK1-TAB Stabilization and Regulation of Non-Canonical NF-kappaB Mutations in KRAS drive the oncogenic phenotype in a variety of tumors of epithelial origin.	('Pancreatic Cancer', 'Disease', (47, 64))	('oncogenic', 'CPA', (162, 171))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (47, 64))	('drive', 'PosReg', (152, 157))	('tumors', 'Disease', (198, 204))	('KRAS', 'Gene', (30, 34))	('KRAS', 'Gene', (147, 151))	('TAK1', 'Gene', '6885', (69, 73))	('KRAS', 'Gene', '3845', (147, 151))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('TAK1', 'Gene', (69, 73))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('GSK-3alpha', 'Gene', (0, 10))	('Mutations', 'Var', (134, 143))	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (47, 64))	('GSK-3alpha', 'Gene', '2931', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('KRAS', 'Gene', '3845', (30, 34))
20167	23547054	Numerous epithelial-derived cancers express mutated/activated KRAS, and many of these cancers depend upon KRAS-induced signaling for regulation of growth, survival and metabolism.	('cancers', 'Disease', (28, 35))	('KRAS', 'Gene', '3845', (106, 110))	('KRAS', 'Gene', (62, 66))	('mutated/activated', 'Var', (44, 61))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('KRAS', 'Gene', '3845', (62, 66))	('regulation of growth', 'biological_process', 'GO:0040008', ('133', '153'))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('metabolism', 'biological_process', 'GO:0008152', ('168', '178'))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('depend', 'Reg', (94, 100))	('KRAS', 'Gene', (106, 110))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))
20168	23547054	For example, the great majority of pancreatic ductal adenocarcinomas (PDAC) exhibit mutations in KRAS.	('KRAS', 'Gene', (97, 101))	('KRAS', 'Gene', '3845', (97, 101))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (35, 68))	('exhibit', 'Reg', (76, 83))	('mutations', 'Var', (84, 93))	('PDAC', 'Chemical', '-', (70, 74))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (35, 67))	('pancreatic ductal adenocarcinomas', 'Disease', (35, 68))
20169	23547054	However, specific targeting of mutant oncogenic KRAS has been a therapeutic challenge.	('mutant', 'Var', (31, 37))	('KRAS', 'Gene', (48, 52))	('KRAS', 'Gene', '3845', (48, 52))
20183	23547054	Previous work has demonstrated that constitutive NF-kappaB activity is dependent upon IKK in pancreatic cancer cell lines and knockout of IKKbeta suppresses tumor growth/progression in a KRAS/INK4a null animal model of pancreatic cancer.	('KRAS', 'Gene', (187, 191))	('pancreatic cancer', 'Disease', 'MESH:D010190', (93, 110))	('INK4a', 'Gene', '1029', (192, 197))	('IKKbeta', 'Gene', '3551', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('suppresses', 'NegReg', (146, 156))	('pancreatic cancer', 'Disease', 'MESH:D010190', (219, 236))	('pancreatic cancer', 'Disease', (93, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('IKKbeta', 'Gene', (138, 145))	('pancreatic cancer', 'Disease', (219, 236))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (93, 110))	('activity', 'MPA', (59, 67))	('tumor', 'Disease', (157, 162))	('NF-kappaB', 'Protein', (49, 58))	('INK4a', 'Gene', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('IKK', 'molecular_function', 'GO:0008384', ('86', '89'))	('KRAS', 'Gene', '3845', (187, 191))	('knockout', 'Var', (126, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (219, 236))
20196	23547054	Here we investigate the roles of GSK-3alpha, GSK-3beta, and TAK1 downstream of mutant KRAS in driving constitutive NF-kappaB signaling, proliferation and survival in pancreatic cancer cells.	('GSK-3alpha', 'Gene', '2931', (33, 43))	('KRAS', 'Gene', (86, 90))	('GSK-3beta', 'Gene', (45, 54))	('GSK-3beta', 'Gene', '2932', (45, 54))	('mutant', 'Var', (79, 85))	('GSK-3alpha', 'Gene', (33, 43))	('KRAS', 'Gene', '3845', (86, 90))	('pancreatic cancer', 'Disease', (166, 183))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (166, 183))	('GSK', 'molecular_function', 'GO:0050321', ('45', '48'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (166, 183))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('constitutive NF-kappaB signaling', 'MPA', (102, 134))	('GSK', 'molecular_function', 'GO:0050321', ('33', '36'))
20201	23547054	Consistent with previous reports, we observed a decrease in proliferation of two well characterized KRAS+ pancreatic cancer cell lines, Panc-1 and MiaPaCa-2, upon treatment with the selective GSK-3 inhibitor, AR-A014418 in a dose dependent manner (Fig.	('KRAS', 'Gene', (100, 104))	('pancreatic cancer', 'Disease', 'MESH:D010190', (106, 123))	('GSK-3', 'Gene', (192, 197))	('KRAS', 'Gene', '3845', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Panc-1', 'CellLine', 'CVCL:0480', (136, 142))	('AR-A014418', 'Var', (209, 219))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (147, 156))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (106, 123))	('GSK-3', 'Gene', '56637', (192, 197))	('decrease', 'NegReg', (48, 56))	('proliferation', 'CPA', (60, 73))	('AR-A014418', 'Chemical', 'MESH:C479831', (209, 219))	('GSK', 'molecular_function', 'GO:0050321', ('192', '195'))	('pancreatic cancer', 'Disease', (106, 123))
20209	23547054	Consistent with previous reports, GSK-3 inhibition suppressed phosphorylation of IKK and of RelA/p65 (Fig.	('inhibition', 'Var', (40, 50))	('IKK', 'molecular_function', 'GO:0008384', ('81', '84'))	('IKK', 'Protein', (81, 84))	('GSK-3', 'Gene', (34, 39))	('p65', 'Gene', '5970', (97, 100))	('phosphorylation', 'MPA', (62, 77))	('GSK-3', 'Gene', '56637', (34, 39))	('RelA', 'Gene', '5970', (92, 96))	('GSK', 'molecular_function', 'GO:0050321', ('34', '37'))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))	('suppressed', 'NegReg', (51, 61))	('p65', 'Gene', (97, 100))	('RelA', 'Gene', (92, 96))
20210	23547054	Interestingly GSK-3 inhibition also decreased the levels of TAK1, upstream IKK kinase.	('IKK', 'molecular_function', 'GO:0008384', ('75', '78'))	('GSK-3', 'Gene', (14, 19))	('inhibition', 'Var', (20, 30))	('TAK1', 'MPA', (60, 64))	('levels', 'MPA', (50, 56))	('GSK-3', 'Gene', '56637', (14, 19))	('GSK', 'molecular_function', 'GO:0050321', ('14', '17'))	('decreased', 'NegReg', (36, 45))
20212	23547054	To determine whether TAK1 is active in pancreatic cancer cell lines, we examined the status of TAK1- TAB1 binding in pancreatic cancer cells and questioned if mutant KRAS affects TAK1-TAB1 interaction.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (39, 56))	('interaction', 'Interaction', (189, 200))	('binding', 'Interaction', (106, 113))	('mutant', 'Var', (159, 165))	('pancreatic cancer', 'Disease', (117, 134))	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('KRAS', 'Gene', (166, 170))	('affects', 'Reg', (171, 178))	('binding', 'molecular_function', 'GO:0005488', ('106', '113'))	('KRAS', 'Gene', '3845', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('pancreatic cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('pancreatic cancer', 'Disease', 'MESH:D010190', (39, 56))
20215	23547054	2A) indicating that mutant KRAS promotes TAK1-TAB1 interaction.	('TAK1-TAB1', 'Protein', (41, 50))	('KRAS', 'Gene', '3845', (27, 31))	('interaction', 'Interaction', (51, 62))	('promotes', 'PosReg', (32, 40))	('mutant', 'Var', (20, 26))	('KRAS', 'Gene', (27, 31))
20217	23547054	These data demonstrate that mutant KRAS drives constitutive TAK1 activity in pancreatic cancer cell lines via stabilizing TAK1.	('activity', 'MPA', (65, 73))	('stabilizing', 'MPA', (110, 121))	('drives', 'PosReg', (40, 46))	('KRAS', 'Gene', (35, 39))	('mutant', 'Var', (28, 34))	('TAK1', 'Protein', (122, 126))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('KRAS', 'Gene', '3845', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('pancreatic cancer', 'Disease', (77, 94))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
20219	23547054	siRNA mediated TAK1 knockdown resulted in diminished phosphorylation of IkappaBalpha (Serine 32/36), stabilization of total IkappaBalpha levels and reduced phosphorylation of p65/RelA, indicating reduced canonical NF-kappaB activation (Fig.	('canonical', 'MPA', (204, 213))	('phosphorylation', 'biological_process', 'GO:0016310', ('156', '171'))	('IkappaBalpha', 'Gene', (72, 84))	('RelA', 'Gene', (179, 183))	('diminished', 'NegReg', (42, 52))	('TAK1', 'Gene', (15, 19))	('knockdown', 'Var', (20, 29))	('IkappaBalpha', 'Gene', '4792', (72, 84))	('IkappaBalpha', 'Gene', (124, 136))	('RelA', 'Gene', '5970', (179, 183))	('activation', 'PosReg', (224, 234))	('IkappaBalpha', 'Gene', '4792', (124, 136))	('phosphorylation', 'MPA', (53, 68))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('214', '234'))	('p65', 'Gene', (175, 178))	('phosphorylation', 'MPA', (156, 171))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))	('reduced', 'NegReg', (196, 203))	('reduced', 'NegReg', (148, 155))	('Serine', 'Chemical', 'MESH:D012694', (86, 92))	('p65', 'Gene', '5970', (175, 178))
20222	23547054	siRNA mediated TAK1 depletion significantly reduced the cell index of MiaPaCa-2 cells relative to the non-targeting control throughout the time-course in an MTS assay (Fig.	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (70, 79))	('depletion', 'Var', (20, 29))	('reduced', 'NegReg', (44, 51))	('TAK1', 'Gene', (15, 19))	('cell index', 'MPA', (56, 66))
20224	23547054	Importantly, this effect of TAK1 depletion was specific to cells harboring mutant KRAS, as knockdown of TAK1 did not decrease cell proliferation in HPDE6 cells unlike HPDEKR+ (Fig.	('cell proliferation', 'CPA', (126, 144))	('TAK1', 'Gene', (104, 108))	('cell proliferation', 'biological_process', 'GO:0008283', ('126', '144'))	('mutant', 'Var', (75, 81))	('KRAS', 'Gene', (82, 86))	('HPDE6', 'CellLine', 'CVCL:4376', (148, 153))	('KRAS', 'Gene', '3845', (82, 86))
20228	23547054	Again the inhibitory effect of TAK1 inhibitor on cell proliferation was specific to mutant KRAS harboring cells.	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('TAK1', 'Gene', (31, 35))	('cell proliferation', 'CPA', (49, 67))	('mutant', 'Var', (84, 90))	('inhibitory effect', 'NegReg', (10, 27))	('KRAS', 'Gene', (91, 95))	('KRAS', 'Gene', '3845', (91, 95))
20234	23547054	Overall, these data suggest that TAK1 is active downstream of mutant KRAS in pancreatic cancer cells and mediates constitutive NF-kappaB signaling to regulate proliferation by altering cell cycle progression.	('KRAS', 'Gene', (69, 73))	('cell cycle progression', 'CPA', (185, 207))	('mutant', 'Var', (62, 68))	('KRAS', 'Gene', '3845', (69, 73))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('constitutive NF-kappaB signaling', 'MPA', (114, 146))	('proliferation', 'CPA', (159, 172))	('cell cycle', 'biological_process', 'GO:0007049', ('185', '195'))	('regulate', 'Reg', (150, 158))	('altering', 'Reg', (176, 184))	('signaling', 'biological_process', 'GO:0023052', ('137', '146'))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('TAK1', 'Gene', (33, 37))	('pancreatic cancer', 'Disease', (77, 94))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
20241	23547054	To determine if the loss in TAK1 protein levels is due to proteasome-dependent degradation, Panc-1 and MiaPaCa-2 cells were treated with AR-A014418 in the presence of proteasome inhibitor (MG-132).	('proteasome', 'cellular_component', 'GO:0000502', ('167', '177'))	('AR-A014418', 'Chemical', 'MESH:C479831', (137, 147))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (103, 112))	('proteasome', 'molecular_function', 'GO:0004299', ('58', '68'))	('AR-A014418', 'Var', (137, 147))	('protein levels', 'MPA', (33, 47))	('TAK1', 'Gene', (28, 32))	('proteasome', 'cellular_component', 'GO:0000502', ('58', '68'))	('loss', 'NegReg', (20, 24))	('Panc-1', 'CellLine', 'CVCL:0480', (92, 98))	('degradation', 'biological_process', 'GO:0009056', ('79', '90'))	('MG-132', 'Chemical', 'MESH:C072553', (189, 195))	('proteasome', 'molecular_function', 'GO:0004299', ('167', '177'))
20243	23547054	To demonstrate that the decrease in TAK1 levels was not an off-target effect of AR-A01448, siRNA was used to transiently knockdown GSK-3alpha and/or GSK-3beta in Panc-1 and MiaPaCa-2 cells.	('knockdown', 'Var', (121, 130))	('GSK-3alpha', 'Gene', (131, 141))	('GSK-3beta', 'Gene', (149, 158))	('GSK', 'molecular_function', 'GO:0050321', ('131', '134'))	('GSK-3beta', 'Gene', '2932', (149, 158))	('TAK1 levels', 'MPA', (36, 47))	('GSK', 'molecular_function', 'GO:0050321', ('149', '152'))	('AR-A', 'Gene', '5063', (80, 84))	('GSK-3alpha', 'Gene', '2931', (131, 141))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (173, 182))	('AR-A', 'Gene', (80, 84))	('Panc-1', 'CellLine', 'CVCL:0480', (162, 168))
20244	23547054	48 hours after siRNA transfection, a decrease in TAK1 levels was observed with knockdown of GSK-3alpha but not of GSK-3beta (Fig.	('decrease', 'NegReg', (37, 45))	('GSK-3alpha', 'Gene', '2931', (92, 102))	('GSK', 'molecular_function', 'GO:0050321', ('92', '95'))	('TAK1 levels', 'MPA', (49, 60))	('GSK-3beta', 'Gene', '2932', (114, 123))	('GSK-3beta', 'Gene', (114, 123))	('GSK-3alpha', 'Gene', (92, 102))	('GSK', 'molecular_function', 'GO:0050321', ('114', '117'))	('knockdown', 'Var', (79, 88))
20249	23547054	Consistent with previous studies, expression of oncogenic KRAS led to the upregulation of GSK-3 isoforms (Fig.	('KRAS', 'Gene', (58, 62))	('GSK', 'molecular_function', 'GO:0050321', ('90', '93'))	('KRAS', 'Gene', '3845', (58, 62))	('GSK-3', 'Gene', (90, 95))	('upregulation', 'PosReg', (74, 86))	('upregulation of GSK', 'biological_process', 'GO:1902949', ('74', '93'))	('oncogenic', 'Var', (48, 57))	('GSK-3', 'Gene', '56637', (90, 95))
20258	23547054	Overall, these data and those described above demonstrate that mutant KRAS induces TAK1-TAB1 interaction that is stabilized by GSK-3alpha leading to higher TAK1-dependent NF-kappaB activity in pancreatic cancer cells.	('GSK', 'molecular_function', 'GO:0050321', ('127', '130'))	('mutant', 'Var', (63, 69))	('GSK-3alpha', 'Gene', (127, 137))	('pancreatic cancer', 'Disease', 'MESH:D010190', (193, 210))	('KRAS', 'Gene', (70, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (193, 210))	('TAK1-dependent NF-kappaB activity', 'MPA', (156, 189))	('GSK-3alpha', 'Gene', '2931', (127, 137))	('KRAS', 'Gene', '3845', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('interaction', 'Interaction', (93, 104))	('pancreatic cancer', 'Disease', (193, 210))	('higher', 'PosReg', (149, 155))	('TAK1-TAB1', 'Protein', (83, 92))	('induces', 'Reg', (75, 82))
20267	23547054	Upon processing of p100, p52 accumulates in the nucleus to promote transcription of its target genes.	('p52', 'Gene', (25, 28))	('p52', 'Gene', '4791', (25, 28))	('nucleus', 'cellular_component', 'GO:0005634', ('48', '55'))	('promote', 'PosReg', (59, 66))	('transcription', 'biological_process', 'GO:0006351', ('67', '80'))	('p100', 'Var', (19, 23))	('transcription', 'MPA', (67, 80))
20271	23547054	The functional importance of the non-canonical NF-kappaB pathway was measured via the effect of p100 knockdown on the cell index of pancreatic cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('p100', 'Gene', (96, 100))	('pancreatic cancer', 'Disease', (132, 149))	('non-canonical NF-kappaB pathway', 'Pathway', (33, 64))	('pancreatic cancer', 'Disease', 'MESH:D010190', (132, 149))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 149))	('knockdown', 'Var', (101, 110))
20272	23547054	As compared to the non-targeting control, p100 knockdown suppressed the cell index of Panc-1 cells in a cell impedance assay (Fig.	('p100', 'Gene', (42, 46))	('Panc-1', 'CellLine', 'CVCL:0480', (86, 92))	('knockdown', 'Var', (47, 56))	('cell index', 'MPA', (72, 82))	('suppressed', 'NegReg', (57, 67))
20275	23547054	These results may explain why knockdown of GSK-3alpha (that affects both canonical and non-canonical NF-kappaB) leads to a greater suppression of cell growth as compared to knockdown of GSK-3beta or TAK1 (Fig.	('cell growth', 'CPA', (146, 157))	('GSK-3beta', 'Gene', '2932', (186, 195))	('GSK-3beta', 'Gene', (186, 195))	('suppression', 'NegReg', (131, 142))	('GSK-3alpha', 'Gene', (43, 53))	('GSK', 'molecular_function', 'GO:0050321', ('43', '46'))	('cell growth', 'biological_process', 'GO:0016049', ('146', '157'))	('knockdown', 'Var', (30, 39))	('GSK', 'molecular_function', 'GO:0050321', ('186', '189'))	('GSK-3alpha', 'Gene', '2931', (43, 53))
20284	23547054	Overall these data indicate that GSK-3 inhibition suppresses pancreatic tumor growth with a concomitant decrease in TAK1-TAB activity.	('inhibition', 'Var', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('TAK1-TAB', 'Protein', (116, 124))	('pancreatic tumor', 'Disease', (61, 77))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (61, 77))	('suppresses', 'NegReg', (50, 60))	('activity', 'MPA', (125, 133))	('pancreatic tumor', 'Disease', 'MESH:D010190', (61, 77))	('decrease', 'NegReg', (104, 112))	('GSK-3', 'Gene', (33, 38))	('GSK-3', 'Gene', '56637', (33, 38))	('GSK', 'molecular_function', 'GO:0050321', ('33', '36'))
20287	23547054	Supervised gene expression analyses were conducted to quantify gene expression changes in the tumors, after 2 or 8 hours of AR-A014418 treatment (Fig.	('gene expression', 'biological_process', 'GO:0010467', ('63', '78'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('AR-A014418', 'Chemical', 'MESH:C479831', (124, 134))	('gene expression', 'biological_process', 'GO:0010467', ('11', '26'))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('AR-A014418', 'Var', (124, 134))
20288	23547054	GSK-3 inhibition led to a statistically significant change in expression (based on SAM analysis) for 470 genes, of which 155 changed more than 2 fold (Fig.	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('changed', 'Reg', (125, 132))	('GSK-3', 'Gene', '56637', (0, 5))	('expression', 'MPA', (62, 72))	('change', 'Reg', (52, 58))	('inhibition', 'Var', (6, 16))	('GSK-3', 'Gene', (0, 5))
20293	23547054	For example, we observe a decrease in the expression of pro-proliferative genes like c-Myc, TERT, and cIAP2 with GSK-3 inhibition.	('TERT', 'Gene', (92, 96))	('c-Myc', 'Gene', (85, 90))	('TERT', 'Gene', '7015', (92, 96))	('cIAP2', 'Gene', (102, 107))	('decrease', 'NegReg', (26, 34))	('GSK-3', 'Gene', '56637', (113, 118))	('cIAP2', 'Gene', '330', (102, 107))	('expression', 'MPA', (42, 52))	('inhibition', 'Var', (119, 129))	('c-Myc', 'Gene', '4609', (85, 90))	('GSK-3', 'Gene', (113, 118))	('GSK', 'molecular_function', 'GO:0050321', ('113', '116'))
20294	23547054	Mutant KRAS is expressed in virtually all pancreatic cancers as well as in other epithelial-derived cancers where it serves as a key oncogenic factor, promoting proliferation and survival.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('KRAS', 'Gene', '3845', (7, 11))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (42, 60))	('cancers', 'Disease', (53, 60))	('promoting', 'PosReg', (151, 160))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('survival', 'CPA', (179, 187))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('pancreatic cancers', 'Disease', 'MESH:D010190', (42, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('pancreatic cancers', 'Disease', (42, 60))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (42, 59))	('Mutant', 'Var', (0, 6))	('proliferation', 'CPA', (161, 174))	('KRAS', 'Gene', (7, 11))	('cancers', 'Disease', (100, 107))
20308	23547054	While Singh et al argue against the pro-survival role of TAK1 in pancreatic cancer cells, another group showed that inhibition of TAK1 leads to a proapoptotic phenotype in pancreatic cancer cells, by suppressing NF-kappaB Our results supports aspects of each of these studies, as we observe a reduction in NF-kappaB activity and cell proliferation with inhibition of TAK1 in pancreatic cancer cells (Fig.	('NF-kappaB', 'MPA', (212, 221))	('cell proliferation', 'CPA', (329, 347))	('reduction', 'NegReg', (293, 302))	('inhibition', 'Var', (353, 363))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (375, 392))	('NF-kappaB', 'Protein', (306, 315))	('pancreatic cancer', 'Disease', 'MESH:D010190', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('suppressing', 'NegReg', (200, 211))	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('activity', 'MPA', (316, 324))	('pancreatic cancer', 'Disease', (172, 189))	('pancreatic cancer', 'Disease', 'MESH:D010190', (375, 392))	('TAK1', 'Gene', (367, 371))	('pancreatic cancer', 'Disease', (65, 82))	('pancreatic cancer', 'Disease', (375, 392))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (172, 189))
20310	23547054	However, inhibition of TAK1 leads to G2/M arrest in pancreatic cancer cells (Supplementary S4), which presumably causes a decrease in cell proliferation.	('cell proliferation', 'CPA', (134, 152))	('pancreatic cancer', 'Disease', (52, 69))	('M arrest', 'Disease', 'MESH:D006323', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('decrease', 'NegReg', (122, 130))	('pancreatic cancer', 'Disease', 'MESH:D010190', (52, 69))	('M arrest', 'Disease', (40, 48))	('TAK1', 'Gene', (23, 27))	('inhibition', 'Var', (9, 19))	('cell proliferation', 'biological_process', 'GO:0008283', ('134', '152'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (52, 69))
20316	23547054	The in vitro results were reproduced in vivo when human pancreatic tumor explants were treated with AR-A014418 (Fig.	('pancreatic tumor', 'Phenotype', 'HP:0002894', (56, 72))	('AR-A014418', 'Chemical', 'MESH:C479831', (100, 110))	('AR-A014418', 'Var', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('pancreatic tumor', 'Disease', 'MESH:D010190', (56, 72))	('human', 'Species', '9606', (50, 55))	('pancreatic tumor', 'Disease', (56, 72))
20318	23547054	The interaction between GSK-3alpha and TAK1 was found in non-transformed HPDE cells, suggesting that GSK-3alpha can interact with TAK1 irrespective of presence or absence of mutant KRAS.	('GSK', 'molecular_function', 'GO:0050321', ('24', '27'))	('GSK-3alpha', 'Gene', '2931', (101, 111))	('GSK', 'molecular_function', 'GO:0050321', ('101', '104'))	('GSK-3alpha', 'Gene', '2931', (24, 34))	('GSK-3alpha', 'Gene', (101, 111))	('KRAS', 'Gene', '3845', (181, 185))	('interact', 'Interaction', (116, 124))	('KRAS', 'Gene', (181, 185))	('TAK1', 'Gene', (130, 134))	('GSK-3alpha', 'Gene', (24, 34))	('mutant', 'Var', (174, 180))
20319	23547054	However, mutant KRAS upregulates the expression of GSK-3 (Supplementary S9), which then promotes the stabilization of the active TAK1-TAB1 complex.	('promotes', 'PosReg', (88, 96))	('stabilization', 'MPA', (101, 114))	('mutant', 'Var', (9, 15))	('TAK1-TAB1', 'Protein', (129, 138))	('GSK-3', 'Gene', (51, 56))	('KRAS', 'Gene', (16, 20))	('upregulates', 'PosReg', (21, 32))	('KRAS', 'Gene', '3845', (16, 20))	('active', 'MPA', (122, 128))	('expression', 'MPA', (37, 47))	('GSK-3', 'Gene', '56637', (51, 56))	('GSK', 'molecular_function', 'GO:0050321', ('51', '54'))
20321	23547054	The mechanistic link between GSK-3alpha and TAK1 is unclear since there is no consensus substrate motif of GSK-3 (S/T-XXX-S/T) in TAK1.	('GSK', 'molecular_function', 'GO:0050321', ('29', '32'))	('GSK-3', 'Gene', '56637', (29, 34))	('GSK-3', 'Gene', (107, 112))	('GSK-3alpha', 'Gene', (29, 39))	('S/T-XXX-S/T', 'Var', (114, 125))	('GSK-3', 'Gene', '56637', (107, 112))	('GSK-3', 'Gene', (29, 34))	('GSK', 'molecular_function', 'GO:0050321', ('107', '110'))	('GSK-3alpha', 'Gene', '2931', (29, 39))
20328	23547054	GSK-3 inhibition, or knockdown of GSK-3alpha (but not GSK-3beta) leads to significantly reduced p100 processing in pancreatic cancer cells (Fig.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('GSK-3', 'Gene', (34, 39))	('GSK-3', 'Gene', '56637', (54, 59))	('GSK', 'molecular_function', 'GO:0050321', ('34', '37'))	('GSK', 'molecular_function', 'GO:0050321', ('54', '57'))	('knockdown', 'Var', (21, 30))	('GSK-3', 'Gene', (0, 5))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('GSK-3alpha', 'Gene', '2931', (34, 44))	('GSK-3', 'Gene', '56637', (34, 39))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('inhibition', 'NegReg', (6, 16))	('reduced', 'NegReg', (88, 95))	('p100', 'Protein', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('GSK-3', 'Gene', '56637', (0, 5))	('pancreatic cancer', 'Disease', (115, 132))	('GSK-3beta', 'Gene', '2932', (54, 63))	('GSK-3', 'Gene', (54, 59))	('GSK-3beta', 'Gene', (54, 63))	('GSK-3alpha', 'Gene', (34, 44))
20329	23547054	Importantly, we demonstrate a significant reduction in cell proliferation of pancreatic cancer cells, upon knocking down p100 subunit (Fig.	('knocking down', 'Var', (107, 120))	('pancreatic cancer', 'Disease', (77, 94))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('cell proliferation', 'biological_process', 'GO:0008283', ('55', '73'))	('p100 subunit', 'Protein', (121, 133))	('cell proliferation', 'CPA', (55, 73))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('reduction', 'NegReg', (42, 51))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
20330	23547054	We also saw a decrease in p100 and p52 levels upon TAK1 inhibition, which is consistent with p100 being a known transcriptional target of canonical NF-kappaB (data not shown).	('TAK1', 'Gene', (51, 55))	('p52', 'Gene', (35, 38))	('p52', 'Gene', '4791', (35, 38))	('decrease', 'NegReg', (14, 22))	('inhibition', 'Var', (56, 66))
20331	23547054	Interestingly we observed a decrease in nuclear accumulation of p52 subunit upon GSK-3alpha knockdown while, the cytoplasmic levels of p100 and p52 remained unchanged (Fig.	('p52', 'Gene', (64, 67))	('GSK-3alpha', 'Gene', '2931', (81, 91))	('p52', 'Gene', '4791', (64, 67))	('GSK', 'molecular_function', 'GO:0050321', ('81', '84'))	('knockdown', 'Var', (92, 101))	('p52', 'Gene', (144, 147))	('p52', 'Gene', '4791', (144, 147))	('nuclear accumulation', 'MPA', (40, 60))	('GSK-3alpha', 'Gene', (81, 91))	('decrease', 'NegReg', (28, 36))
20340	23547054	To analyze the effect of GSK-3 inhibition on NF-kappaB target gene expression, we compared the gene expression profile of tumors, before and after treatment with AR-A014418.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('gene expression', 'biological_process', 'GO:0010467', ('62', '77'))	('AR-A014418', 'Chemical', 'MESH:C479831', (162, 172))	('GSK-3', 'Gene', (25, 30))	('gene expression', 'biological_process', 'GO:0010467', ('95', '110'))	('GSK', 'molecular_function', 'GO:0050321', ('25', '28'))	('AR-A014418', 'Var', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('GSK-3', 'Gene', '56637', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
20354	23547054	The following human siRNA (siGenome SMARTpool) was purchased from Dharmacon as a pool of four annealed dsRNA oligonucleotides: MAP3K7 (M-003790-06), GSK-3alpha(M-003009-01), GSK-3beta (M-003010-03), NF-kappaB2 (M-003918-02), and non-targeting control#3 (D001201-03).	('GSK-3alpha', 'Gene', '2931', (149, 159))	('M-003918-02', 'Var', (211, 222))	('oligonucleotides', 'Chemical', 'MESH:D009841', (109, 125))	('human', 'Species', '9606', (14, 19))	('GSK-3alpha', 'Gene', (149, 159))	('D001201-03', 'Var', (254, 264))	('M-003010-03', 'Var', (185, 196))	('GSK', 'molecular_function', 'GO:0050321', ('149', '152'))	('GSK', 'molecular_function', 'GO:0050321', ('174', '177'))	('MAP3K7', 'Gene', (127, 133))	('MAP3K', 'molecular_function', 'GO:0004709', ('127', '132'))	('M-003790-06', 'Var', (135, 146))	('GSK-3beta', 'Gene', '2932', (174, 183))	('GSK-3beta', 'Gene', (174, 183))	('MAP3K7', 'Gene', '6885', (127, 133))
20357	23547054	The cells were then treated with the indicated concentrations of AR-A014418 for indicated times and cellular proliferation measured using the CellTiter 96 Aqueous solution, in accordance to the manufacturer's protocol (Promega).	('cellular proliferation', 'CPA', (100, 122))	('AR-A014418', 'Chemical', 'MESH:C479831', (65, 75))	('AR-A014418', 'Var', (65, 75))
20364	23547054	Two weeks later, GSK-3 inhibitor, AR-A014418 or vehicle control, DMSO was given intraperitonealy at 120mg/kg twice a day for two days.	('AR-A014418', 'Var', (34, 44))	('GSK-3', 'Gene', (17, 22))	('GSK', 'molecular_function', 'GO:0050321', ('17', '20'))	('GSK-3', 'Gene', '56637', (17, 22))	('DMSO', 'Chemical', 'MESH:D004121', (65, 69))	('AR-A014418', 'Chemical', 'MESH:C479831', (34, 44))
20368	23547054	Inhibition of GSK-3 strongly suppresses growth of human pancreatic tumor explants with downregulation of certain oncogenic NF-kappaB target genes such as c-myc and TERT.	('suppresses', 'NegReg', (29, 39))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (56, 72))	('GSK-3', 'Gene', (14, 19))	('TERT', 'Gene', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('TERT', 'Gene', '7015', (164, 168))	('Inhibition of GSK', 'biological_process', 'GO:1902948', ('0', '17'))	('GSK-3', 'Gene', '56637', (14, 19))	('downregulation', 'NegReg', (87, 101))	('pancreatic tumor', 'Disease', 'MESH:D010190', (56, 72))	('Inhibition', 'Var', (0, 10))	('GSK', 'molecular_function', 'GO:0050321', ('14', '17'))	('human', 'Species', '9606', (50, 55))	('c-myc', 'Gene', '4609', (154, 159))	('pancreatic tumor', 'Disease', (56, 72))	('c-myc', 'Gene', (154, 159))
20523	21499210	To identify activated PSC proteins that effect these changes, GO terms that relate to these functions were probed and the resulting list of proteins is presented in Supplemental Table 2 (Supplemental Digital Content 2, http://links.lww.com/MPA/A37).	('PSC', 'Gene', (22, 25))	('PSC', 'Gene', '100653366', (22, 25))	('changes', 'Var', (53, 60))
20558	21499210	In some cancers, the gene for UCHL1 is methylated, and restoration of UCHL1 expression inhibited proliferation in hepatocellular carcinoma.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('UCHL1', 'Gene', (70, 75))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (114, 138))	('cancers', 'Disease', (8, 15))	('hepatocellular carcinoma', 'Disease', (114, 138))	('restoration', 'Var', (55, 66))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (114, 138))	('UCHL1', 'Gene', '7345', (30, 35))	('proliferation', 'CPA', (97, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('UCHL1', 'Gene', (30, 35))	('expression', 'MPA', (76, 86))	('inhibited', 'NegReg', (87, 96))	('UCHL1', 'Gene', '7345', (70, 75))
20580	21499210	EZR is a mediator of cell-integrin interactions and high expression of EZR has been associated with prostate and pancreatic cancer progression.	('EZR', 'Gene', '7430', (0, 3))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('EZR', 'Gene', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('pancreatic cancer', 'Disease', (113, 130))	('associated', 'Reg', (84, 94))	('prostate', 'Disease', (100, 108))	('EZR', 'Gene', '7430', (71, 74))	('pancreatic cancer', 'Disease', 'MESH:D010190', (113, 130))	('high expression', 'Var', (52, 67))	('EZR', 'Gene', (0, 3))
20605	19435817	Many tumors have acquired genetic alterations in the signaling pathways that regulate NF-kappaB activation.	('signaling pathways', 'Pathway', (53, 71))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('86', '106'))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('NF-kappaB', 'Gene', '4790', (86, 95))	('genetic alterations', 'Var', (26, 45))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('NF-kappaB', 'Gene', (86, 95))
20607	19435817	In different models of pancreatic tumor, inhibiting constitutive NF-kappaB activation by expression of an IkappaBalpha phosphorylation mutant suppresses tumorigenicity by reducing expression of antiapoptotic proteins Bcl-x(L) and Bcl-2 and inhibits liver metastasis and angiogenic potential by reducing in vivo expression of vascular endothelial growth factor (VEGF; refs.).	('Bcl-2', 'molecular_function', 'GO:0015283', ('230', '235'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('325', '359'))	('vascular endothelial growth factor', 'Gene', '7422', (325, 359))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (23, 39))	('activation', 'PosReg', (75, 85))	('Bcl-x(L', 'Gene', (217, 224))	('NF-kappaB', 'Gene', '4790', (65, 74))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('65', '85'))	('VEGF', 'Gene', '7422', (361, 365))	('reducing', 'NegReg', (294, 302))	('vascular endothelial growth factor', 'Gene', (325, 359))	('tumor', 'Disease', (34, 39))	('VEGF', 'Gene', (361, 365))	('pancreatic tumor', 'Disease', (23, 39))	('mutant', 'Var', (135, 141))	('tumor', 'Disease', (153, 158))	('Bcl-x(L)', 'Gene', '598', (217, 225))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('pancreatic tumor', 'Disease', 'MESH:D010190', (23, 39))	('liver metastasis', 'Disease', (249, 265))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('inhibiting', 'NegReg', (41, 51))	('expression', 'MPA', (180, 190))	('Bcl-2', 'Gene', (230, 235))	('IkappaBalpha', 'Gene', (106, 118))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('reducing', 'NegReg', (171, 179))	('suppresses', 'NegReg', (142, 152))	('inhibits', 'NegReg', (240, 248))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('angiogenic potential', 'CPA', (270, 290))	('NF-kappaB', 'Gene', (65, 74))	('liver metastasis', 'Disease', 'MESH:D009362', (249, 265))	('IkappaBalpha', 'Gene', '4792', (106, 118))	('Bcl-2', 'Gene', '596', (230, 235))
20612	19435817	Neutralization of IL-1alpha activity suppressed the constitutive activation of NF-kappaB and the expression of its downstream target gene, urokinase-type plasminogen activator (uPA), in metastatic pancreatic cancer cell lines.	('urokinase-type plasminogen activator', 'molecular_function', 'GO:0008243', ('139', '175'))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('65', '88'))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('NF-kappaB', 'Gene', (79, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (197, 214))	('urokinase-type plasminogen activator', 'Gene', (139, 175))	('NF-kappaB', 'Gene', '4790', (79, 88))	('Neutralization', 'Var', (0, 14))	('pancreatic cancer', 'Disease', (197, 214))	('expression', 'MPA', (97, 107))	('suppressed', 'NegReg', (37, 47))	('urokinase-type plasminogen activator', 'Gene', '5328', (139, 175))	('constitutive activation', 'MPA', (52, 75))	('uPA', 'molecular_function', 'GO:0008243', ('177', '180'))	('IL-1', 'molecular_function', 'GO:0005149', ('18', '22'))	('uPA', 'Gene', (177, 180))	('IL-1alpha', 'Gene', (18, 27))	('uPA', 'Gene', '5328', (177, 180))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (197, 214))
20615	19435817	In malignant cells, exogenous recombinant IL-1 induces secretion of growth, invasiveness promoting, and angiogenic factors.	('exogenous recombinant', 'Var', (20, 41))	('secretion of growth', 'MPA', (55, 74))	('IL-1', 'Gene', '3552', (42, 46))	('IL-1', 'Gene', (42, 46))	('IL-1', 'molecular_function', 'GO:0005149', ('42', '46'))	('secretion', 'biological_process', 'GO:0046903', ('55', '64'))	('invasiveness promoting', 'CPA', (76, 98))	('angiogenic factors', 'CPA', (104, 122))
20623	19435817	Short hairpin RNA (shRNA) to knock down IL-1alpha completely suppressed the spread of the highly metastatic L3.6pl pancreatic cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('suppressed', 'NegReg', (61, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('knock down', 'Var', (29, 39))	('IL-1', 'molecular_function', 'GO:0005149', ('40', '44'))	('pancreatic cancer', 'Disease', (115, 132))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('IL-1alpha', 'Gene', (40, 49))
20629	19435817	1C, unlabeled wild-type (WT) but not mutant NF-kappaB oligonucleotides completely blocked NF-kappaB activation by competition, and p65 antibody further retarded NF-kappaB shift in the gel, as antibody binding resulted in a larger complex.	('NF-kappaB', 'Gene', '4790', (161, 170))	('NF-kappaB', 'Gene', '4790', (44, 53))	('antibody', 'molecular_function', 'GO:0003823', ('135', '143'))	('antibody', 'cellular_component', 'GO:0019815', ('192', '200'))	('NF-kappaB', 'Gene', '4790', (90, 99))	('antibody', 'cellular_component', 'GO:0042571', ('135', '143'))	('p65', 'Gene', (131, 134))	('activation', 'MPA', (100, 110))	('binding', 'Interaction', (201, 208))	('antibody', 'cellular_component', 'GO:0019814', ('192', '200'))	('antibody', 'cellular_component', 'GO:0019815', ('135', '143'))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('90', '110'))	('blocked', 'NegReg', (82, 89))	('p65', 'Gene', '5970', (131, 134))	('mutant', 'Var', (37, 43))	('antibody', 'molecular_function', 'GO:0003823', ('192', '200'))	('oligonucleotides', 'Chemical', 'MESH:D009841', (54, 70))	('antibody', 'cellular_component', 'GO:0042571', ('192', '200'))	('binding', 'molecular_function', 'GO:0005488', ('201', '208'))	('antibody', 'cellular_component', 'GO:0019814', ('135', '143'))	('NF-kappaB', 'Gene', (161, 170))	('NF-kappaB', 'Gene', (44, 53))	('retarded', 'Disease', (152, 160))	('NF-kappaB', 'Gene', (90, 99))	('retarded', 'Disease', 'MESH:D008607', (152, 160))
20641	19435817	3A), IL-1alpha expression significantly increased the low-anchorage growth for MiaPaCa-2 cells, especially in the less permissive soft agar higher concentration (Fig.	('expression', 'Var', (15, 25))	('IL-1', 'molecular_function', 'GO:0005149', ('5', '9'))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (79, 88))	('IL-1alpha', 'Gene', (5, 14))	('low-anchorage growth', 'CPA', (54, 74))	('increased', 'PosReg', (40, 49))	('agar', 'Chemical', 'MESH:D000362', (135, 139))
20649	19435817	To determine the roles of the NF-kappaB activation in IL-1alpha-induced pancreatic tumor metastatic processes, we used retroviral infection to generate stable clones (MiaPaCa-2/IL-1alpha/IkappaBalphaM) that expressed IkappaBalphaM (IkappaBalpha S32, 36A) with mutated PEST domain to increase its stability and these clones were pooled.	('IL-1', 'molecular_function', 'GO:0005149', ('177', '181'))	('IkappaBalpha', 'Gene', '4792', (232, 244))	('mutated', 'Var', (260, 267))	('pancreatic tumor', 'Disease', (72, 88))	('stability', 'MPA', (296, 305))	('increase', 'PosReg', (283, 291))	('IkappaBalpha', 'Gene', (187, 199))	('pancreatic tumor', 'Disease', 'MESH:D010190', (72, 88))	('IkappaBalpha', 'Gene', '4792', (187, 199))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('PEST domain', 'Gene', (268, 279))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('30', '50'))	('NF-kappaB', 'Gene', (30, 39))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (167, 176))	('NF-kappaB', 'Gene', '4790', (30, 39))	('IkappaBalpha', 'Gene', (217, 229))	('IkappaBalpha', 'Gene', (232, 244))	('IkappaBalpha', 'Gene', '4792', (217, 229))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (72, 88))	('IL-1', 'molecular_function', 'GO:0005149', ('54', '58'))
20653	19435817	The expression of the NF-kappaB downstream target genes uPA, VEGF, and IL-8 was inhibited by I BaM (Fig.	('VEGF', 'Gene', '7422', (61, 65))	('uPA', 'Gene', '5328', (56, 59))	('uPA', 'molecular_function', 'GO:0008243', ('56', '59'))	('IL-8', 'Gene', '3576', (71, 75))	('inhibited', 'NegReg', (80, 89))	('IL-8', 'Gene', (71, 75))	('NF-kappaB', 'Gene', (22, 31))	('expression', 'MPA', (4, 14))	('VEGF', 'Gene', (61, 65))	('I BaM', 'Var', (93, 98))	('IL-8', 'molecular_function', 'GO:0005153', ('71', '75'))	('uPA', 'Gene', (56, 59))	('NF-kappaB', 'Gene', '4790', (22, 31))
20657	19435817	Likewise, the in vitro cell invasion was also inhibited by the expression of IkappaBalphaM, as shown in Fig.	('IkappaBalpha', 'Gene', '4792', (77, 89))	('IkappaBalpha', 'Gene', (77, 89))	('inhibited', 'NegReg', (46, 55))	('in vitro cell invasion', 'CPA', (14, 36))	('expression', 'Var', (63, 73))
20665	19435817	To determine the in vivo antimetastatic effect of silencing IL-1alpha, a group of 20 mice was orthotopically inoculated with L3.6pl or L3.6plIL-1alphashRNA cells.	('mice', 'Species', '10090', (85, 89))	('silencing', 'Var', (50, 59))	('L3.6plIL-1alphashRNA', 'Var', (135, 155))	('IL-1', 'molecular_function', 'GO:0005149', ('60', '64'))	('IL-1alpha', 'Gene', (60, 69))
20666	19435817	7B), the mice bearing orthotopic L3.6pl pancreatic tumors had a diffuse pattern of abdominal metastasis at necropsy, and the mice bearing orthotopic L3.6plIL-1alphashRNA pancreatic tumors developed significantly fewer metastatic lesions, and in some of them, no metastatic lesion as indicated by the green fluorescent protein signal could be identified in the abdomen (Fig.	('L3.6pl', 'Var', (33, 39))	('pancreatic tumors', 'Disease', 'MESH:D010190', (170, 187))	('mice', 'Species', '10090', (125, 129))	('pancreatic tumors', 'Disease', (170, 187))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('abdominal metastasis', 'CPA', (83, 103))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (40, 57))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (170, 186))	('protein', 'cellular_component', 'GO:0003675', ('318', '325'))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('pancreatic tumors', 'Disease', 'MESH:D010190', (40, 57))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (170, 187))	('mice', 'Species', '10090', (9, 13))	('pancreatic tumors', 'Disease', (40, 57))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (40, 56))	('metastatic lesions', 'CPA', (218, 236))	('fewer', 'NegReg', (212, 217))
20667	19435817	Thus, our results indicate that independently of any activity on the orthotopic primary, silencing of IL-1alpha significantly reduces metastasis from pancreatic cancer cells.	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('reduces', 'NegReg', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('metastasis from', 'CPA', (134, 149))	('IL-1', 'molecular_function', 'GO:0005149', ('102', '106'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('IL-1alpha', 'Gene', (102, 111))	('silencing', 'Var', (89, 98))	('pancreatic cancer', 'Disease', (150, 167))
20673	19435817	In an in vitro model of pancreatic cancer, recombinant IL-1alpha was shown to enhance the adhesion of metastatic cells to extracellular matrix proteins by inducing the alpha6-integrin subunit.	('pancreatic cancer', 'Disease', (24, 41))	('enhance', 'PosReg', (78, 85))	('inducing', 'PosReg', (155, 163))	('recombinant', 'Var', (43, 54))	('pancreatic cancer', 'Disease', 'MESH:D010190', (24, 41))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('122', '142'))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('adhesion', 'CPA', (90, 98))	('alpha6-integrin subunit', 'Protein', (168, 191))	('IL-1alpha', 'Gene', (55, 64))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (24, 41))	('IL-1', 'molecular_function', 'GO:0005149', ('55', '59'))
20677	19435817	In a model of fibrosarcoma cells, the transfection of the active form of IL-1alpha resulted in its cytosolic and membrane-associated expression and increased the immunogenicity of malignant cells in vivo.	('IL-1alpha', 'Gene', (73, 82))	('membrane', 'cellular_component', 'GO:0016020', ('113', '121'))	('increased', 'PosReg', (148, 157))	('immunogenicity of malignant cells', 'CPA', (162, 195))	('transfection', 'Var', (38, 50))	('fibrosarcoma', 'Disease', (14, 26))	('IL-1', 'molecular_function', 'GO:0005149', ('73', '77'))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (14, 26))	('fibrosarcoma', 'Disease', 'MESH:D005354', (14, 26))
20684	19435817	Further studies showed that inhibition of constitutive NF-kappaB activity by a phosphorylation-defective mutant IkappaBalpha (S32, 36A) completely suppressed the liver metastasis and the tumorigenic phenotype of pancreatic cancer cell lines, suggesting that constitutive NF-kappaB activity plays a key role in pancreatic cancer metastasis and tumor progression.	('activity', 'MPA', (65, 73))	('pancreatic cancer', 'Disease', 'MESH:D010190', (212, 229))	('pancreatic cancer metastasis', 'Disease', 'MESH:D009362', (310, 338))	('IkappaBalpha', 'Gene', '4792', (112, 124))	('tumor', 'Disease', (187, 192))	('NF-kappaB', 'Gene', (271, 280))	('mutant', 'Var', (105, 111))	('pancreatic cancer', 'Disease', (212, 229))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('phosphorylation', 'biological_process', 'GO:0016310', ('79', '94'))	('NF-kappaB', 'Gene', '4790', (271, 280))	('liver metastasis', 'Disease', (162, 178))	('NF-kappaB', 'Gene', (55, 64))	('tumor', 'Disease', (343, 348))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (310, 327))	('pancreatic cancer metastasis', 'Disease', (310, 338))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (212, 229))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('NF-kappaB', 'Gene', '4790', (55, 64))	('suppressed', 'NegReg', (147, 157))	('liver metastasis', 'Disease', 'MESH:D009362', (162, 178))	('pancreatic cancer', 'Disease', 'MESH:D010190', (310, 327))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('IkappaBalpha', 'Gene', (112, 124))
20709	19435817	The competition was done with a 50-fold excess of unlabeled WT or mutant kappaB oligonucleotides.	('oligonucleotides', 'Chemical', 'MESH:D009841', (80, 96))	('kappaB oligonucleotides', 'Protein', (73, 96))	('mutant', 'Var', (66, 72))
20733	33925948	A number of mechanisms have been proposed to explain resistance to gemcitabine, a standard of care for this malignancy, among which is included aberrant miRNA expression.	('miRNA expression', 'MPA', (153, 169))	('aberrant', 'Var', (144, 152))	('malignancy', 'Disease', 'MESH:D009369', (108, 118))	('malignancy', 'Disease', (108, 118))	('gemcitabine', 'Chemical', 'MESH:C056507', (67, 78))
20735	33925948	The low expression of miR-217 in pancreatic cancer patients was confirmed in two gene expression datasets (GSE41372 and GSE60980), and the prognostic value of two target genes (ANLN and TRPS1), was estimated on clinical data from the Tumor Cancer Genome Atlas (TCGA).	('ANLN', 'Gene', '54443', (177, 181))	('Tumor', 'Phenotype', 'HP:0002664', (234, 239))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('Tumor Cancer', 'Disease', (234, 246))	('Tumor Cancer', 'Disease', 'MESH:D009369', (234, 246))	('miR-217', 'Gene', '406999', (22, 29))	('miR-217', 'Gene', (22, 29))	('patients', 'Species', '9606', (51, 59))	('pancreatic cancer', 'Disease', (33, 50))	('GSE41372', 'Var', (107, 115))	('TRPS1', 'Gene', (186, 191))	('TRPS1', 'Gene', '7227', (186, 191))	('ANLN', 'Gene', (177, 181))	('Cancer', 'Phenotype', 'HP:0002664', (240, 246))	('gene expression', 'biological_process', 'GO:0010467', ('81', '96'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (33, 50))	('GSE60980', 'Var', (120, 128))
20740	33925948	Due to the lack of early specific symptoms and late diagnosis, surgery is a valid curative option in only 15 to 20% of PDAC carriers, while for the remaining patients gemcitabine-based chemotherapy represents the mainstay treatment.	('carriers', 'Var', (124, 132))	('gemcitabine', 'Chemical', 'MESH:C056507', (167, 178))	('PDAC', 'Gene', (119, 123))	('patients', 'Species', '9606', (158, 166))	('PDAC', 'Chemical', '-', (119, 123))
20749	33925948	By modulating gene expression, miRNAs influence several biological processes, among which are development, differentiation, proliferation, and apoptosis; when their expression is dysregulated, alterations of such processes may trigger carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (235, 249))	('modulating', 'Reg', (3, 13))	('carcinogenesis', 'Disease', (235, 249))	('differentiation', 'CPA', (107, 122))	('proliferation', 'CPA', (124, 137))	('expression', 'MPA', (165, 175))	('influence', 'Reg', (38, 47))	('alterations', 'Var', (193, 204))	('gene expression', 'biological_process', 'GO:0010467', ('14', '29'))	('apoptosis', 'CPA', (143, 152))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('development', 'CPA', (94, 105))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('gene expression', 'MPA', (14, 29))	('trigger', 'Reg', (227, 234))
20750	33925948	Beside a plethora of studies documenting the role of miRNAs in cancer onset and progression, many reports have also demonstrated that miRNAs may impact on the outcome of anticancer therapies, either by enhancing drug efficacy or by inducing chemoresistance.	('plethora', 'Phenotype', 'HP:0001050', (9, 17))	('enhancing drug efficacy', 'Phenotype', 'HP:0020173', (202, 225))	('impact', 'Reg', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('miRNAs', 'Var', (134, 140))	('drug efficacy', 'CPA', (212, 225))	('cancer', 'Disease', (174, 180))	('enhancing', 'PosReg', (202, 211))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('inducing', 'Reg', (232, 240))	('chemoresistance', 'CPA', (241, 256))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (63, 69))
20781	33925948	As a first approach we examined two independent datasets available at the GEO repository under the accession numbers GSE41372 and GSE60980, in order to screen differentially expressed miRNAs and mRNAs between pancreatic cancer and normal tissue.	('pancreatic cancer', 'Disease', 'MESH:D010190', (209, 226))	('GSE60980', 'Var', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (209, 226))	('pancreatic cancer', 'Disease', (209, 226))
20792	33925948	We next performed a dose-response (1 nM, 5 nM, and 10 nM) and time-course (24 h and 48 h) of miR-217 transfection in BxPC-3 and PANC-1 cells (Figure 3B,C, respectively) to establish miRNA over-expression.	('miR-217', 'Gene', '406999', (93, 100))	('PANC-1', 'CellLine', 'CVCL:0480', (128, 134))	('miR-217', 'Gene', (93, 100))	('transfection', 'Var', (101, 113))	('BxPC-3', 'CellLine', 'CVCL:0186', (117, 123))
20809	33925948	The only significant result was obtained for the comparison Mock + Gem vs. miR-217 + Gem (adj p value = 0.0015) in S phase (Figure 6B) by the post hoc Tukey's multiple comparisons test.	('miR-217', 'Gene', (75, 82))	('S phase', 'biological_process', 'GO:0051320', ('115', '122'))	('Mock + Gem', 'Var', (60, 70))	('miR-217', 'Gene', '406999', (75, 82))
20819	33925948	Interestingly, we found the expression of these genes to be affected by miR-217 overexpression, further supporting the key role of miR-217 in mediating gemcitabine efficacy.	('affected', 'Reg', (60, 68))	('miR-217', 'Gene', (72, 79))	('miR-217', 'Gene', '406999', (131, 138))	('miR-217', 'Gene', (131, 138))	('expression', 'MPA', (28, 38))	('overexpression', 'Var', (80, 94))	('gemcitabine', 'Chemical', 'MESH:C056507', (152, 163))	('miR-217', 'Gene', '406999', (72, 79))
20821	33925948	Multiple mechanisms of gemcitabine resistance have been discovered, including inefficient drug uptake, enzymatic drug inactivation, impairment of apoptosis, increased expression of drug efflux transporters, activation of epithelial-mesenchymal transition, stemness pathways and aberrant expression of miRNAs.	('uptake', 'biological_process', 'GO:0098739', ('95', '101'))	('drug uptake', 'MPA', (90, 101))	('stemness', 'CPA', (256, 264))	('impairment', 'NegReg', (132, 142))	('efflux', 'biological_process', 'GO:0140352', ('186', '192'))	('expression', 'MPA', (167, 177))	('expression', 'MPA', (287, 297))	('inefficient', 'NegReg', (78, 89))	('aberrant', 'Var', (278, 286))	('apoptosis', 'CPA', (146, 155))	('activation', 'PosReg', (207, 217))	('miRNAs', 'Gene', (301, 307))	('epithelial-mesenchymal transition', 'CPA', (221, 254))	('gemcitabine', 'Chemical', 'MESH:C056507', (23, 34))	('uptake', 'biological_process', 'GO:0098657', ('95', '101'))	('apoptosis', 'biological_process', 'GO:0097194', ('146', '155'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('221', '254'))	('apoptosis', 'biological_process', 'GO:0006915', ('146', '155'))	('increased', 'PosReg', (157, 166))	('drug efflux transporters', 'MPA', (181, 205))	('efflux', 'biological_process', 'GO:0140115', ('186', '192'))
20826	33925948	It is known that miR-217 levels are inversely correlated with resistance to several chemotherapeutics and that its ectopic expression increases sensitivity of lung and cervical cancer cells to cisplatin, of leukemia cells to doxorubicin, imatinib, and dasatinib, and of gastric cancer cells to doxorubicin and paclitaxel.	('doxorubicin', 'Chemical', 'MESH:D004317', (225, 236))	('cancer', 'Disease', (177, 183))	('gastric cancer', 'Disease', (270, 284))	('leukemia', 'Disease', (207, 215))	('cisplatin', 'Chemical', 'MESH:D002945', (193, 202))	('leukemia', 'Disease', 'MESH:D007938', (207, 215))	('cancer', 'Disease', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('miR-217', 'Gene', '406999', (17, 24))	('sensitivity', 'MPA', (144, 155))	('ectopic expression', 'Var', (115, 133))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('doxorubicin', 'Chemical', 'MESH:D004317', (294, 305))	('gastric cancer', 'Disease', 'MESH:D013274', (270, 284))	('miR-217', 'Gene', (17, 24))	('dasatinib', 'Chemical', 'MESH:D000069439', (252, 261))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('paclitaxel', 'Chemical', 'MESH:D017239', (310, 320))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('gastric cancer', 'Phenotype', 'HP:0012126', (270, 284))	('increases', 'PosReg', (134, 143))	('resistance to several chemotherapeutics', 'MPA', (62, 101))	('imatinib', 'Chemical', 'MESH:D000068877', (238, 246))	('leukemia', 'Phenotype', 'HP:0001909', (207, 215))
20832	33925948	Since the percentage of total apoptotic cells was not significantly modified, we speculate that miR-217 transfection could have speeded up apoptosis.	('miR-217', 'Gene', (96, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('139', '148'))	('apoptosis', 'biological_process', 'GO:0006915', ('139', '148'))	('transfection', 'Var', (104, 116))	('miR-217', 'Gene', '406999', (96, 103))	('apoptosis', 'CPA', (139, 148))
20833	33925948	As an alternative, co-treatment with miR-217 and gemcitabine could have induced necrotic, rather than apoptotic, cell death, since late apoptotic and necrotic cells share positivity to both Annexin V and propidium iodide staining.	('propidium iodide', 'Chemical', 'MESH:D011419', (204, 220))	('necrotic', 'Disease', 'MESH:D009336', (150, 158))	('apoptotic, cell death', 'biological_process', 'GO:0006915', ('102', '123'))	('gemcitabine', 'Chemical', 'MESH:C056507', (49, 60))	('Annexin V', 'Gene', '308', (190, 199))	('necrotic', 'Disease', (80, 88))	('co-treatment', 'Var', (19, 31))	('induced', 'Reg', (72, 79))	('miR-217', 'Gene', '406999', (37, 44))	('Annexin V', 'Gene', (190, 199))	('miR-217', 'Gene', (37, 44))	('death', 'Disease', 'MESH:D003643', (118, 123))	('necrotic', 'Disease', 'MESH:D009336', (80, 88))	('death', 'Disease', (118, 123))	('necrotic', 'Disease', (150, 158))
20857	33164330	Gene chip, also known as DNA chip or DNA microarray, with high flux, high integration, miniaturization, automation, etc can detect the expression levels of thousands of gene transcripts in parallel and quickly and has been widely used in mutant gene testing, differential gene screening, gene library mapping, drug targets, tumour typing, polymorphism detection, etc.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('detect', 'MPA', (124, 130))	('tumour', 'Disease', (324, 330))	('mutant', 'Var', (238, 244))	('expression', 'MPA', (135, 145))	('tumour', 'Phenotype', 'HP:0002664', (324, 330))	('tumour', 'Disease', 'MESH:D009369', (324, 330))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))
20860	33164330	The three pancreatic cancer metastasis-related gene chip data used in this study (GSE19279, 4  GSE42952, 5  GSE71729  6 ) were derived from the National Bioinformatics Center (NCBI) Gene Chip Public Database (GEO).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('pancreatic cancer metastasis', 'Disease', 'MESH:D010190', (10, 38))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (10, 27))	('pancreatic cancer metastasis', 'Disease', (10, 38))	('GSE19279', 'Var', (82, 90))
20861	33164330	7  Among them, gse19279 was included in 9 cases, including 4 cases of primary pancreatic cancer and 5 cases of metastatic pancreatic cancer; gse42952 included 23 cases, including 12 cases of primary pancreatic cancer and 11 cases of metastatic pancreatic cancer; gse71729 included 206 cases, including 145 Primary pancreatic cancer and 61 metastatic pancreatic cancer.	('pancreatic cancer', 'Disease', (199, 216))	('pancreatic cancer', 'Disease', 'MESH:D010190', (244, 261))	('primary', 'Disease', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('pancreatic cancer', 'Disease', (350, 367))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (122, 139))	('gse71729', 'Chemical', '-', (263, 271))	('pancreatic cancer', 'Disease', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('pancreatic cancer', 'Disease', (244, 261))	('gse71729', 'Var', (263, 271))	('pancreatic cancer', 'Disease', 'MESH:D010190', (314, 331))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('gse42952', 'Chemical', '-', (141, 149))	('pancreatic cancer', 'Disease', 'MESH:D010190', (122, 139))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('Primary pancreatic cancer', 'Disease', 'MESH:D010190', (306, 331))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (244, 261))	('pancreatic cancer', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('pancreatic cancer', 'Disease', 'MESH:D010190', (350, 367))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('gse19279', 'Chemical', '-', (15, 23))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))	('Primary pancreatic cancer', 'Disease', (306, 331))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (314, 331))
20896	33164330	In this study, 109 genes of differentially expressed genes were found by analysing the gene chip data (GSE19279, GSE42952, GSE71729) related to pancreatic cancer metastasis in the GEO database, of which 49 were up-regulated and 60 were down-regulated.	('GSE71729', 'Var', (123, 131))	('GSE42952', 'Var', (113, 121))	('down-regulated', 'NegReg', (236, 250))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('pancreatic cancer metastasis', 'Disease', 'MESH:D010190', (144, 172))	('up-regulated', 'PosReg', (211, 223))	('GSE19279', 'Var', (103, 111))	('related', 'Reg', (133, 140))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (144, 161))	('pancreatic cancer metastasis', 'Disease', (144, 172))
20902	33164330	Li et al 16  have reported that activation of PPARgamma can up-regulate the tumour suppressor gene PTEN, thereby inhibiting the expression of MMP-2, thus impairing the migration and invasion of pancreatic cancer cell lines.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (194, 211))	('PPARgamma', 'Gene', '5468', (46, 55))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('MMP-2', 'Gene', (142, 147))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('tumour', 'Disease', (76, 82))	('pancreatic cancer', 'Disease', 'MESH:D010190', (194, 211))	('activation', 'Var', (32, 42))	('expression', 'MPA', (128, 138))	('PTEN', 'Gene', (99, 103))	('MMP-2', 'molecular_function', 'GO:0004228', ('142', '147'))	('PPARgamma', 'Gene', (46, 55))	('inhibiting', 'NegReg', (113, 123))	('pancreatic cancer', 'Disease', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('PTEN', 'Gene', '5728', (99, 103))	('MMP-2', 'Gene', '4313', (142, 147))	('up-regulate', 'PosReg', (60, 71))	('impairing', 'NegReg', (154, 163))
20909	33164330	Gong et al 21  have found that inhibition of FASN in hepatocellular carcinoma cell lines reduces the migration and invasion by reducing the HIF-1alpha/IGFBP1 pathway.	('reducing', 'NegReg', (127, 135))	('FASN', 'Gene', (45, 49))	('HIF-1alpha', 'Gene', '3091', (140, 150))	('FASN', 'Gene', '2194', (45, 49))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (53, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('hepatocellular carcinoma', 'Disease', (53, 77))	('inhibition', 'Var', (31, 41))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (53, 77))	('HIF-1alpha', 'Gene', (140, 150))	('reduces', 'NegReg', (89, 96))
20914	33164330	These results suggest that the abnormal expression of the above genes is closely related to the metastasis and prognosis of pancreatic cancer and thus has certain clinical significance for the judgement of the progression and prognosis of pancreatic cancer.	('expression', 'MPA', (40, 50))	('metastasis', 'CPA', (96, 106))	('abnormal', 'Var', (31, 39))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (239, 256))	('pancreatic cancer', 'Disease', (124, 141))	('related', 'Reg', (81, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('pancreatic cancer', 'Disease', (239, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (124, 141))	('pancreatic cancer', 'Disease', 'MESH:D010190', (239, 256))
20934	33271944	In turn, PSCs induce cancer cell proliferation and colony formation while at the same time decreasing apoptosis, thus increasing cancer cell survival.	('cell proliferation', 'biological_process', 'GO:0008283', ('28', '46'))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('increasing', 'PosReg', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('decreasing', 'NegReg', (91, 101))	('apoptosis', 'CPA', (102, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('cancer', 'Disease', (129, 135))	('PSCs', 'Var', (9, 13))	('induce', 'PosReg', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('formation', 'biological_process', 'GO:0009058', ('58', '67'))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('colony formation', 'CPA', (51, 67))
20936	33271944	Interestingly, supporting this active role of PSCs in PC metastasis, an earlier study by our group using an orthotopic model of pancreatic cancer reported the world-first finding that PSCs from the primary tumour can travel to distant metastatic sites, where they likely facilitate the seeding and growth of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('growth', 'CPA', (298, 304))	('facilitate', 'PosReg', (271, 281))	('PSCs', 'Var', (184, 188))	('pancreatic cancer', 'Disease', 'MESH:D010190', (128, 145))	('PC', 'Phenotype', 'HP:0002894', (54, 56))	('pancreatic cancer', 'Disease', (128, 145))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('tumour', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', (308, 314))	('seeding', 'CPA', (286, 293))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (128, 145))	('tumour', 'Disease', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('cancer', 'Disease', (139, 145))
20966	33271944	Given that HGF is the only known ligand for c-MET and that both HGF and c-MET are associated with aggressive disease, there has been an increased interest in targeting this pathway.	('HGF', 'Gene', (64, 67))	('associated', 'Reg', (82, 92))	('aggressive disease', 'Disease', 'MESH:D001523', (98, 116))	('c-MET', 'Var', (72, 77))	('aggressive disease', 'Disease', (98, 116))	('ligand', 'molecular_function', 'GO:0005488', ('33', '39'))
20988	33271944	With regard to the movement of cancer cells across the endothelial cell barrier during metastasis, HGF facilitates cancer cell-endothelial cell contact through phosphorylation of focal adhesion kinase (FAK) and reduces occludin, the primary protein in endothelial tight junctions.	('HGF', 'Var', (99, 102))	('focal adhesion kinase', 'Gene', (179, 200))	('FAK', 'Gene', (202, 205))	('occludin', 'Gene', '100506658', (219, 227))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('phosphorylation', 'MPA', (160, 175))	('focal adhesion', 'cellular_component', 'GO:0005925', ('179', '193'))	('FAK', 'Gene', '5747', (202, 205))	('phosphorylation', 'biological_process', 'GO:0016310', ('160', '175'))	('cancer', 'Disease', (31, 37))	('FAK', 'molecular_function', 'GO:0004717', ('202', '205'))	('occludin', 'Gene', (219, 227))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('men', 'Species', '9606', (23, 26))	('focal adhesion kinase', 'Gene', '5747', (179, 200))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('facilitates', 'PosReg', (103, 114))	('protein', 'cellular_component', 'GO:0003675', ('241', '248'))	('reduces', 'NegReg', (211, 218))	('cancer', 'Disease', 'MESH:D009369', (31, 37))
20991	33271944	Recent studies have also demonstrated that PSCs facilitate perineural invasion of pancreatic cancer and this process is mediated via the HGF/c-MET pathway.	('facilitate', 'PosReg', (48, 58))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PSCs', 'Var', (43, 47))	('HGF/c-MET pathway', 'Pathway', (137, 154))	('pancreatic cancer', 'Disease', (82, 99))	('perineural invasion', 'CPA', (59, 78))	('pancreatic cancer', 'Disease', 'MESH:D010190', (82, 99))
20993	33271944	However, Qian and colleagues have demonstrated in vitro that patient tumour derived fibroblasts expressing HGF could initiate an apparent invasion-stimulating response in pancreatic cancer cells with high expression of c-MET but not in cells with low expression of c-MET.	('tumour', 'Disease', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('patient', 'Species', '9606', (61, 68))	('c-MET', 'Protein', (219, 224))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (171, 188))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('HGF', 'Gene', (107, 110))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('pancreatic cancer', 'Disease', (171, 188))	('high', 'Var', (200, 204))	('pancreatic cancer', 'Disease', 'MESH:D010190', (171, 188))	('invasion-stimulating response', 'CPA', (138, 167))
20994	33271944	Another in vitro study demonstrated the invasiveness of a pancreatic cancer cell line (PK8) that was enhanced by conditioned medium from fibroblast cell line (MRC5) under hypoxic conditions; importantly this effect was reduced by neutralizing HGF in the conditioned medium.	('pancreatic cancer', 'Disease', (58, 75))	('pancreatic cancer', 'Disease', 'MESH:D010190', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('neutralizing', 'Var', (230, 242))	('invasiveness', 'CPA', (40, 52))	('enhanced', 'PosReg', (101, 109))	('MRC5', 'CellLine', 'CVCL:0440', (159, 163))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (58, 75))
21008	33271944	Aberrant MET activation is known to impart gemcitabine resistance (See review).	('Aberrant', 'Var', (0, 8))	('MET', 'Gene', '79811', (9, 12))	('activation', 'PosReg', (13, 23))	('gemcitabine resistance', 'MPA', (43, 65))	('MET', 'Gene', (9, 12))	('gemcitabine', 'Chemical', 'MESH:C056507', (43, 54))
21013	33271944	Notably, HGF/c-MET inhibition has been shown in preclinical models to increase drug delivery and improve chemotherapeutic response both in genetically engineered mouse models and orthotopic models of pancreatic cancer.	('increase', 'PosReg', (70, 78))	('inhibition', 'Var', (19, 29))	('HGF/c-MET', 'Protein', (9, 18))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (200, 217))	('mouse', 'Species', '10090', (162, 167))	('pancreatic cancer', 'Disease', (200, 217))	('pancreatic cancer', 'Disease', 'MESH:D010190', (200, 217))	('drug delivery', 'MPA', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('chemotherapeutic', 'MPA', (105, 121))	('improve', 'PosReg', (97, 104))
21022	33271944	There have been some encouraging data pertinent to HGF and/or c-MET inhibitors in clinical trials (mostly phase I/II trials) in several non-pancreatic cancers.	('pancreatic cancers', 'Phenotype', 'HP:0002894', (140, 158))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('c-MET', 'Protein', (62, 67))	('HGF', 'Protein', (51, 54))	('pancreatic cancers', 'Disease', 'MESH:D010190', (140, 158))	('pancreatic cancers', 'Disease', (140, 158))	('inhibitors', 'Var', (68, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))
21031	33271944	Michieli and colleagues showed that the transforming potential displayed by mutant forms of MET found in human cancer is sensitive to, and can be entirely dependent on, the availability of the ligand HGF.	('human', 'Species', '9606', (105, 110))	('MET', 'Gene', (92, 95))	('mutant', 'Var', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('ligand', 'molecular_function', 'GO:0005488', ('193', '199'))	('cancer', 'Disease', (111, 117))	('transforming potential', 'CPA', (40, 62))	('MET', 'Gene', '79811', (92, 95))
21032	33271944	Moreover, the mutant MET-induced transformation of cells in their study was inhibited by HGF antagonists and increased by HGF stimulation, supporting the concept of HGF as a potentially useful target molecule.	('MET', 'Gene', (21, 24))	('mutant', 'Var', (14, 20))	('transformation', 'CPA', (33, 47))	('increased', 'PosReg', (109, 118))	('inhibited', 'NegReg', (76, 85))	('HGF', 'Protein', (89, 92))	('MET', 'Gene', '79811', (21, 24))
21041	33271944	Interestingly, YYB102 binds to the alpha chain of HGF thus more efficiently blocking HGF from binding c-MET, thereby leading to almost total inhibition of the signalling events downstream of the HGF-c-MET complex.	('inhibition', 'NegReg', (141, 151))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('alpha chain', 'Gene', '2217', (35, 46))	('YYB102', 'Chemical', '-', (15, 21))	('alpha chain', 'Gene', (35, 46))	('binding', 'Interaction', (94, 101))	('HGF', 'Protein', (85, 88))	('blocking', 'NegReg', (76, 84))	('signalling', 'biological_process', 'GO:0023052', ('159', '169'))	('YYB102', 'Var', (15, 21))	('c-MET', 'Protein', (102, 107))	('signalling events downstream', 'MPA', (159, 187))
21042	33271944	In addition, YYB101 has 10-100-fold higher affinity for HGF than AMG102, making it a potentially superior HGF neutralising antibody when compared to AMG102.	('antibody', 'cellular_component', 'GO:0042571', ('123', '131'))	('higher', 'PosReg', (36, 42))	('antibody', 'cellular_component', 'GO:0019815', ('123', '131'))	('antibody', 'cellular_component', 'GO:0019814', ('123', '131'))	('HGF', 'Protein', (56, 59))	('affinity', 'Interaction', (43, 51))	('AMG102', 'Chemical', 'MESH:C524459', (65, 71))	('AMG102', 'Chemical', 'MESH:C524459', (149, 155))	('antibody', 'molecular_function', 'GO:0003823', ('123', '131'))	('YYB101', 'Var', (13, 19))
21058	33271944	In PC, crizotinib was specifically shown to inhibit peritoneal dissemination via suppressing HGF/MET signaling and RhoA activation.	('crizotinib', 'Var', (7, 17))	('suppressing', 'NegReg', (81, 92))	('inhibit', 'NegReg', (44, 51))	('RhoA', 'Gene', (115, 119))	('RhoA', 'Gene', '387', (115, 119))	('MET', 'Gene', '79811', (97, 100))	('peritoneal dissemination', 'CPA', (52, 76))	('crizotinib', 'Chemical', 'MESH:D000077547', (7, 17))	('PC', 'Phenotype', 'HP:0002894', (3, 5))	('MET', 'Gene', (97, 100))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))
21060	33271944	Several clinical reports described secondary MET mutations as mechanisms for crizotinib resistance, see Review One such report by Zhang and colleagues also discussed the case of a patient who simultaneously acquired four rare resistance mutations (G1163R, D1228H, D1228A, and Y1230H) after the development of crizotinib resistance.	('D1228H', 'Mutation', 'rs121913671', (256, 262))	('crizotinib', 'Chemical', 'MESH:D000077547', (77, 87))	('Y1230H', 'Var', (276, 282))	('Y1230H', 'Mutation', 'rs121913247', (276, 282))	('MET', 'Gene', '79811', (45, 48))	('MET', 'Gene', (45, 48))	('D1228A', 'Var', (264, 270))	('D1228H', 'Var', (256, 262))	('men', 'Species', '9606', (301, 304))	('crizotinib', 'Chemical', 'MESH:D000077547', (309, 319))	('D1228A', 'Mutation', 'p.D1228A', (264, 270))	('patient', 'Species', '9606', (180, 187))	('G1163R', 'Mutation', 'p.G1163R', (248, 254))	('G1163R', 'Var', (248, 254))
21065	33271944	HGF-induced endothelial cell motility was strongly reduced by INC280.	('INC280', 'Chemical', 'MESH:C000613976', (62, 68))	('reduced', 'NegReg', (51, 58))	('cell motility', 'biological_process', 'GO:0048870', ('24', '37'))	('INC280', 'Var', (62, 68))
21069	33271944	There are other phase II studies assessing the efficacy and safety of capmatinib monotherapy/combination therapy in patients with papillary renal cell carcinoma (NCT02019693), melanoma (NCT02159066) and solid tumours (NCT03040973).	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (130, 160))	('tumours', 'Phenotype', 'HP:0002664', (209, 216))	('solid tumours', 'Disease', (203, 216))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('melanoma', 'Disease', (176, 184))	('NCT02019693', 'Var', (162, 173))	('papillary renal cell carcinoma', 'Disease', (130, 160))	('capmatinib', 'Chemical', 'MESH:C000613976', (70, 80))	('patients', 'Species', '9606', (116, 124))	('capmatinib', 'Gene', (70, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('solid tumours', 'Disease', 'MESH:D009369', (203, 216))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (140, 160))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (130, 160))	('NCT02159066', 'Var', (186, 197))	('NCT03040973', 'Var', (218, 229))
21082	32871962	Our findings will show the effect of high expression of miRNA-21 on the prognosis of patients with pancreatic cancer.	('pancreatic cancer', 'Disease', (99, 116))	('high', 'Var', (37, 41))	('miRNA-21', 'Gene', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('patients', 'Species', '9606', (85, 93))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (99, 116))	('miRNA-21', 'Gene', '406991', (56, 64))	('pancreatic cancer', 'Disease', 'MESH:D010190', (99, 116))
21125	32871962	This meta-analysis will provide more accurate and objective evidence for the relationship between high miRNA-21 expression and pancreatic cancer survival.	('pancreatic cancer', 'Disease', (127, 144))	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('miRNA-21', 'Gene', (103, 111))	('high', 'Var', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))	('miRNA-21', 'Gene', '406991', (103, 111))	('expression', 'MPA', (112, 122))
21132	31842285	Intriguingly, we also found that abrogation of DDB1 expression increased PDAC cell sensitivity to gemcitabine (GEM).	('sensitivity to gemcitabine', 'MPA', (83, 109))	('DDB1', 'Gene', (47, 51))	('increased', 'PosReg', (63, 72))	('abrogation', 'Var', (33, 43))	('gemcitabine', 'Chemical', 'MESH:C056507', (98, 109))	('GEM', 'Chemical', 'MESH:C056507', (111, 114))	('PDAC', 'Disease', 'MESH:D010195', (73, 77))	('PDAC', 'Disease', (73, 77))	('PDAC', 'Phenotype', 'HP:0006725', (73, 77))
21133	31842285	Mechanistically, DDB1 knockdown was associated with an increase in deoxycytidine kinase expression in vivo and in vitro.	('deoxycytidine kinase', 'Gene', (67, 87))	('DDB1', 'Gene', (17, 21))	('increase', 'PosReg', (55, 63))	('knockdown', 'Var', (22, 31))	('deoxycytidine kinase', 'Gene', '1633', (67, 87))
21147	31842285	Inhibition of SNAI1 reduced the number of tumor-bearing mice and increased the membrane staining of E-cadherin, which supports that EMT is a key step towards cancer progression and metastasis in PDAC.	('PDAC', 'Disease', 'MESH:D010195', (195, 199))	('reduced', 'NegReg', (20, 27))	('E-cadherin', 'Gene', (100, 110))	('tumor', 'Disease', (42, 47))	('cancer', 'Disease', (158, 164))	('PDAC', 'Phenotype', 'HP:0006725', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('E-cadherin', 'Gene', '12550', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('membrane', 'cellular_component', 'GO:0016020', ('79', '87'))	('increased', 'PosReg', (65, 74))	('Inhibition', 'Var', (0, 10))	('SNAI1', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('EMT', 'biological_process', 'GO:0001837', ('132', '135'))	('membrane staining', 'MPA', (79, 96))	('PDAC', 'Disease', (195, 199))	('mice', 'Species', '10090', (56, 60))	('cadherin', 'molecular_function', 'GO:0008014', ('102', '110'))
21149	31842285	The deletion of DDB1 abrogates the self-renewing capacity of hepatocytes and results in the compensatory proliferation of DDB1-expressing hepatocytes, thus leading to hepatocellular carcinoma.	('DDB1', 'Gene', (16, 20))	('leading to', 'Reg', (156, 166))	('results in', 'Reg', (77, 87))	('abrogates', 'NegReg', (21, 30))	('deletion', 'Var', (4, 12))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (167, 191))	('compensatory', 'MPA', (92, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('hepatocellular carcinoma', 'Disease', (167, 191))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (167, 191))	('self-renewing capacity of hepatocytes', 'CPA', (35, 72))
21157	31842285	By analyzing the publicly assessable data for of PDAC within the Gene Expression Profiling Interactive Analysis (GEPIA) dataset, we found that DDB1 transcription was increased significantly in pancreatic cancer tissues and varied in different stages (Figure 1A,B); high mRNA expression of DDB1 was associated with shorter overall survival (OS) (p = 0.012) but not disease-free survival (DFS) (p = 0.22; Figure 1C).	('DDB1', 'Gene', (143, 147))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (193, 210))	('increased', 'PosReg', (166, 175))	('Gene Expression', 'biological_process', 'GO:0010467', ('65', '80'))	('overall survival', 'MPA', (322, 338))	('DDB1', 'Gene', (289, 293))	('PDAC', 'Disease', 'MESH:D010195', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('transcription', 'MPA', (148, 161))	('shorter', 'NegReg', (314, 321))	('high mRNA', 'Var', (265, 274))	('PDAC', 'Disease', (49, 53))	('PDAC', 'Phenotype', 'HP:0006725', (49, 53))	('pancreatic cancer', 'Disease', (193, 210))	('pancreatic cancer', 'Disease', 'MESH:D010190', (193, 210))	('transcription', 'biological_process', 'GO:0006351', ('148', '161'))
21162	31842285	High DDB1 expression was associated with a poorer median survival of 11.5 months, which was 10.1 months shorter than that of patients with low expression (Figure 1F; p = 0.002).	('DDB1', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (125, 133))
21168	31842285	To verify whether DDB1 is involved in PDAC cell motility, we performed wound healing and transwell assays in control and DDB1 knockdown cells.	('PDAC', 'Disease', 'MESH:D010195', (38, 42))	('DDB1', 'Gene', (121, 125))	('PDAC', 'Disease', (38, 42))	('PDAC', 'Phenotype', 'HP:0006725', (38, 42))	('wound healing', 'biological_process', 'GO:0042060', ('71', '84'))	('knockdown', 'Var', (126, 135))	('cell motility', 'biological_process', 'GO:0048870', ('43', '56'))
21171	31842285	Consistent with the cellular phenotype, DDB1 knockdown was associated with decreased SNAI1, ZEB1 and VIMENTIN expression at both the mRNA and protein levels (Figure 2H,I), indicating that DDB1 knockdown was inversely correlated with an EMT phenotype in PDAC cells.	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('EMT', 'biological_process', 'GO:0001837', ('236', '239'))	('PDAC', 'Disease', (253, 257))	('ZEB1', 'Gene', '6935', (92, 96))	('VIMENTIN', 'Gene', '7431', (101, 109))	('PDAC', 'Phenotype', 'HP:0006725', (253, 257))	('SNAI1', 'Gene', (85, 90))	('ZEB1', 'Gene', (92, 96))	('expression', 'MPA', (110, 120))	('VIMENTIN', 'cellular_component', 'GO:0045098', ('101', '109'))	('VIMENTIN', 'cellular_component', 'GO:0045099', ('101', '109'))	('DDB1', 'Gene', (40, 44))	('PDAC', 'Disease', 'MESH:D010195', (253, 257))	('VIMENTIN', 'Gene', (101, 109))	('knockdown', 'Var', (45, 54))	('decreased', 'NegReg', (75, 84))
21172	31842285	As EMT-like phenotypes are well known for their relationship with chemoresistance, we hypothesized that the abrogation of DDB1 expression might sensitize PDAC cells to GEM treatment.	('DDB1', 'Gene', (122, 126))	('abrogation', 'Var', (108, 118))	('PDAC', 'Disease', 'MESH:D010195', (154, 158))	('PDAC', 'Disease', (154, 158))	('sensitize', 'Reg', (144, 153))	('PDAC', 'Phenotype', 'HP:0006725', (154, 158))	('GEM', 'Chemical', 'MESH:C056507', (168, 171))	('EMT', 'biological_process', 'GO:0001837', ('3', '6'))
21173	31842285	We tested this by using a cell viability assay to analyze whether silencing DDB1 would affect GEM treatment.	('silencing', 'Var', (66, 75))	('affect', 'Reg', (87, 93))	('GEM', 'Chemical', 'MESH:C056507', (94, 97))	('DDB1', 'Gene', (76, 80))	('GEM treatment', 'CPA', (94, 107))
21175	31842285	A colony formation assay also confirmed that silencing DDB1 could further reduce the colony formation ability of GEM-treated MiaPaCa-2 and PANC-1 cells compared to control cells (Figure 3B,C).	('silencing', 'Var', (45, 54))	('PANC-1', 'CellLine', 'CVCL:0480', (139, 145))	('formation', 'biological_process', 'GO:0009058', ('92', '101'))	('reduce', 'NegReg', (74, 80))	('colony formation ability', 'CPA', (85, 109))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (125, 134))	('DDB1', 'Gene', (55, 59))	('formation', 'biological_process', 'GO:0009058', ('9', '18'))	('GEM', 'Chemical', 'MESH:C056507', (113, 116))
21180	31842285	In vivo data confirmed the increased sensitivity to GEM treatment in DDB1 knockdown PDAC cells.	('increased', 'PosReg', (27, 36))	('PDAC', 'Disease', (84, 88))	('PDAC', 'Phenotype', 'HP:0006725', (84, 88))	('GEM', 'Chemical', 'MESH:C056507', (52, 55))	('knockdown', 'Var', (74, 83))	('DDB1', 'Gene', (69, 73))	('sensitivity', 'MPA', (37, 48))	('PDAC', 'Disease', 'MESH:D010195', (84, 88))
21183	31842285	More importantly, Ki-67 expression was reduced in shDDB1 groups treated with PBS and was remarkably reduced in shDDB1 groups treated with GEM; these results indicated a decreased cell proliferation rate in the shDDB1 groups, especially when sensitized by GEM (Figure 4D).	('shDDB1', 'Var', (210, 216))	('cell proliferation rate', 'CPA', (179, 202))	('expression', 'MPA', (24, 34))	('reduced', 'NegReg', (100, 107))	('GEM', 'Chemical', 'MESH:C056507', (138, 141))	('cell proliferation', 'biological_process', 'GO:0008283', ('179', '197'))	('reduced', 'NegReg', (39, 46))	('decreased', 'NegReg', (169, 178))	('GEM', 'Chemical', 'MESH:C056507', (255, 258))	('Ki-67', 'Protein', (18, 23))
21189	31842285	Therefore, we suspected that dCK may mediate the increased sensitivity of PDAC cells to GEM treatment caused by DDB1 knockdown.	('dCK', 'Gene', '43828', (29, 32))	('dCK', 'Gene', (29, 32))	('DDB1', 'Gene', (112, 116))	('PDAC', 'Disease', (74, 78))	('PDAC', 'Phenotype', 'HP:0006725', (74, 78))	('GEM', 'Chemical', 'MESH:C056507', (88, 91))	('PDAC', 'Disease', 'MESH:D010195', (74, 78))	('knockdown', 'Var', (117, 126))
21190	31842285	Indeed, our qRT-PCR and Western blotting results showed dCK upregulation after DDB1 deletion in the MiaPaCa-2 and PANC-1 cell lines (Figure 4E,F).	('PANC-1', 'CellLine', 'CVCL:0480', (114, 120))	('deletion', 'Var', (84, 92))	('DDB1', 'Gene', (79, 83))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (100, 109))	('upregulation', 'PosReg', (60, 72))	('dCK', 'Gene', '43828', (56, 59))	('dCK', 'Gene', (56, 59))
21203	31842285	Nucleolar sirtuin 7 (SIRT7) promotes DDB1 deacetylation, resulting in a decrease in DDB1-CUL4 activity and contributing to apoptosis in cells treated with 5-fluorouracil; in addition, sensitivity to cisplatin treatment could be stimulated by silencing DDB1.	('deacetylation', 'MPA', (42, 55))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (155, 169))	('cisplatin', 'Chemical', 'MESH:D002945', (199, 208))	('SIRT7', 'Gene', (21, 26))	('stimulated', 'PosReg', (228, 238))	('SIRT7', 'Gene', '51547', (21, 26))	('DDB1-CUL4 activity', 'MPA', (84, 102))	('sirtuin 7', 'Gene', '51547', (10, 19))	('silencing', 'Var', (242, 251))	('sirtuin 7', 'Gene', (10, 19))	('apoptosis', 'CPA', (123, 132))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('decrease', 'NegReg', (72, 80))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))	('DDB1', 'Gene', (37, 41))	('DDB1', 'Gene', (252, 256))
21206	31842285	We found decreased mesenchymal markers and increased epithelial markers in DDB1 knockdown PDAC cells compared to normal PDAC cells.	('PDAC', 'Disease', (90, 94))	('PDAC', 'Phenotype', 'HP:0006725', (90, 94))	('DDB1', 'Gene', (75, 79))	('knockdown', 'Var', (80, 89))	('PDAC', 'Disease', 'MESH:D010195', (120, 124))	('PDAC', 'Disease', (120, 124))	('PDAC', 'Phenotype', 'HP:0006725', (120, 124))	('epithelial markers', 'MPA', (53, 71))	('PDAC', 'Disease', 'MESH:D010195', (90, 94))	('decreased', 'NegReg', (9, 18))	('increased', 'PosReg', (43, 52))	('mesenchymal markers', 'CPA', (19, 38))
21207	31842285	Numerous studies have suggested that EMT is pivotal for PDAC invasion and metastasis, but genetically engineered mouse models with SNAI1 deletion failed to alter the progression of PDAC.	('PDAC', 'Phenotype', 'HP:0006725', (56, 60))	('EMT', 'biological_process', 'GO:0001837', ('37', '40'))	('PDAC', 'Disease', 'MESH:D010195', (181, 185))	('deletion', 'Var', (137, 145))	('PDAC', 'Disease', (181, 185))	('PDAC', 'Disease', 'MESH:D010195', (56, 60))	('PDAC', 'Phenotype', 'HP:0006725', (181, 185))	('PDAC', 'Disease', (56, 60))	('mouse', 'Species', '10090', (113, 118))	('SNAI1', 'Gene', (131, 136))
21212	31842285	The results of the present study suggest that DDB1 knockdown can increase dCK expression in PDAC cells.	('increase', 'PosReg', (65, 73))	('dCK', 'Gene', '43828', (74, 77))	('dCK', 'Gene', (74, 77))	('PDAC', 'Disease', (92, 96))	('PDAC', 'Phenotype', 'HP:0006725', (92, 96))	('DDB1', 'Gene', (46, 50))	('PDAC', 'Disease', 'MESH:D010195', (92, 96))	('knockdown', 'Var', (51, 60))
21216	31842285	We found that dCK was also associated with SNAI1 expression at both the RNA and protein levels, and it is possible that DDB1 induces GEM resistance through novel mechanisms.	('GEM resistance', 'CPA', (133, 147))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('associated', 'Reg', (27, 37))	('expression', 'MPA', (49, 59))	('SNAI1', 'Gene', (43, 48))	('dCK', 'Gene', '43828', (14, 17))	('induces', 'PosReg', (125, 132))	('dCK', 'Gene', (14, 17))	('RNA', 'cellular_component', 'GO:0005562', ('72', '75'))	('DDB1', 'Var', (120, 124))	('GEM', 'Chemical', 'MESH:C056507', (133, 136))
21229	31842285	Patients could be divided into 2 groups based on their scores (-/+ as low expression and ++/+++ as high expression).	('Patients', 'Species', '9606', (0, 8))	('-/+', 'Var', (63, 66))	('++/+++', 'Var', (89, 95))
21263	31615457	The most recent clinical trial on adjuvant chemotherapy for pancreatic cancer, the PRODIGE 24/CCTG PA.6 trial, reported a median survival of 54.4 months and a three-year survival rate of 63.4% in patients receiving a modified regimen of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) after curative surgery.	('CCTG', 'Gene', (94, 98))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('CCTG', 'Gene', '7203', (94, 98))	('patients', 'Species', '9606', (196, 204))	('irinotecan', 'Chemical', 'MESH:C051890', (250, 260))	('pancreatic cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('modified', 'Var', (217, 225))	('oxaliplatin', 'Chemical', 'MESH:C030110', (237, 248))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('fluorouracil', 'Chemical', 'MESH:D005472', (262, 274))	('leucovorin', 'Chemical', 'MESH:D002955', (280, 290))
21300	31615457	In the univariate Cox proportional hazard regression model predicting OS, five covariates showed p <= 0.2; these were histologic grade, lymphovascular invasion, perineural invasion, pathologic T stage, and preoperative CA19-9 >= 100 U/mL.	('CA19-9 >= 100 U/mL', 'Var', (219, 237))	('Cox', 'Gene', '1351', (18, 21))	('lymphovascular invasion', 'CPA', (136, 159))	('Cox', 'Gene', (18, 21))	('perineural invasion', 'CPA', (161, 180))
21315	31615457	The recent study demonstrated that the modified-FOLFIRINOX regimen showed significantly longer survival than did gemcitabine among patients with resected pancreatic cancer.	('patients', 'Species', '9606', (131, 139))	('gemcitabine', 'Chemical', 'MESH:C056507', (113, 124))	('pancreatic cancer', 'Disease', 'MESH:D010190', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('survival', 'MPA', (95, 103))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (154, 171))	('modified-FOLFIRINOX', 'Var', (39, 58))	('longer', 'PosReg', (88, 94))	('pancreatic cancer', 'Disease', (154, 171))
21341	30644396	macrophage inhibitory cytokine-1, K-ras, mesothelin, PSCA, mucins, SMAD4 and p53 mutations) have been receiving attention as potential PDAC diagnostic and prognostic biomarkers, and many are currently undergoing validation for early detection and prediction of PDAC progression.	('K-ras', 'Gene', '3845', (34, 39))	('PSCA', 'Gene', (53, 57))	('mesothelin', 'Gene', '10232', (41, 51))	('SMAD4', 'Gene', (67, 72))	('PDAC', 'Chemical', '-', (261, 265))	('macrophage inhibitory cytokine-1', 'Gene', '9518', (0, 32))	('p53', 'Gene', (77, 80))	('PSCA', 'Gene', '8000', (53, 57))	('PDAC', 'Chemical', '-', (135, 139))	('p53', 'Gene', '7157', (77, 80))	('mutations', 'Var', (81, 90))	('macrophage inhibitory cytokine-1', 'Gene', (0, 32))	('K-ras', 'Gene', (34, 39))	('SMAD4', 'Gene', '4089', (67, 72))	('mesothelin', 'Gene', (41, 51))
21350	30644396	Further functional and survival analysis of the identified miRNA-mRNA interacting pairs, identified an association with pathways linked to cancer progression and survival.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('association', 'Reg', (103, 114))	('miRNA-mRNA interacting pairs', 'Var', (59, 87))	('pathways', 'Pathway', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (139, 145))
21363	30644396	The miRNA meta-analysis identified 23 consistently and significantly DE miRNAs; 7 upregulated (miRNA-218-2*, miRNA-1249, miRNA-1254, miRNA-653, miRNA-132*, miRNA-143*, miRNA-877*) 16 downregulated (miRNA-27b*, miRNA-548d-3p, miRNA-604, miRNA-148a, miRNA-151-3p, miRNA-29b, miRNA-130b, miRNA-200c, miRNA-217, miRNA-29a, miRNA-194, miRNA-548b-3p, miRNA-376c, miRNA-335, miRNA-379, miRNA-27b) in CP (tissue and plasma) compared to normal, P value <= 0.05 (miRNA CP meta-signature).	('miRNA-130b', 'Var', (273, 283))	('miRNA-21', 'Gene', '406991', (95, 103))	('miRNA-27b', 'Gene', '407019', (379, 388))	('miRNA-132', 'Gene', '406921', (144, 153))	('miRNA-21', 'Gene', (95, 103))	('miRNA-548b-3p', 'Var', (330, 343))	('miRNA-335', 'Gene', (357, 366))	('miRNA-200c', 'Var', (285, 295))	('downregulated', 'NegReg', (183, 196))	('miRNA-151-3p', 'Var', (248, 260))	('miRNA-27b', 'Gene', (198, 207))	('miRNA-376c', 'Var', (345, 355))	('miRNA-29a', 'Gene', '407021', (308, 317))	('upregulated', 'PosReg', (82, 93))	('miRNA-1249', 'Var', (109, 119))	('miRNA-29a', 'Gene', (308, 317))	('miRNA-194', 'Var', (319, 328))	('miRNA-1254', 'Var', (121, 131))	('miRNA-877', 'Gene', '100126314', (168, 177))	('miRNA-335', 'Gene', '442904', (357, 366))	('miRNA-604', 'Var', (225, 234))	('miRNA-143*', 'Var', (156, 166))	('miRNA-27b', 'Gene', (379, 388))	('miRNA-653', 'Var', (133, 142))	('miRNA-29b', 'Var', (262, 271))	('miRNA-148a', 'Var', (236, 246))	('miRNA-132', 'Gene', (144, 153))	('miRNA-21', 'Gene', '406991', (297, 305))	('miRNA-379', 'Var', (368, 377))	('miRNA-27b', 'Gene', '407019', (198, 207))	('miRNA-21', 'Gene', (297, 305))	('miRNA-877', 'Gene', (168, 177))
21369	30644396	miRNA-130b, 148a, 151-3p, 194, 200c, 217, 29a, 29b, 548d-3p, 604, 335, 379, 27b were all found to be downregulated in CP and PDAC groups as compared to HC, P value < 0.05 (Table 2).	('miRNA-130b', 'Var', (0, 10))	('downregulated', 'NegReg', (101, 114))	('PDAC', 'Disease', (125, 129))	('PDAC', 'Chemical', '-', (125, 129))
21408	30644396	The upregulated TFs in MPDAC are known to be involved in shorter survival of cancer patients (PU1), metastasis (TP63), vasculogenesis (FLI-1) and cellular functions including cell proliferation, DNA damage and repair, apoptosis and stress response (FOXO1).	('vasculogenesis', 'CPA', (119, 133))	('FLI-1', 'Gene', '2313', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('MPDAC', 'Chemical', '-', (23, 28))	('TP63', 'Gene', (112, 116))	('cell proliferation', 'biological_process', 'GO:0008283', ('175', '193'))	('vasculogenesis', 'biological_process', 'GO:0001570', ('119', '133'))	('MPDAC', 'Gene', (23, 28))	('apoptosis', 'biological_process', 'GO:0097194', ('218', '227'))	('cell proliferation', 'CPA', (175, 193))	('apoptosis', 'biological_process', 'GO:0006915', ('218', '227'))	('patients', 'Species', '9606', (84, 92))	('PU1', 'Gene', (94, 97))	('FLI-1', 'Gene', (135, 140))	('TP63', 'Gene', '8626', (112, 116))	('upregulated', 'PosReg', (4, 15))	('metastasis', 'CPA', (100, 110))	('FOXO1', 'Gene', '2308', (249, 254))	('apoptosis', 'CPA', (218, 227))	('cancer', 'Disease', (77, 83))	('TFs', 'Var', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('FOXO1', 'Gene', (249, 254))	('shorter', 'NegReg', (57, 64))	('PU1', 'Gene', '6688', (94, 97))	('DNA', 'cellular_component', 'GO:0005574', ('195', '198'))
21422	30644396	The results showed that both miRNA-29a and miRNA-29b were able to clearly discriminate between better versus poor survivors (P-value 0.06 and 0.01, respectively), indicating their prognostic role in PDAC.	('miRNA-29a', 'Gene', '407021', (29, 38))	('PDAC', 'Chemical', '-', (199, 203))	('miRNA-29a', 'Gene', (29, 38))	('miRNA-29b', 'Var', (43, 52))	('PDAC', 'Disease', (199, 203))
21427	30644396	Genetic variation and expression of AKAP13, a protein kinase, is associated to regulation of cancer and response to cardiac hypertrophy.	('cancer', 'Disease', (93, 99))	('Genetic variation', 'Var', (0, 17))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cardiac hypertrophy', 'Disease', (116, 135))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('AKAP13', 'Gene', '11214', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('associated', 'Reg', (65, 75))	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (116, 135))	('AKAP13', 'Gene', (36, 42))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (116, 135))	('regulation', 'Disease', (79, 89))	('regulation', 'biological_process', 'GO:0065007', ('79', '89'))
21429	30644396	From the meta-analysis, network analysis, and survival analysis data the most potent miRNA that appeared promising for further validation was miRNA-29a and miRNA-29b.	('miRNA-29a', 'Gene', (142, 151))	('miRNA-29b', 'Var', (156, 165))	('miRNA-29a', 'Gene', '407021', (142, 151))
21443	30644396	The preprocessing of the microarray data using Z normalization brought the data from many studies into consistent ranges that allowed the identification of persistently dysregulated miRNAs in CP and PDAC in both tissue and blood samples.	('miRNAs', 'Var', (182, 188))	('dysregulated', 'PosReg', (169, 181))	('PDAC', 'Chemical', '-', (199, 203))
21458	30644396	miRNA-29b has been shown to critically affect cancer progression by functioning as a tumor suppressor.	('tumor', 'Disease', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor suppressor', 'biological_process', 'GO:0051726', ('85', '101'))	('cancer', 'Disease', (46, 52))	('affect', 'Reg', (39, 45))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('85', '101'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('miRNA-29b', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
21474	30644396	miRNA-29 also plays a critical role in regulating tumor stromal deposition and cancer growth, thereby implying that modulation of miRNA-29 expression may be a therapeutically beneficial target to enhance the efficacy of chemotherapy for the improved treatment of PDAC.	('enhance', 'PosReg', (196, 203))	('modulation', 'Var', (116, 126))	('PDAC', 'Disease', (263, 267))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('miRNA-29', 'Gene', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('PDAC', 'Chemical', '-', (263, 267))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('tumor', 'Disease', (50, 55))
21515	29435134	Therefore, in our study we decided to assess the ability of AgNPs to kill pancreatic cancer cells, and then to identify the molecular mechanism underlying this effect.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('AgNPs', 'Var', (60, 65))	('kill', 'CPA', (69, 73))	('pancreatic cancer', 'Disease', (74, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
21519	29435134	Moreover, AgNPs significantly elevated the level of tumor suppressor p53 protein as well as necroptosis- and autophagy-related proteins: RIP-1, RIP-3, MLKL and LC3-II, respectively.	('MLKL', 'Gene', (151, 155))	('autophagy-related', 'CPA', (109, 126))	('RIP-1', 'Gene', '8737', (137, 142))	('tumor', 'Disease', (52, 57))	('elevated', 'PosReg', (30, 38))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('RIP-3', 'Gene', '11035', (144, 149))	('level', 'MPA', (43, 48))	('MLKL', 'Gene', '197259', (151, 155))	('RIP-1', 'Gene', (137, 142))	('AgNPs', 'Var', (10, 15))	('LC3', 'Gene', '84557', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('autophagy', 'biological_process', 'GO:0016236', ('109', '118'))	('necroptosis', 'biological_process', 'GO:0070266', ('92', '103'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('52', '68'))	('necroptosis', 'biological_process', 'GO:0097528', ('92', '103'))	('RIP-3', 'Gene', (144, 149))	('autophagy', 'biological_process', 'GO:0006914', ('109', '118'))	('necroptosis-', 'CPA', (92, 104))	('tumor suppressor', 'biological_process', 'GO:0051726', ('52', '68'))	('LC3', 'Gene', (160, 163))
21557	29435134	2.6 nm AgNPs exerted about 16-fold higher cytotoxicity than 18 nm AgNPs.	('cytotoxicity', 'Disease', (42, 54))	('AgNPs', 'Var', (7, 12))	('cytotoxicity', 'Disease', 'MESH:D064420', (42, 54))	('higher', 'PosReg', (35, 41))
21579	29435134	Moreover, we found PANC-1 cells increase in size with multiple nuclei (multinucleation) after exposure to 2.6 nm AgNPs at concentration of 0.5 mug/mL (Figure 6D).	('increase', 'PosReg', (32, 40))	('AgNPs', 'Var', (113, 118))	('rat', 'Species', '10116', (129, 132))	('PANC-1', 'CellLine', 'CVCL:0480', (19, 25))	('mug', 'molecular_function', 'GO:0043739', ('143', '146'))
21595	29435134	Statistically significant increase of RIP3 and MLKL protein level was found after treatment with 2.5 mug/mL 2.6 nm AgNPs and after exposure to 25 mug/mL and 50 mug/mL 18 nm AgNPs.	('MLKL', 'Gene', (47, 51))	('mug', 'molecular_function', 'GO:0043739', ('101', '104'))	('mug', 'molecular_function', 'GO:0043739', ('146', '149'))	('RIP3', 'Gene', '11035', (38, 42))	('mug', 'molecular_function', 'GO:0043739', ('160', '163'))	('2.6 nm AgNPs', 'Var', (108, 120))	('MLKL', 'Gene', '197259', (47, 51))	('AgNPs', 'Var', (115, 120))	('RIP3', 'Gene', (38, 42))	('increase', 'PosReg', (26, 34))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
21610	29435134	In our previous study, we demonstrated that AgNO3 exerted more cytotoxic effect against human gingival fibroblast cells in comparison to 10 nm AgNPs.	('AgNO3', 'Chemical', 'MESH:D012835', (44, 49))	('cytotoxic effect', 'CPA', (63, 79))	('rat', 'Species', '10116', (33, 36))	('AgNO3', 'Var', (44, 49))	('human', 'Species', '9606', (88, 93))
21622	29435134	found that AgNPs may be approximately 2-fold more cytotoxic to acute myeloid leukemia compared to healthy human bone marrow cells.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (63, 85))	('human', 'Species', '9606', (106, 111))	('leukemia', 'Phenotype', 'HP:0001909', (77, 85))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (63, 85))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (69, 85))	('AgNPs', 'Var', (11, 16))	('acute myeloid leukemia', 'Disease', (63, 85))
21632	29435134	What is more, AgNPs showed more than a hundred thousand-fold higher efficiency compared with gemcitabine to decrease pancreatic cancer cell viability and induced pancreatic cancer cells death.	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('higher', 'PosReg', (61, 67))	('induced', 'Reg', (154, 161))	('pancreatic cancer', 'Disease', (117, 134))	('pancreatic cancer', 'Disease', (162, 179))	('AgNPs', 'Var', (14, 19))	('pancreatic cancer', 'Disease', 'MESH:D010190', (162, 179))	('gemcitabine', 'Chemical', 'MESH:C056507', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('decrease', 'NegReg', (108, 116))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (162, 179))
21654	29435134	found that human squamous carcinoma cells exposed to 10 nm AgNPs resulted in an increase of pro-apoptotic proteins (Bax).	('Bax', 'Gene', '581', (116, 119))	('human', 'Species', '9606', (11, 16))	('squamous carcinoma', 'Disease', 'MESH:D002294', (17, 35))	('increase', 'PosReg', (80, 88))	('squamous carcinoma', 'Disease', (17, 35))	('AgNPs', 'Var', (59, 64))	('Bax', 'Gene', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (17, 35))
21658	29435134	We noticed that both 2.6 and 18 nm AgNPs caused an elevation of p53 protein level in PANC-1 cells.	('PANC-1', 'CellLine', 'CVCL:0480', (85, 91))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('AgNPs', 'Var', (35, 40))	('elevation', 'PosReg', (51, 60))	('p53 protein level', 'MPA', (64, 81))
21661	29435134	Also, AgNPs are known to induce p53-mediated apoptosis in human breast cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('human', 'Species', '9606', (58, 63))	('AgNPs', 'Var', (6, 11))	('induce', 'PosReg', (25, 31))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('p53-mediated apoptosis', 'CPA', (32, 54))	('breast cancer', 'Disease', (64, 77))
21665	29435134	indicated that activation of p53 enhanced autophagy levels in cells, which might contribute to the tumor suppressor functions of p53.	('tumor', 'Disease', (99, 104))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('99', '115'))	('autophagy levels in cells', 'CPA', (42, 67))	('autophagy', 'biological_process', 'GO:0006914', ('42', '51'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('99', '115'))	('p53', 'Gene', (29, 32))	('activation', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('autophagy', 'biological_process', 'GO:0016236', ('42', '51'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('enhanced', 'PosReg', (33, 41))
21671	29435134	It has been found that inhibition of autophagy may be a new therapeutic approach in the treatment of pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (101, 118))	('inhibition', 'Var', (23, 33))	('pancreatic cancer', 'Disease', (101, 118))	('pancreatic cancer', 'Disease', 'MESH:D010190', (101, 118))	('autophagy', 'biological_process', 'GO:0016236', ('37', '46'))	('autophagy', 'CPA', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('autophagy', 'biological_process', 'GO:0006914', ('37', '46'))
21677	29435134	Indeed, in our study we have observed that 2.6 and 18 nm AgNPs-induced apoptotic as well necroptotic PANC-1 cell death was associated with increased level of autophagy markers (LC-3) and formation of autophagosomes.	('autophagy', 'biological_process', 'GO:0016236', ('158', '167'))	('cell death', 'biological_process', 'GO:0008219', ('108', '118'))	('formation of autophagosomes', 'CPA', (187, 214))	('formation', 'biological_process', 'GO:0009058', ('187', '196'))	('LC-3', 'Gene', '84557', (177, 181))	('increased', 'PosReg', (139, 148))	('PANC-1', 'CellLine', 'CVCL:0480', (101, 107))	('AgNPs-induced', 'Gene', (57, 70))	('autophagy', 'biological_process', 'GO:0006914', ('158', '167'))	('2.6', 'Var', (43, 46))	('level', 'MPA', (149, 154))	('LC-3', 'Gene', (177, 181))	('apoptotic', 'CPA', (71, 80))
21722	29435134	M300F- 500) (3:1 ratio) with 2 mM L-glutamine adjusted to 1.5 g/L sodium bicarbonate and supplemented with 5% FBS, 10 ng/ml human recombinant EGF, 5.5 mM D-glucose (1g/L) and 750 ng/mL puromycin, at 37 C in a humidified atmosphere of 5% CO2.	('sodium bicarbonate', 'Chemical', 'MESH:D017693', (66, 84))	('M300F- 500', 'Var', (0, 10))	('FBS', 'Disease', (110, 113))	('rat', 'Species', '10116', (17, 20))	('glutamine', 'Chemical', 'MESH:D005973', (36, 45))	('EGF', 'molecular_function', 'GO:0005154', ('142', '145'))	('human', 'Species', '9606', (124, 129))	('CO2', 'Chemical', '-', (237, 240))	('D-glucose', 'Chemical', 'MESH:D005947', (154, 163))	('FBS', 'Disease', 'MESH:D005198', (110, 113))	('puromycin', 'Chemical', 'MESH:D011691', (185, 194))	('M300F', 'Mutation', 'p.M300F', (0, 5))
21762	29435134	The samples (40 mug protein per lane) were boiled for 5 minutes and separated by SDS-PAGE on polyacrylamide gel and transferred onto nitrocellulose membrane, which was blocked with 5% non-fat dry milk-PBST buffer (phosphate-buffered saline (PBS) containing 0.1% Tween-20) for 1 hour at room temperature and incubated at 4 C overnight with rabbit polyclonal antibody: anti-Bax, anti-Bcl-2, anti-RIP-1, anti-RIP-3, anti-LC3, anti-p53, and goat polyclonal anti-MLKL (diluted 1:500).	('RIP-3', 'Gene', '11035', (406, 411))	('goat', 'Species', '9925', (437, 441))	('antibody', 'cellular_component', 'GO:0019814', ('357', '365'))	('rat', 'Species', '10116', (72, 75))	('LC3', 'Gene', (418, 421))	('SDS', 'Chemical', 'MESH:D012967', (81, 84))	('PBS', 'Chemical', '-', (241, 244))	('MLKL', 'Gene', (458, 462))	('PBS', 'Chemical', '-', (201, 204))	('RIP-1', 'Gene', '8737', (394, 399))	('Bax', 'Gene', (372, 375))	('membrane', 'cellular_component', 'GO:0016020', ('148', '156'))	('Bcl-2', 'Gene', (382, 387))	('antibody', 'molecular_function', 'GO:0003823', ('357', '365'))	('Bax', 'Gene', '581', (372, 375))	('antibody', 'cellular_component', 'GO:0042571', ('357', '365'))	('RIP-3', 'Gene', (406, 411))	('MLKL', 'Gene', '197259', (458, 462))	('rat', 'Species', '10116', (296, 299))	('LC3', 'Gene', '84557', (418, 421))	('mug', 'molecular_function', 'GO:0043739', ('16', '19'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('382', '387'))	('RIP-1', 'Gene', (394, 399))	('boiled', 'Phenotype', 'HP:0020083', (43, 49))	('Bcl-2', 'Gene', '596', (382, 387))	('Tween', 'Chemical', 'MESH:D011136', (262, 267))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('rabbit', 'Species', '9986', (339, 345))	('antibody', 'cellular_component', 'GO:0019815', ('357', '365'))	('anti-p53', 'Var', (423, 431))
21776	29435134	Our results lead us to assume that AgNPs could bypass drug resistance by inducing mixed type of cell death in pancreatic ductal adenocarcinoma cells.	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (110, 142))	('cell death', 'biological_process', 'GO:0008219', ('96', '106'))	('inducing', 'Reg', (73, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('drug resistance', 'biological_process', 'GO:0042493', ('54', '69'))	('AgNPs', 'Var', (35, 40))	('mixed type of cell death', 'CPA', (82, 106))	('drug resistance', 'biological_process', 'GO:0009315', ('54', '69'))	('drug resistance', 'Phenotype', 'HP:0020174', (54, 69))	('pancreatic ductal adenocarcinoma', 'Disease', (110, 142))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (110, 142))
21815	29061632	S-1 administration will be suspended in case of neutrophils <1000/mm3, platelets <70 000/mm3, serum bilirubin level >=3.1 mg/dL, AST (aspartate transaminase) /ALT (alanine transaminase) >=200 U/L, serum creatinine >=1.5 mg/dL, diarrhoea greater than or equal to Common Terminology Criteria for Adverse Events (CTCAE) grade 2, stomatitis greater than or equal to CTCAE grade 2, febrile neutropaenia greater than or equal to CTCAE grade 3 or other non-haematological toxicity greater than or equal to CTCAE grade 3.	('stomatitis', 'Phenotype', 'HP:0010280', (326, 336))	('febrile neutropaenia', 'Disease', 'MESH:D064147', (377, 397))	('diarrhoea', 'Disease', (227, 236))	('S-1', 'Gene', (0, 3))	('AST', 'Gene', (129, 132))	('diarrhoea', 'Disease', 'MESH:D003967', (227, 236))	('creatinine', 'Chemical', 'MESH:D003404', (203, 213))	('>=3.1', 'Var', (116, 121))	('toxicity', 'Disease', 'MESH:D064420', (465, 473))	('diarrhoea', 'Phenotype', 'HP:0002014', (227, 236))	('<70 000/mm3', 'Var', (81, 92))	('ALT', 'molecular_function', 'GO:0004021', ('159', '162'))	('Adverse', 'Disease', (294, 301))	('bilirubin', 'Chemical', 'MESH:D001663', (100, 109))	('stomatitis', 'Disease', 'MESH:D013280', (326, 336))	('aspartate transaminase', 'Gene', (134, 156))	('stomatitis', 'Disease', (326, 336))	('toxicity', 'Disease', (465, 473))	('AST', 'Gene', '26503', (129, 132))	('S-1', 'Gene', '5707', (0, 3))	('aspartate transaminase', 'Gene', '26503', (134, 156))	('>=200 U/L', 'Var', (186, 195))	('febrile neutropaenia', 'Disease', (377, 397))	('serum bilirubin level', 'Phenotype', 'HP:0002904', (94, 115))
21816	29061632	S-1 administration will be discontinued until all of the following conditions are met: neutrophils >=2.5x10^9/L, platelets >= 75x10^9/L, serum bilirubin level <=3.0 mg/dL, AST/ALT <=150 U/L, serum creatinine <=1.2 mg/dL, diarrhoea less than or equal to CTCAE grade 1, stomatitis less than or equal to CTCAE grade 1, no febrile neutropaenia and other non-haematological toxicity less than or equal to CTCAE grade 2.	('diarrhoea', 'Phenotype', 'HP:0002014', (221, 230))	('stomatitis', 'Disease', 'MESH:D013280', (268, 278))	('stomatitis', 'Disease', (268, 278))	('S-1', 'Gene', (0, 3))	('creatinine', 'Chemical', 'MESH:D003404', (197, 207))	('bilirubin', 'Chemical', 'MESH:D001663', (143, 152))	('serum bilirubin level', 'Phenotype', 'HP:0002904', (137, 158))	('AST', 'Gene', '26503', (172, 175))	('>= 75x10^9/L', 'Var', (123, 135))	('stomatitis', 'Phenotype', 'HP:0010280', (268, 278))	('serum bilirubin level', 'MPA', (137, 158))	('febrile neutropaenia', 'Disease', (319, 339))	('febrile neutropaenia', 'Disease', 'MESH:D064147', (319, 339))	('diarrhoea', 'Disease', (221, 230))	('toxicity', 'Disease', 'MESH:D064420', (369, 377))	('ALT', 'molecular_function', 'GO:0004021', ('176', '179'))	('diarrhoea', 'Disease', 'MESH:D003967', (221, 230))	('AST', 'Gene', (172, 175))	('S-1', 'Gene', '5707', (0, 3))	('toxicity', 'Disease', (369, 377))
21818	29061632	RT will be interrupted in case of neutrophils <500/mm3, platelets <25 000/mm3, serum bilirubin level >=3.1 mg/dL, AST >=200 U/L, serum creatinine >=1.5 mg/dL, diarrhoea greater than or equal to CTCAE grade 3, febrile neutropaenia greater than or equal to CTCAE grade 3 or other non-haematological toxicity greater than or equal to CTCAE grade 3.	('<25 000/mm3', 'Var', (66, 77))	('febrile neutropaenia', 'Disease', (209, 229))	('toxicity', 'Disease', (297, 305))	('bilirubin', 'Chemical', 'MESH:D001663', (85, 94))	('serum bilirubin level', 'MPA', (79, 100))	('neutrophils <500/mm3', 'Var', (34, 54))	('>=3.1', 'Var', (101, 106))	('febrile neutropaenia', 'Disease', 'MESH:D064147', (209, 229))	('AST', 'Gene', (114, 117))	('creatinine', 'Chemical', 'MESH:D003404', (135, 145))	('diarrhoea', 'Disease', (159, 168))	('serum creatinine', 'MPA', (129, 145))	('AST', 'Gene', '26503', (114, 117))	('serum bilirubin level', 'Phenotype', 'HP:0002904', (79, 100))	('toxicity', 'Disease', 'MESH:D064420', (297, 305))	('diarrhoea', 'Disease', 'MESH:D003967', (159, 168))	('diarrhoea', 'Phenotype', 'HP:0002014', (159, 168))
21819	29061632	RT must be delayed until all of the following conditions are met: neutrophils >=500/mm3, platelets >=25 000/mm3, serum bilirubin level <=3.0 mg/dL, AST/ALT <=150 U/L, serum creatinine <=1.2 mg/dL, diarrhoea less than or equal to CTCAE grade 2, no febrile neutropaenia and other non-haematological toxicity less than or equal to CTCAE grade 2.	('bilirubin', 'Chemical', 'MESH:D001663', (119, 128))	('toxicity', 'Disease', (297, 305))	('>=25 000/mm3', 'Var', (99, 111))	('serum bilirubin level', 'Phenotype', 'HP:0002904', (113, 134))	('diarrhoea', 'Disease', 'MESH:D003967', (197, 206))	('febrile neutropaenia', 'Disease', 'MESH:D064147', (247, 267))	('diarrhoea', 'Phenotype', 'HP:0002014', (197, 206))	('ALT', 'molecular_function', 'GO:0004021', ('152', '155'))	('AST', 'Gene', (148, 151))	('>=500/mm3', 'Var', (78, 87))	('creatinine', 'Chemical', 'MESH:D003404', (173, 183))	('serum bilirubin level', 'MPA', (113, 134))	('diarrhoea', 'Disease', (197, 206))	('febrile neutropaenia', 'Disease', (247, 267))	('toxicity', 'Disease', 'MESH:D064420', (297, 305))	('AST', 'Gene', '26503', (148, 151))
21877	28466015	Evaluation of Plasma MicroRNAs as Diagnostic and Prognostic Biomarkers in Pancreatic Adenocarcinoma: miR-196a and miR-210 Could Be Negative and Positive Prognostic Markers, Respectively Background.	('miR-21', 'Gene', '406991', (114, 120))	('miR-210', 'Gene', (114, 121))	('miR-210', 'Gene', '406992', (114, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('Pancreatic Adenocarcinoma', 'Disease', 'MESH:D010190', (74, 99))	('Pancreatic Adenocarcinoma', 'Phenotype', 'HP:0006725', (74, 99))	('miR-21', 'Gene', (114, 120))	('Pancreatic Adenocarcinoma', 'Disease', (74, 99))	('miR-196a', 'Var', (101, 109))
21884	28466015	The aberrant expression of several miRNAs, considered as diagnostic markers of malignancies, has been widely reported.	('malignancies', 'Disease', 'MESH:D009369', (79, 91))	('aberrant', 'Var', (4, 12))	('malignancies', 'Disease', (79, 91))
21885	28466015	reported 6 new miRNA-based biomarkers (miR-20a, miR-24, miR-25, miR-99a, miR-185, and miR-191) along with miR-21 and indicated that they were highly sensitive and specific in distinguishing various stages of PDAC from cancer-free pancreatic tissues.	('PDAC', 'Disease', (208, 212))	('miR-99a', 'Gene', '407055', (64, 71))	('miR-191', 'Gene', '406966', (86, 93))	('miR-185', 'Gene', '406961', (73, 80))	('miR-191', 'Gene', (86, 93))	('miR-99a', 'Gene', (64, 71))	('miR-24', 'Var', (48, 54))	('miR-25', 'Var', (56, 62))	('miRNA-based', 'MPA', (15, 26))	('cancer-free pancreatic', 'Disease', 'MESH:D010190', (218, 240))	('miR-20a', 'Var', (39, 46))	('miR-185', 'Gene', (73, 80))	('cancer-free pancreatic', 'Disease', (218, 240))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
21905	28466015	Interestingly, miR-20a was found to act as a tumor suppressor in breast cancer and inhibit the proliferation and invasion of pancreatic cells by negatively regulating STAT-3 protein expression due to its possible double-sided role in tumors.	('invasion of pancreatic cells', 'CPA', (113, 141))	('STAT-3', 'Gene', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('expression', 'MPA', (182, 192))	('tumor suppressor', 'biological_process', 'GO:0051726', ('45', '61'))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('45', '61'))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('breast cancer', 'Disease', (65, 78))	('tumors', 'Disease', (234, 240))	('miR-20a', 'Var', (15, 22))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('inhibit', 'NegReg', (83, 90))	('negatively regulating', 'NegReg', (145, 166))	('STAT-3', 'Gene', '6774', (167, 173))
21910	28466015	MiR-196a has been well believed to be associated with abnormal apoptosis, invasion, and proliferation of pancreatic cancer cells by downregulating ING5 expression.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (105, 122))	('MiR-196a', 'Var', (0, 8))	('associated', 'Reg', (38, 48))	('invasion', 'CPA', (74, 82))	('ING5', 'Gene', '84289', (147, 151))	('downregulating', 'NegReg', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('ING5', 'Gene', (147, 151))
21917	28466015	Moreover, further validation was performed in a breast cancer cell line (MCF-7) or tissue, neck cancer tissue to confirm that miR-210 was an independent negative prognostic factor for breast cancer and neck cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('neck cancer', 'Phenotype', 'HP:0012288', (202, 213))	('miR-210', 'Var', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('neck cancer', 'Phenotype', 'HP:0012288', (91, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('neck cancer', 'Disease', 'MESH:D006258', (91, 102))	('neck', 'cellular_component', 'GO:0044326', ('202', '206'))	('neck cancer', 'Disease', (91, 102))	('MCF-7', 'CellLine', 'CVCL:0031', (73, 78))	('neck cancer', 'Disease', 'MESH:D006258', (202, 213))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('breast cancer', 'Disease', (184, 197))	('neck', 'cellular_component', 'GO:0044326', ('91', '95'))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('negative', 'NegReg', (153, 161))	('neck cancer', 'Disease', (202, 213))
21925	27922049	Furthermore, we found that assessing KIAA1199 autoantibody increased the sensitivity of detecting pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (98, 115))	('KIAA1199', 'Var', (37, 45))	('pancreatic cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('increased', 'PosReg', (59, 68))	('pancreatic cancer', 'Disease', 'MESH:D010190', (98, 115))
21926	27922049	These results indicate the potential benefits of using KIAA1199 as a biomarker for early-stage pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (95, 112))	('pancreatic cancer', 'Disease', (95, 112))	('KIAA1199', 'Var', (55, 63))	('pancreatic cancer', 'Disease', 'MESH:D010190', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
21940	27922049	Additionally, CDKN2A encoding p16 and TP53 are frequently mutated in pancreatic cancer (>50% and 60-70%, respectively), leading to an uncontrolled cell cycle and bypass of DNA damage repair.	('pancreatic cancer', 'Disease', (69, 86))	('p16', 'Gene', (30, 33))	('cell cycle', 'biological_process', 'GO:0007049', ('147', '157'))	('CDKN2A', 'Gene', '1029', (14, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (69, 86))	('TP53', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('leading to', 'Reg', (120, 130))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('p16', 'Gene', '1029', (30, 33))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (69, 86))	('uncontrolled', 'MPA', (134, 146))	('mutated', 'Var', (58, 65))	('CDKN2A', 'Gene', (14, 20))	('TP53', 'Gene', '7157', (38, 42))
21941	27922049	Moreover, mutational inactivation of Smad4 (DPC4) contributes to invasive pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('DPC4', 'Gene', '4089', (44, 48))	('DPC4', 'Gene', (44, 48))	('Smad4', 'Gene', (37, 42))	('Smad4', 'Gene', '4089', (37, 42))	('contributes', 'Reg', (50, 61))	('invasive pancreatic cancer', 'Disease', 'MESH:D010190', (65, 91))	('mutational inactivation', 'Var', (10, 33))	('invasive pancreatic cancer', 'Disease', (65, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
21947	27922049	Several mutations in KIAA1199 were identified in patients with hearing loss, suggesting that KIAA1199 plays a role in auditory development.	('hearing loss', 'Disease', 'MESH:D034381', (63, 75))	('identified', 'Reg', (35, 45))	('hearing', 'biological_process', 'GO:0007605', ('63', '70'))	('hearing loss', 'Phenotype', 'HP:0000365', (63, 75))	('mutations', 'Var', (8, 17))	('KIAA1199', 'Gene', (21, 29))	('patients', 'Species', '9606', (49, 57))	('hearing loss', 'Disease', (63, 75))
21948	27922049	KIAA1199 also contributes to breast cancer cell migration with induction of epithelial-mesenchymal transition via calcium signaling.	('calcium signaling', 'biological_process', 'GO:0019722', ('114', '131'))	('calcium', 'Chemical', 'MESH:D002118', (114, 121))	('cell migration', 'biological_process', 'GO:0016477', ('43', '57'))	('contributes', 'Reg', (14, 25))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('76', '109'))	('KIAA1199', 'Var', (0, 8))	('epithelial-mesenchymal transition', 'CPA', (76, 109))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
21949	27922049	KIAA1199 also activates Wnt signaling for colorectal cancer cell proliferation.	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('Wnt signaling', 'Pathway', (24, 37))	('colorectal cancer', 'Disease', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('KIAA1199', 'Var', (0, 8))	('activates', 'PosReg', (14, 23))	('signaling', 'biological_process', 'GO:0023052', ('28', '37'))	('colorectal cancer', 'Disease', 'MESH:D015179', (42, 59))
21951	27922049	Moreover, KIAA1199 is a potential biomarker of gastric carcinoma.	('gastric carcinoma', 'Disease', (47, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (47, 64))	('KIAA1199', 'Var', (10, 18))	('gastric carcinoma', 'Disease', 'MESH:D013274', (47, 64))
21952	27922049	In this study, our comprehensive approaches suggest that KIAA1199 is a biomarker for pancreatic cancer.	('pancreatic cancer', 'Disease', (85, 102))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('KIAA1199', 'Var', (57, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))
21957	27922049	Transmembrane protein sequence analysis using the TMHMM 2.0 server (http://www.cbs.dtu.dk/services/TMHMM/) showed that KIAA1199 harbors a signal peptide (SP), transmembrane domain, and SP cleavage site (Fig.	('SP', 'Chemical', 'MESH:D021382', (154, 156))	('KIAA1199', 'Var', (119, 127))	('SP', 'Chemical', 'MESH:D021382', (185, 187))	('transmembrane', 'cellular_component', 'GO:0044214', ('159', '172'))	('transmembrane', 'cellular_component', 'GO:0016021', ('159', '172'))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('transmembrane domain', 'MPA', (159, 179))
21962	27922049	Fluorescent immunohistochemistry results showed that KIAA1199 is only detected in the cytosol of human PDAC cells (71.8%; N = 149) but is undetectable in normal pancreatic cells (0%; N = 53) (Fig.	('KIAA1199', 'Var', (53, 61))	('PDAC', 'Chemical', '-', (103, 107))	('human', 'Species', '9606', (97, 102))	('cytosol', 'cellular_component', 'GO:0005829', ('86', '93'))	('pancreatic', 'Disease', 'MESH:D010195', (161, 171))	('PDAC', 'Phenotype', 'HP:0006725', (103, 107))	('pancreatic', 'Disease', (161, 171))
21984	27922049	These results suggest that KIAA1199 is specifically but heterogeneously expressed in PanIN lesions in a pancreatic cancer mouse model and in human samples.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('PanIN', 'Disease', (85, 90))	('pancreatic cancer', 'Disease', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('KIAA1199', 'Var', (27, 35))	('human', 'Species', '9606', (141, 146))	('mouse', 'Species', '10090', (122, 127))
21992	27922049	Then, we performed dot blot assays using KIAA1119 protein (C-terminus) and mouse IgG (a positive control).	('KIAA1119', 'Var', (41, 49))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('IgG', 'Gene', '16059', (81, 84))	('mouse', 'Species', '10090', (75, 80))	('IgG', 'Gene', (81, 84))
22002	27922049	Of note, KIAA1199 autoantibody was not found in two pancreatic cancer samples (C21 and C22) that expressed CA19-9 (Fig.	('pancreatic cancer', 'Disease', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (52, 69))	('C21', 'Gene', (79, 82))	('CA19-9', 'Var', (107, 113))	('C21', 'Gene', '79718', (79, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (52, 69))
22004	27922049	Despite the implication of KIAA1199 in several human diseases including cancer, the molecular mechanism of KIAA1199 remains ambiguous.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('KIAA1199', 'Var', (27, 35))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('human', 'Species', '9606', (47, 52))	('cancer', 'Disease', (72, 78))
22005	27922049	Dysregulation of KIAA1199 is associated with nonsyndromic deafness and rheumatoid arthritis.	('nonsyndromic deafness', 'Disease', (45, 66))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (71, 91))	('Dysregulation', 'Var', (0, 13))	('deafness', 'Phenotype', 'HP:0000365', (58, 66))	('KIAA1199', 'Gene', (17, 25))	('rheumatoid arthritis', 'Disease', (71, 91))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (71, 91))	('associated', 'Reg', (29, 39))	('arthritis', 'Phenotype', 'HP:0001369', (82, 91))	('nonsyndromic deafness', 'Disease', 'MESH:C580334', (45, 66))
22007	27922049	In gastric cancer, KIAA1119 is a potential prognostic and lymph node metastatic marker.	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('KIAA1119', 'Var', (19, 27))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
22008	27922049	Moreover, KIAA1199 is highly expressed in adenoma, implying the potential application of KIAA1199 as a biomarker for early stages of cancer.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('adenoma', 'Disease', 'MESH:D000236', (42, 49))	('cancer', 'Disease', (133, 139))	('adenoma', 'Disease', (42, 49))	('KIAA1199', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
22011	27922049	Because KIAA1199 is upregulated and secreted in human pancreatic cancer cells, KIAA1199 could be a useful biomarker.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (54, 71))	('human', 'Species', '9606', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('upregulated', 'PosReg', (20, 31))	('pancreatic cancer', 'Disease', (54, 71))	('KIAA1199', 'Var', (79, 87))	('pancreatic cancer', 'Disease', 'MESH:D010190', (54, 71))	('KIAA1199', 'Gene', (8, 16))
22028	27922049	Human pancreatic cancer and PanIN tissue microarrays were purchased from US Biomax (PA207, BIC14011a, PA242b; Rockville, MD) and were immunostained with anti-KIAA1199 antibody (Abcam, Cambridge, UK; Santa Cruz Biotechnology, Dallas, TX), as previously described.	('Human', 'Species', '9606', (0, 5))	('pancreatic cancer', 'Disease', 'MESH:D010190', (6, 23))	('antibody', 'cellular_component', 'GO:0019815', ('167', '175'))	('antibody', 'cellular_component', 'GO:0019814', ('167', '175'))	('antibody', 'molecular_function', 'GO:0003823', ('167', '175'))	('PA242b', 'Var', (102, 108))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (6, 23))	('antibody', 'cellular_component', 'GO:0042571', ('167', '175'))	('pancreatic cancer', 'Disease', (6, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
22100	27869176	As a result, combinations of CDH3, LFNG, and PLAU were significantly associated with overall survival (log-rank test p-value: 2.376 x 10-5; Fig.	('CDH3', 'Gene', '1001', (29, 33))	('LFNG', 'Gene', (35, 39))	('combinations', 'Var', (13, 25))	('LFNG', 'Gene', '3955', (35, 39))	('PLAU', 'Gene', (45, 49))	('associated with', 'Reg', (69, 84))	('overall survival', 'MPA', (85, 101))	('CDH3', 'Gene', (29, 33))
22140	27869176	For the stable isotope labeling by amino acids in cell culture (SILAC) experiment, we labeled PC-1.0 cells with heavy [13C6, 15N2] L-lysine and [13C6, 15N4] L-arginine, and PC-1 cells with light [4, 4, 5, 5-D4] L-lysine and [13C6] L-arginine (Thermo Fisher Scientific, MA, USA) in RPMI-1640 medium.	('PC-1', 'Gene', '7163', (173, 177))	('13C6] L-arginine', 'Chemical', '-', (225, 241))	('[13C6] L-arginine', 'Var', (224, 241))	('13C6, 15N2] L-lysine', 'Chemical', '-', (119, 139))	('RPMI-1640 medium', 'Chemical', '-', (281, 297))	('13C6, 15N4] L-arginine', 'Chemical', '-', (145, 167))	('PC-1', 'Gene', (94, 98))	('[13C6', 'Var', (144, 149))	('PC-1', 'Gene', '7163', (94, 98))	('PC-1', 'Gene', (173, 177))	(', 5-D4] L-lysine', 'Chemical', '-', (203, 219))
22151	27869176	Carbamidomethylation (+57.0215 Da) served as the fixed modification, and oxidation of methionine (+15.999 Da) and protein N-terminal acetylations (+42.0106 Da) were variable modifications.	('+57.0215 Da', 'Var', (22, 33))	('+15.999 Da', 'Var', (98, 108))	('+42.0106 Da', 'Var', (147, 158))	('oxidation of methionine', 'MPA', (73, 96))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('methionine', 'Chemical', 'MESH:D008715', (86, 96))	('protein N-terminal acetylations', 'MPA', (114, 145))
22152	27869176	Light (Lys4, +4.0251 Da and Arg6, +6.0201 Da) and heavy labels (Lys8, +8.0142 Da and Arg10, +10.0083 Da) were also considered variable modifications.	('Arg10', 'Var', (85, 90))	('Lys8', 'Var', (64, 68))	('Lys8', 'Chemical', '-', (64, 68))	('Lys4', 'Var', (7, 11))	('Lys4', 'Chemical', '-', (7, 11))	('Arg6', 'Chemical', '-', (28, 32))	('Arg10', 'Chemical', '-', (85, 90))	('Lys4', 'molecular_function', 'GO:0004409', ('7', '11'))
22209	24453292	To evaluate the effect of HbA1c level on overall survival in each disease stage, we performed separate Kaplan-Meier analyses for R-PDA, BL-PDA, and M-PDA patients with HbA1c values >=6.5% or <6.5% (Figure 2).	('HbA1', 'Gene', '3039', (26, 30))	('HbA1', 'Gene', '3039', (168, 172))	('>=6.5%', 'Var', (181, 187))	('HbA1', 'Gene', (26, 30))	('R-PDA', 'Chemical', '-', (129, 134))	('HbA1', 'Gene', (168, 172))	('PDA', 'Chemical', '-', (131, 134))	('PDA', 'Chemical', '-', (139, 142))	('patients', 'Species', '9606', (154, 162))	('PDA', 'Phenotype', 'HP:0006725', (131, 134))	('HbA1c', 'Phenotype', 'HP:0040217', (26, 31))	('BL-PDA', 'Disease', (136, 142))	('PDA', 'Phenotype', 'HP:0006725', (139, 142))	('HbA1c', 'Phenotype', 'HP:0040217', (168, 173))	('BL-PDA', 'Chemical', '-', (136, 142))	('R-PDA', 'Disease', (129, 134))	('PDA', 'Chemical', '-', (150, 153))	('rat', 'Species', '10116', (98, 101))	('PDA', 'Phenotype', 'HP:0006725', (150, 153))
22211	24453292	OS was superior in R-PDA patients with HbA1c values <6.5 (21.9 months, 95% CI 14.0-29.8 months) compared to R-PDA patients with HbA1c values >=6.5% (10.9 months, 95% CI 3.4-18.4 months) (p=0.041).	('<6.5', 'Var', (52, 56))	('PDA', 'Phenotype', 'HP:0006725', (21, 24))	('R-PDA', 'Disease', (19, 24))	('HbA1', 'Gene', (39, 43))	('R-PDA', 'Chemical', '-', (108, 113))	('HbA1c', 'Phenotype', 'HP:0040217', (128, 133))	('HbA1', 'Gene', '3039', (128, 132))	('R-PDA', 'Chemical', '-', (19, 24))	('patients', 'Species', '9606', (25, 33))	('PDA', 'Phenotype', 'HP:0006725', (110, 113))	('HbA1c', 'Phenotype', 'HP:0040217', (39, 44))	('patients', 'Species', '9606', (114, 122))	('HbA1', 'Gene', (128, 132))	('HbA1', 'Gene', '3039', (39, 43))
22212	24453292	BL-PDA patients with HbA1c values <6.5 (16.4 months, 95% CI 11.3-21.5 months) compared to BL-PDA patients with HbA1c values >=6.5% (11.7 months, 95% CI 8.9-14.6 months) had improved OS; however, this did not approach significance (p=0.101).	('HbA1', 'Gene', (111, 115))	('HbA1c', 'Phenotype', 'HP:0040217', (21, 26))	('HbA1', 'Gene', '3039', (21, 25))	('PDA', 'Phenotype', 'HP:0006725', (3, 6))	('HbA1c', 'Phenotype', 'HP:0040217', (111, 116))	('OS', 'MPA', (182, 184))	('HbA1', 'Gene', (21, 25))	('PDA', 'Phenotype', 'HP:0006725', (93, 96))	('improved', 'PosReg', (173, 181))	('BL-PDA', 'Chemical', '-', (0, 6))	('HbA1', 'Gene', '3039', (111, 115))	('BL-PDA', 'Chemical', '-', (90, 96))	('<6.5', 'Var', (34, 38))	('patients', 'Species', '9606', (7, 15))	('patients', 'Species', '9606', (97, 105))
22213	24453292	There was no difference in survival between M-PDA patients with baseline HbA1c <6.5% and those with baseline HbA1c >=6.5% (P>>0.05).	('<6.5', 'Var', (79, 83))	('patients', 'Species', '9606', (50, 58))	('HbA1', 'Gene', (109, 113))	('PDA', 'Chemical', '-', (46, 49))	('HbA1c', 'Phenotype', 'HP:0040217', (73, 78))	('M-PDA', 'Disease', (44, 49))	('HbA1', 'Gene', '3039', (73, 77))	('PDA', 'Phenotype', 'HP:0006725', (46, 49))	('HbA1c', 'Phenotype', 'HP:0040217', (109, 114))	('HbA1', 'Gene', (73, 77))	('HbA1', 'Gene', '3039', (109, 113))
22259	24520195	EUS-guided fine-needle aspiration (EUS-FNA) may be used to assess cyst fluid cytology, and also to detect cyst fluid amylase level, carcinoembryonic antigen level, and DNA molecular analysis in certain cases.	('cyst fluid amylase level', 'MPA', (106, 130))	('carcinoembryonic antigen', 'Gene', (132, 156))	('cyst', 'MPA', (66, 70))	('molecular analysis', 'Var', (172, 190))	('aspiration', 'Phenotype', 'HP:0002835', (23, 33))	('DNA', 'cellular_component', 'GO:0005574', ('168', '171'))	('detect', 'Reg', (99, 105))	('carcinoembryonic antigen', 'Gene', '1084', (132, 156))
22283	24520195	Another study showed evidence of VHL gene alterations not only in VHL-disease-associated cysts, but also in sporadic microcystic (serous) adenomas; thus implying that changes in the VHL tumor suppressor gene play an important role in the pathogenesis of these types of cysts, regardless of whether or not the individual has VHL disease.	('VHL', 'Disease', 'MESH:D006623', (33, 36))	('VHL', 'Disease', 'MESH:D006623', (182, 185))	('VHL', 'Disease', (66, 69))	('VHL disease', 'Disease', (324, 335))	('VHL', 'Disease', 'MESH:D006623', (324, 327))	('VHL-disease', 'Disease', (66, 77))	('VHL tumor', 'Disease', (182, 191))	('VHL-disease', 'Disease', 'MESH:D006623', (66, 77))	('sporadic microcystic (serous) adenomas', 'Disease', 'MESH:D000236', (108, 146))	('pathogenesis', 'biological_process', 'GO:0009405', ('238', '250'))	('VHL tumor', 'Disease', 'MESH:D006623', (182, 191))	('VHL', 'Disease', (33, 36))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('186', '202'))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('VHL', 'Disease', (182, 185))	('VHL', 'Disease', 'MESH:D006623', (66, 69))	('VHL', 'Disease', (324, 327))	('tumor suppressor', 'biological_process', 'GO:0051726', ('186', '202'))	('alterations', 'Reg', (42, 53))	('changes', 'Var', (167, 174))	('VHL disease', 'Disease', 'MESH:D006623', (324, 335))	('cysts', 'Disease', (89, 94))
22301	24520195	IPMNs with adenomatous or borderline changes have been shown to have an excellent prognosis if resected; however, the prognosis is less favorable when findings of carcinoma in situ or invasive carcinoma are present.	('adenomatous', 'Disease', 'MESH:D011125', (11, 22))	('IPMNs', 'Disease', (0, 5))	('invasive carcinoma', 'Disease', 'MESH:D009361', (184, 202))	('carcinoma in situ', 'Disease', 'MESH:D002278', (163, 180))	('adenomatous', 'Disease', (11, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('invasive carcinoma', 'Disease', (184, 202))	('carcinoma in situ', 'Disease', (163, 180))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (163, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('borderline changes', 'Var', (26, 44))
22310	24520195	Interestingly, on cyst fluid DNA analysis studies of IPMNs, the histological grade of dysplasia increases with the frequency of mutations in the k-ras gene.	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('dysplasia increases', 'Disease', 'MESH:D019586', (86, 105))	('mutations', 'Var', (128, 137))	('k-ras', 'Gene', '3845', (145, 150))	('dysplasia increases', 'Disease', (86, 105))	('k-ras', 'Gene', (145, 150))
22311	24520195	These findings suggest that k-ras gene mutations play a significant role in the process of carcinogenesis for these mucinous PCNs.	('PCNs', 'Chemical', '-', (125, 129))	('k-ras', 'Gene', (28, 33))	('k-ras', 'Gene', '3845', (28, 33))	('mucin', 'Gene', (116, 121))	('mutations', 'Var', (39, 48))	('mucin', 'Gene', '100508689', (116, 121))
22342	24520195	In another study evaluating the accuracy of CT versus MRI-MRCP in the characterization of IPMN disease, ductal connection was found on 73% of MRCP scans and only 18% of CT scans.	('MRCP', 'Var', (142, 146))	('found', 'Reg', (126, 131))	('IPMN disease', 'Disease', 'MESH:D000077779', (90, 102))	('IPMN disease', 'Disease', (90, 102))	('ductal connection', 'Disease', (104, 121))
22370	24520195	The presence of CA 72-4 in cyst fluid has, however, been shown to be indicative of a mucinous lesion.	('presence', 'Var', (4, 12))	('mucinous lesion', 'Disease', 'MESH:D002288', (85, 100))	('CA 72-4', 'Var', (16, 23))	('mucinous lesion', 'Disease', (85, 100))
22374	24520195	A recent study showed that the presence of a k-ras gene mutation is diagnostic of a mucinous cyst.	('mucin', 'Gene', (84, 89))	('k-ras', 'Gene', '3845', (45, 50))	('k-ras', 'Gene', (45, 50))	('mucin', 'Gene', '100508689', (84, 89))	('mutation', 'Var', (56, 64))	('mucinous cyst', 'Phenotype', 'HP:0200040', (84, 97))
22375	24520195	Furthermore, cyst fluid demonstrating large amounts of DNA, high-amplitude mutations, or a mutational sequence of k-ras mutation followed by allelic loss ("loss of heterozygosity") is highly suspicious for malignancy.	('malignancy', 'Disease', 'MESH:D009369', (206, 216))	('loss', 'NegReg', (149, 153))	('malignancy', 'Disease', (206, 216))	('mutation', 'Var', (120, 128))	('k-ras', 'Gene', '3845', (114, 119))	('k-ras', 'Gene', (114, 119))	('mutations', 'Var', (75, 84))	('mutational sequence', 'Var', (91, 110))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))
22376	24520195	Another recent study demonstrated that GNAS gene mutations were found in 66% of IPMNs, and either GNAS or k-ras mutations were present in 96% of IPMNs.	('k-ras', 'Gene', (106, 111))	('GNAS', 'Gene', (39, 43))	('mutations', 'Var', (49, 58))	('GNAS', 'Gene', (98, 102))	('IPMNs', 'Disease', (80, 85))	('found', 'Reg', (64, 69))	('GNAS', 'Gene', '2778', (39, 43))	('GNAS', 'Gene', '2778', (98, 102))	('k-ras', 'Gene', '3845', (106, 111))
22390	24520195	Features on CT, MRI, or EUS such as an obstructed common bile duct in a patient with a lesion of the pancreatic head, an enhanced solid component to the cyst, and MPD size >=10 mm are highly suspicious for malignancy and are thus termed "high-risk stigmata" (Table 3).	('lesion of the pancreatic', 'Disease', 'MESH:D010182', (87, 111))	('malignancy', 'Disease', 'MESH:D009369', (206, 216))	('malignancy', 'Disease', (206, 216))	('>=10 mm', 'Var', (172, 179))	('enhanced', 'PosReg', (121, 129))	('lesion of the pancreatic', 'Disease', (87, 111))	('obstructed common bile duct', 'Disease', (39, 66))	('patient', 'Species', '9606', (72, 79))
22413	24520195	In addition, high-grade cellular atypia on EUS-FNA results, as opposed to "positive cytology," was also found to be a high-risk factor for malignancy in BD-IPMNs.	('BD-IPMNs', 'Disease', (153, 161))	('high-grade cellular atypia', 'Var', (13, 39))	('BD-IPMN', 'Chemical', '-', (153, 160))	('malignancy', 'Disease', 'MESH:D009369', (139, 149))	('malignancy', 'Disease', (139, 149))
22465	22761793	Thymosin-beta 4 was found significantly increased in sera of mice with PanIN lesions.	('lesions', 'Var', (77, 84))	('PanIN', 'Disease', (71, 76))	('mice', 'Species', '10090', (61, 65))	('Thymosin-beta 4', 'Gene', '19241', (0, 15))	('increased', 'PosReg', (40, 49))	('sera', 'molecular_function', 'GO:0004617', ('53', '57'))	('Thymosin-beta 4', 'Gene', (0, 15))
22481	22761793	We further substantiate ALB1 expression as part of a hepatic transdifferentiation program of precursor lesions and provide evidence for increased serum levels of TMSB4X in mice with PanIN lesions.	('ALB1', 'Gene', '11657', (24, 28))	('lesions', 'Var', (188, 195))	('transdifferentiation', 'biological_process', 'GO:0060290', ('61', '81'))	('serum levels', 'MPA', (146, 158))	('ALB1', 'Gene', (24, 28))	('TMSB4X', 'Var', (162, 168))	('mice', 'Species', '10090', (172, 176))	('increased', 'PosReg', (136, 145))
22520	22761793	We next visualized m/z 2829 on the tissue sections demonstrating specificity of this peak for PanIN regions in the heat map illustration (Figure 2D, upper panel), whereas a peak at m/z 6645, which was unique for normal tissue specifically re-visualized in regions with morphologically normal pancreatic tissue (Figure 2D, lower panel).	('m/z 6645', 'Var', (181, 189))	('pancreatic', 'Disease', 'MESH:D010195', (292, 302))	('pancreatic', 'Disease', (292, 302))	('m/z', 'Var', (19, 22))
22523	22761793	The m/z 2790 species was identified as a peptide representing the amino-terminus of the mature form of serum Albumin (ALB1), whereas both, the m/z 2812 and the m/z 2829 species represented two different peptides belonging to the carboxy-terminus of Thymosin beta-4 (TMSB4X).	('Thymosin beta-4', 'Gene', '19241', (249, 264))	('Albumin', 'Gene', (109, 116))	('peptides', 'Chemical', 'MESH:D010455', (203, 211))	('m/z 2790', 'Var', (4, 12))	('ALB1', 'Gene', '11657', (118, 122))	('Albumin', 'Gene', '11657', (109, 116))	('ALB1', 'Gene', (118, 122))	('m/z', 'Var', (143, 146))	('Thymosin beta-4', 'Gene', (249, 264))
22525	22761793	The manually verified peptide identifications of ALB1 and TMSB4X and the corresponding MS/MS spectra are listed in Table 2 and available in the Supplemental Material (Figure S1).	('ALB1', 'Gene', (49, 53))	('ALB1', 'Gene', '11657', (49, 53))	('TMSB4X', 'Var', (58, 64))	('men', 'Species', '9606', (150, 153))
22539	22761793	For quantification we stained sections from 10 Ptf1a+/Cre;Kras+/G12D mice with PanINs and found all of them to be positive for TMSB4X.	('Ptf1a', 'Gene', '19213', (47, 52))	('Ptf1a', 'Gene', (47, 52))	('mice', 'Species', '10090', (69, 73))	('positive', 'Reg', (114, 122))	('G12D', 'Mutation', 'rs121913529', (64, 68))	('TMSB4X', 'Var', (127, 133))
22558	22761793	Here, we identified two proteins, namely ALB1 and TMSB4X, which represent statistically significant MALDI IMS peaks.	('TMSB4X', 'Var', (50, 56))	('ALB1', 'Gene', (41, 45))	('ALB1', 'Gene', '11657', (41, 45))
22564	22761793	The confirmation of increased ALB1 and TMSB4X expression on protein level using Western Blot and immunohistological stainings in murine and human PanIN lesions verifies the principal ability of MALDI-IMS and subsequent LC-MS/MS analysis to identify the respective proteins or peptides from peaks measured in situ.	('increased', 'PosReg', (20, 29))	('human', 'Species', '9606', (140, 145))	('ALB1', 'Gene', (30, 34))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('lesions', 'Var', (152, 159))	('murine', 'Species', '10090', (129, 135))	('peptides', 'Chemical', 'MESH:D010455', (276, 284))	('TMSB4X', 'Gene', (39, 45))	('expression', 'MPA', (46, 56))	('ALB1', 'Gene', '11657', (30, 34))
22573	22761793	In a recent paper, MacDonald and colleagues provide evidence that acinar cells start to express liver-restricted genes after modulation of the acinar cell specifying complex PTF1.	('liver-restricted genes', 'Gene', (96, 118))	('modulation', 'Var', (125, 135))	('PTF1', 'Species', '32651', (174, 178))
22574	22761793	Thus, activation of oncogenic KrasG12D in acinar cells may lead to downregulation of PTF1 activity and subsequent expression of liver-restricted genes.	('downregulation', 'NegReg', (67, 81))	('activity', 'MPA', (90, 98))	('PTF1', 'Species', '32651', (85, 89))	('expression', 'MPA', (114, 124))	('PTF1', 'Gene', (85, 89))	('activation', 'PosReg', (6, 16))	('KrasG12D', 'Var', (30, 38))
22576	22761793	However, the subsequent approach of its utility as human serum biomarker for PDAC identification failed to show significant differences, although staining for TMSB4X on human tissue depicted specific expression in PanINs and PDAC tissue.	('PDAC', 'Phenotype', 'HP:0006725', (225, 229))	('TMSB4X', 'Var', (159, 165))	('PDAC', 'Phenotype', 'HP:0006725', (77, 81))	('human', 'Species', '9606', (51, 56))	('human', 'Species', '9606', (169, 174))	('PDAC', 'Chemical', '-', (225, 229))	('expression', 'MPA', (200, 210))	('PDAC', 'Chemical', '-', (77, 81))
22578	22761793	ALB1 is no suitable candidate for obvious reasons, while TMSB4X is a protein that has been identified in a variety of pathological conditions, potentially arguing against this protein as specific enough within the aimed clinical context.	('ALB1', 'Gene', '11657', (0, 4))	('ALB1', 'Gene', (0, 4))	('TMSB4X', 'Var', (57, 63))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))
22595	21673052	Also, we have shown that neutralization of VEGF by treatment with bevacizumab (Avastin) leads to feedback activation of Sp1 and subsequent upregulation of expression of VEGF and other factors, leading to Avastin resistance, whereas blockade of Sp1 expression and function sensitizes tumors to Avastin and/or reverses Avastin resistance.	('Sp1', 'Gene', (120, 123))	('Sp', 'Chemical', 'MESH:C000604007', (120, 122))	('leading to', 'Reg', (193, 203))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('Avastin', 'Chemical', 'MESH:D000068258', (79, 86))	('Avastin', 'Chemical', 'MESH:D000068258', (317, 324))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('Avastin', 'Chemical', 'MESH:D000068258', (293, 300))	('VEGF', 'Gene', (43, 47))	('bevacizumab', 'Chemical', 'MESH:D000068258', (66, 77))	('tumors', 'Disease', (283, 289))	('activation', 'PosReg', (106, 116))	('neutralization', 'Var', (25, 39))	('VEGF', 'Gene', (169, 173))	('Sp', 'Chemical', 'MESH:C000604007', (244, 246))	('Avastin', 'Chemical', 'MESH:D000068258', (204, 211))	('tumors', 'Disease', 'MESH:D009369', (283, 289))	('upregulation', 'PosReg', (139, 151))	('expression', 'MPA', (155, 165))	('sensitizes', 'Reg', (272, 282))	('Avastin resistance', 'MPA', (204, 222))
22643	21673052	In our previous studies, we have already demonstrated a dose-dependent antitumor activity of MIT.	('MIT', 'Chemical', 'MESH:C066851', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('MIT', 'Var', (93, 96))	('tumor', 'Disease', (75, 80))
22683	21673052	However, further deletion of Sp1-binding sites eliminated the ability of MIT to suppress Sp1 (Fig.	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('MIT', 'Chemical', 'MESH:C066851', (73, 76))	('eliminated', 'NegReg', (47, 57))	('Sp', 'Chemical', 'MESH:C000604007', (89, 91))	('suppress', 'NegReg', (80, 88))	('ability', 'MPA', (62, 69))	('deletion', 'Var', (17, 25))	('Sp1', 'MPA', (89, 92))	('Sp', 'Chemical', 'MESH:C000604007', (29, 31))
22690	21673052	Clearly, the ectopic Sp1 overexpression led to resistance to BA in both BxPC-3 and PANC-1 cells (Fig.	('PANC-1', 'Gene', (83, 89))	('BxPC-3', 'CellLine', 'CVCL:0186', (72, 78))	('Sp1', 'Gene', (21, 24))	('ectopic', 'Var', (13, 20))	('resistance to BA', 'MPA', (47, 63))	('Sp', 'Chemical', 'MESH:C000604007', (21, 23))	('led to', 'Reg', (40, 46))	('PANC-1', 'Gene', '104066', (83, 89))	('BA', 'Chemical', 'MESH:C002070', (61, 63))	('overexpression', 'PosReg', (25, 39))
22739	21681824	DNA Mismatch Repair Network Gene Polymorphism as a Susceptibility Factor for Pancreatic Cancer DNA repair plays a critical role in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('DNA repair', 'biological_process', 'GO:0006281', ('95', '105'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('human', 'Species', '9606', (131, 136))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (77, 94))	('cancers', 'Disease', (137, 144))	('Mismatch Repair', 'biological_process', 'GO:0006298', ('4', '19'))	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (77, 94))	('Polymorphism', 'Var', (33, 45))	('Pancreatic Cancer', 'Disease', (77, 94))
22740	21681824	We hypothesized that DNA mismatch repair gene variants are associated with risk of pancreatic cancer.	('mismatch repair', 'biological_process', 'GO:0006298', ('25', '40'))	('pancreatic cancer', 'Disease', (83, 100))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('associated', 'Reg', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('variants', 'Var', (46, 54))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))
22741	21681824	We retrospectively genotyped 102 single-nucleotide polymorphisms (SNPs) of 13 mismatch repair related genes in 706 patients with pancreatic cancer and 706 cancer-free controls using the mass spectroscopy-based MassArray method.	('patients', 'Species', '9606', (115, 123))	('single-nucleotide polymorphisms', 'Var', (33, 64))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mismatch repair', 'biological_process', 'GO:0006298', ('78', '93'))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('mismatch repair related genes', 'Gene', (78, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('pancreatic cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
22744	21681824	Adjusting for multiple comparisons, MGMT I143V AG/GG, PMS2 IVS1-1121C>T TC/TT, and PMS2L3 Ex1+118C>T CT/TT genotypes showed significant main effects on pancreatic cancer risk at FDR <1% with OR (95% CI) of 0.60 (0.46-0.80), 1.44 (1.14-1.81) and 5.54 (2.10-14.61), respectively (P<=0.0015).	('PMS2L3', 'Gene', '5387', (83, 89))	('PMS2', 'Gene', (54, 58))	('I143V', 'Mutation', 'rs2308321', (41, 46))	('PMS2', 'Gene', (83, 87))	('MGMT', 'Gene', (36, 40))	('PMS2', 'Gene', '5395', (83, 87))	('pancreatic cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('MGMT', 'Gene', '4255', (36, 40))	('pancreatic cancer', 'Disease', 'MESH:D010190', (152, 169))	('MGMT', 'molecular_function', 'GO:0003908', ('36', '40'))	('Ex1+118C>T', 'Mutation', 'c.EX1+118C>T', (90, 100))	('I143V AG/GG', 'Var', (41, 52))	('PMS2L3', 'Gene', (83, 89))	('IVS1-1121C>T', 'Mutation', 'c.IVS1-1121C>T', (59, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (152, 169))	('PMS2', 'Gene', '5395', (54, 58))
22746	21681824	MGMT I143V GG, MGMT K178R GG, MSH6 G39E AG/AA, PMS2L3 IVS3+9A>G GA and TP73 IVS1-7449G>C CG/CC genotypes correlated with a higher level of ENU-induced DNA adducts.	('ENU', 'Chemical', 'MESH:D005038', (139, 142))	('I143V', 'Mutation', 'rs2308321', (5, 10))	('PMS2L3', 'Gene', '5387', (47, 53))	('TP73', 'Gene', '7161', (71, 75))	('MGMT', 'Gene', '4255', (0, 4))	('MGMT', 'Gene', '4255', (15, 19))	('K178R', 'Mutation', 'rs2308327', (20, 25))	('TP73', 'Gene', (71, 75))	('MSH6', 'Gene', (30, 34))	('I143V', 'Var', (5, 10))	('MSH6', 'Gene', '2956', (30, 34))	('G39E', 'Mutation', 'rs1042821', (35, 39))	('ENU-induced DNA adducts', 'MPA', (139, 162))	('IVS3+9A>G', 'Mutation', 'c.IVS3+9A>G', (54, 63))	('MGMT', 'Gene', (0, 4))	('PMS2L3', 'Gene', (47, 53))	('IVS1-7449G>C', 'Var', (76, 88))	('MGMT', 'Gene', (15, 19))	('IVS1-7449G>C', 'Mutation', 'c.IVS1-7449G>C', (76, 88))	('MGMT', 'molecular_function', 'GO:0003908', ('0', '4'))	('MGMT', 'molecular_function', 'GO:0003908', ('15', '19'))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))
22747	21681824	Haplotypes of MGMT, MSH6, PMS2, PMS2L3, and TP73 were significantly associated with pancreatic cancer risk (P<=0.0015).	('MGMT', 'Gene', (14, 18))	('associated with', 'Reg', (68, 83))	('PMS2L3', 'Gene', '5387', (32, 38))	('pancreatic cancer', 'Disease', 'MESH:D010190', (84, 101))	('PMS2', 'Gene', '5395', (32, 36))	('PMS2', 'Gene', '5395', (26, 30))	('MGMT', 'molecular_function', 'GO:0003908', ('14', '18'))	('pancreatic cancer', 'Disease', (84, 101))	('TP73', 'Gene', '7161', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Haplotypes', 'Var', (0, 10))	('MGMT', 'Gene', '4255', (14, 18))	('MSH6', 'Gene', (20, 24))	('MSH6', 'Gene', '2956', (20, 24))	('PMS2', 'Gene', (32, 36))	('TP73', 'Gene', (44, 48))	('PMS2', 'Gene', (26, 30))	('PMS2L3', 'Gene', (32, 38))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (84, 101))
22748	21681824	Our findings suggest that mismatch repair gene variants may affect susceptibility to pancreatic cancer.	('pancreatic cancer', 'Disease', (85, 102))	('mismatch repair gene', 'Gene', (26, 46))	('variants', 'Var', (47, 55))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mismatch repair', 'biological_process', 'GO:0006298', ('26', '41'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('affect', 'Reg', (60, 66))
22750	21681824	It is a notoriously aggressive and difficult-to-treat malignancy expressing global genomic instability (e.g., mutation, translocation, and deletion) and aneuploidy.	('translocation', 'Var', (120, 133))	('deletion', 'Var', (139, 147))	('aneuploidy', 'Disease', (153, 163))	('mutation', 'Var', (110, 118))	('malignancy', 'Disease', 'MESH:D009369', (54, 64))	('aneuploidy', 'Disease', 'MESH:D000782', (153, 163))	('malignancy', 'Disease', (54, 64))
22751	21681824	Five to ten percent of pancreatic cancer patients have inherited germline disorders, including mutations of genes responsible for Peutz-Jeghers syndrome (STK11), hereditary pancreatitis (PRSS1, SPINK1), Lynch syndrome (MLH1, MSH2), familial atypical multiple-mole melanoma (p16), cystic fibrosis (CTFR), hereditary breast-ovarian cancer (BRCA1, BRCA2), familial adenomatous polyposis (APC), or family X site-specific pancreatic cancer (PALLD).	('p16', 'Gene', (274, 277))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cystic fibrosis', 'Disease', (280, 295))	('familial adenomatous polyposis', 'Disease', (353, 383))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (417, 434))	('BRCA1', 'Gene', '672', (338, 343))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (353, 383))	('BRCA2', 'Gene', '675', (345, 350))	('p16', 'Gene', '1029', (274, 277))	('BRCA1', 'Gene', (338, 343))	('pancreatic cancer', 'Disease', (23, 40))	('PALLD', 'Gene', (436, 441))	('PALLD', 'Gene', '23022', (436, 441))	('cystic fibrosis', 'Disease', 'MESH:D003550', (280, 295))	('ovarian cancer', 'Phenotype', 'HP:0100615', (322, 336))	('Lynch syndrome', 'Disease', (203, 217))	('APC', 'cellular_component', 'GO:0005680', ('385', '388'))	('PRSS1', 'Gene', (187, 192))	('Peutz-Jeghers syndrome', 'Disease', 'MESH:D010580', (130, 152))	('STK11', 'Gene', (154, 159))	('pancreatitis', 'Phenotype', 'HP:0001733', (173, 185))	('PRSS1', 'Gene', '5644', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (428, 434))	('hereditary breast-ovarian cancer', 'Disease', (304, 336))	('pancreatic cancer', 'Disease', 'MESH:D010190', (417, 434))	('MLH1', 'Gene', (219, 223))	('inherited germline disorders', 'Disease', (55, 83))	('mutations', 'Var', (95, 104))	('Lynch syndrome', 'Disease', 'MESH:D003123', (203, 217))	('melanoma', 'Disease', 'MESH:D008545', (264, 272))	('STK11', 'molecular_function', 'GO:0033868', ('154', '159'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (23, 40))	('APC', 'Disease', 'MESH:D011125', (385, 388))	('STK11', 'Gene', '6794', (154, 159))	('MLH1', 'Gene', '4292', (219, 223))	('patients', 'Species', '9606', (41, 49))	('APC', 'Disease', (385, 388))	('pancreatic cancer', 'Disease', (417, 434))	('inherited germline disorders', 'Disease', 'MESH:D030342', (55, 83))	('MSH2', 'Gene', (225, 229))	('BRCA2', 'Gene', (345, 350))	('mole', 'Phenotype', 'HP:0003764', (259, 263))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (362, 383))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('hereditary breast-ovarian cancer', 'Disease', 'MESH:D061325', (304, 336))	('Peutz-Jeghers syndrome', 'Disease', (130, 152))	('hereditary pancreatitis', 'Disease', (162, 185))	('hereditary pancreatitis', 'Disease', 'MESH:C537262', (162, 185))	('SPINK1', 'Gene', (194, 200))	('SPINK1', 'Gene', '6690', (194, 200))	('pancreatic cancer', 'Disease', 'MESH:D010190', (23, 40))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('MSH2', 'Gene', '4436', (225, 229))	('melanoma', 'Disease', (264, 272))
22753	21681824	Most pancreatic cancers harbor genetic alterations in KRAS2, p16, TP53, or SMAD4.	('KRAS2', 'Gene', (54, 59))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (5, 22))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('p16', 'Gene', (61, 64))	('KRAS2', 'Gene', '3845', (54, 59))	('pancreatic cancers', 'Disease', (5, 23))	('SMAD4', 'Gene', (75, 80))	('pancreatic cancers', 'Disease', 'MESH:D010190', (5, 23))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('p16', 'Gene', '1029', (61, 64))	('SMAD4', 'Gene', '4089', (75, 80))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (5, 23))	('genetic alterations', 'Var', (31, 50))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
22759	21681824	To test the hypothesis that genetic variants in MMR modify the risk of pancreatic cancer, we evaluated 13 genes encoding key nodes for DNA mismatch recognition and removal (MutS homolog 2 [MSH2], MSH3, MSH6, MutL homolog 1 [MLH1], MLH3, postmeiotic segregation increased 1 [PMS1], PMS2, PMS2-like 3 [PMS2L3], exonuclease I [EXO1], and three prime repair exonuclease 1 [TREX1]), or MMR interaction component O6-methylguanine-DNA methyltransferase [MGMT], or MMR-induced apoptosis transducer (tumor protein 73 [TP73]), or MMR regulator RecQ protein-like/DNA helicase Q1-like (RECQL).	('MGMT', 'Gene', '4255', (447, 451))	('RecQ protein-like/DNA helicase Q1-like', 'Gene', '5965', (534, 572))	('MMR', 'biological_process', 'GO:0006298', ('520', '523'))	('TP73', 'Gene', (509, 513))	('TREX1', 'Gene', '11277', (369, 374))	('PMS2', 'Gene', '5395', (281, 285))	('postmeiotic segregation increased 1', 'Gene', '5378', (237, 272))	('protein', 'cellular_component', 'GO:0003675', ('497', '504'))	('postmeiotic segregation increased 1', 'Gene', (237, 272))	('PMS2', 'Gene', (300, 304))	('MSH3', 'Gene', (196, 200))	('EXO1', 'Gene', '9156', (324, 328))	('MutS homolog 2', 'Gene', (173, 187))	('MGMT', 'molecular_function', 'GO:0003908', ('447', '451'))	('MLH3', 'Gene', '27030', (231, 235))	('pancreatic cancer', 'Disease', (71, 88))	('MSH3', 'Gene', '4437', (196, 200))	('RECQL', 'Gene', '5965', (574, 579))	('MMR', 'biological_process', 'GO:0006298', ('457', '460'))	('apoptosis', 'biological_process', 'GO:0006915', ('469', '478'))	('MutS homolog 2', 'Gene', '4436', (173, 187))	('TREX1', 'Gene', (369, 374))	('MLH3', 'Gene', (231, 235))	('PMS2', 'Gene', '5395', (287, 291))	('PMS2L3', 'Gene', '5387', (300, 306))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (407, 445))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MutL homolog 1', 'Gene', (208, 222))	('tumor', 'Phenotype', 'HP:0002664', (491, 496))	('MMR', 'biological_process', 'GO:0006298', ('48', '51'))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('DNA', 'cellular_component', 'GO:0005574', ('424', '427'))	('MSH2', 'Gene', (189, 193))	('RECQL', 'Gene', (574, 579))	('pancreatic cancer', 'Disease', 'MESH:D010190', (71, 88))	('RecQ protein-like/DNA helicase Q1-like', 'Gene', (534, 572))	('PMS1', 'Gene', (274, 278))	('PMS1', 'Gene', '5378', (274, 278))	('MSH6', 'Gene', (202, 206))	('MGMT', 'Gene', (447, 451))	('PMS2', 'Gene', (281, 285))	('PMS2-like 3', 'Gene', (287, 298))	('MSH6', 'Gene', '2956', (202, 206))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('three prime repair exonuclease 1', 'Gene', '11277', (335, 367))	('protein', 'cellular_component', 'GO:0003675', ('539', '546'))	('MSH2', 'Gene', '4436', (189, 193))	('MLH1', 'Gene', (224, 228))	('O6-methylguanine-DNA methyltransferase', 'Gene', (407, 445))	('PMS2', 'Gene', '5395', (300, 304))	('PMS2', 'Gene', (287, 291))	('MutL homolog 1', 'Gene', '4292', (208, 222))	('TP73', 'Gene', '7161', (509, 513))	('three prime repair exonuclease 1', 'Gene', (335, 367))	('tumor', 'Disease', (491, 496))	('PMS2L3', 'Gene', (300, 306))	('MLH1', 'Gene', '4292', (224, 228))	('DNA', 'cellular_component', 'GO:0005574', ('552', '555'))	('variants', 'Var', (36, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('469', '478'))	('MMR', 'biological_process', 'GO:0006298', ('381', '384'))	('EXO1', 'Gene', (324, 328))	('tumor', 'Disease', 'MESH:D009369', (491, 496))	('PMS2-like 3', 'Gene', '5387', (287, 298))
22764	21681824	MMR (MLH1, MSH2, MSH6, and PMS2) germline mutations cause Lynch syndrome/hereditary nonpolyposis colorectal cancer.	('Lynch syndrome', 'Disease', 'MESH:D003123', (58, 72))	('PMS2', 'Gene', (27, 31))	('MLH1', 'Gene', (5, 9))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (73, 114))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (73, 114))	('MSH6', 'Gene', '2956', (17, 21))	('hereditary nonpolyposis colorectal cancer', 'Disease', (73, 114))	('PMS2', 'Gene', '5395', (27, 31))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cause', 'Reg', (52, 57))	('MSH2', 'Gene', (11, 15))	('MSH6', 'Gene', (17, 21))	('MSH2', 'Gene', '4436', (11, 15))	('Lynch syndrome', 'Disease', (58, 72))	('MMR', 'biological_process', 'GO:0006298', ('0', '3'))	('mutations', 'Var', (42, 51))	('MLH1', 'Gene', '4292', (5, 9))
22774	21681824	We examined 102 single-nucleotide polymorphisms (SNPs) of the 13 genes in 706 pancreatic cancer patients and 706 controls.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('single-nucleotide polymorphisms', 'Var', (16, 47))	('patients', 'Species', '9606', (96, 104))	('pancreatic cancer', 'Disease', (78, 95))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
22791	21681824	The heterozygous and homozygous genotypes were combined if the homozygous variant had a very low frequency (number of homozygote < 4) or if the homozygous and heterozygous genotypes exerted a similar effect on the risk for pancreatic cancer.	('pancreatic cancer', 'Disease', (223, 240))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('pancreatic cancer', 'Disease', 'MESH:D010190', (223, 240))	('variant', 'Var', (74, 81))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (223, 240))
22798	21681824	Most of the 102 SNPs followed HWE; exceptions were MGMT IVS4-44836G>A, MLH1 I219V, MSH2 IVS11-62G>A, PMS2 P470S, N775S, -153C>G, PMS2L3 IVS3+9A>G, and RECQL IVS8+190A>G in both cases and controls (P<0.05).	('MLH1', 'Gene', (71, 75))	('IVS4-44836G>A', 'Var', (56, 69))	('IVS4-44836G>A', 'Mutation', 'c.IVS4-44836G>A', (56, 69))	('PMS2', 'Gene', (101, 105))	('MGMT', 'Gene', (51, 55))	('MLH1', 'Gene', '4292', (71, 75))	('-153C>G', 'Mutation', 'rs772643900', (120, 127))	('N775S', 'Mutation', 'rs17420802', (113, 118))	('IVS8+190A>G', 'Mutation', 'c.IVS8+190A>G', (157, 168))	('P470S', 'Mutation', 'rs1805321', (106, 111))	('PMS2', 'Gene', (129, 133))	('IVS11-62G>A', 'Var', (88, 99))	('IVS11-62G>A', 'Mutation', 'c.IVS11-62G>A', (88, 99))	('IVS3+9A>G', 'Mutation', 'c.IVS3+9A>G', (136, 145))	('MSH2', 'Gene', (83, 87))	('PMS2L3', 'Gene', (129, 135))	('RECQL', 'Gene', '5965', (151, 156))	('PMS2', 'Gene', '5395', (101, 105))	('N775S', 'Var', (113, 118))	('MGMT', 'Gene', '4255', (51, 55))	('RECQL', 'Gene', (151, 156))	('PMS2L3', 'Gene', '5387', (129, 135))	('MSH2', 'Gene', '4436', (83, 87))	('I219V', 'Mutation', 'rs1799977', (76, 81))	('MGMT', 'molecular_function', 'GO:0003908', ('51', '55'))	('PMS2', 'Gene', '5395', (129, 133))	('I219V', 'Var', (76, 81))
22800	21681824	MGMT I143V AG/GG, PMS2 IVS1-1121C>T TC/TT, and PMS2L3 Ex1+118C>T CT/TT remained statistically significant predictors for altered pancreatic cancer risk after adjusting for multiple comparisons (P<=0.0015).	('MGMT', 'Gene', (0, 4))	('PMS2', 'Gene', '5395', (47, 51))	('Ex1+118C>T', 'Mutation', 'c.EX1+118C>T', (54, 64))	('PMS2L3', 'Gene', (47, 53))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('IVS1-1121C>T', 'Mutation', 'c.IVS1-1121C>T', (23, 35))	('I143V', 'Mutation', 'rs2308321', (5, 10))	('altered pancreatic cancer', 'Disease', (121, 146))	('PMS2', 'Gene', (18, 22))	('I143V AG/GG', 'Var', (5, 16))	('PMS2L3', 'Gene', '5387', (47, 53))	('PMS2', 'Gene', '5395', (18, 22))	('MGMT', 'molecular_function', 'GO:0003908', ('0', '4'))	('altered pancreatic cancer', 'Disease', 'MESH:D010190', (121, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('PMS2', 'Gene', (47, 51))	('MGMT', 'Gene', '4255', (0, 4))
22802	21681824	The square-root transformed value (mean +- SE) of O6-EtGua (fmol/mug DNA) was 9.3 +- 0.4 in 123 patients with pancreatic cancer and 8.8 +- 0.2 in 122 non-cancer controls (p=0.19).	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (110, 127))	('O6-EtGua', 'Chemical', 'MESH:C007673', (50, 58))	('mug', 'molecular_function', 'GO:0043739', ('65', '68'))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('pancreatic cancer', 'Disease', (110, 127))	('non-cancer', 'Disease', (150, 160))	('pancreatic cancer', 'Disease', 'MESH:D010190', (110, 127))	('non-cancer', 'Disease', 'MESH:D009369', (150, 160))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('O6-EtGua', 'Var', (50, 58))
22803	21681824	We found that MGMT I143V, MGMT K178R, MSH6 G32E, PMS2L3 IVS3+9A>G and TP73 IVS1-7449G>C genotypes correlated with O6-EtGua level (p<0.05).	('MGMT', 'Gene', (14, 18))	('G32E', 'Mutation', 'p.G32E', (43, 47))	('correlated', 'Reg', (98, 108))	('MGMT', 'Gene', '4255', (26, 30))	('K178R', 'Mutation', 'rs2308327', (31, 36))	('MSH6', 'Gene', (38, 42))	('TP73', 'Gene', '7161', (70, 74))	('MSH6', 'Gene', '2956', (38, 42))	('I143V', 'Mutation', 'rs2308321', (19, 24))	('MGMT', 'molecular_function', 'GO:0003908', ('14', '18'))	('MGMT', 'Gene', '4255', (14, 18))	('O6-EtGua level', 'MPA', (114, 128))	('TP73', 'Gene', (70, 74))	('MGMT', 'Gene', (26, 30))	('IVS3+9A>G', 'Mutation', 'c.IVS3+9A>G', (56, 65))	('PMS2L3', 'Gene', (49, 55))	('MGMT', 'molecular_function', 'GO:0003908', ('26', '30'))	('G32E', 'Var', (43, 47))	('O6-EtGua', 'Chemical', 'MESH:C007673', (114, 122))	('IVS1-7449G>C', 'Mutation', 'c.IVS1-7449G>C', (75, 87))	('PMS2L3', 'Gene', '5387', (49, 55))
22807	21681824	The associations manifested the effects of MGMT AATA of IVS4-44836G>A, IVS4-75473G>A; IVS4-7901C>T, IVS5+23129G>A; MSH6 G39E AG/AA (protective), IVS4-101G>C CC; PMS2 IVS1-1121C>T TC/TT, IVS7+442G>T GT/TT; PMS2L3 IVS3+9A>G GA/GG, IVS2-1578A>G AG, Ex1+118C>T CT/TT; and TP73 IVS1-7449G>C CG/CC (protective) and A610A GA/AA genotypes on pancreatic cancer risk.	('PMS2L3', 'Gene', (205, 211))	('IVS4-101G>C CC', 'Var', (145, 159))	('PMS2', 'Gene', '5395', (161, 165))	('IVS4-44836G>A', 'Mutation', 'c.IVS4-44836G>A', (56, 69))	('pancreatic cancer', 'Disease', (334, 351))	('Ex1+118C>T CT/TT', 'Var', (246, 262))	('IVS4-101G>C', 'Mutation', 'c.IVS4-101G>C', (145, 156))	('IVS5+23129G>A', 'Var', (100, 113))	('IVS4-7901C>T', 'Mutation', 'c.IVS4-7901C>T', (86, 98))	('IVS4-75473G>A', 'Mutation', 'c.IVS4-75473G>A', (71, 84))	('TP73', 'Gene', '7161', (268, 272))	('IVS7+442G>T', 'Mutation', 'c.IVS7+442G>T', (186, 197))	('IVS2-1578A>G', 'Var', (229, 241))	('PMS2L3', 'Gene', '5387', (205, 211))	('MGMT', 'Gene', (43, 47))	('IVS2-1578A>G', 'Mutation', 'c.IVS2-1578A>G', (229, 241))	('PMS2', 'Gene', '5395', (205, 209))	('Ex1+118C>T', 'Mutation', 'c.EX1+118C>T', (246, 256))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (334, 351))	('PMS2', 'Gene', (161, 165))	('A610A', 'Var', (309, 314))	('IVS5+23129G>A', 'Mutation', 'c.IVS5+23129G>A', (100, 113))	('MGMT', 'molecular_function', 'GO:0003908', ('43', '47'))	('IVS4-7901C>T', 'Var', (86, 98))	('TP73', 'Gene', (268, 272))	('MSH6', 'Gene', (115, 119))	('G39E', 'Mutation', 'rs1042821', (120, 124))	('MSH6', 'Gene', '2956', (115, 119))	('IVS1-1121C>T', 'Mutation', 'c.IVS1-1121C>T', (166, 178))	('IVS3+9A>G', 'Mutation', 'c.IVS3+9A>G', (212, 221))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('PMS2', 'Gene', (205, 209))	('pancreatic cancer', 'Disease', 'MESH:D010190', (334, 351))	('MGMT', 'Gene', '4255', (43, 47))	('IVS1-7449G>C', 'Mutation', 'c.IVS1-7449G>C', (273, 285))
22808	21681824	With this study, we demonstrated a significant association between MMR network gene variants and risk of pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (105, 122))	('MMR network gene', 'Gene', (67, 83))	('MMR', 'biological_process', 'GO:0006298', ('67', '70'))	('pancreatic cancer', 'Disease', (105, 122))	('pancreatic cancer', 'Disease', 'MESH:D010190', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('variants', 'Var', (84, 92))
22810	21681824	As a multifunctional system, MMR maintains genome stability by removing mismatched or distorted DNA structures and stimulates the apoptosis cascade when cells are overwhelmed with genotoxic or cytotoxic damage.	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('apoptosis', 'CPA', (130, 139))	('MMR', 'biological_process', 'GO:0006298', ('29', '32'))	('genome', 'MPA', (43, 49))	('mismatched', 'Var', (72, 82))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('genotoxic', 'Disease', (180, 189))	('stimulates', 'PosReg', (115, 125))	('DNA structures', 'Protein', (96, 110))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('removing', 'NegReg', (63, 71))	('genotoxic', 'Disease', 'None', (180, 189))
22812	21681824	Through failure to recognize or repair the mismatched base-pairs/IDLs or failure to activate apoptosis signaling, MMR dysfunction may promote tumor development by accumulating replication errors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('MMR dysfunction', 'Disease', (114, 129))	('MMR dysfunction', 'Disease', 'MESH:C536143', (114, 129))	('promote', 'PosReg', (134, 141))	('apoptosis signaling', 'Pathway', (93, 112))	('apoptosis signaling', 'biological_process', 'GO:0006915', ('93', '112'))	('accumulating', 'PosReg', (163, 175))	('tumor', 'Disease', (142, 147))	('mismatched base-pairs/IDLs', 'Var', (43, 69))	('MMR', 'biological_process', 'GO:0006298', ('114', '117'))	('replication', 'MPA', (176, 187))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
22814	21681824	The observed association between MMR genetic variation and risk of pancreatic cancer supports the notion that MMR may contribute to pancreatic carcinogenesis.	('contribute', 'Reg', (118, 128))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (132, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (67, 84))	('pancreatic carcinogenesis', 'Disease', (132, 157))	('MMR', 'biological_process', 'GO:0006298', ('110', '113'))	('genetic variation', 'Var', (37, 54))	('MMR', 'Gene', (33, 36))	('pancreatic cancer', 'Disease', 'MESH:D010190', (67, 84))	('pancreatic cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('MMR', 'biological_process', 'GO:0006298', ('33', '36'))
22815	21681824	A recent field synopsis on low-penetrance variants in DNA repair genes and cancer susceptibility revealed sparse association signals with strong epidemiological credibility.	('DNA repair genes', 'Gene', (54, 70))	('DNA repair', 'biological_process', 'GO:0006281', ('54', '64'))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('variants', 'Var', (42, 50))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))
22817	21681824	We observed that MGMT I143V and K178R (in linkage) variant alleles were significantly related to decreased risk of pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('K178R', 'Mutation', 'rs2308327', (32, 37))	('pancreatic cancer', 'Disease', (115, 132))	('MGMT', 'molecular_function', 'GO:0003908', ('17', '21'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('I143V', 'Mutation', 'rs2308321', (22, 27))	('decreased', 'NegReg', (97, 106))	('K178R', 'Var', (32, 37))	('MGMT', 'Gene', '4255', (17, 21))	('MGMT', 'Gene', (17, 21))
22818	21681824	Consistently, the I143V variant has been reported as acting alone or interacting with dietary factors to reduce risk of colorectal cancer or breast cancer.	('reduce', 'NegReg', (105, 111))	('colorectal cancer', 'Disease', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('I143V', 'Var', (18, 23))	('breast cancer', 'Disease', (141, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('I143V', 'Mutation', 'rs2308321', (18, 23))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))
22819	21681824	We found that MGMT I143V GG and K178R GG genotypes correlated with increased DNA damage level.	('MGMT', 'Gene', (14, 18))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('K178R', 'Mutation', 'rs2308327', (32, 37))	('DNA damage level', 'MPA', (77, 93))	('I143V', 'Mutation', 'rs2308321', (19, 24))	('MGMT', 'molecular_function', 'GO:0003908', ('14', '18'))	('increased', 'PosReg', (67, 76))	('K178R', 'Var', (32, 37))	('MGMT', 'Gene', '4255', (14, 18))
22820	21681824	MGMT is the major enzyme to remove O6Et-Gua.	('MGMT', 'Gene', (0, 4))	('MGMT', 'molecular_function', 'GO:0003908', ('0', '4'))	('O6Et-Gua', 'Var', (35, 43))	('Gua', 'Chemical', 'MESH:D006147', (40, 43))	('MGMT', 'Gene', '4255', (0, 4))
22821	21681824	I143V polymorphism is located close to the alkyl group acceptor pocket at codon 145, which may affect the acceptance of an alkyl group.	('I143V', 'Var', (0, 5))	('I143V', 'Mutation', 'rs2308321', (0, 5))	('acceptance of an alkyl group', 'MPA', (106, 134))	('affect', 'Reg', (95, 101))
22822	21681824	We observed the interaction of I143V with smoking.	('interaction', 'Interaction', (16, 27))	('I143V', 'Var', (31, 36))	('I143V', 'Mutation', 'rs2308321', (31, 36))
22824	21681824	The variant allele of PMS2 IVS1-1121C>T, which was associated with increased pancreatic cancer risk, had also been associated with increased risk of ovarian cancer.	('PMS2', 'Gene', '5395', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('ovarian cancer', 'Disease', (149, 163))	('increased pancreatic cancer', 'Phenotype', 'HP:0002894', (67, 94))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('associated', 'Reg', (115, 125))	('IVS1-1121C>T', 'Mutation', 'c.IVS1-1121C>T', (27, 39))	('ovarian cancer', 'Phenotype', 'HP:0100615', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ovarian cancer', 'Disease', 'MESH:D010051', (149, 163))	('IVS1-1121C>T', 'Var', (27, 39))	('pancreatic cancer', 'Disease', (77, 94))	('PMS2', 'Gene', (22, 26))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
22825	21681824	IVS1-1121C>T is located close to the R20Q variant, which is defective in activating the p73-dependent apoptotic response to cisplatin.	('R20Q', 'Var', (37, 41))	('R20Q', 'Mutation', 'rs10254120', (37, 41))	('cisplatin', 'Chemical', 'MESH:D002945', (124, 133))	('p73', 'Gene', '7161', (88, 91))	('activating', 'PosReg', (73, 83))	('p73', 'Gene', (88, 91))	('IVS1-1121C>T', 'Mutation', 'c.IVS1-1121C>T', (0, 12))	('response to cisplatin', 'biological_process', 'GO:0072718', ('112', '133'))	('IVS1-1121C>T', 'Var', (0, 12))
22826	21681824	PMS2L3 Ex1+118C>T (5'UTR) and IVS3+9A>G were related to pancreatic cancer risk.	('IVS3+9A>G', 'Var', (30, 39))	('IVS3+9A>G', 'Mutation', 'c.IVS3+9A>G', (30, 39))	('Ex1+118C>T', 'Mutation', 'c.EX1+118C>T', (7, 17))	('pancreatic cancer', 'Disease', (56, 73))	('pancreatic cancer', 'Disease', 'MESH:D010190', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('PMS2L3', 'Gene', (0, 6))	('related', 'Reg', (45, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (56, 73))	('PMS2L3', 'Gene', '5387', (0, 6))
22828	21681824	PMS2L3 IVS3+9A>G GA genotype correlated with increased DNA damage level.	('increased', 'PosReg', (45, 54))	('IVS3+9A>G', 'Var', (7, 16))	('IVS3+9A>G', 'Mutation', 'c.IVS3+9A>G', (7, 16))	('PMS2L3', 'Gene', (0, 6))	('DNA damage level', 'MPA', (55, 71))	('PMS2L3', 'Gene', '5387', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))
22829	21681824	GA genotype carriers may be less active in recognizing O6Et-Gua-mimic mismatches but more effective to activate apoptosis to clear the damaged cells.	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('apoptosis', 'CPA', (112, 121))	('activate', 'PosReg', (103, 111))	('O6Et-Gua-mimic mismatches', 'Var', (55, 80))	('Gua', 'Chemical', 'MESH:D006147', (60, 63))	('mismatches', 'Var', (70, 80))
22830	21681824	We found that haplotypes of MGMT, MSH6, PMS2, PMS2L3, and TP73 correlated with pancreatic cancer risk.	('PMS2L3', 'Gene', (46, 52))	('pancreatic cancer', 'Disease', (79, 96))	('TP73', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('haplotypes', 'Var', (14, 24))	('PMS2', 'Gene', '5395', (40, 44))	('MGMT', 'Gene', (28, 32))	('PMS2L3', 'Gene', '5387', (46, 52))	('correlated with', 'Reg', (63, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (79, 96))	('PMS2', 'Gene', '5395', (46, 50))	('PMS2', 'Gene', (40, 44))	('MGMT', 'molecular_function', 'GO:0003908', ('28', '32'))	('MSH6', 'Gene', (34, 38))	('pancreatic cancer', 'Disease', 'MESH:D010190', (79, 96))	('MGMT', 'Gene', '4255', (28, 32))	('TP73', 'Gene', '7161', (58, 62))	('MSH6', 'Gene', '2956', (34, 38))	('PMS2', 'Gene', (46, 50))
22831	21681824	MSH6 haplotype demonstrated the protective effect of the G39E variant against pancreatic cancer.	('G39E', 'Var', (57, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('MSH6', 'Gene', '2956', (0, 4))	('G39E', 'Mutation', 'rs1042821', (57, 61))	('pancreatic cancer', 'Disease', (78, 95))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))	('MSH6', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
22832	21681824	G39E had been related consistently to decreased breast cancer risk.	('decreased', 'NegReg', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('G39E', 'Var', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Disease', (48, 61))	('G39E', 'Mutation', 'rs1042821', (0, 4))
22833	21681824	G39E AG/AA genotype showed increased DNA damage level, which may be less effective to recognize O6Et-Gua-mimic mismatches to initiate the MMR machinery, but act more efficiently to activate apoptosis pathway to maintain the genome stability.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('G39E', 'Mutation', 'rs1042821', (0, 4))	('maintain', 'Reg', (211, 219))	('increased', 'PosReg', (27, 36))	('apoptosis pathway', 'Pathway', (190, 207))	('mismatches', 'Var', (111, 121))	('DNA damage level', 'MPA', (37, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('190', '199'))	('activate', 'PosReg', (181, 189))	('apoptosis', 'biological_process', 'GO:0097194', ('190', '199'))	('Gua', 'Chemical', 'MESH:D006147', (101, 104))	('MMR', 'biological_process', 'GO:0006298', ('138', '141'))	('genome stability', 'CPA', (224, 240))
22835	21681824	Interaction of p73 isoform TA with truncated DeltaN regulates differentiation, proliferation, and apoptosis.	('proliferation', 'CPA', (79, 92))	('differentiation', 'CPA', (62, 77))	('DeltaN', 'Gene', (45, 51))	('apoptosis', 'CPA', (98, 107))	('Interaction', 'Interaction', (0, 11))	('truncated', 'Var', (35, 44))	('p73', 'Gene', '7161', (15, 18))	('p73', 'Gene', (15, 18))	('regulates', 'Reg', (52, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))
22836	21681824	We found that TP73 genetic variation may modify cancer susceptibility, which supports a role for p73 in pancreatic carcinogenesis.	('TP73', 'Gene', '7161', (14, 18))	('TP73', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('pancreatic carcinogenesis', 'Disease', (104, 129))	('p73', 'Gene', '7161', (97, 100))	('p73', 'Gene', (97, 100))	('genetic variation', 'Var', (19, 36))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (104, 129))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('modify', 'Reg', (41, 47))
22837	21681824	TP73 IVS1-7449G>C CG/CC genotype showed increased DNA damage level, which may be more effective in inducing apoptosis with the DNA damage accumulation and genome instability.	('inducing', 'Reg', (99, 107))	('TP73', 'Gene', '7161', (0, 4))	('TP73', 'Gene', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('increased', 'PosReg', (40, 49))	('IVS1-7449G>C CG/CC', 'Var', (5, 23))	('IVS1-7449G>C', 'Mutation', 'c.IVS1-7449G>C', (5, 17))	('apoptosis', 'CPA', (108, 117))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))	('DNA damage level', 'MPA', (50, 66))
22838	21681824	Previously we reported that RECQL Ex15+159A>C predicted clinical outcome in pancreatic cancer.	('RECQL', 'Gene', (28, 33))	('pancreatic cancer', 'Disease', (76, 93))	('Ex15+159A>C', 'Var', (34, 45))	('RECQL', 'Gene', '5965', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('pancreatic cancer', 'Disease', 'MESH:D010190', (76, 93))	('predicted', 'Reg', (46, 55))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))
22850	21681824	To conclude, we observed an association between MMR polymorphism and pancreatic cancer risk, providing supporting evidence of a role for MMR dysfunction in pancreatic carcinogenesis.	('MMR', 'Gene', (48, 51))	('pancreatic cancer', 'Disease', (69, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('polymorphism', 'Var', (52, 64))	('MMR', 'biological_process', 'GO:0006298', ('137', '140'))	('pancreatic carcinogenesis', 'Disease', (156, 181))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (69, 86))	('MMR dysfunction', 'Disease', (137, 152))	('MMR dysfunction', 'Disease', 'MESH:C536143', (137, 152))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (156, 181))	('MMR', 'biological_process', 'GO:0006298', ('48', '51'))
22895	21197415	NPC-1C antibody-binding competition assays were performed by coating microtiter plates with serum-free conditioned medium from CFPAC-1 tumor cells shown to secrete the variant MUC5AC antigen into the culture medium.	('antibody', 'cellular_component', 'GO:0019815', ('7', '15'))	('CFPAC-1', 'CellLine', 'CVCL:1119', (127, 134))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('antibody', 'cellular_component', 'GO:0019814', ('7', '15'))	('binding', 'molecular_function', 'GO:0005488', ('16', '23'))	('antibody', 'molecular_function', 'GO:0003823', ('7', '15'))	('MUC5AC', 'Gene', (176, 182))	('tumor', 'Disease', (135, 140))	('antibody', 'cellular_component', 'GO:0042571', ('7', '15'))	('MUC5AC', 'Gene', '4586', (176, 182))	('NPC', 'cellular_component', 'GO:0005643', ('0', '3'))	('CFPAC-1', 'Gene', (127, 134))	('variant', 'Var', (168, 175))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
22901	21197415	Previous titration of biotinylated-NPC-1C antibody demonstrated 10 mug/mL to be an optimal concentration for immunohistochemical detection of the variant MUC5AC antigen.	('antibody', 'cellular_component', 'GO:0019814', ('42', '50'))	('antibody', 'molecular_function', 'GO:0003823', ('42', '50'))	('variant', 'Var', (146, 153))	('mug', 'molecular_function', 'GO:0043739', ('67', '70'))	('MUC5AC', 'Gene', '4586', (154, 160))	('antibody', 'cellular_component', 'GO:0042571', ('42', '50'))	('MUC5AC', 'Gene', (154, 160))	('NPC', 'cellular_component', 'GO:0005643', ('35', '38'))	('antibody', 'cellular_component', 'GO:0019815', ('42', '50'))	('biotin', 'Chemical', 'MESH:D001710', (22, 28))
22914	21197415	We rapidly determined that the variant MUC5AC antigen was shed into the supernatant of many cultured human colorectal and pancreatic tumor cells, but not by other tumor cell lines such as prostate or lung tumor cells.	('MUC5AC', 'Gene', '4586', (39, 45))	('lung tumor', 'Disease', (200, 210))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('colorectal', 'Disease', 'MESH:D015179', (107, 117))	('lung tumor', 'Phenotype', 'HP:0100526', (200, 210))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('prostate', 'Disease', (188, 196))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('variant', 'Var', (31, 38))	('prostate', 'Disease', 'MESH:D011472', (188, 196))	('lung tumor', 'Disease', 'MESH:D008175', (200, 210))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('MUC5AC', 'Gene', (39, 45))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (122, 138))	('human', 'Species', '9606', (101, 106))	('tumor', 'Disease', (133, 138))	('colorectal', 'Disease', (107, 117))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('pancreatic tumor', 'Disease', (122, 138))	('tumor', 'Disease', (205, 210))	('pancreatic tumor', 'Disease', 'MESH:D010190', (122, 138))
22920	21197415	Together the results demonstrate that NPC-1C binds specifically to a variant MUC5AC antigen expressed by colorectal and pancreatic tumor cells, but not MUC5AC secreted by other tumor cell types.	('colorectal', 'Disease', 'MESH:D015179', (105, 115))	('variant', 'Var', (69, 76))	('NPC', 'cellular_component', 'GO:0005643', ('38', '41'))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('MUC5AC', 'Gene', '4586', (77, 83))	('binds', 'Interaction', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('colorectal', 'Disease', (105, 115))	('MUC5AC', 'Gene', '4586', (152, 158))	('pancreatic tumor', 'Disease', (120, 136))	('tumor', 'Disease', (131, 136))	('MUC5AC', 'Gene', (152, 158))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (120, 136))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('MUC5AC', 'Gene', (77, 83))	('tumor', 'Disease', (177, 182))	('pancreatic tumor', 'Disease', 'MESH:D010190', (120, 136))
22923	21197415	Figure 2 shows that NPC-1C antibody was capable of measuring the cognate antigen expressed by LS174T in this ELISA format.	('antibody', 'cellular_component', 'GO:0042571', ('27', '35'))	('cognate antigen expressed', 'MPA', (65, 90))	('NPC', 'cellular_component', 'GO:0005643', ('20', '23'))	('antibody', 'cellular_component', 'GO:0019815', ('27', '35'))	('LS174T', 'Var', (94, 100))	('LS174T', 'CellLine', 'CVCL:1384', (94, 100))	('antibody', 'cellular_component', 'GO:0019814', ('27', '35'))	('antibody', 'molecular_function', 'GO:0003823', ('27', '35'))	('measuring', 'MPA', (51, 60))
22927	21197415	The proof-of-concept to demonstrate that the NPC-1C antibody ELISA test could be utilized to detect the variant MUC5AC antigen in human serum specimens was demonstrated with a small number of serum samples from colorectal cancer patients.	('patients', 'Species', '9606', (229, 237))	('MUC5AC', 'Gene', '4586', (112, 118))	('colorectal cancer', 'Disease', 'MESH:D015179', (211, 228))	('antibody', 'cellular_component', 'GO:0042571', ('52', '60'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (211, 228))	('antibody', 'cellular_component', 'GO:0019815', ('52', '60'))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('antibody', 'cellular_component', 'GO:0019814', ('52', '60'))	('antibody', 'molecular_function', 'GO:0003823', ('52', '60'))	('MUC5AC', 'Gene', (112, 118))	('colorectal cancer', 'Disease', (211, 228))	('NPC', 'cellular_component', 'GO:0005643', ('45', '48'))	('variant', 'Var', (104, 111))	('human', 'Species', '9606', (130, 135))
22929	21197415	The results demonstrate a range of variant MUC5AC antigen shed into the blood of these colorectal cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('shed', 'Reg', (58, 62))	('patients', 'Species', '9606', (105, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('MUC5AC', 'Gene', (43, 49))	('colorectal cancer', 'Disease', (87, 104))	('variant', 'Var', (35, 42))	('colorectal cancer', 'Disease', 'MESH:D015179', (87, 104))	('MUC5AC', 'Gene', '4586', (43, 49))
22930	21197415	A larger number of serum samples were procured to test the utility of the serum-based ELISA in detecting the variant MUC5AC antigen.	('variant', 'Var', (109, 116))	('MUC5AC', 'Gene', (117, 123))	('MUC5AC', 'Gene', '4586', (117, 123))
22943	21197415	From patients that donated multiple serum samples, the amount of variant MUC5AC biomarker detected in the assay was plotted versus the time of the blood draw.	('MUC5AC', 'Gene', (73, 79))	('MUC5AC', 'Gene', '4586', (73, 79))	('patients', 'Species', '9606', (5, 13))	('variant', 'Var', (65, 72))
22944	21197415	As shown in Figure 6, some patients appeared to express similar amounts of the variant MUC5AC antigen during the 2- or 3-month period when blood was drawn (subjects 5, 14, 15, 19, 25, 28, 29), whereas some patients appeared to experience an increase in this tumor-specific antigen expression (subjects 1, 2, 7, 33, 39) or a decrease in the biomarker expression (subjects 18, 22, 23, 28, 34, 36, 40).	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('increase', 'PosReg', (241, 249))	('tumor', 'Disease', (258, 263))	('MUC5AC', 'Gene', (87, 93))	('biomarker expression', 'MPA', (340, 360))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (206, 214))	('MUC5AC', 'Gene', '4586', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('decrease', 'NegReg', (324, 332))	('expression', 'MPA', (281, 291))	('variant', 'Var', (79, 86))
22946	21197415	It was not possible within the 3-month time period of the blood collections to determine whether a correlation exists between the rate of variant MUC5AC increase or decrease and the outcome of the disease in these patients.	('patients', 'Species', '9606', (214, 222))	('decrease', 'NegReg', (165, 173))	('increase', 'PosReg', (153, 161))	('MUC5AC', 'Gene', (146, 152))	('MUC5AC', 'Gene', '4586', (146, 152))	('variant', 'Var', (138, 145))
22947	21197415	A number of tumor tissue specimens were procured to examine the level and incidence of variant MUC5AC antigen expression in colorectal and pancreatic cancer patients.	('MUC5AC', 'Gene', '4586', (95, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (139, 156))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('colorectal and pancreatic cancer', 'Disease', 'MESH:D010190', (124, 156))	('patients', 'Species', '9606', (157, 165))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('MUC5AC', 'Gene', (95, 101))	('tumor', 'Disease', (12, 17))	('variant', 'Var', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
22949	21197415	Representative examples of the staining results to detect the variant MUC5AC antigen are shown in Figure 7.	('MUC5AC', 'Gene', (70, 76))	('MUC5AC', 'Gene', '4586', (70, 76))	('variant', 'Var', (62, 69))
22951	21197415	In the colorectal cancer tissues, frequent staining of secreted variant MUC5AC antigen was observed in the luminal spaces of the tissues (panel (d)).	('colorectal cancer', 'Phenotype', 'HP:0003003', (7, 24))	('MUC5AC', 'Gene', (72, 78))	('variant', 'Var', (64, 71))	('colorectal cancer', 'Disease', (7, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('MUC5AC', 'Gene', '4586', (72, 78))	('colorectal cancer', 'Disease', 'MESH:D015179', (7, 24))
22962	21197415	Several research laboratories have demonstrated the association of aberrantly expressed MUC5AC in colorectal and pancreatic cancers.	('pancreatic cancers', 'Phenotype', 'HP:0002894', (113, 131))	('aberrantly expressed', 'Var', (67, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('association', 'Interaction', (52, 63))	('MUC5AC', 'Gene', (88, 94))	('colorectal and pancreatic cancers', 'Disease', 'MESH:D010190', (98, 131))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('MUC5AC', 'Gene', '4586', (88, 94))
22964	21197415	However, none of these appear as specific as the NPC-1C antibody in defining the variant MUC5AC antigen expressed in colorectal and pancreatic patient serum as compared with normal healthy donors, or as compared with MUC5AC antigen expressed by other tumor types.	('antibody', 'cellular_component', 'GO:0019815', ('56', '64'))	('pancreatic', 'Disease', 'MESH:D010195', (132, 142))	('tumor', 'Disease', (251, 256))	('patient', 'Species', '9606', (143, 150))	('MUC5AC', 'Gene', '4586', (89, 95))	('antibody', 'cellular_component', 'GO:0019814', ('56', '64'))	('antibody', 'molecular_function', 'GO:0003823', ('56', '64'))	('pancreatic', 'Disease', (132, 142))	('MUC5AC', 'Gene', '4586', (217, 223))	('colorectal', 'Disease', 'MESH:D015179', (117, 127))	('variant', 'Var', (81, 88))	('antibody', 'cellular_component', 'GO:0042571', ('56', '64'))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('NPC', 'cellular_component', 'GO:0005643', ('49', '52'))	('MUC5AC', 'Gene', (217, 223))	('MUC5AC', 'Gene', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('colorectal', 'Disease', (117, 127))
23015	20665496	Secondary analyses also examined BMI categorized according to NIH guidelines of underweight (<18.5 kg/m2), normal weight (referent group, 18.5-24.99 kg.m2), overweight (25.0-29.99 kg/m2), obese class I (30.0-34.99 kg/m2) obese class II (35.0-39.99 kg/m2), and obese class III (>=40.0 kg/m2).	('30.0-34.99 kg/m2', 'Var', (203, 219))	('obese', 'Disease', (221, 226))	('obese', 'Disease', 'MESH:D009765', (260, 265))	('obese', 'Disease', 'MESH:D009765', (188, 193))	('obese class I', 'Phenotype', 'HP:0025499', (221, 234))	('35.0-39.99 kg/m2', 'Var', (237, 253))	('overweight', 'Phenotype', 'HP:0025502', (157, 167))	('obese', 'Disease', (260, 265))	('obese', 'Disease', (188, 193))	('obese', 'Disease', 'MESH:D009765', (221, 226))	('obese class I', 'Phenotype', 'HP:0025499', (260, 273))	('obese class I', 'Phenotype', 'HP:0025499', (188, 201))	('obese class III', 'Phenotype', 'HP:0025501', (260, 275))
23028	20665496	In weight loss categories (None, >0 and <=10%, or >10%), there was a significant association (p=0.009) with decreased survival seen with higher weight loss, adjusted for age, stage, and sex.	('<=10%', 'Var', (40, 45))	('survival', 'MPA', (118, 126))	('weight loss', 'Disease', (144, 155))	('weight loss categories', 'Disease', 'MESH:D015431', (3, 25))	('weight loss', 'Phenotype', 'HP:0001824', (144, 155))	('weight loss', 'Phenotype', 'HP:0001824', (3, 14))	('decreased', 'NegReg', (108, 117))	('weight loss', 'Disease', 'MESH:D015431', (144, 155))	('weight loss', 'Disease', 'MESH:D015431', (3, 14))	('weight loss categories', 'Disease', (3, 25))	('>10%', 'Var', (50, 54))
23046	20665496	It could be argued that BMI may affect stage at presentation, or likelihood of a patient undergoing surgery, thus influencing survival.	('patient', 'Species', '9606', (81, 88))	('stage', 'MPA', (39, 44))	('BMI', 'Var', (24, 27))	('affect', 'Reg', (32, 38))	('influencing', 'Reg', (114, 125))	('survival', 'MPA', (126, 134))
23074	20215540	Activated Smo induces nuclear localization of the Gli family of transcription factors, resulting in transcription of hedgehog specific target genes, including Gli1 and Ptch.	('Ptch', 'Gene', '5727', (168, 172))	('Gli', 'Gene', (159, 162))	('localization', 'biological_process', 'GO:0051179', ('30', '42'))	('Ptch', 'Gene', (168, 172))	('Gli', 'Gene', '2735', (159, 162))	('transcription', 'biological_process', 'GO:0006351', ('64', '77'))	('nuclear localization', 'MPA', (22, 42))	('hedgehog', 'Gene', (117, 125))	('induces', 'Reg', (14, 21))	('Activated', 'Var', (0, 9))	('transcription', 'MPA', (100, 113))	('Gli', 'Gene', (50, 53))	('transcription', 'biological_process', 'GO:0006351', ('100', '113'))	('Smo', 'Gene', (10, 13))	('hedgehog', 'Gene', '42737', (117, 125))	('Gli', 'Gene', '2735', (50, 53))
23075	20215540	Constitutive activation of the pathway results in cell proliferation and tumor formation and commonly occurs as a result of activating mutations in Smo or inactivating mutations in the tumor suppressor gene Ptch.	('inactivating mutations', 'Var', (155, 177))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cell proliferation', 'CPA', (50, 68))	('tumor', 'Disease', (185, 190))	('Ptch', 'Gene', '5727', (207, 211))	('mutations', 'Var', (135, 144))	('Ptch', 'Gene', (207, 211))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('Smo', 'Gene', (148, 151))	('results in', 'Reg', (39, 49))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('185', '201'))	('tumor', 'Disease', (73, 78))	('activating', 'PosReg', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('185', '201'))	('formation', 'biological_process', 'GO:0009058', ('79', '88'))	('activation', 'PosReg', (13, 23))
23080	20215540	Furthermore, cyclopamine therapy inhibits development of tumor metastases in xenografted mice and prolongs survival in a mouse model of pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('cyclopamine', 'Var', (13, 24))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor metastases', 'Disease', (57, 73))	('prolongs', 'NegReg', (98, 106))	('mice', 'Species', '10090', (89, 93))	('tumor metastases', 'Disease', 'MESH:D009362', (57, 73))	('cyclopamine', 'Chemical', 'MESH:C000541', (13, 24))	('mouse', 'Species', '10090', (121, 126))	('survival', 'CPA', (107, 115))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('inhibits', 'NegReg', (33, 41))	('pancreatic cancer', 'Disease', (136, 153))
23082	20215540	Previously, a cell-autonomous role for Hedgehog signaling has been described in tumor types driven by mutations in Hedgehog pathway components, such as medulloblastoma and basal cell carcinoma.	('Hedgehog', 'Gene', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (172, 192))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (172, 192))	('basal cell carcinoma', 'Disease', (172, 192))	('medulloblastoma', 'Disease', (152, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('tumor', 'Disease', (80, 85))	('medulloblastoma', 'Phenotype', 'HP:0002885', (152, 167))	('mutations', 'Var', (102, 111))	('Hedgehog', 'Gene', (115, 123))	('Hedgehog', 'Gene', '42737', (115, 123))	('medulloblastoma', 'Disease', 'MESH:D008527', (152, 167))	('Hedgehog', 'Gene', '42737', (39, 47))	('driven by', 'Reg', (92, 101))
23113	20215540	The following primer sets were used for Taqman assays (Applied Biosystems): Taqman Gene Expression Assays Hs00170665_m1 (hSmo), Hs00179843_m1 (hShh), Hs00171790_m1 (hGli1), Hs00257977_m1 (hGli2), 18S rRNA VIC-MGB probe dye.	('Gene Expression', 'biological_process', 'GO:0010467', ('83', '98'))	('hGli1', 'Gene', (165, 170))	('hGli1', 'Gene', '2735', (165, 170))	('Hs00179843_m1', 'Var', (128, 141))	('hGli2', 'Gene', (188, 193))	('Hs00171790_m1', 'Var', (150, 163))	('Hs00170665_m1', 'Var', (106, 119))	('Hs00257977_m1', 'Var', (173, 186))	('hGli2', 'Gene', '2736', (188, 193))
23147	20215540	To further investigate the role of SMO expression in transducing the Shh signal, we transiently knocked down SMO expression in another overexpressing CAF, CAF26, and then stimulated them with ShhN ligand.	('SMO', 'Gene', '6608', (35, 38))	('CAF', 'Gene', '8850', (155, 158))	('CAF', 'Gene', (150, 153))	('ligand', 'molecular_function', 'GO:0005488', ('197', '203'))	('SMO', 'Gene', (35, 38))	('CAF', 'Gene', '8850', (150, 153))	('CAF', 'Gene', (155, 158))	('SMO', 'Gene', '6608', (109, 112))	('knocked', 'Var', (96, 103))	('SMO', 'Gene', (109, 112))	('CAF26', 'Chemical', '-', (155, 160))
23148	20215540	Using siRNA we were able to knock down SMO with 90% efficiency (Fig.3a) which resulted in a 70% (P=0.007) reduction in Gli1 mRNA expression in CAF26 (Fig.3b).	('reduction', 'NegReg', (106, 115))	('Gli1 mRNA expression', 'MPA', (119, 139))	('CAF26', 'Chemical', '-', (143, 148))	('SMO', 'Gene', '6608', (39, 42))	('SMO', 'Gene', (39, 42))	('knock down', 'Var', (28, 38))
23221	31703359	Moreover, the role of immunity in PDAC remains unclear; the B- and T cells of PDAC patients can be induced to recognize some tumor-associated antigens, such as Wilms' tumor gene 1 (WT1), mucin 1 (MUC1), human telomerase reverse transcriptase (hTERT), mutated K-RAS, and carcinoembryonic antigen (CEA).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('WT1', 'Gene', '7490', (181, 184))	('hTERT', 'Gene', (243, 248))	('mucin 1', 'Gene', (187, 194))	('MUC1', 'Gene', (196, 200))	('MUC1', 'Gene', '4582', (196, 200))	('carcinoembryonic antigen', 'Gene', '1084', (270, 294))	("Wilms' tumor gene 1", 'Gene', (160, 179))	('mutated', 'Var', (251, 258))	('CEA', 'Gene', (296, 299))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (160, 172))	('patients', 'Species', '9606', (83, 91))	('transcriptase', 'molecular_function', 'GO:0003968', ('228', '241'))	("Wilms' tumor gene 1", 'Gene', '7490', (160, 179))	('tumor', 'Disease', (167, 172))	('CEA', 'Gene', '1084', (296, 299))	('transcriptase', 'molecular_function', 'GO:0034062', ('228', '241'))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('mucin 1', 'Gene', '4582', (187, 194))	('K-RAS', 'Gene', (259, 264))	('hTERT', 'Gene', '7015', (243, 248))	('human', 'Species', '9606', (203, 208))	('carcinoembryonic antigen', 'Gene', (270, 294))	('WT1', 'Gene', (181, 184))	('tumor', 'Disease', (125, 130))	('K-RAS', 'Gene', '3845', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('transcriptase', 'molecular_function', 'GO:0003899', ('228', '241'))
23232	31703359	The combination of taxanes and gemcitabine and the fluoropyrimidine-based therapy had better survival benefit than most combination therapies, including the combination of antiangiogenesis and gemcitabine, the combination of EGFR inhibitors and gemcitabine, and the combination of fluoropyrimidine and gemcitabine.	('EGFR', 'molecular_function', 'GO:0005006', ('225', '229'))	('survival benefit', 'CPA', (93, 109))	('gemcitabine', 'Chemical', 'MESH:C056507', (31, 42))	('gemcitabine', 'Chemical', 'MESH:C056507', (302, 313))	('EGFR', 'Gene', '1956', (225, 229))	('inhibitors', 'Var', (230, 240))	('taxanes', 'Chemical', 'MESH:D043823', (19, 26))	('antiangiogenesis', 'CPA', (172, 188))	('fluoropyrimidine', 'Chemical', '-', (281, 297))	('EGFR', 'Gene', (225, 229))	('gemcitabine', 'Chemical', 'MESH:C056507', (193, 204))	('gemcitabine', 'Chemical', 'MESH:C056507', (245, 256))	('fluoropyrimidine', 'Chemical', '-', (51, 67))
23239	31703359	Statistically significant increasing of ORR were shown in the combination of fluoropyrimidine and gemcitabine (RR: 2.00; 95% CI: 1.57-2.54; p < 0.0001; heterogeneity: p = 0.35; I2 = 11%), the use of fluoropyrimidine-based therapies (RR: 3.38; 95% CI: 2.01-5.65; p < 0.00001; heterogeneity: single study), and the use of fluoropyrimidine alone (RR: 1.64; 95% CI: 1.09-2.47; p = 0.002; heterogeneity: single study), versus gemcitabine alone.	('fluoropyrimidine', 'Chemical', '-', (199, 215))	('gemcitabine', 'Chemical', 'MESH:C056507', (98, 109))	('increasing', 'PosReg', (26, 36))	('fluoropyrimidine', 'Var', (320, 336))	('fluoropyrimidine', 'Chemical', '-', (77, 93))	('gemcitabine', 'Chemical', 'MESH:C056507', (421, 432))	('ORR', 'MPA', (40, 43))	('fluoropyrimidine', 'Chemical', '-', (320, 336))
23242	31703359	In the hematological toxicities, as compared to gemcitabine alone, fluoropyrimidine-based increased the risk the neutropenia (OR: 3.04; 95% CI: 1.88-4.90; p < 0.00001; heterogeneity: single trial).	('hematological toxicities', 'Disease', (7, 31))	('neutropenia', 'Disease', 'MESH:D009503', (113, 124))	('neutropenia', 'Phenotype', 'HP:0001875', (113, 124))	('hematological toxicities', 'Disease', 'MESH:D006402', (7, 31))	('fluoropyrimidine', 'Chemical', '-', (67, 83))	('gemcitabine', 'Chemical', 'MESH:C056507', (48, 59))	('neutropenia', 'Disease', (113, 124))	('fluoropyrimidine-based', 'Var', (67, 89))
23244	31703359	On the other hand, patients treated with combination of taxanes and gemcitabine had higher neutropenia (OR: 1.62; 95% CI: 1.22-2.16; p = 0.00009; heterogeneity: I2 = 0%) and leukopenia (OR: 2.25; 95% CI: 1.60-3.16; p < 0.00001; heterogeneity: single trial).	('neutropenia', 'Phenotype', 'HP:0001875', (91, 102))	('leukopenia', 'Disease', 'MESH:D007970', (174, 184))	('patients', 'Species', '9606', (19, 27))	('taxanes', 'Chemical', 'MESH:D043823', (56, 63))	('neutropenia', 'Disease', 'MESH:D009503', (91, 102))	('leukopenia', 'Phenotype', 'HP:0001882', (174, 184))	('neutropenia', 'Disease', (91, 102))	('combination', 'Interaction', (41, 52))	('gemcitabine', 'Var', (68, 79))	('leukopenia', 'Disease', (174, 184))	('higher', 'PosReg', (84, 90))	('gemcitabine', 'Chemical', 'MESH:C056507', (68, 79))
23246	31703359	Moreover, increasing risks of diarrhea were observed in the use of the combination of taxanes and gemcitabine, fluoropyrimidine alone, and fluoropyrimidine-based (OR: 5.71; 95% CI: 1.69-19.29; p = 0.005; heterogeneity: I2 = 0%; OR: 3.86; 95% CI: 1.54-9.65; heterogeneity: I2 = 12%; OR: 0.84, 95% CI: 2.29-26.81; heterogeneity: single trial), as compared to gemcitabine alone.	('diarrhea', 'Phenotype', 'HP:0002014', (30, 38))	('fluoropyrimidine', 'Chemical', '-', (111, 127))	('gemcitabine', 'Chemical', 'MESH:C056507', (98, 109))	('gemcitabine', 'Chemical', 'MESH:C056507', (357, 368))	('diarrhea', 'Disease', (30, 38))	('diarrhea', 'Disease', 'MESH:D003967', (30, 38))	('fluoropyrimidine', 'Chemical', '-', (139, 155))	('fluoropyrimidine-based', 'Var', (139, 161))	('taxanes', 'Chemical', 'MESH:D043823', (86, 93))
23247	31703359	A higher risk of stomatitis was found in the combination of fluoropyrimidine and gemcitabine than in the gemcitabine alone (OR: 3.91; 95% CI: 1.28-11.97; p = 0.02; heterogeneity: I2 = 0%).	('stomatitis', 'Disease', 'MESH:D013280', (17, 27))	('stomatitis', 'Disease', (17, 27))	('fluoropyrimidine', 'Chemical', '-', (60, 76))	('stomatitis', 'Phenotype', 'HP:0010280', (17, 27))	('combination', 'Interaction', (45, 56))	('gemcitabine', 'Chemical', 'MESH:C056507', (105, 116))	('fluoropyrimidine', 'Var', (60, 76))	('gemcitabine', 'Chemical', 'MESH:C056507', (81, 92))
23249	31703359	Hand-foot syndrome occurred most in the combination of fluoropyrimidine and gemcitabine (OR: 7.16; 95% CI: 1.27-40.51; p = 0.03; heterogeneity: I2 = 0%).	('fluoropyrimidine', 'Chemical', '-', (55, 71))	('combination', 'Interaction', (40, 51))	('Hand-foot syndrome', 'Disease', (0, 18))	('fluoropyrimidine', 'Var', (55, 71))	('Hand-foot syndrome', 'Disease', 'MESH:D060831', (0, 18))	('gemcitabine', 'Chemical', 'MESH:C056507', (76, 87))
23265	31703359	Both KRAS/BRAF mutation and gene amplification may have contributed to resistance mechanisms.	('mutation', 'Var', (15, 23))	('gene amplification', 'Var', (28, 46))	('contributed', 'Reg', (56, 67))	('KRAS', 'Gene', (5, 9))	('KRAS', 'Gene', '3845', (5, 9))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))
23266	31703359	Nearly 90% of patients with PDAC possess KRAS mutations, and half of the remaining patients harbor BRAF mutations.	('KRAS', 'Gene', '3845', (41, 45))	('mutations', 'Var', (46, 55))	('patients', 'Species', '9606', (83, 91))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('PDAC', 'Disease', (28, 32))	('KRAS', 'Gene', (41, 45))	('patients', 'Species', '9606', (14, 22))
23267	31703359	KRAS/BRAF mutations cause increasing signaling of proliferation despite the inhibition of TKIs.	('inhibition', 'NegReg', (76, 86))	('KRAS', 'Gene', '3845', (0, 4))	('BRAF', 'Gene', '673', (5, 9))	('increasing', 'PosReg', (26, 36))	('BRAF', 'Gene', (5, 9))	('proliferation', 'CPA', (50, 63))	('TKIs', 'Protein', (90, 94))	('signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('mutations', 'Var', (10, 19))	('KRAS', 'Gene', (0, 4))	('signaling', 'MPA', (37, 46))
23311	31772762	PDAC is characterized by well-defined genetic modifications; however, epigenetic alterations have recently been recognized as important contributors to PDAC development and progression, as well as potential therapeutic targets.	('PDAC', 'Disease', (152, 156))	('PDAC', 'Phenotype', 'HP:0006725', (152, 156))	('PDAC', 'Disease', (0, 4))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('PDAC', 'Disease', 'MESH:D021441', (0, 4))	('epigenetic alterations', 'Var', (70, 92))	('PDAC', 'Disease', 'MESH:D021441', (152, 156))
23312	31772762	Epigenetic alterations to oncogenes and tumor suppressor genes affect tumor progression and are associated with PDAC patient survival post-diagnosis.	('Epigenetic alterations', 'Var', (0, 22))	('affect', 'Reg', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('PDAC', 'Disease', 'MESH:D021441', (112, 116))	('associated with', 'Reg', (96, 111))	('tumor', 'Disease', (70, 75))	('PDAC', 'Disease', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('oncogenes', 'Gene', (26, 35))	('PDAC', 'Phenotype', 'HP:0006725', (112, 116))	('patient', 'Species', '9606', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))
23313	31772762	The principle epigenetic mechanisms that influence tumor-associated gene expression are: DNA methylation; histone modification, including histone acetylation, deacetylation and methylation; and microRNAs.	('acetyl', 'Chemical', 'MESH:C011632', (161, 167))	('deacetylation', 'MPA', (159, 172))	('DNA methylation', 'biological_process', 'GO:0006306', ('89', '104'))	('influence', 'Reg', (41, 50))	('histone modification', 'biological_process', 'GO:0016570', ('106', '126'))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('methyl', 'Chemical', 'MESH:C031105', (93, 99))	('tumor', 'Disease', (51, 56))	('histone acetylation', 'biological_process', 'GO:0016573', ('138', '157'))	('methylation', 'MPA', (177, 188))	('methylation', 'Var', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('methylation', 'biological_process', 'GO:0032259', ('177', '188'))	('histone acetylation', 'MPA', (138, 157))	('histone modification', 'MPA', (106, 126))	('methyl', 'Chemical', 'MESH:C031105', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('acetyl', 'Chemical', 'MESH:C011632', (146, 152))	('gene expression', 'biological_process', 'GO:0010467', ('68', '83'))
23319	31772762	The subunits of NR complexes are known to be mutated or replaced with other complexes in more than 20% of human cancers.	('human', 'Species', '9606', (106, 111))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutated', 'Var', (45, 52))
23322	31772762	Conversely, deacetylation has the opposite effect and results in a more closed chromatin structure that suppresses gene expression.	('suppresses', 'NegReg', (104, 114))	('chromatin', 'cellular_component', 'GO:0000785', ('79', '88'))	('more', 'PosReg', (67, 71))	('acetyl', 'Chemical', 'MESH:C011632', (14, 20))	('gene expression', 'biological_process', 'GO:0010467', ('115', '130'))	('deacetylation', 'Var', (12, 25))	('gene expression', 'MPA', (115, 130))
23328	31772762	The aberrant expression levels of mucinous glycoproteins, such as MUC17, has earlier been correlated with PDAC pathogenicity and progression.	('expression levels', 'MPA', (13, 30))	('correlated', 'Reg', (90, 100))	('aberrant', 'Var', (4, 12))	('PDAC', 'Disease', (106, 110))	('PDAC', 'Disease', 'MESH:D021441', (106, 110))	('PDAC', 'Phenotype', 'HP:0006725', (106, 110))	('MUC17', 'Gene', '140453', (66, 71))	('MUC17', 'Gene', (66, 71))
23336	31772762	It will be essential to overcome these challenges to deepen our understanding of the importance of specific DNA-protein interactions and to identify the functionally relevant DNA and protein modifications which create microenvironmental conditions favorable for PDAC development and growth.	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('interactions', 'Interaction', (120, 132))	('modifications', 'Var', (191, 204))	('PDAC', 'Disease', 'MESH:D021441', (262, 266))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('PDAC', 'Disease', (262, 266))	('PDAC', 'Phenotype', 'HP:0006725', (262, 266))	('DNA', 'cellular_component', 'GO:0005574', ('175', '178'))
23339	31772762	Promoter hypermethylation is primarily associated with gene silencing, as methylation interferes with the transcription factor binding to the promoter, resulting in the suppression of gene expression.	('methylation', 'Var', (74, 85))	('gene expression', 'MPA', (184, 199))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('106', '134'))	('methyl', 'Chemical', 'MESH:C031105', (14, 20))	('interferes', 'NegReg', (86, 96))	('gene silencing', 'biological_process', 'GO:0016458', ('55', '69'))	('suppression', 'NegReg', (169, 180))	('gene expression', 'biological_process', 'GO:0010467', ('184', '199'))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('methyl', 'Chemical', 'MESH:C031105', (74, 80))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))	('transcription factor binding to the', 'Interaction', (106, 141))	('Promoter hypermethylation', 'Var', (0, 25))
23340	31772762	Conversely, promoter hypomethylation is associated with an increased expression of the corresponding gene product.	('methyl', 'Chemical', 'MESH:C031105', (25, 31))	('increased', 'PosReg', (59, 68))	('promoter hypomethylation', 'Var', (12, 36))	('expression', 'MPA', (69, 79))
23341	31772762	Cancer-associated genes, such as tumor suppressor genes, frequently display promoter hypermethylation which reduces their expression and results in unchecked tumor cell proliferation.	('promoter hypermethylation', 'Var', (76, 101))	('tumor', 'Disease', (158, 163))	('expression', 'MPA', (122, 132))	('methyl', 'Chemical', 'MESH:C031105', (90, 96))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('reduces', 'NegReg', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (33, 38))	('results in', 'Reg', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cell proliferation', 'biological_process', 'GO:0008283', ('164', '182'))
23371	31772762	In addition, the ICGC database houses 2800 cancer whole genome data on "somatic mutations, somatic structural variations, copy number alterations, germline variations, RNA expression profiles, gene fusions and phenotypic annotations", and researchers have conducted pan-cancer analyses on these data.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('variations', 'Var', (110, 120))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))
23377	31772762	Circulating tumor cells and tumor DNA not only give insight into the genomic mutations and copy number alterations, but are now regularly used to generate information about the epigenomes, transcriptomes and the metabolomes of tumors.	('tumor', 'Disease', (28, 33))	('alterations', 'Var', (103, 114))	('tumor', 'Disease', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', (12, 17))	('copy number alterations', 'Var', (91, 114))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
23378	31772762	Recently, liquid biopsies were used to detect tumor-specific methylation changes in cancer patients well before clinical diagnosis of breast and ovarian cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('patients', 'Species', '9606', (91, 99))	('methylation', 'Var', (61, 72))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('ovarian cancer', 'Phenotype', 'HP:0100615', (145, 159))	('tumor', 'Disease', (46, 51))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('methyl', 'Chemical', 'MESH:C031105', (61, 67))	('breast and ovarian cancer', 'Disease', 'MESH:D061325', (134, 159))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
23384	31772762	In addition, the complexity of IPMNs evolution has been shown to vary by early and late driver gene mutations.	('IPMNs', 'Disease', (31, 36))	('mutations', 'Var', (100, 109))	('IPMNs', 'Disease', 'MESH:D002285', (31, 36))
23402	31772762	However, recent evidence suggests that this widely held assumption may not always hold true, as transcription factors have been shown to bind to both methylated and unmethylated DNA.	('methylated', 'Var', (150, 160))	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('transcription', 'biological_process', 'GO:0006351', ('96', '109'))	('methyl', 'Chemical', 'MESH:C031105', (167, 173))	('bind', 'Interaction', (137, 141))	('methyl', 'Chemical', 'MESH:C031105', (150, 156))
23407	31772762	Studies have started to identify cell subtypes based on epigenetic signatures in PDAC, and these subtypes have differential survival rates and responses to treatment (reviewed in Reference).	('epigenetic signatures', 'Var', (56, 77))	('PDAC', 'Disease', (81, 85))	('PDAC', 'Phenotype', 'HP:0006725', (81, 85))	('PDAC', 'Disease', 'MESH:D021441', (81, 85))
23410	31772762	In terms of the samples collected from patients, availability will be limited to those who have a diagnosis (meaning generally a later stage diagnosis), thereby limiting the length of time to impact survival and the ability to understand early, fundamentally important alteration/mutations and develop effective early detection biomarkers.	('patients', 'Species', '9606', (39, 47))	('survival', 'CPA', (199, 207))	('impact', 'Reg', (192, 198))	('limiting', 'NegReg', (161, 169))	('alteration/mutations', 'Var', (269, 289))
23434	31309741	However, while CETN1 could be an ideal target for the diagnosis and treatment of PDAC and prostate cancer in patients expressing this biomarker due to its specific expression and role in cell division ; the anti-CETN1 antibodies available on the market do not sufficiently discriminate between CETN1 and CETN2, hampering their use as effective oncology biomarker detectors and therapeutics.	('prostate cancer', 'Disease', 'MESH:D011471', (90, 105))	('patients', 'Species', '9606', (109, 117))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('PDAC', 'Phenotype', 'HP:0006725', (81, 85))	('cell division', 'biological_process', 'GO:0051301', ('187', '200'))	('anti-CETN1', 'Var', (207, 217))	('oncology', 'Phenotype', 'HP:0002664', (344, 352))	('anti-CETN1', 'Gene', (207, 217))	('prostate cancer', 'Disease', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('PDAC', 'Chemical', '-', (81, 85))
23494	31309741	Although most of the 177Lu-69-11 antibody was still in circulation at 1 hour post administration, it clearly localized to the tumors in the right flank of the mice by 24 hours, with the tumor uptake progressively increasing until 72 hours.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('uptake', 'biological_process', 'GO:0098739', ('192', '198'))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('antibody', 'cellular_component', 'GO:0019815', ('33', '41'))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (186, 191))	('antibody', 'cellular_component', 'GO:0019814', ('33', '41'))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('uptake', 'biological_process', 'GO:0098657', ('192', '198'))	('antibody', 'molecular_function', 'GO:0003823', ('33', '41'))	('mice', 'Species', '10090', (159, 163))	('177Lu-69-11', 'Var', (21, 32))	('antibody', 'cellular_component', 'GO:0042571', ('33', '41'))	('tumor', 'Disease', (126, 131))
23502	31309741	Figure 4 shows the changes in the tumor volume for 213Bi-69-11 (Figure 4A) and 213Bi-76-6 (Figure 4B), compared to the control groups.	('tumor', 'Disease', (34, 39))	('213Bi-69-11', 'Var', (51, 62))	('changes', 'Reg', (19, 26))	('213Bi', 'Chemical', '-', (79, 84))	('213Bi', 'Chemical', '-', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('213Bi-76-6', 'Var', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
23519	31309741	The beta-emitting radionuclides historically chosen for radiolabeling of targeting antibodies - 131I, 90Y, and 177Lu, with their long range energy deposition characteristics and relatively long half-lives that result in a prolonged duration of radiation delivery, might not be physically and radiobiologically effective enough to deliver adequately cytotoxic radiation doses to counteract the aggressive nature of PDAC.	('90Y', 'Var', (102, 105))	('radionuclides', 'Chemical', 'MESH:D011868', (18, 31))	('177Lu', 'Var', (111, 116))	('antibodies - 131I', 'Var', (83, 100))	('PDAC', 'Chemical', '-', (414, 418))	('radiation delivery', 'MPA', (244, 262))	('PDAC', 'Phenotype', 'HP:0006725', (414, 418))
23539	31166958	We hypothesized that the presence of the A5.1 polymorphism in the MICA gene, which encodes a truncated MICA protein, is associated with higher s-MICA levels and increased pancreatic cancer risk.	('MICA', 'Gene', '100507436', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('A5.1 polymorphism', 'Var', (41, 58))	('MICA', 'Gene', (66, 70))	('MICA', 'Gene', (103, 107))	('MICA', 'Gene', '100507436', (66, 70))	('higher', 'PosReg', (136, 142))	('MICA', 'Gene', (145, 149))	('pancreatic cancer', 'Disease', 'MESH:D010190', (171, 188))	('MICA', 'Gene', '100507436', (145, 149))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (171, 188))	('polymorphism', 'Var', (46, 58))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('pancreatic cancer', 'Disease', (171, 188))	('increased pancreatic cancer', 'Phenotype', 'HP:0002894', (161, 188))	('presence', 'Var', (25, 33))
23542	31166958	Unconditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI) for pancreatic cancer associated with MICA alleles.	('MICA', 'Gene', (148, 152))	('MICA', 'Gene', '100507436', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('alleles', 'Var', (153, 160))	('pancreatic cancer', 'Disease', (114, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (114, 131))	('associated', 'Reg', (132, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))
23543	31166958	After multivariate adjustment, participants with at least one copy of the A5.1 allele versus no A5.1 allele had 1.35 (95% CI: 1.05-1.74) times greater s-MICA levels (1.65 times higher for cases and 1.28, for controls) and increased risk of pancreatic cancer (OR = 1.91, 95% CI: 1.05-3.48).	('A5.1', 'Var', (74, 78))	('pancreatic cancer', 'Disease', (240, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('pancreatic cancer', 'Disease', 'MESH:D010190', (240, 257))	('greater', 'PosReg', (143, 150))	('MICA', 'Gene', (153, 157))	('MICA', 'Gene', '100507436', (153, 157))	('participants', 'Species', '9606', (31, 43))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (240, 257))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (222, 257))	('men', 'Species', '9606', (25, 28))
23544	31166958	Our study suggests higher risk of pancreatic cancer among those with the MICA A5.1 polymorphism, which may be explained by an increase in s-MICA secretion and impaired immune response.	('MICA', 'Gene', (73, 77))	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('MICA', 'Gene', '100507436', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('polymorphism', 'Var', (83, 95))	('immune response', 'biological_process', 'GO:0006955', ('168', '183'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('increase', 'PosReg', (126, 134))	('MICA', 'Gene', (140, 144))	('secretion', 'biological_process', 'GO:0046903', ('145', '154'))	('MICA', 'Gene', '100507436', (140, 144))	('pancreatic cancer', 'Disease', (34, 51))
23555	31166958	The binding affinity of MICA to NKG2D receptor on immune cells and its shedding into circulation may be modulated, in part, by polymorphisms in the MICA gene.	('modulated', 'Reg', (104, 113))	('NKG2D receptor', 'Gene', (32, 46))	('MICA', 'Gene', (148, 152))	('MICA', 'Gene', '100507436', (148, 152))	('polymorphisms', 'Var', (127, 140))	('NKG2D receptor', 'Gene', '22914', (32, 46))	('binding affinity', 'Interaction', (4, 20))	('shedding', 'MPA', (71, 79))	('MICA', 'Gene', (24, 28))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))	('MICA', 'Gene', '100507436', (24, 28))
23558	31166958	The transmembrane domain of the MICA protein is encoded by alleles characterized by a variable number of short tandem repeat (STR) polymorphisms, consisting of 4, 5, 6, 7, 8, 9 and 10 GCT repeats, designated as A4, A5, A6, A7, A8, A9, A10 respectively.	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('transmembrane', 'cellular_component', 'GO:0016021', ('4', '17'))	('MICA', 'Gene', '100507436', (32, 36))	('MICA', 'Gene', (32, 36))	('polymorphisms', 'Var', (131, 144))	('transmembrane', 'cellular_component', 'GO:0044214', ('4', '17'))
23561	31166958	Recent papers have demonstrated that the MICA A5.1 polymorphism modulates cancer susceptibility in several cancer types including cervical cancer, oral squamous cell carcinoma and hepatocellular carcinoma.	('MICA', 'Gene', '100507436', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('polymorphism', 'Var', (51, 63))	('modulates', 'Reg', (64, 73))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (180, 204))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('oral squamous cell carcinoma and hepatocellular carcinoma', 'Disease', 'MESH:D002294', (147, 204))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('cancer', 'Disease', (107, 113))	('MICA', 'Gene', (41, 45))	('cancer', 'Disease', (139, 145))
23563	31166958	We hypothesized that the presence of the A5.1 MICA allele is associated with higher circulating s-MICA levels and increased pancreatic cancer risk.	('pancreatic cancer', 'Disease', (124, 141))	('MICA', 'Gene', (46, 50))	('higher', 'PosReg', (77, 83))	('increased pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 141))	('pancreatic cancer', 'Disease', 'MESH:D010190', (124, 141))	('increased', 'PosReg', (114, 123))	('MICA', 'Gene', '100507436', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('MICA', 'Gene', (98, 102))	('MICA', 'Gene', '100507436', (98, 102))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (124, 141))	('presence', 'Var', (25, 33))
23582	31166958	Five MICA STR polymorphisms were identified in this study: A4, A5, A6, A9 and A5.1.	('MICA', 'Gene', (5, 9))	('MICA', 'Gene', '100507436', (5, 9))	('A5.1', 'Var', (78, 82))
23593	31166958	Unconditional logistic regression was used to calculate the odds ratio (OR) and 95% CI for pancreatic cancer associated with the MICA A5.1 polymorphism using the dominant and additive genetic models.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('MICA', 'Gene', (129, 133))	('MICA', 'Gene', '100507436', (129, 133))	('polymorphism', 'Var', (139, 151))	('pancreatic cancer', 'Disease', (91, 108))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))
23597	31166958	Our second exploratory analysis examined the association between four other MICA STR polymorphisms (A4, A5, A6, and A9) and pancreatic cancer risk using unconditional logistic regression.	('pancreatic cancer', 'Disease', (124, 141))	('MICA', 'Gene', (76, 80))	('MICA', 'Gene', '100507436', (76, 80))	('pancreatic cancer', 'Disease', 'MESH:D010190', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (124, 141))	('A9', 'Var', (116, 118))	('examined', 'Reg', (32, 40))
23599	31166958	Further, we evaluated the association of eight cancer-associated MICA-SNPs (rs1051792, rs1051794, rs1051798, rs1051799, rs1063635, rs1131896, rs1131898, rs1140700) with pancreatic cancer risk in our study as well as the association between a functional SNP MICA-129 (rs1051792) and s-MICA levels, as it has been previously reported to modulate s-MICA shedding.	('MICA', 'Gene', (284, 288))	('rs1051794', 'Var', (87, 96))	('rs1051798', 'Mutation', 'rs1051798', (98, 107))	('MICA', 'Gene', '100507436', (65, 69))	('rs1131898', 'Mutation', 'rs1131898', (142, 151))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (169, 186))	('rs1051794', 'Mutation', 'rs1051794', (87, 96))	('rs1063635', 'Var', (120, 129))	('cancer', 'Disease', (47, 53))	('MICA', 'Gene', (346, 350))	('rs1051792', 'Mutation', 'rs1051792', (267, 276))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('MICA', 'Gene', (257, 261))	('cancer', 'Disease', (180, 186))	('rs1131896', 'Mutation', 'rs1131896', (131, 140))	('rs1063635', 'Mutation', 'rs1063635', (120, 129))	('rs1051792', 'Mutation', 'rs1051792', (76, 85))	('rs1131896', 'Var', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('pancreatic cancer', 'Disease', 'MESH:D010190', (169, 186))	('rs1131898', 'Var', (142, 151))	('MICA', 'Gene', '100507436', (284, 288))	('rs1051792', 'Var', (267, 276))	('MICA', 'Gene', (65, 69))	('rs1051799', 'Mutation', 'rs1051799', (109, 118))	('rs1051799', 'Var', (109, 118))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('rs1051792', 'Var', (76, 85))	('rs1140700', 'Mutation', 'rs1140700', (153, 162))	('rs1051798', 'Var', (98, 107))	('pancreatic cancer', 'Disease', (169, 186))	('rs1140700', 'Var', (153, 162))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('MICA', 'Gene', '100507436', (346, 350))	('MICA', 'Gene', '100507436', (257, 261))
23618	31166958	No pancreatic cancer cases with detectable s-MICA level had the MICA-129 Met / Met genotype (S3 Table).	('Met /', 'Var', (73, 78))	('pancreatic cancer', 'Disease', (3, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('MICA', 'Gene', (64, 68))	('MICA', 'Gene', '100507436', (64, 68))	('MICA', 'Gene', (45, 49))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('MICA', 'Gene', '100507436', (45, 49))
23627	31166958	In contrast, null associations were reported in studies that examined associations between the MICA A5.1 polymorphism and colorectal cancer, gastric cancer, and melanoma.	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('gastric cancer', 'Phenotype', 'HP:0012126', (141, 155))	('colorectal cancer', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('polymorphism', 'Var', (105, 117))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))	('MICA', 'Gene', (95, 99))	('gastric cancer', 'Disease', (141, 155))	('MICA', 'Gene', '100507436', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('gastric cancer', 'Disease', 'MESH:D013274', (141, 155))
23628	31166958	Our findings of higher s-MICA levels and increased pancreatic cancer risk in participants with the MICA A5.1 polymorphism may be explained by changes in the s-MICA A5.1 protein, as a result of the polymorphism.	('higher', 'PosReg', (16, 22))	('increased', 'PosReg', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('participants', 'Species', '9606', (77, 89))	('pancreatic cancer', 'Disease', (51, 68))	('MICA', 'Gene', (159, 163))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('MICA', 'Gene', '100507436', (159, 163))	('pancreatic cancer', 'Disease', 'MESH:D010190', (51, 68))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (51, 68))	('MICA', 'Gene', (99, 103))	('polymorphism', 'Var', (109, 121))	('MICA', 'Gene', (25, 29))	('MICA', 'Gene', '100507436', (99, 103))	('increased pancreatic cancer', 'Phenotype', 'HP:0002894', (41, 68))	('MICA', 'Gene', '100507436', (25, 29))	('changes', 'Reg', (142, 149))
23629	31166958	The A5.1 polymorphism causes a premature stop codon in the transmembrane region of the MICA gene sequence, which results in a truncated MICA protein around its cytoplasmic tail.	('MICA', 'Gene', (87, 91))	('MICA', 'Gene', '100507436', (87, 91))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('transmembrane', 'cellular_component', 'GO:0044214', ('59', '72'))	('transmembrane', 'cellular_component', 'GO:0016021', ('59', '72'))	('truncated', 'MPA', (126, 135))	('polymorphism', 'Var', (9, 21))	('results in', 'Reg', (113, 123))	('MICA', 'Gene', (136, 140))	('MICA', 'Gene', '100507436', (136, 140))	('A5.1', 'Gene', (4, 8))
23632	31166958	Our exploratory findings of higher s-MICA levels in participants with the MICA-129 Val / Val polymorphism, another MICA SNPs which modulates s-MICA shedding, also highlights the importance of MICA polymorphisms on s-MICA shedding.	('Val', 'Chemical', 'MESH:D014633', (83, 86))	('polymorphism', 'Var', (93, 105))	('participants', 'Species', '9606', (52, 64))	('MICA', 'Gene', (115, 119))	('MICA', 'Gene', (74, 78))	('MICA', 'Gene', '100507436', (192, 196))	('higher', 'PosReg', (28, 34))	('MICA', 'Gene', '100507436', (74, 78))	('MICA', 'Gene', '100507436', (143, 147))	('MICA', 'Gene', (143, 147))	('MICA', 'Gene', (37, 41))	('MICA', 'Gene', '100507436', (115, 119))	('MICA', 'Gene', '100507436', (37, 41))	('MICA', 'Gene', (192, 196))	('Val', 'Chemical', 'MESH:D014633', (89, 92))	('MICA', 'Gene', (216, 220))	('Val', 'Var', (83, 86))	('MICA', 'Gene', '100507436', (216, 220))
23633	31166958	Further, our findings of a positive association between the A5.1 polymorphism and pancreatic cancer risk are concordant with biological mechanisms explaining MICA shedding into circulation and its interaction with immune cells.	('MICA', 'Gene', '100507436', (158, 162))	('polymorphism', 'Var', (65, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('positive', 'PosReg', (27, 35))	('A5.1', 'Gene', (60, 64))	('pancreatic cancer', 'Disease', (82, 99))	('MICA', 'Gene', (158, 162))	('pancreatic cancer', 'Disease', 'MESH:D010190', (82, 99))
23637	31166958	To the best of our knowledge, our study is the first study that documented an association between A5.1 polymorphism and pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('polymorphism', 'Var', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('A5.1', 'Gene', (98, 102))	('men', 'Species', '9606', (68, 71))	('pancreatic cancer', 'Disease', (120, 137))
23643	31166958	In summary, our results are in line with our hypothesis that participants with the A5.1 MICA polymorphism have higher s-MICA levels and are predisposed to pancreatic cancer development.	('participants', 'Species', '9606', (61, 73))	('MICA', 'Gene', '100507436', (120, 124))	('polymorphism', 'Var', (93, 105))	('pancreatic cancer', 'Disease', (155, 172))	('MICA', 'Gene', (88, 92))	('men', 'Species', '9606', (180, 183))	('MICA', 'Gene', '100507436', (88, 92))	('pancreatic cancer', 'Disease', 'MESH:D010190', (155, 172))	('higher', 'PosReg', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('MICA', 'Gene', (120, 124))	('predisposed', 'Reg', (140, 151))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (155, 172))
23645	31166958	Further studies are warranted to validate our finding and examine this association in multi-ethnic population settings to determine if the mechanisms of action of functional MICA variants are shared among different populations.	('MICA', 'Gene', (174, 178))	('variants', 'Var', (179, 187))	('MICA', 'Gene', '100507436', (174, 178))
23650	30399449	The CD133high population of cancer cells are not only capable of self-renewal, proliferation, but also highly metastatic and resistant to therapy.	('proliferation', 'CPA', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('self-renewal', 'CPA', (65, 77))	('CD133high', 'Var', (4, 13))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('rat', 'Species', '10116', (86, 89))
23656	30399449	PROM1 mutations are harbored in the populations suffering from retinitis pigmentosa, macular degeneration and cone-rod retinal dystrophy.	('retinitis pigmentosa', 'Disease', (63, 83))	('retinal dystrophy', 'Disease', (119, 136))	('retinitis pigmentosa', 'Disease', 'MESH:D012174', (63, 83))	('retinal dystrophy', 'Disease', 'MESH:D058499', (119, 136))	('rod retinal dystrophy', 'Phenotype', 'HP:0000510', (115, 136))	('macular degeneration', 'Phenotype', 'HP:0000608', (85, 105))	('PROM1', 'Gene', (0, 5))	('rat', 'Species', '10116', (99, 102))	('PROM1', 'Gene', '8842', (0, 5))	('macular degeneration', 'Disease', (85, 105))	('retinal dystrophy', 'Phenotype', 'HP:0000556', (119, 136))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (63, 83))	('cone-rod retinal dystrophy', 'Phenotype', 'HP:0000548', (110, 136))	('retinitis', 'Phenotype', 'HP:0032118', (63, 72))	('mutations', 'Var', (6, 15))
23660	30399449	This is because cancer cells that express high levels of CD133 are more metastatic and resistant to chemotherapy and radiation therapy.	('more', 'PosReg', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('metastatic', 'CPA', (72, 82))	('high levels', 'Var', (42, 53))	('cancer', 'Disease', (16, 22))	('CD133', 'Gene', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
23661	30399449	Given that CD133+ cells are capable of self-renewal, proliferation and differentiation into different types of cells, known as stem cell properties, CD133+ cancer cells are cancer stem cells (CSCs).	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', (173, 179))	('rat', 'Species', '10116', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('CD133+', 'Var', (149, 155))
23677	30399449	A major body of evidence has demonstrated that the isolated CD133+ cancer cells from patients are capable of forming cancers in immune-comprised xenograft mice, implicating the involvement of CSCs in cancer initiation.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer initiation', 'Disease', 'MESH:D009369', (200, 217))	('CD133+', 'Var', (60, 66))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer initiation', 'Disease', (200, 217))	('rat', 'Species', '10116', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('patients', 'Species', '9606', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('mice', 'Species', '10090', (155, 159))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (117, 123))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancer', 'Disease', (200, 206))	('cancers', 'Disease', (117, 124))
23679	30399449	It suggested that CD133+ colon cancer cells are the colon cancer initiating cells.	('colon cancer', 'Disease', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('colon cancer', 'Disease', 'MESH:D015179', (52, 64))	('colon cancer', 'Phenotype', 'HP:0003003', (25, 37))	('colon cancer', 'Disease', 'MESH:D015179', (25, 37))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))	('CD133+', 'Var', (18, 24))	('colon cancer', 'Disease', (25, 37))
23682	30399449	In addition to recapitulating the parental heterogeneous cancer phenotype, the isolated CD133+ ovarian tumor cells have a higher tumor-forming ability in vivo as compared to the CD133- ovarian tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Disease', (57, 63))	('ovarian tumor', 'Phenotype', 'HP:0100615', (95, 108))	('ovarian tumor', 'Disease', (185, 198))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', (129, 134))	('ovarian tumor', 'Disease', 'MESH:D010051', (185, 198))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (193, 198))	('CD133+', 'Var', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('higher', 'PosReg', (122, 128))	('tumor', 'Disease', (103, 108))	('ovarian tumor', 'Disease', (95, 108))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ovarian tumor', 'Disease', 'MESH:D010051', (95, 108))	('ovarian tumor', 'Phenotype', 'HP:0100615', (185, 198))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))
23684	30399449	It clearly showed that CD133 is sufficient to initiate tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CD133', 'Var', (23, 28))
23688	30399449	In several pancreatic cancer cell lines as well as human PDAC patient xenografts, FACS sorted CD133+ population was DCLK1high and acetylated alpha-tubulinhigh.	('PDAC', 'Disease', (57, 61))	('pancreatic cancer', 'Disease', 'MESH:D010190', (11, 28))	('PDAC', 'Disease', 'MESH:D021441', (57, 61))	('alpha-tubulin', 'Gene', (141, 154))	('pancreatic cancer', 'Disease', (11, 28))	('DCLK1high', 'Var', (116, 125))	('patient', 'Species', '9606', (62, 69))	('PDAC', 'Phenotype', 'HP:0006725', (57, 61))	('human', 'Species', '9606', (51, 56))	('acetyl', 'Chemical', 'MESH:C011632', (130, 136))	('alpha-tubulin', 'Gene', '10376', (141, 154))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (11, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
23690	30399449	In head and neck cancer initiating cells (HNCIC), knockdown of CD133 reduced the stemness gene expressions of OCT4 and NANOG, enhanced epithelial differentiation and promoted apoptosis.	('cancer', 'Disease', (17, 23))	('neck', 'cellular_component', 'GO:0044326', ('12', '16'))	('promoted', 'PosReg', (166, 174))	('CD133', 'Gene', (63, 68))	('head and neck cancer', 'Phenotype', 'HP:0012288', (3, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('OCT4', 'Gene', (110, 114))	('knockdown', 'Var', (50, 59))	('stemness gene', 'Disease', 'MESH:D058495', (81, 94))	('enhanced', 'PosReg', (126, 134))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('epithelial differentiation', 'CPA', (135, 161))	('stemness gene', 'Disease', (81, 94))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))	('NANOG', 'Gene', '79923', (119, 124))	('reduced', 'NegReg', (69, 76))	('apoptosis', 'CPA', (175, 184))	('NANOG', 'Gene', (119, 124))	('OCT4', 'Gene', '5460', (110, 114))
23691	30399449	In addition, these effects were also observed in the tumor tissues from the shCD133 derived xenograft mice, indicating that CD133 initiates tumor formation via upregulation of cell stemness and downregulation of cell differentiation as well as cell death.	('cell stemness', 'CPA', (176, 189))	('mice', 'Species', '10090', (102, 106))	('downregulation', 'NegReg', (194, 208))	('upregulation', 'PosReg', (160, 172))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cell death', 'biological_process', 'GO:0008219', ('244', '254'))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('downregulation of cell differentiation', 'biological_process', 'GO:0045596', ('194', '232'))	('formation', 'biological_process', 'GO:0009058', ('146', '155'))	('cell death', 'CPA', (244, 254))	('tumor', 'Disease', (53, 58))	('CD133', 'Var', (124, 129))	('cell differentiation', 'CPA', (212, 232))	('tumor', 'Disease', (140, 145))
23693	30399449	Primary heterogeneous glioblastoma can be derived from either CD133+ or CD133- CSCs.	('glioblastoma', 'Disease', (22, 34))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('CD133+', 'Var', (62, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('CD133-', 'Var', (72, 78))
23698	30399449	Blockade of Notch through its gene silencing or a gamma secretase inhibitor suppressed the glioblastoma tumor formation in the xenograted mice.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('rat', 'Species', '10116', (132, 135))	('gene silencing', 'Var', (30, 44))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('formation', 'biological_process', 'GO:0009058', ('110', '119'))	('mice', 'Species', '10090', (138, 142))	('suppressed', 'NegReg', (76, 86))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (91, 109))	('glioblastoma tumor', 'Disease', (91, 109))	('gene silencing', 'biological_process', 'GO:0016458', ('30', '44'))
23699	30399449	In addition, this Notch inhibition decreased several CSC markers including CD133, nestin, Bmi1 and OLIG2.	('Notch', 'Var', (18, 23))	('Bmi1', 'Gene', '648', (90, 94))	('OLIG2', 'Gene', (99, 104))	('nestin', 'Gene', '10763', (82, 88))	('CSC', 'Disease', (53, 56))	('CD133', 'Gene', (75, 80))	('decreased', 'NegReg', (35, 44))	('OLIG2', 'Gene', '10215', (99, 104))	('nestin', 'Gene', (82, 88))	('Bmi1', 'Gene', (90, 94))
23700	30399449	In a xenograft mouse model, the size of tumor derived from the high CD133+ HEK293 cells is dramatically larger than that from the low CD133+ HEK293 cells, suggesting that a role of CD133 in regulating cell growth during cancer development.	('high CD133+ HEK293', 'Var', (63, 81))	('HEK293', 'CellLine', 'CVCL:0045', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('HEK293', 'CellLine', 'CVCL:0045', (141, 147))	('cancer', 'Disease', (220, 226))	('cell growth', 'biological_process', 'GO:0016049', ('201', '212'))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('mouse', 'Species', '10090', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('larger', 'PosReg', (104, 110))
23707	30399449	Knockout of DCLK1 specifically in the pancreas reduced KrasG12D-induced PanIN formations and the size of the formed PanIN lesions.	('DCLK1', 'Gene', (12, 17))	('PanIN', 'Disease', (116, 121))	('PanIN', 'Disease', 'MESH:D018290', (72, 77))	('KrasG12D-induced', 'Var', (55, 71))	('PanIN', 'Disease', (72, 77))	('PanIN', 'Disease', 'MESH:D018290', (116, 121))	('Knockout', 'Var', (0, 8))	('reduced', 'NegReg', (47, 54))
23713	30399449	Furthermore, inhibition of STAT3 by short hairpin RNA or pharmacological compounds, Stattic and LLL12 in this population decreased cancer cell metabolic activity, CD133 protein level and gene expressions that are associated with cell proliferation including cyclin D1, survivin, Bcl-2, and Notch.	('cancer', 'Disease', (131, 137))	('CD133 protein level', 'MPA', (163, 182))	('Bcl-2', 'Gene', (279, 284))	('Bcl-2', 'Gene', '596', (279, 284))	('inhibition', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('decreased', 'NegReg', (121, 130))	('gene expressions', 'MPA', (187, 203))	('cell proliferation', 'biological_process', 'GO:0008283', ('229', '247'))	('RNA', 'cellular_component', 'GO:0005562', ('50', '53'))	('cyclin D1', 'Gene', '595', (258, 267))	('cyclin', 'molecular_function', 'GO:0016538', ('258', '264'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('279', '284'))	('rat', 'Species', '10116', (241, 244))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cyclin D1', 'Gene', (258, 267))
23714	30399449	The STAT3 inhibition also led to a smaller size of the CD133+/ALDH+-generated xenograft tumors.	('rat', 'Species', '10116', (72, 75))	('inhibition', 'NegReg', (10, 20))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('ALDH', 'molecular_function', 'GO:0004030', ('62', '66'))	('CD133+/ALDH+-generated', 'Var', (55, 77))	('smaller', 'NegReg', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
23720	30399449	In addition, overexpressed CD133 promotes the attachment of ovarian adenocarcinoma cells including Kuramochi, OVCA429 and Skov3IP cells to mesothelial cells in vitro and the mesothelium in ex vivo.	('promotes', 'PosReg', (33, 41))	('attachment of ovarian adenocarcinoma', 'Disease', 'MESH:D010051', (46, 82))	('CD133', 'Gene', (27, 32))	('attachment of ovarian adenocarcinoma', 'Disease', (46, 82))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (60, 82))	('overexpressed', 'Var', (13, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
23722	30399449	CD133+ cancer cells selected from cultured human pancreatic cancer cell lines KP-2 and SUIT-2 showed elevated anchorage-independent growth as compared to the CD133-population in the same cell lines, implicating that CD133 promotes cancer cell transformation, invasiveness, and metastasis.	('promotes', 'PosReg', (222, 230))	('elevated', 'PosReg', (101, 109))	('metastasis', 'CPA', (277, 287))	('CD133', 'Var', (216, 221))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (49, 66))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (231, 237))	('cancer', 'Disease', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('pancreatic cancer', 'Disease', 'MESH:D010190', (49, 66))	('pancreatic cancer', 'Disease', (49, 66))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('invasiveness', 'CPA', (259, 271))	('cancer', 'Disease', (60, 66))	('anchorage-independent growth', 'CPA', (110, 138))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (43, 48))
23723	30399449	In addition, CXCR4 was highly expressed in these CD133+ isolated cells and knockdown of CXCR4 by small interfering RNA diminished CD133-mediated cell migration and invasion.	('CXCR4', 'molecular_function', 'GO:0038147', ('13', '18'))	('rat', 'Species', '10116', (153, 156))	('diminished', 'NegReg', (119, 129))	('cell migration', 'biological_process', 'GO:0016477', ('145', '159'))	('small interfering', 'Var', (97, 114))	('RNA', 'cellular_component', 'GO:0005562', ('115', '118'))	('CXCR4', 'molecular_function', 'GO:0038147', ('88', '93'))
23724	30399449	Similarly, as compared to the CD133+/CXCR4- cells isolated from a highly metastatic pancreatic cancer cell line L3.6pl, CD133+/CXCR4+ cells from the same parental cells were able to intravasate into the portal vein in a xenograft mouse model.	('mouse', 'Species', '10090', (230, 235))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (84, 101))	('CD133+/CXCR4+', 'Var', (120, 133))	('pancreatic cancer', 'Disease', (84, 101))	('CXCR4', 'molecular_function', 'GO:0038147', ('37', '42'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('intravasate into the portal vein', 'MPA', (182, 214))	('CXCR4', 'molecular_function', 'GO:0038147', ('127', '132'))
23726	30399449	Silencing of CD133 in Capan1M9 cells that have high levels of endogenous CD133 inhibits Capan1M9-induced lung and liver metastases in mice possibly through downregulation of genes that modulate epithelial-mesenchymal transition (EMT) process such as Slug and N-Cadherin.	('Capan1M9-induced', 'Gene', (88, 104))	('mice', 'Species', '10090', (134, 138))	('downregulation', 'NegReg', (156, 170))	('Slug', 'Gene', (250, 254))	('CD133', 'Gene', (73, 78))	('inhibits', 'NegReg', (79, 87))	('Cadherin', 'molecular_function', 'GO:0008014', ('261', '269'))	('Capan1M9', 'CellLine', 'CVCL:0A59', (88, 96))	('liver metastases', 'Disease', (114, 130))	('Capan1M9', 'CellLine', 'CVCL:0A59', (22, 30))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('194', '227'))	('Slug', 'Gene', '20583', (250, 254))	('liver metastases', 'Disease', 'MESH:D009362', (114, 130))	('EMT', 'biological_process', 'GO:0001837', ('229', '232'))	('Silencing', 'Var', (0, 9))	('CD133', 'Gene', (13, 18))
23728	30399449	It also has been shown that ectopically expressed CD133 induced EMT and more invasive cells of MIA PaCa-2 through activation of NF-kappaB.	('activation', 'PosReg', (114, 124))	('invasive cells of MIA PaCa-2', 'CPA', (77, 105))	('NF-kappaB', 'Protein', (128, 137))	('ectopically expressed', 'Var', (28, 49))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('114', '137'))	('induced', 'PosReg', (56, 63))	('CD133', 'Gene', (50, 55))	('EMT', 'biological_process', 'GO:0001837', ('64', '67'))	('more', 'PosReg', (72, 76))	('EMT', 'CPA', (64, 67))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (95, 105))
23729	30399449	Furthermore, either silencing of PROM1 by shRNA technique or inhibition of NF-kappaB activation by introduction of an IKKbeta mutant or by a pharmacological BAY 11-7085 treatment, all of them abolished CD133 mediated invasiveness of MIA PaCa-2 cells.	('abolished', 'NegReg', (192, 201))	('PROM1', 'Gene', (33, 38))	('BAY 11-7085', 'Chemical', 'MESH:C416282', (157, 168))	('inhibition', 'NegReg', (61, 71))	('CD133 mediated invasiveness of MIA PaCa-2 cells', 'CPA', (202, 249))	('IKKbeta', 'Gene', '1147', (118, 125))	('IKKbeta', 'Gene', (118, 125))	('PROM1', 'Gene', '8842', (33, 38))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (233, 243))	('activation', 'PosReg', (85, 95))	('NF-kappaB', 'Protein', (75, 84))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('75', '95'))	('silencing', 'NegReg', (20, 29))	('mutant', 'Var', (126, 132))
23734	30399449	Treating AsPC-1 cells with the EGFR inhibitor Gefitinib reversed the effect on cancer cell migration induced by ectopically expressed CD133.	('rat', 'Species', '10116', (94, 97))	('EGFR', 'Gene', '1956', (31, 35))	('AsPC-1', 'CellLine', 'CVCL:0152', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('EGFR', 'Gene', (31, 35))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('Gefitinib', 'Chemical', 'MESH:C419708', (46, 55))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('CD133', 'Gene', (134, 139))	('cancer', 'Disease', (79, 85))	('ectopically expressed', 'Var', (112, 133))	('cell migration', 'biological_process', 'GO:0016477', ('86', '100'))
23736	30399449	Of note, it has been shown that upon using the lineage tracing technique to track endogenous CD133+ cells in a transgenic mouse model during the development of colon cancer metastasis, CD133 is expressed in the colon cancer epithelium.	('colon cancer', 'Disease', 'MESH:D015179', (160, 172))	('colon cancer metastasis', 'Disease', (160, 183))	('colon cancer', 'Disease', (211, 223))	('colon cancer metastasis', 'Disease', 'MESH:D015179', (160, 183))	('CD133', 'Var', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('colon cancer', 'Phenotype', 'HP:0003003', (160, 172))	('mouse', 'Species', '10090', (122, 127))	('colon cancer', 'Phenotype', 'HP:0003003', (211, 223))	('colon cancer', 'Disease', 'MESH:D015179', (211, 223))
23756	30399449	Among them, colorectal cancer is the best reported cancer type for the presence of the CD133+/CD44+ population in the metastatic site liver at an early stage of the disease.	('colorectal cancer', 'Disease', (12, 29))	('rectal cancer', 'Phenotype', 'HP:0100743', (16, 29))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('CD133+/CD44+', 'Var', (87, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
23761	30399449	Overexpression of CD133 in a head and neck squamous cell carcinoma (HNSCC) cell line rendered the cells insensitive to 5-FU-or cisplatin-induced cell death.	('CD133', 'Gene', (18, 23))	('5-FU', 'Chemical', 'MESH:D005472', (119, 123))	('HNSCC', 'Phenotype', 'HP:0012288', (68, 73))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (38, 66))	('neck squamous cell carcinoma', 'Disease', (38, 66))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (29, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('neck', 'cellular_component', 'GO:0044326', ('38', '42'))	('cell death', 'biological_process', 'GO:0008219', ('145', '155'))	('Overexpression', 'Var', (0, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))
23762	30399449	Furthermore, the CD133+ HNSCCs were arrested at the G0/G1 phase of the cell cycle in response to 5-FU and cisplatin treatment.	('CD133+', 'Var', (17, 23))	('G1 phase', 'biological_process', 'GO:0051318', ('55', '63'))	('cell cycle', 'biological_process', 'GO:0007049', ('71', '81'))	('5-FU', 'Chemical', 'MESH:D005472', (97, 101))	('HNSCCs', 'Disease', (24, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('HNSCC', 'Phenotype', 'HP:0012288', (24, 29))	('HNSCCs', 'Disease', 'MESH:C535575', (24, 30))
23763	30399449	Similarly, ectopic expression of CD133 in rat C6 glioma cells increased the drug resistance of camptothecin and doxorubicin via upregulation of p-glycoprotein 1 (multidrug resistance protein 1/MDR1) transcription and ABC transporter activity.	('increased', 'PosReg', (62, 71))	('activity', 'MPA', (233, 241))	('upregulation', 'PosReg', (128, 140))	('transcription', 'MPA', (199, 212))	('CD133', 'Gene', (33, 38))	('MDR1', 'Gene', '24646', (193, 197))	('drug resistance', 'Phenotype', 'HP:0020174', (76, 91))	('ABC transporter', 'molecular_function', 'GO:0140359', ('217', '232'))	('MDR1', 'Gene', (193, 197))	('p-glycoprotein 1', 'Gene', (144, 160))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('ectopic expression', 'Var', (11, 29))	('glioma', 'Disease', (49, 55))	('multidrug resistance protein', 'molecular_function', 'GO:0008559', ('162', '190'))	('multidrug resistance protein 1', 'Gene', '24646', (162, 192))	('p-glycoprotein', 'molecular_function', 'GO:0008559', ('144', '158'))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('ABC', 'Enzyme', (217, 220))	('transcription', 'biological_process', 'GO:0006351', ('199', '212'))	('MDR', 'molecular_function', 'GO:0004745', ('193', '196'))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('drug resistance', 'Phenotype', 'HP:0020174', (167, 182))	('multidrug resistance protein 1', 'Gene', (162, 192))	('drug resistance', 'biological_process', 'GO:0009315', ('76', '91'))	('drug resistance', 'biological_process', 'GO:0042493', ('76', '91'))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('C6', 'CellLine', 'CVCL:X905', (46, 48))	('camptothecin', 'Chemical', 'MESH:D002166', (95, 107))	('p-glycoprotein 1', 'Gene', '24646', (144, 160))	('transporter activity', 'molecular_function', 'GO:0005215', ('221', '241'))	('rat', 'Species', '10116', (42, 45))
23765	30399449	In cultured human gastric cancer cells, knockdown of CD133 rendered cells more sensitive to 5-FU induced cell death.	('gastric cancer', 'Disease', (18, 32))	('more', 'PosReg', (74, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (18, 32))	('CD133', 'Gene', (53, 58))	('knockdown', 'Var', (40, 49))	('sensitive to 5-FU induced', 'MPA', (79, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('human', 'Species', '9606', (12, 17))	('cell death', 'biological_process', 'GO:0008219', ('105', '115'))	('5-FU', 'Chemical', 'MESH:D005472', (92, 96))
23767	30399449	Blockade of this pathway via the PI3K/Akt inhibitor LY294002 in CD133-expressed gastric cancer cells has the same effect as shCD133-expressed cells in response to 5-FU treatment.	('gastric cancer', 'Disease', (80, 94))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))	('LY294002', 'Var', (52, 60))	('PI3', 'Gene', (33, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('5-FU', 'Chemical', 'MESH:D005472', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('LY294002', 'Chemical', 'MESH:C085911', (52, 60))	('PI3', 'Gene', '5266', (33, 36))
23769	30399449	Colorectal cancer cells that are CD133high/CD44high survived better than CD133low/CD44low cancer cells after exposure to a high dose of gamma irradiation.	('survived', 'CPA', (52, 60))	('better', 'PosReg', (61, 67))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('rectal cancer', 'Phenotype', 'HP:0100743', (4, 17))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('Colorectal cancer', 'Disease', (0, 17))	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', (90, 96))	('CD133high/CD44high', 'Var', (33, 51))
23770	30399449	In addition, Akt expression was higher in the CD133high/CD44high cells as compared to the CD133low/CD44low cancer cells.	('CD133high/CD44high', 'Var', (46, 64))	('higher', 'PosReg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('expression', 'MPA', (17, 27))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('Akt', 'Pathway', (13, 16))
23773	30399449	Given that CD133 plays a pivotal role in regulating cancer metastasis and therapeutic resistance and that both of cancer metastasis and drug resistance are the major contributors to cancer death, targeting CD133 in cancer patients who have metastatic disease would be the best strategy to bring down the death toll of cancer.	('cancer', 'Disease', (318, 324))	('cancer metastasis', 'Disease', (52, 69))	('patients', 'Species', '9606', (222, 230))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('drug resistance', 'biological_process', 'GO:0009315', ('136', '151'))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('drug resistance', 'biological_process', 'GO:0042493', ('136', '151'))	('cancer', 'Disease', (215, 221))	('cancer metastasis', 'Disease', (114, 131))	('cancer', 'Disease', (182, 188))	('cancer death', 'Disease', 'MESH:D003643', (182, 194))	('cancer metastasis', 'Disease', 'MESH:D009362', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('CD133', 'Gene', (206, 211))	('drug resistance', 'Phenotype', 'HP:0020174', (136, 151))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer metastasis', 'Disease', 'MESH:D009362', (114, 131))	('cancer death', 'Disease', (182, 194))	('cancer', 'Disease', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('targeting', 'Var', (196, 205))	('rat', 'Species', '10116', (279, 282))	('cancer', 'Disease', (114, 120))
23781	30399449	The in vitro effect of CD133-MMAF conjugates was verified in Hep3B xenografted SCID mice that anti-CD133-MMAF treatment delayed tumor growth in vivo.	('SCID', 'Gene', (79, 83))	('anti-CD133-MMAF', 'Var', (94, 109))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('delayed', 'NegReg', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('SCID', 'Gene', '19090', (79, 83))	('Hep3B', 'CellLine', 'CVCL:0326', (61, 66))	('mice', 'Species', '10090', (84, 88))
23782	30399449	Another invention includes to conjugate anti-CD133 monoclonal antibody to nanoparticles that were loaded with anti-cancer drug paclitaxel.	('antibody', 'cellular_component', 'GO:0019814', ('62', '70'))	('cancer', 'Disease', (115, 121))	('antibody', 'molecular_function', 'GO:0003823', ('62', '70'))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('anti-CD133', 'Var', (40, 50))	('antibody', 'cellular_component', 'GO:0042571', ('62', '70'))	('antibody', 'cellular_component', 'GO:0019815', ('62', '70'))	('paclitaxel', 'Chemical', 'MESH:D017239', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
23787	30399449	CART-CD133 treatment has been tested in CD133high glioblastoma stem cells in vitro and in an orthotopic tumor model in vivo.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('CART-CD133', 'Gene', (0, 10))	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('CD133high', 'Var', (40, 49))	('CART-CD133', 'Gene', '8842', (0, 10))	('tumor', 'Disease', (104, 109))	('glioblastoma', 'Disease', (50, 62))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
23800	30399449	It would be of most importance to evaluate if the blockade of CD133 alternatively results in selections for other cancer stem cell markers that could compensate the loss of CD133, and what the final outcome of cancer metastasis as well as drug resistance is in animal models capitulating human cancers.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('loss', 'Var', (165, 169))	('blockade', 'Var', (50, 58))	('human', 'Species', '9606', (288, 293))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancer', 'Disease', (294, 300))	('cancer metastasis', 'Disease', (210, 227))	('cancers', 'Disease', (294, 301))	('results in', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('drug resistance', 'biological_process', 'GO:0009315', ('239', '254'))	('CD133', 'Gene', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('drug resistance', 'biological_process', 'GO:0042493', ('239', '254'))	('CD133', 'Gene', (173, 178))	('cancer metastasis', 'Disease', 'MESH:D009362', (210, 227))	('drug resistance', 'Phenotype', 'HP:0020174', (239, 254))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', (114, 120))
23819	30108679	Furthermore, pharmacologic inhibition of desmoplasia in combination with chemotherapy slowed PDAC progression to a greater extent than PDAC alone, thereby highlighting desmoplasia as a potential therapeutic target in PDAC.	('PDAC', 'Phenotype', 'HP:0006725', (135, 139))	('desmoplasia', 'Disease', 'None', (168, 179))	('desmoplasia', 'Disease', 'None', (41, 52))	('PDAC', 'Chemical', '-', (217, 221))	('PDAC', 'Chemical', '-', (93, 97))	('pharmacologic', 'Var', (13, 26))	('slowed', 'NegReg', (86, 92))	('PDAC', 'Chemical', '-', (135, 139))	('PDAC', 'Phenotype', 'HP:0006725', (217, 221))	('PDAC', 'Disease', (93, 97))	('PDAC', 'Phenotype', 'HP:0006725', (93, 97))	('desmoplasia', 'Disease', (168, 179))	('desmoplasia', 'Disease', (41, 52))
23839	30108679	For instance, collagen I potentiates proliferation and chemoresistance of PDAC cells and limits T-cell accumulation near cancer cells.	('collagen', 'Var', (14, 22))	('chemoresistance', 'CPA', (55, 70))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('PDAC', 'Phenotype', 'HP:0006725', (74, 78))	('T-cell accumulation', 'CPA', (96, 115))	('PDAC', 'Chemical', '-', (74, 78))	('proliferation', 'CPA', (37, 50))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('collagen', 'molecular_function', 'GO:0005202', ('14', '22'))	('potentiates', 'PosReg', (25, 36))	('limits', 'NegReg', (89, 95))	('cancer', 'Disease', (121, 127))
23848	30108679	However, inhibition of SHH for short term using pharmacological agents or its ablation at genetic level have suggested a dichotomous role of this pathway in PDAC pathobiology.	('PDAC', 'Disease', (157, 161))	('PDAC', 'Phenotype', 'HP:0006725', (157, 161))	('SHH', 'Gene', (23, 26))	('inhibition', 'Var', (9, 19))	('PDAC', 'Chemical', '-', (157, 161))
23850	30108679	generated SKPC (Pdx1-Cre;SHHfl/fl;KrasLSL-G12D/+;P53fl/+;Rosa26LSL-YFP/+) mice to deplete SHH expression in pancreatic epithelium.	('G12D', 'Mutation', 'rs121913529', (42, 46))	('SHH', 'Gene', (90, 93))	('Pdx1', 'Gene', (16, 20))	('deplete', 'NegReg', (82, 89))	('mice', 'Species', '10090', (74, 78))	('Pdx1', 'Gene', '18609', (16, 20))	('P53fl/+', 'Var', (49, 56))
23855	30108679	Unexpectedly, SKPC mice had decreased survival and increased metastasis.	('SKPC', 'Var', (14, 18))	('decreased', 'NegReg', (28, 37))	('increased', 'PosReg', (51, 60))	('metastasis', 'CPA', (61, 71))	('mice', 'Species', '10090', (19, 23))
23863	30108679	Collectively, these data suggest several mechanisms through which SHH deletion may contribute to PDAC progression.	('deletion', 'Var', (70, 78))	('SHH', 'Gene', (66, 69))	('PDAC', 'Phenotype', 'HP:0006725', (97, 101))	('PDAC', 'Chemical', '-', (97, 101))	('PDAC', 'Disease', (97, 101))	('contribute', 'Reg', (83, 93))
23864	30108679	First, changes in differentiation status, expression of EMT markers, and the persistence of PanIN lesion are plausibly due to disruption of SHH signaling that impairs production of CAF-derived factors required for suppression of observed neoplastic cell phenotypes.	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('disruption', 'Var', (126, 136))	('PanIN lesion', 'Disease', (92, 104))	('EMT', 'Gene', (56, 59))	('changes', 'Reg', (7, 14))	('EMT', 'biological_process', 'GO:0001837', ('56', '59'))	('CAF', 'Gene', (181, 184))	('PanIN lesion', 'Disease', 'MESH:D051437', (92, 104))	('CAF', 'Gene', '104272', (181, 184))	('impairs', 'NegReg', (159, 166))	('EMT', 'Gene', '16428', (56, 59))	('production of', 'MPA', (167, 180))
23870	30108679	This is consistent with observations of prolonged pancreatic inflammation and persistence of inflammation and PanIN lesions in response to cearulein treatment and induction of Kras-G12D in Gli1fl/+ animals.	('inflammation', 'Disease', (93, 105))	('PanIN lesions', 'Disease', (110, 123))	('Gli1', 'Gene', (189, 193))	('inflammation', 'biological_process', 'GO:0006954', ('61', '73'))	('prolonged pancreatic inflammation', 'Disease', 'MESH:D007249', (40, 73))	('prolonged pancreatic inflammation', 'Disease', (40, 73))	('prolonged pancreatic inflammation', 'Phenotype', 'HP:0006280', (40, 73))	('PanIN lesions', 'Disease', 'MESH:D051437', (110, 123))	('Gli1', 'Gene', '14632', (189, 193))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('pancreatic inflammation', 'Phenotype', 'HP:0001733', (50, 73))	('G12D', 'Mutation', 'rs121913529', (181, 185))	('inflammation', 'Disease', 'MESH:D007249', (93, 105))	('Kras-G12D', 'Var', (176, 185))	('inflammation', 'biological_process', 'GO:0006954', ('93', '105'))
23871	30108679	showed that smoothenedfl/fl Pdx-Cre and Ela-Cre mice exhibited persistent acinar-to-ductal metaplasia seven days after cerulein treatment compared to wild-type mice, which showed complete recovery, suggesting that loss of HH signaling in pancreatic epithelium impairs the resolution of pancreatic inflammation.	('smoothened', 'Gene', '319757', (12, 22))	('metaplasia', 'Disease', 'MESH:D008679', (91, 101))	('pancreatic epithelium impairs', 'Disease', (238, 267))	('resolution', 'CPA', (272, 282))	('signaling', 'biological_process', 'GO:0023052', ('225', '234'))	('mice', 'Species', '10090', (48, 52))	('Ela', 'Gene', '100038489', (40, 43))	('metaplasia', 'Disease', (91, 101))	('inflammation', 'biological_process', 'GO:0006954', ('297', '309'))	('pancreatic inflammation', 'Phenotype', 'HP:0001733', (286, 309))	('pancreatic inflammation', 'Disease', (286, 309))	('pancreatic inflammation', 'Disease', 'MESH:D007249', (286, 309))	('mice', 'Species', '10090', (160, 164))	('loss', 'Var', (214, 218))	('pancreatic epithelium impairs', 'Disease', 'MESH:D010182', (238, 267))	('smoothened', 'Gene', (12, 22))	('metaplasia', 'biological_process', 'GO:0036074', ('91', '101'))	('Ela', 'Gene', (40, 43))
23872	30108679	Similarly, SHH deletion increased intratumoral vascular density, which was not the result of loss of SHH signaling in endothelium.	('SHH', 'Gene', (11, 14))	('deletion', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('tumor', 'Disease', (39, 44))	('increased', 'PosReg', (24, 33))
23873	30108679	These findings are confirmed in a subcutaneous PDAC model in which PDAC lines were co-injected with WT fibroblasts or fibroblast with homozygous deletion of SHH co-receptors (GAS1-/- and BOC-/- or GAS1-/-, BOC-/- and CDON-/-).	('SHH', 'Gene', (157, 160))	('PDAC', 'Chemical', '-', (47, 51))	('PDAC', 'Phenotype', 'HP:0006725', (67, 71))	('GAS', 'molecular_function', 'GO:0034005', ('197', '200'))	('CDON', 'Gene', '57810', (217, 221))	('CDON', 'Gene', (217, 221))	('GAS1', 'Gene', '14451', (197, 201))	('PDAC', 'Phenotype', 'HP:0006725', (47, 51))	('GAS', 'molecular_function', 'GO:0034005', ('175', '178'))	('GAS1', 'Gene', (197, 201))	('PDAC', 'Chemical', '-', (67, 71))	('GAS1', 'Gene', '14451', (175, 179))	('GAS1', 'Gene', (175, 179))	('deletion', 'Var', (145, 153))
23879	30108679	It is, however, difficult to understand the impact of SHH co-receptor deletion on the course of the disease given that tumors in SKPC mice were smaller whereas GAS1-/-, BOC-/- tumors were larger compared to respective controls.	('deletion', 'Var', (70, 78))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mice', 'Species', '10090', (134, 138))	('GAS', 'molecular_function', 'GO:0034005', ('160', '163'))	('tumors', 'Disease', (119, 125))	('GAS1', 'Gene', '14451', (160, 164))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('smaller', 'NegReg', (144, 151))	('GAS1', 'Gene', (160, 164))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
23880	30108679	Regardless, these findings are, to some extent, mirrored in an Ela-myc model of PDAC, in which deletion of Galectin-1, a promoter of SHH signaling in PDAC, resulted in decreased angiogenesis, desmoplasia, and prolonged survival of mice.	('PDAC', 'Chemical', '-', (150, 154))	('deletion', 'Var', (95, 103))	('PDAC', 'Phenotype', 'HP:0006725', (150, 154))	('angiogenesis', 'biological_process', 'GO:0001525', ('178', '190'))	('Galectin-1', 'Gene', (107, 117))	('decreased', 'NegReg', (168, 177))	('signaling', 'biological_process', 'GO:0023052', ('137', '146'))	('Ela', 'Gene', '100038489', (63, 66))	('Ela', 'Gene', (63, 66))	('survival', 'CPA', (219, 227))	('mice', 'Species', '10090', (231, 235))	('Galectin', 'molecular_function', 'GO:0001577', ('107', '115'))	('Galectin-1', 'Gene', '16852', (107, 117))	('prolonged', 'PosReg', (209, 218))	('desmoplasia', 'Disease', 'None', (192, 203))	('PDAC', 'Chemical', '-', (80, 84))	('angiogenesis', 'CPA', (178, 190))	('desmoplasia', 'Disease', (192, 203))	('PDAC', 'Phenotype', 'HP:0006725', (80, 84))
23884	30108679	Phase I trials of IPI-926 showed potential, but a phase II trial was halted due to decreased survival in patients receiving IPI-926.	('IPI-926', 'Var', (124, 131))	('survival', 'MPA', (93, 101))	('patients', 'Species', '9606', (105, 113))	('decreased', 'NegReg', (83, 92))	('IPI-926', 'Chemical', 'MESH:C541444', (18, 25))	('IPI-926', 'Chemical', 'MESH:C541444', (124, 131))
23888	30108679	However due to the pleiotropic effects of SHH deletion, it is challenging to tease out the intricacies of the interplay between SHH and desmoplasia in PDAC initiation and progression.	('deletion', 'Var', (46, 54))	('SHH', 'Gene', (42, 45))	('PDAC', 'Chemical', '-', (151, 155))	('tease out', 'Phenotype', 'HP:0001061', (77, 86))	('desmoplasia', 'Disease', (136, 147))	('PDAC', 'Disease', (151, 155))	('PDAC', 'Phenotype', 'HP:0006725', (151, 155))	('desmoplasia', 'Disease', 'None', (136, 147))
23902	30108679	demonstrated that knockdown of focal adhesion kinase (FAK) signaling in PDAC cells abrogated FAP-positive CAFs and collagen I deposition and allowed for T-cell-dependent inhibition of tumor progression and increased survival of mice.	('FAP', 'Gene', '14089', (93, 96))	('FAK', 'Gene', '14083', (54, 57))	('increased', 'PosReg', (206, 215))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('focal adhesion', 'cellular_component', 'GO:0005925', ('31', '45'))	('FAK', 'molecular_function', 'GO:0004717', ('54', '57'))	('mice', 'Species', '10090', (228, 232))	('tumor', 'Disease', (184, 189))	('collagen', 'molecular_function', 'GO:0005202', ('115', '123'))	('knockdown', 'Var', (18, 27))	('abrogated', 'NegReg', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('CAF', 'Gene', (106, 109))	('CAF', 'Gene', '104272', (106, 109))	('FAP', 'Gene', (93, 96))	('FAK', 'Gene', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('inhibition', 'NegReg', (170, 180))	('survival', 'CPA', (216, 224))	('PDAC', 'Chemical', '-', (72, 76))	('PDAC', 'Phenotype', 'HP:0006725', (72, 76))
23916	30108679	In contrast, radiographic assessment of apparent diffusion coefficient (ADC) correlated inversely with epithelial cellularity and positively with stromal content assessed by Movat's staining, which is consistent with findings in KPTC (KrasLSLG12D/WT;Ptf1a-CRE;Tp53fl/WT;Ela-Tgfa) and other mouse models.	('inversely', 'NegReg', (88, 97))	('Ela', 'Gene', '100038489', (270, 273))	('G12D', 'Mutation', 'rs121913529', (242, 246))	('apparent diffusion coefficient', 'MPA', (40, 70))	('epithelial cellularity', 'CPA', (103, 125))	('KrasLSLG12D/WT', 'Var', (235, 249))	('Ela', 'Gene', (270, 273))	('Ptf1', 'Species', '32651', (250, 254))	('mouse', 'Species', '10090', (290, 295))
23917	30108679	Importantly, ADC correlated with longer patient survival in 96 early stage patients.	('patient', 'Species', '9606', (40, 47))	('patients', 'Species', '9606', (75, 83))	('ADC', 'Var', (13, 16))	('patient survival', 'CPA', (40, 56))	('patient', 'Species', '9606', (75, 82))	('longer', 'PosReg', (33, 39))
23929	30108679	Additionally, such insight will allow the generation of mouse models with conditional deletion of ECM components to begin to address the role of ECM in PDAC progression in vivo.	('PDAC', 'Disease', (152, 156))	('PDAC', 'Phenotype', 'HP:0006725', (152, 156))	('mouse', 'Species', '10090', (56, 61))	('conditional deletion', 'Var', (74, 94))	('PDAC', 'Chemical', '-', (152, 156))
24027	29077749	For CD8+ T cell blockade in vitro, high anti-Gal KO mice (n = 10) were generated and then vaccinated with either alpha-gal(-) (n = 5) or alpha-gal(+) PDAC-ly (n = 5), respectively, in a similar manner as described above in the section describing PDAC tumor lysate vaccination.	('alpha-gal', 'Var', (137, 146))	('alpha-gal(-)', 'Gene', '14594', (113, 125))	('PDAC', 'Chemical', '-', (150, 154))	('tumor', 'Disease', (251, 256))	('alpha-gal(-', 'Gene', (113, 124))	('rat', 'Species', '10116', (75, 78))	('ly', 'Chemical', 'MESH:D008239', (177, 179))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('ly', 'Chemical', 'MESH:D008239', (257, 259))	('mice', 'Species', '10090', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('PDAC', 'Chemical', '-', (246, 250))	('PDAC-ly', 'Chemical', '-', (150, 157))	('Gal', 'Chemical', 'MESH:C101993', (45, 48))	('ly', 'Chemical', 'MESH:D008239', (155, 157))
24067	29077749	The NACRT treatment schedule was as follows: 50.4 Gy (1.8 Gy/day, 5 times per week, 28 fractions total of preoperative radiation) and administered concurrently with 30-min intravenous infusion of gemcitabine on days 1, 8, 22, and 29 or S-1 orally on days 1-5, 8-12, 22-26 and 29-33.	('NACRT', 'Chemical', '-', (4, 9))	('S-1', 'Gene', (236, 239))	('gemcitabine', 'Chemical', 'MESH:C056507', (196, 207))	('rat', 'Species', '10116', (112, 115))	('ly', 'Chemical', 'MESH:D008239', (157, 159))	('50.4 Gy', 'Var', (45, 52))	('ly', 'Chemical', 'MESH:D008239', (244, 246))	('S-1', 'Gene', '13628', (236, 239))
24080	29077749	As shown in Fig 2A-2C, vaccination with alpha-gal(+) PDAC-ly resulted in a 16- to 32-fold increase in the production of anti-PANC-1, anti-MIAPaCa-2 or anti-BxPC-3 IgG compared with vaccination with alpha-gal(-) PDAC-ly.	('alpha-gal(-', 'Gene', (198, 209))	('PANC-1', 'Gene', (125, 131))	('increase', 'PosReg', (90, 98))	('IgG', 'Gene', '16059', (163, 166))	('PDAC-ly', 'Chemical', '-', (53, 60))	('production', 'MPA', (106, 116))	('alpha-gal(+) PDAC-ly', 'Var', (40, 60))	('IgG', 'Gene', (163, 166))	('anti-MIAPaCa-2', 'MPA', (133, 147))	('PANC-1', 'Gene', '104066', (125, 131))	('PDAC-ly', 'Chemical', '-', (211, 218))	('alpha-gal(-)', 'Gene', '14594', (198, 210))	('MIAPaCa-2', 'CellLine', 'CVCL:0428', (138, 147))
24081	29077749	In contrast, five vaccinations with either alpha-gal(-) N-ly or alpha-gal(+) N-ly did not elicit a significant anti-PDAC cell IgG response.	('IgG', 'Gene', '16059', (126, 129))	('ly', 'Chemical', 'MESH:D008239', (79, 81))	('IgG', 'Gene', (126, 129))	('alpha-gal(-', 'Gene', (43, 54))	('alpha-gal(+) N-ly', 'Var', (64, 81))	('N', 'Chemical', 'MESH:D009584', (77, 78))	('ly', 'Chemical', 'MESH:D008239', (58, 60))	('PDAC', 'Chemical', '-', (116, 120))	('N', 'Chemical', 'MESH:D009584', (56, 57))	('alpha-gal(-)', 'Gene', '14594', (43, 55))
24085	29077749	As shown in Fig 4A and 4B, vaccination with alpha-gal(+) PDAC-ly resulted in an 8-fold increase in the production of both anti-MUC1 IgG and anti-mesothelin IgG compared with alpha-gal(-) PDAC-ly vaccination.	('alpha-gal(-', 'Gene', (174, 185))	('increase', 'PosReg', (87, 95))	('IgG', 'Gene', '16059', (156, 159))	('IgG', 'Gene', '16059', (132, 135))	('alpha-gal(+) PDAC-ly', 'Var', (44, 64))	('IgG', 'Gene', (132, 135))	('anti-mesothelin', 'Protein', (140, 155))	('production', 'MPA', (103, 113))	('IgG', 'Gene', (156, 159))	('PDAC-ly', 'Chemical', '-', (187, 194))	('PDAC-ly', 'Chemical', '-', (57, 64))	('alpha-gal(-)', 'Gene', '14594', (174, 186))
24090	29077749	The numbers of ELISPOT spots of alpha-gal(+) PDAC-ly vaccinated KO mice were significantly greater than those of alpha-gal(-) PDAC-ly vaccinated KO mice (MUC1: P = 0.0008; mesothelin: P = 0.029).	('alpha-gal(-)', 'Gene', '14594', (113, 125))	('ly', 'Chemical', 'MESH:D008239', (131, 133))	('PDAC-ly', 'Chemical', '-', (126, 133))	('alpha-gal(-', 'Gene', (113, 124))	('alpha-gal(+) PDAC-ly', 'Var', (32, 52))	('PDAC-ly', 'Chemical', '-', (45, 52))	('ly', 'Chemical', 'MESH:D008239', (50, 52))	('ly', 'Chemical', 'MESH:D008239', (88, 90))	('mice', 'Species', '10090', (148, 152))	('greater', 'PosReg', (91, 98))	('mice', 'Species', '10090', (67, 71))
24096	29077749	Furthermore, the number of spots in the presence of MUC1 peptide was significantly higher in the alpha-gal(+) PDAC-ly vaccinated group compared with the alpha-gal(-) PDAC-ly group (P = 0.049; Fig 5B).	('spots', 'MPA', (27, 32))	('alpha-gal(+) PDAC-ly', 'Var', (97, 117))	('ly', 'Chemical', 'MESH:D008239', (80, 82))	('ly', 'Chemical', 'MESH:D008239', (115, 117))	('PDAC-ly', 'Chemical', '-', (166, 173))	('alpha-gal(-)', 'Gene', '14594', (153, 165))	('alpha-gal(-', 'Gene', (153, 164))	('ly', 'Chemical', 'MESH:D008239', (171, 173))	('PDAC-ly', 'Chemical', '-', (110, 117))	('MUC1 peptide', 'Protein', (52, 64))	('higher', 'PosReg', (83, 89))
24098	29077749	Moreover, the number of spots following stimulation with mesothelin peptide was significantly higher in the alpha-gal(+) PDAC-ly vaccinated group compared with the alpha-gal(-) PDAC-ly group (P = 0.021; Fig 5D).	('spots', 'MPA', (24, 29))	('alpha-gal(-', 'Gene', (164, 175))	('alpha-gal(-)', 'Gene', '14594', (164, 176))	('ly', 'Chemical', 'MESH:D008239', (91, 93))	('PDAC-ly', 'Chemical', '-', (121, 128))	('ly', 'Chemical', 'MESH:D008239', (182, 184))	('ly', 'Chemical', 'MESH:D008239', (126, 128))	('PDAC-ly', 'Chemical', '-', (177, 184))	('higher', 'PosReg', (94, 100))	('alpha-gal(+) PDAC-ly', 'Var', (108, 128))	('stimulation', 'PosReg', (40, 51))
24099	29077749	In the analysis of CD8+ T cell depletion in vitro and in vivo, depletion in both situations with anti-CD8+ mAb significantly blocked the elicited increase in the number of spots for both MUC1- and mesothelin-specific T cells in alpha-gal(+) PDAC-ly vaccinated KO mice (Fig 5B and 5D).	('blocked', 'NegReg', (125, 132))	('increase', 'PosReg', (146, 154))	('PDAC-ly', 'Chemical', '-', (241, 248))	('ly', 'Chemical', 'MESH:D008239', (246, 248))	('ly', 'Chemical', 'MESH:D008239', (122, 124))	('depletion', 'Var', (63, 72))	('mice', 'Species', '10090', (263, 267))	('ly', 'Chemical', 'MESH:D008239', (10, 12))
24102	29077749	Splenocytes treated in vitro with anti-CD8 mAb displayed 129.3 +- 75.8 spots in the presence of MUC1 peptide stimulation (P = 0.0050) and 117.3 +- 46.5 spots in the presence of mesothelin peptide stimulation (P = 0.0054), respectively.	('ly', 'Chemical', 'MESH:D008239', (232, 234))	('MUC1 peptide stimulation', 'MPA', (96, 120))	('anti-CD8', 'Var', (34, 42))
24103	29077749	Splenocytes treated in vivo with anti-CD8 mAb displayed 85.3 +- 30.8 spots in the presence of MUC1 peptide stimulation (P = 0.0037) and 120.0 +- 84.0 spots in the presence of mesothelin peptide stimulation (P = 0.0055), respectively.	('anti-CD8', 'Var', (33, 41))	('ly', 'Chemical', 'MESH:D008239', (230, 232))	('MUC1 peptide stimulation', 'MPA', (94, 118))
24116	29077749	In vivo tumor growth and representative images of NOD/SCID mice treated with either alpha-gal(-) N-ly, alpha-gal(+) N-ly, alpha-gal(-) PDAC-ly, or alpha-gal(+) PDAC-ly are shown in Fig 6A and 6B.	('N', 'Chemical', 'MESH:D009584', (116, 117))	('NOD', 'Gene', '1822', (50, 53))	('SCID', 'Disease', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ly', 'Chemical', 'MESH:D008239', (99, 101))	('NOD', 'Gene', (50, 53))	('PDAC-ly', 'Chemical', '-', (160, 167))	('alpha-gal(-)', 'Gene', '14594', (84, 96))	('alpha-gal(-', 'Gene', (84, 95))	('mice', 'Species', '10090', (59, 63))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('PDAC-ly', 'Chemical', '-', (135, 142))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('alpha-gal(-', 'Gene', (122, 133))	('alpha-gal(-)', 'Gene', '14594', (122, 134))	('alpha-gal(+) N-ly', 'Var', (103, 120))	('tumor', 'Disease', (8, 13))	('alpha-gal(+) PDAC-ly', 'Var', (147, 167))	('SCID', 'Disease', 'MESH:D053632', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('ly', 'Chemical', 'MESH:D008239', (118, 120))	('ly', 'Chemical', 'MESH:D008239', (140, 142))	('ly', 'Chemical', 'MESH:D008239', (165, 167))
24117	29077749	NOD/SCID mice that received splenocytes from untreated control mice or alpha-gal(-) N-ly, alpha-gal(+) N-ly, and alpha-gal(-) PDAC-ly vaccinated KO mice developed large tumors, whereas alpha-gal(+) PDAC-ly vaccinated mice exhibited significantly slower tumor growth (Fig 6A and 6B).	('ly', 'Chemical', 'MESH:D008239', (131, 133))	('N', 'Chemical', 'MESH:D009584', (84, 85))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('mice', 'Species', '10090', (148, 152))	('SCID', 'Disease', 'MESH:D053632', (4, 8))	('ly', 'Chemical', 'MESH:D008239', (243, 245))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('ly', 'Chemical', 'MESH:D008239', (105, 107))	('NOD', 'Gene', '1822', (0, 3))	('SCID', 'Disease', (4, 8))	('tumor', 'Disease', (169, 174))	('PDAC-ly', 'Chemical', '-', (198, 205))	('alpha-gal(-)', 'Gene', '14594', (113, 125))	('PDAC-ly', 'Chemical', '-', (126, 133))	('NOD', 'Gene', (0, 3))	('alpha-gal(-', 'Gene', (113, 124))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('mice', 'Species', '10090', (217, 221))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Disease', (253, 258))	('mice', 'Species', '10090', (9, 13))	('N', 'Chemical', 'MESH:D009584', (103, 104))	('ly', 'Chemical', 'MESH:D008239', (86, 88))	('alpha-gal(-', 'Gene', (71, 82))	('alpha-gal(+', 'Var', (90, 101))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mice', 'Species', '10090', (63, 67))	('ly', 'Chemical', 'MESH:D008239', (203, 205))	('tumors', 'Disease', (169, 175))	('alpha-gal(-)', 'Gene', '14594', (71, 83))
24125	29077749	The final cause of death for adoptive transferred NOD/SCID mice from untreated, alpha-gal(-) N-ly, alpha-gal(+) N-ly, alpha-gal(-) PDAC-ly, and alpha-gal(+) PDAC-ly groups was cancer death.	('NOD', 'Gene', '1822', (50, 53))	('SCID', 'Disease', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('NOD', 'Gene', (50, 53))	('mice', 'Species', '10090', (59, 63))	('ly', 'Chemical', 'MESH:D008239', (114, 116))	('cancer death', 'Disease', 'MESH:D003643', (176, 188))	('ly', 'Chemical', 'MESH:D008239', (162, 164))	('ly', 'Chemical', 'MESH:D008239', (136, 138))	('cancer death', 'Disease', (176, 188))	('PDAC-ly', 'Chemical', '-', (157, 164))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('N', 'Chemical', 'MESH:D009584', (112, 113))	('alpha-gal(-', 'Gene', (80, 91))	('ly', 'Chemical', 'MESH:D008239', (95, 97))	('alpha-gal(+', 'Var', (99, 110))	('SCID', 'Disease', 'MESH:D053632', (54, 58))	('alpha-gal(-)', 'Gene', '14594', (118, 130))	('PDAC-ly', 'Chemical', '-', (131, 138))	('N', 'Chemical', 'MESH:D009584', (93, 94))	('alpha-gal(-', 'Gene', (118, 129))	('alpha-gal(-)', 'Gene', '14594', (80, 92))
24131	29077749	In comparison, extensive recruitment of CD4+ and CD8+ T cells and macrophages was detected in tumor lesions of alpha-gal(+) PDAC-ly vaccinated KO mice (Fig 7).	('tumor lesions', 'Disease', 'MESH:D051437', (94, 107))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('alpha-gal(+', 'Var', (111, 122))	('mice', 'Species', '10090', (146, 150))	('PDAC-ly', 'Chemical', '-', (124, 131))	('tumor lesions', 'Disease', (94, 107))	('CD4', 'Gene', (40, 43))	('CD4', 'Gene', '12504', (40, 43))
24132	29077749	Furthermore, strong disruption of PDAC cells in tumor lesions was observed in alpha-gal(+) PDAC-ly vaccinated KO mice, whereas a large number of viable PDAC cells was found in tumor lesions of alpha-gal(-) N-ly/alpha-gal(+) N-ly vaccinated KO mice and alpha-gal(-) PDAC-ly vaccinated KO mice.	('tumor lesions', 'Disease', (48, 61))	('ly', 'Chemical', 'MESH:D008239', (226, 228))	('tumor lesions', 'Disease', 'MESH:D051437', (176, 189))	('mice', 'Species', '10090', (243, 247))	('alpha-gal(-)', 'Gene', '14594', (252, 264))	('alpha-gal(+) PDAC-ly', 'Var', (78, 98))	('ly', 'Chemical', 'MESH:D008239', (208, 210))	('tumor lesions', 'Disease', 'MESH:D051437', (48, 61))	('alpha-gal(-)', 'Gene', '14594', (193, 205))	('mice', 'Species', '10090', (113, 117))	('ly', 'Chemical', 'MESH:D008239', (96, 98))	('alpha-gal(-', 'Gene', (193, 204))	('PDAC', 'Chemical', '-', (91, 95))	('PDAC', 'Chemical', '-', (34, 38))	('ly', 'Chemical', 'MESH:D008239', (270, 272))	('PDAC', 'Chemical', '-', (265, 269))	('PDAC', 'Chemical', '-', (152, 156))	('N', 'Chemical', 'MESH:D009584', (224, 225))	('PDAC-ly', 'Chemical', '-', (91, 98))	('mice', 'Species', '10090', (287, 291))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('PDAC-ly', 'Chemical', '-', (265, 272))	('tumor lesions', 'Disease', (176, 189))	('disruption', 'NegReg', (20, 30))	('N', 'Chemical', 'MESH:D009584', (206, 207))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('alpha-gal(-', 'Gene', (252, 263))
24133	29077749	These histological results suggest that the marked prolongation of survival of mice treated with alpha-gal(+) PDAC-ly vaccination is attributable to the strong antitumor response induced by alpha-gal(+) PDAC-ly vaccine treatment.	('tumor', 'Disease', (164, 169))	('alpha-gal(+) PDAC-ly', 'Var', (97, 117))	('survival', 'CPA', (67, 75))	('mice', 'Species', '10090', (79, 83))	('PDAC-ly', 'Chemical', '-', (203, 210))	('PDAC-ly', 'Chemical', '-', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('prolongation', 'PosReg', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
24141	29077749	Accordingly, alpha-gal(+) PDAC tumor lysates originating from preoperatively treated tumor specimens were also able to elicit a significant antitumor immune response.	('immune response', 'biological_process', 'GO:0006955', ('150', '165'))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('elicit', 'Reg', (119, 125))	('tumor', 'Disease', (31, 36))	('ly', 'Chemical', 'MESH:D008239', (9, 11))	('ly', 'Chemical', 'MESH:D008239', (37, 39))	('ly', 'Chemical', 'MESH:D008239', (74, 76))	('rat', 'Species', '10116', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('alpha-gal(+', 'Var', (13, 24))	('PDAC', 'Chemical', '-', (26, 30))
24156	29077749	Importantly, unprocessed PDAC membranes do not bind M86 anti-Gal mAb.	('M86', 'Var', (52, 55))	('PDAC', 'Chemical', '-', (25, 29))	('ly', 'Chemical', 'MESH:D008239', (9, 11))	('Gal', 'Chemical', 'MESH:C101993', (61, 64))	('bind', 'Interaction', (47, 51))
24166	29077749	The in vitro and in vivo data of the present study indicate that alpha-gal(+) PDAC tumor lysate vaccination can induce remarkable antitumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('alpha-gal(+', 'Var', (65, 76))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('ly', 'Chemical', 'MESH:D008239', (89, 91))	('PDAC', 'Chemical', '-', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', (134, 139))
24245	27671335	However, PANC1OR cells exhibit significantly enhanced PDT response relative to PANC1 cells (Figure 6B and Figure 6C).	('PDT', 'MPA', (54, 57))	('PANC1', 'CellLine', 'CVCL:0480', (79, 84))	('enhanced', 'PosReg', (45, 53))	('PANC1OR', 'Var', (9, 16))	('PANC1', 'CellLine', 'CVCL:0480', (9, 14))
24256	27671335	Additionally, PANC1+ FCM increases EMT marker expression and causes similar effects on oxaliplatin and PDT treatment response (S4).	('increases', 'PosReg', (25, 34))	('PANC1', 'CellLine', 'CVCL:0480', (14, 19))	('oxaliplatin', 'MPA', (87, 98))	('EMT marker expression', 'MPA', (35, 56))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (87, 98))	('EMT', 'biological_process', 'GO:0001837', ('35', '38'))	('PANC1+ FCM', 'Var', (14, 24))	('PDT treatment response', 'MPA', (103, 125))
24271	28194987	Chromatographic performance of polar metabolites was dramatically improved by mdDiLeu labeling with modified hydrophobicity, enhanced ionization efficiency, and picomole levels of detection limits.	('ionization efficiency', 'MPA', (134, 155))	('improved', 'PosReg', (66, 74))	('mdDiLeu labeling', 'Var', (78, 94))	('mdDiLeu', 'Chemical', '-', (78, 85))	('Chromatographic performance', 'MPA', (0, 27))	('enhanced', 'PosReg', (125, 133))
24274	28194987	Mass difference labeling introduces a fixed mass shift observed in full MS scans of intact precursor ions, with examples such as mass differential tags for relative and absolute quantification (mTRAQ), metabolic stable isotope labeling by amino acids in cell culture (SILAC), formaldehyde dimethylation, and dansylation.	('mass shift', 'MPA', (44, 54))	('Mass difference labeling', 'Var', (0, 24))	('labeling', 'Var', (16, 24))	('metabolic stable isotope labeling', 'MPA', (202, 235))	('formaldehyde', 'Chemical', 'MESH:D005557', (276, 288))
24350	28194987	As with isobaric DiLeu tags, mdDiLeu labeling increases the hydrophobicity and improves the ionization efficiency of amine metabolites, allowing the reproducible separation of amine metabolites using nanoRPLC-MS.	('ionization efficiency', 'MPA', (92, 113))	('mdDiLeu labeling', 'Var', (29, 45))	('increases', 'PosReg', (46, 55))	('mdDiLeu', 'Chemical', '-', (29, 36))	('hydrophobicity', 'MPA', (60, 74))	('improves', 'PosReg', (79, 87))	('amine', 'Chemical', 'MESH:D000588', (117, 122))	('amine', 'Chemical', 'MESH:D000588', (176, 181))
24369	28086830	We selected five differently structured high-affinity sigma-2 ligands (PB28, PB183, PB221, F281 and PB282) to study how they affect the viability of diverse pancreatic cancer cells (human cell lines BxPC3, AsPC1, Mia PaCa-2, and Panc1 and mouse Panc-02, KCKO and KP-02) and how this is reflected in vivo in a tumor model.	('BxPC3', 'CellLine', 'CVCL:0186', (199, 204))	('AsPC1', 'CellLine', 'CVCL:0152', (206, 211))	('affect', 'Reg', (125, 131))	('F281', 'Var', (91, 95))	('PB183', 'Chemical', '-', (77, 82))	('pancreatic cancer', 'Disease', (157, 174))	('Panc1', 'Gene', (229, 234))	('PB221', 'Chemical', '-', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('PB221', 'Var', (84, 89))	('PB282', 'Chemical', '-', (100, 105))	('F281', 'Chemical', '-', (91, 95))	('Panc1', 'Gene', '104066', (229, 234))	('tumor', 'Disease', (309, 314))	('Mia PaCa-2', 'CellLine', 'CVCL:0428', (213, 223))	('human', 'Species', '9606', (182, 187))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (157, 174))	('PB28', 'Chemical', '-', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('PB28', 'Chemical', '-', (100, 104))	('Panc-02', 'CellLine', 'CVCL:D627', (245, 252))	('mouse', 'Species', '10090', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('pancreatic cancer', 'Disease', 'MESH:D010190', (157, 174))	('PB282', 'Var', (100, 105))
24373	28086830	Despite a poor match between in vitro and the in vivo efficacy, daily treatment of C57BL/6 mice bearing Panc02 tumors resulted in promising effects with PB28 and PB282 which were similar compared to the current standard-of-care chemotherapeutic gemcitabine without showing signs of systemic toxicities.	('mice', 'Species', '10090', (91, 95))	('PB28', 'Chemical', '-', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('PB28', 'Chemical', '-', (153, 157))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('Panc02', 'CellLine', 'CVCL:D627', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('systemic toxicities', 'Disease', 'MESH:D010523', (282, 301))	('PB282', 'Chemical', '-', (162, 167))	('Panc02', 'Gene', (104, 110))	('PB28', 'Var', (153, 157))	('PB282', 'Var', (162, 167))	('systemic toxicities', 'Disease', (282, 301))	('gemcitabine', 'Chemical', 'MESH:C056507', (245, 256))
24384	28086830	Several sigma-2 ligands cause tumor selective cytotoxicity and apoptosis, although the mechanism of cell death induction is currently poorly understood but has been shown to involve caspase-dependent and -independent apoptosis, generation of reactive oxygen species (ROS), and autophagy.	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('autophagy', 'CPA', (277, 286))	('ligands', 'Var', (16, 23))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('sigma-2', 'Gene', (8, 15))	('cytotoxicity', 'Disease', (46, 58))	('cytotoxicity', 'Disease', 'MESH:D064420', (46, 58))	('autophagy', 'biological_process', 'GO:0016236', ('277', '286'))	('apoptosis', 'CPA', (217, 226))	('apoptosis', 'biological_process', 'GO:0097194', ('217', '226'))	('apoptosis', 'biological_process', 'GO:0006915', ('217', '226'))	('ROS', 'Chemical', 'MESH:D017382', (267, 270))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (242, 265))	('cell death', 'biological_process', 'GO:0008219', ('100', '110'))	('autophagy', 'biological_process', 'GO:0006914', ('277', '286'))	('apoptosis', 'CPA', (63, 72))	('tumor', 'Disease', (30, 35))
24386	28086830	1, PB28, PB183, PB221, F281 and PB282).	('PB282', 'Var', (32, 37))	('PB282', 'Chemical', '-', (32, 37))	('PB183', 'Chemical', '-', (9, 14))	('F281', 'Var', (23, 27))	('PB28', 'Chemical', '-', (32, 36))	('F281', 'Chemical', '-', (23, 27))	('PB221', 'Chemical', '-', (16, 21))	('PB183', 'Var', (9, 14))	('PB28', 'Chemical', '-', (3, 7))
24390	28086830	Herein we evaluated variants of PB28 in preclinical models for efficacy in addition to define a mechanism of action (mitochondrial superoxide production) that has not been previously linked to a defined receptor mediated process.	('superoxide', 'Chemical', 'MESH:D013481', (131, 141))	('variants', 'Var', (20, 28))	('PB28', 'Gene', (32, 36))	('PB28', 'Chemical', '-', (32, 36))
24440	28086830	1, PB28, PB221, PB183, F281 and PB282) reduced the viability in Panc02 (except for PB282), KCKO and MIAPaCa-2 (Table 1).	('MIAPaCa-2', 'CellLine', 'CVCL:0428', (100, 109))	('PB282', 'Var', (32, 37))	('Panc02', 'CellLine', 'CVCL:D627', (64, 70))	('PB28', 'Chemical', '-', (83, 87))	('PB282', 'Chemical', '-', (32, 37))	('F281', 'Var', (23, 27))	('PB183', 'Var', (16, 21))	('PB183', 'Chemical', '-', (16, 21))	('PB28', 'Var', (3, 7))	('PB28', 'Chemical', '-', (32, 36))	('F281', 'Chemical', '-', (23, 27))	('PB221', 'Var', (9, 14))	('PB282', 'Chemical', '-', (83, 88))	('reduced', 'NegReg', (39, 46))	('PB221', 'Chemical', '-', (9, 14))	('viability', 'MPA', (51, 60))	('PB28', 'Chemical', '-', (3, 7))
24442	28086830	Two cell lines (KP02 and BxPC3) were particularly sensitive to F281 as demonstrated by intermediate anti-proliferative activity (Table 1 EC50 ~ 45 muM).	('anti-proliferative activity', 'MPA', (100, 127))	('muM', 'Gene', (147, 150))	('BxPC3', 'CellLine', 'CVCL:0186', (25, 30))	('F281', 'Var', (63, 67))	('F281', 'Chemical', '-', (63, 67))	('muM', 'Gene', '56925', (147, 150))
24443	28086830	Notable differences were recorded in the effect of the same compounds among cells, such as F281 in Panc02, AsPC-1 and Panc-1 cells (EC50 values = 37 muM, 98 muM or 100 muM, respectively).	('AsPC-1', 'CellLine', 'CVCL:0152', (107, 113))	('Panc02', 'CellLine', 'CVCL:D627', (99, 105))	('muM', 'Gene', (168, 171))	('muM', 'Gene', (157, 160))	('F281', 'Var', (91, 95))	('muM', 'Gene', '56925', (149, 152))	('F281', 'Chemical', '-', (91, 95))	('muM', 'Gene', (149, 152))	('Panc-1', 'Gene', (118, 124))	('Panc-1', 'Gene', '104066', (118, 124))	('muM', 'Gene', '56925', (168, 171))	('muM', 'Gene', '56925', (157, 160))
24444	28086830	Where active, compounds PB221 and F281 displayed the most potent anti-proliferative activity with F281 displaying a certain effect also in the BxPC3 cells.	('F281', 'Var', (98, 102))	('F281', 'Chemical', '-', (98, 102))	('PB221', 'Chemical', '-', (24, 29))	('F281', 'Chemical', '-', (34, 38))	('anti-proliferative activity', 'CPA', (65, 92))	('BxPC3', 'CellLine', 'CVCL:0186', (143, 148))
24448	28086830	To compare caspase-3 activity induced by PB28, PB221, PB183, F281 and PB282, Panc02 mouse adenocarcinoma cells were treated with sigma-2 ligands (200 muM) for 5 h and assayed for cleavage of the proluminescent caspase-3 substrate and subsequent generation of a glow-type luminescent signal.	('caspase-3', 'Gene', (210, 219))	('PB221', 'Chemical', '-', (47, 52))	('PB183', 'Chemical', '-', (54, 59))	('cleavage', 'MPA', (179, 187))	('PB282', 'Chemical', '-', (70, 75))	('F281', 'Chemical', '-', (61, 65))	('PB221', 'Var', (47, 52))	('PB28', 'Chemical', '-', (41, 45))	('glow-type luminescent signal', 'MPA', (261, 289))	('PB28', 'Var', (41, 45))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('11', '29'))	('mouse', 'Species', '10090', (84, 89))	('caspase-3', 'Gene', '12367', (11, 20))	('caspase-3', 'Gene', '12367', (210, 219))	('muM', 'Gene', '56925', (150, 153))	('activity', 'MPA', (21, 29))	('muM', 'Gene', (150, 153))	('PB282', 'Var', (70, 75))	('adenocarcinoma', 'Disease', (90, 104))	('PB28', 'Chemical', '-', (70, 74))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('11', '29'))	('adenocarcinoma', 'Disease', 'MESH:D000230', (90, 104))	('caspase-3', 'Gene', (11, 20))	('Panc02', 'CellLine', 'CVCL:D627', (77, 83))
24449	28086830	PB221 and PB282 similarly induced a strong activation of caspase-3, increasing caspase-3 activity by 15.7 and 11.8 fold (P < 0.001) respectively compared to cells treated with DMSO vehicle only.	('caspase-3', 'Gene', '12367', (57, 66))	('activation', 'PosReg', (43, 53))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('79', '97'))	('caspase-3', 'Gene', (57, 66))	('PB221', 'Chemical', '-', (0, 5))	('PB282', 'Var', (10, 15))	('increasing', 'PosReg', (68, 78))	('PB282', 'Chemical', '-', (10, 15))	('caspase-3', 'Gene', '12367', (79, 88))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('79', '97'))	('caspase-3', 'Gene', (79, 88))	('PB221', 'Var', (0, 5))	('DMSO', 'Chemical', 'MESH:D004121', (176, 180))	('activity', 'MPA', (89, 97))
24450	28086830	PB183 had little effect on caspase-3-like activity (P > 0.05) under these conditions, while PB28 and F281 did not activate at all the caspase-3 at these concentrations, similar to the DMSO control (Fig.	('caspase-3', 'Gene', '12367', (134, 143))	('caspase-3', 'Gene', (27, 36))	('F281', 'Chemical', '-', (101, 105))	('PB183', 'Var', (0, 5))	('caspase-3', 'Gene', (134, 143))	('PB28', 'Chemical', '-', (92, 96))	('PB183', 'Chemical', '-', (0, 5))	('caspase-3', 'Gene', '12367', (27, 36))	('DMSO', 'Chemical', 'MESH:D004121', (184, 188))
24453	28086830	Five hours treatment with PB221 or PB282 caused substantial caspase activation which was completely blocked with Z-DEVD-FMK (Fig.	('Z-DEVD-FMK', 'Chemical', 'MESH:C110772', (113, 123))	('caspase', 'Enzyme', (60, 67))	('PB221', 'Chemical', '-', (26, 31))	('caspase activation', 'biological_process', 'GO:0006919', ('60', '78'))	('activation', 'PosReg', (68, 78))	('PB282', 'Var', (35, 40))	('PB282', 'Chemical', '-', (35, 40))	('PB221', 'Var', (26, 31))
24457	28086830	The impact of antioxidants on PANC02 cell viability was assessed 24 h after treatment with PB28, PB221, PB183, F281 and PB282 (Fig.	('PB28', 'Var', (91, 95))	('PB282', 'Var', (120, 125))	('PB282', 'Chemical', '-', (120, 125))	('PANC02', 'CellLine', 'CVCL:1633', (30, 36))	('PB221', 'Var', (97, 102))	('PB28', 'Chemical', '-', (91, 95))	('F281', 'Var', (111, 115))	('PB28', 'Chemical', '-', (120, 124))	('PB221', 'Chemical', '-', (97, 102))	('F281', 'Chemical', '-', (111, 115))	('PB183', 'Chemical', '-', (104, 109))	('PB183', 'Var', (104, 109))
24460	28086830	Interestingly, alpha-tocopherol protected against sigma-2 receptor ligands induced cell death, but N-acetyl-L-cysteine (NAC) did not, and an even higher levels of cell death was recorded when cells were co-treated with NAC and PB183 or PB282.	('cell death', 'biological_process', 'GO:0008219', ('83', '93'))	('PB282', 'Gene', (236, 241))	('PB282', 'Chemical', '-', (236, 241))	('N-acetyl-L-cysteine', 'Chemical', 'MESH:D000111', (99, 118))	('PB183', 'Chemical', '-', (227, 232))	('sigma-2 receptor', 'Protein', (50, 66))	('NAC', 'Chemical', 'MESH:D000111', (120, 123))	('NAC', 'cellular_component', 'GO:0005854', ('120', '123'))	('NAC', 'cellular_component', 'GO:0005854', ('219', '222'))	('NAC', 'Chemical', 'MESH:D000111', (219, 222))	('cell death', 'biological_process', 'GO:0008219', ('163', '173'))	('cell death', 'CPA', (83, 93))	('PB183', 'Var', (227, 232))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (15, 31))
24464	28086830	Histograms of FACS analysis showed marked increase of mean fluorescence intensity in Panc02 cells treated with 50 muM of PB28, PB221, PB183, F281 or PB282 for 2 h (Fig.	('FACS', 'Gene', '14081', (14, 18))	('F281', 'Chemical', '-', (141, 145))	('Panc02', 'CellLine', 'CVCL:D627', (85, 91))	('PB221', 'Var', (127, 132))	('PB28', 'Chemical', '-', (121, 125))	('muM', 'Gene', '56925', (114, 117))	('PB28', 'Gene', (121, 125))	('PB28', 'Chemical', '-', (149, 153))	('PB183', 'Var', (134, 139))	('PB221', 'Chemical', '-', (127, 132))	('PB183', 'Chemical', '-', (134, 139))	('muM', 'Gene', (114, 117))	('F281', 'Var', (141, 145))	('PB282', 'Chemical', '-', (149, 154))	('mean fluorescence intensity', 'MPA', (54, 81))	('PB282', 'Var', (149, 154))	('FACS', 'Gene', (14, 18))	('increase', 'PosReg', (42, 50))
24468	28086830	Only F281 generated some mitochondrial superoxide in AsPC1 and BxPC3 in line with its cytotoxic effect in these cells.	('BxPC3', 'CellLine', 'CVCL:0186', (63, 68))	('superoxide', 'Chemical', 'MESH:D013481', (39, 49))	('F281', 'Chemical', '-', (5, 9))	('AsPC1', 'CellLine', 'CVCL:0152', (53, 58))	('mitochondrial superoxide', 'MPA', (25, 49))	('F281', 'Var', (5, 9))
24475	28086830	Following conclusion of treatment, tumors were smaller for individual treatment groups PB28 (mean = 369 mm3), (Fig.	('smaller', 'NegReg', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('PB28', 'Var', (87, 91))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('PB28', 'Chemical', '-', (87, 91))
24494	28086830	We showed that, in particular, F281 had a greater capacity to decrease viability in the pancreas cancer cell lines tested, except for Panc1.	('F281', 'Chemical', '-', (31, 35))	('Panc1', 'Gene', '104066', (134, 139))	('pancreas cancer', 'Disease', (88, 103))	('viability', 'MPA', (71, 80))	('Panc1', 'Gene', (134, 139))	('pancreas cancer', 'Disease', 'MESH:D010190', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('decrease', 'NegReg', (62, 70))	('F281', 'Var', (31, 35))	('pancreas cancer', 'Phenotype', 'HP:0002894', (88, 103))
24500	28086830	On the other hand, in this study, the small diffusible hydrophilic antioxidant NAC, a precursor of glutathione, did not protect against cell death by sigma-2 ligands, resulting in an even higher toxicity in co-administration assays with PB183 and PB282.	('cell death', 'biological_process', 'GO:0008219', ('136', '146'))	('toxicity', 'Disease', 'MESH:D064420', (195, 203))	('co-administration', 'Interaction', (207, 224))	('toxicity', 'Disease', (195, 203))	('higher', 'PosReg', (188, 194))	('PB282', 'Gene', (247, 252))	('PB282', 'Chemical', '-', (247, 252))	('NAC', 'cellular_component', 'GO:0005854', ('79', '82'))	('PB183', 'Var', (237, 242))	('NAC', 'Chemical', 'MESH:D000111', (79, 82))	('glutathione', 'Chemical', 'MESH:D005978', (99, 110))	('PB183', 'Chemical', '-', (237, 242))
24504	28086830	However, only PB282 and PB221, at the concentration and time point used, were able to generate a strong caspase-3 activation, which was completely blocked by alpha-tocopherol and by caspase-3 inhibitor Z-DEVD-FMK.	('activation', 'PosReg', (114, 124))	('PB221', 'Var', (24, 29))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (158, 174))	('caspase-3', 'Gene', '12367', (182, 191))	('PB221', 'Chemical', '-', (24, 29))	('PB282', 'Var', (14, 19))	('Z-DEVD-FMK', 'Chemical', 'MESH:C110772', (202, 212))	('PB282', 'Chemical', '-', (14, 19))	('caspase-3', 'Gene', '12367', (104, 113))	('caspase-3', 'Gene', (182, 191))	('caspase-3', 'Gene', (104, 113))
24505	28086830	Since PB28, PB183, PB221 and F281 showed cytotoxicity in Panc02 cells, these results suggest that their cytotoxic activity is caspase-3 independent, except for PB221 that strongly activated caspase-3, but both cytotoxity and caspase-3 activation involved ROS generation.	('ROS', 'Chemical', 'MESH:D017382', (255, 258))	('PB221', 'Chemical', '-', (160, 165))	('PB183', 'Var', (12, 17))	('F281', 'Chemical', '-', (29, 33))	('cytotoxicity', 'Disease', (41, 53))	('caspase-3', 'Gene', '12367', (225, 234))	('ROS generation', 'biological_process', 'GO:1903409', ('255', '269'))	('cytotoxicity', 'Disease', 'MESH:D064420', (41, 53))	('cytotoxity', 'Disease', 'MESH:D064420', (210, 220))	('caspase-3', 'Gene', (190, 199))	('PB183', 'Chemical', '-', (12, 17))	('cytotoxity', 'Disease', (210, 220))	('caspase-3', 'Gene', (126, 135))	('Panc02', 'CellLine', 'CVCL:D627', (57, 63))	('PB221', 'Chemical', '-', (19, 24))	('ROS generation', 'MPA', (255, 269))	('PB221', 'Var', (19, 24))	('caspase-3', 'Gene', '12367', (190, 199))	('PB28', 'Chemical', '-', (6, 10))	('F281', 'Var', (29, 33))	('PB28', 'Gene', (6, 10))	('caspase-3', 'Gene', '12367', (126, 135))	('caspase-3', 'Gene', (225, 234))	('activated', 'PosReg', (180, 189))
24509	28086830	Only F281 generated some mitochondrial superoxide in AsPC1 and BxPC3, where a moderate cytotoxicity was noticed, in line with the hypothesis that mitochondrial superoxide pathway is at least partially responsible for the cytotoxic activity caused by our compounds in pancreatic cancer cells.	('BxPC3', 'CellLine', 'CVCL:0186', (63, 68))	('cytotoxicity', 'Disease', 'MESH:D064420', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (267, 284))	('superoxide', 'Chemical', 'MESH:D013481', (39, 49))	('F281', 'Chemical', '-', (5, 9))	('AsPC1', 'CellLine', 'CVCL:0152', (53, 58))	('superoxide', 'Chemical', 'MESH:D013481', (160, 170))	('mitochondrial superoxide', 'MPA', (25, 49))	('cytotoxicity', 'Disease', (87, 99))	('pancreatic cancer', 'Disease', (267, 284))	('pancreatic cancer', 'Disease', 'MESH:D010190', (267, 284))	('F281', 'Var', (5, 9))
24513	28086830	Although PB282 did not show cytotoxicity in Panc02 cells in vitro, daily treatment with PB28 and PB282 produced an effect statistically similar to gemcitabine alone, while other compounds such as PB221 and F281, that showed good EC50 values in this cell line in vitro, did not perform as well in vivo.	('cytotoxicity', 'Disease', 'MESH:D064420', (28, 40))	('Panc02', 'CellLine', 'CVCL:D627', (44, 50))	('PB28', 'Chemical', '-', (97, 101))	('gemcitabine', 'Chemical', 'MESH:C056507', (147, 158))	('PB28', 'Chemical', '-', (9, 13))	('PB28', 'Chemical', '-', (88, 92))	('PB221', 'Chemical', '-', (196, 201))	('cytotoxicity', 'Disease', (28, 40))	('PB282', 'Var', (97, 102))	('PB282', 'Chemical', '-', (97, 102))	('PB282', 'Chemical', '-', (9, 14))	('F281', 'Chemical', '-', (206, 210))	('PB28', 'Var', (88, 92))
24514	28086830	In particular, PB282 could produce active metabolites, in contrast to PB221, PB183 and F281 that are less effective in vivo despite their higher toxicity in the same tumor in vitro.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('PB282', 'Var', (15, 20))	('PB282', 'Chemical', '-', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('PB183', 'Chemical', '-', (77, 82))	('PB221', 'Chemical', '-', (70, 75))	('toxicity', 'Disease', 'MESH:D064420', (145, 153))	('toxicity', 'Disease', (145, 153))	('F281', 'Chemical', '-', (87, 91))	('active metabolites', 'MPA', (35, 53))
24516	28086830	Along these lines, necropsy and laboratory evaluations demonstrated that PB28, PB221, PB183, F281 and PB282 had no major off-target effects even in naive mice during continuous treatment as they well tolerated the drugs without signs of weight loss and no casualties as a result of drug treatments.	('PB183', 'Chemical', '-', (86, 91))	('weight loss', 'Disease', 'MESH:D015431', (237, 248))	('PB221', 'Gene', (79, 84))	('F281', 'Chemical', '-', (93, 97))	('mice', 'Species', '10090', (154, 158))	('PB282', 'Var', (102, 107))	('PB282', 'Chemical', '-', (102, 107))	('PB28', 'Gene', (73, 77))	('weight loss', 'Disease', (237, 248))	('PB221', 'Chemical', '-', (79, 84))	('weight loss', 'Phenotype', 'HP:0001824', (237, 248))	('PB28', 'Chemical', '-', (102, 106))	('F281', 'Var', (93, 97))	('PB183', 'Var', (86, 91))	('PB28', 'Chemical', '-', (73, 77))
24681	27372424	The chain extension reaction between the deprotected telechelic HPMA copolymers (i.e., d-BP and d-FBP) and the peptidic/PEG linkers was carried out in PBS buffer (pH = 6.8) at 40  C for 48 h. For d-BP, chain extension with the CL, SL and PL gave the multi-block HPMA copolymers MP-c, MP-s and MP-p, correspondingly.	('d-FBP', 'Chemical', '-', (96, 101))	('d-BP', 'Chemical', '-', (87, 91))	('HPMA copolymers', 'Chemical', '-', (262, 277))	('d-BP', 'Var', (196, 200))	('PEG', 'Chemical', 'MESH:D011092', (120, 123))	('MP-p', 'Gene', '10200', (293, 297))	('PBS', 'Chemical', '-', (151, 154))	('HPMA copolymers', 'Chemical', '-', (64, 79))	('MP-s', 'Chemical', 'MESH:C063925', (284, 288))	('SL', 'Disease', 'MESH:C564794', (231, 233))	('d-BP', 'Chemical', '-', (196, 200))	('MP-p', 'Gene', (293, 297))
24684	27372424	However, under the experimental conditions utilized, the chain extension reaction was significantly more efficient for the MPs compared to the FMPs.	('MPs', 'Var', (123, 126))	('more', 'PosReg', (100, 104))	('men', 'Species', '9606', (25, 28))	('chain extension reaction', 'MPA', (57, 81))
24695	27372424	These results demonstrate that MP-c, relative to the controls, is substantially more susceptible to cathepsin S cleavage.	('cathepsin S', 'Gene', '1520', (100, 111))	('susceptible', 'Reg', (85, 96))	('MP-c', 'Var', (31, 35))	('more', 'PosReg', (80, 84))	('cathepsin S', 'Gene', (100, 111))
24700	27372424	Second, cleavage of the cathepsin S-labile backbone of the MP-c generates small fragments with significantly less steric hindrance leading to faster and more complete degradation of the multi-block copolymer.	('cathepsin S', 'Gene', '1520', (24, 35))	('degradation', 'biological_process', 'GO:0009056', ('167', '178'))	('MP-c', 'Gene', (59, 63))	('cleavage', 'Var', (8, 16))	('men', 'Species', '9606', (84, 87))	('degradation', 'MPA', (167, 178))	('copolymer', 'Chemical', '-', (198, 207))	('cathepsin S', 'Gene', (24, 35))
24737	27372424	Moreover, the disparity of the florescence intensity between FMP-c and the other groups was found to increase at the 12 h time point.	('increase', 'PosReg', (101, 109))	('disparity', 'MPA', (14, 23))	('FMP-c', 'Chemical', '-', (61, 66))	('FMP-c', 'Var', (61, 66))	('florescence intensity', 'MPA', (31, 52))
24742	27372424	Overall, the results suggested that phagocytic cells, such as macrophages, are capable of rapidly digesting FMP-c upon internalization and thereby mediate the formation of low-molecular weight polymeric blocks, which are anticipated to be more efficiently cleared from non-target tissues.	('internalization', 'MPA', (119, 134))	('low-molecular weight polymeric blocks', 'MPA', (172, 209))	('FMP-c', 'Chemical', '-', (108, 113))	('formation', 'biological_process', 'GO:0009058', ('159', '168'))	('FMP-c', 'Gene', (108, 113))	('digesting', 'Var', (98, 107))	('polymer', 'Chemical', 'MESH:D011108', (193, 200))
24747	27372424	Although, by the 8 h time point, a higher efflux percentage of the 177Lu-MP-c was observed (74.1 +- 3.50 %) with respect to the controls (68.4 +- 3.99 % for 177Lu-MP-s and 65.8 +- 4.95 % for 177Lu-MP-p).	('MP-p', 'Gene', '10200', (197, 201))	('177Lu-MP-s', 'Var', (157, 167))	('177Lu-MP-c', 'Chemical', '-', (67, 77))	('efflux', 'biological_process', 'GO:0140352', ('42', '48'))	('MP-p', 'Gene', (197, 201))	('efflux', 'MPA', (42, 48))	('177Lu', 'Chemical', 'MESH:C000615061', (67, 72))	('177Lu', 'Chemical', 'MESH:C000615061', (191, 196))	('177Lu', 'Chemical', 'MESH:C000615061', (157, 162))	('efflux', 'biological_process', 'GO:0140115', ('42', '48'))	('177Lu-MP-s', 'Chemical', '-', (157, 167))
24753	27372424	At all time points investigated, 177Lu-MP-c demonstrated significantly higher overall clearance (p < 0.05) than the other two multi-block copolymers.	('higher', 'PosReg', (71, 77))	('177Lu-MP-c', 'Chemical', '-', (33, 43))	('copolymers', 'Chemical', '-', (138, 148))	('177Lu-MP-c', 'Var', (33, 43))	('clearance', 'MPA', (86, 95))
24755	27372424	Given the serum stability of the 177Lu-MPs, this suggests to us that the inclusion of a cathepsin S-cleavable peptide into the backbone of the copolymer was more readily cleaved and cleared, most likely by phagocytic cells, relative to the scrambled and non-cleavable controls.	('cleaved', 'MPA', (170, 177))	('177Lu-MPs', 'Chemical', '-', (33, 42))	('copolymer', 'Chemical', '-', (143, 152))	('cathepsin S', 'Gene', (88, 99))	('cathepsin S', 'Gene', '1520', (88, 99))	('inclusion', 'Var', (73, 82))	('cleared', 'MPA', (182, 189))
24757	27372424	By 24 h post-administration, 177Lu-MP-c had achieved a statistically better clearance of 9.05 +- 0.76 %ID/g compared to 14.63 +- 3.37 and 14.93 +- 2.58 for 177Lu-MP-s and 177Lu-MP-p, correspondingly.	('ID/g', 'MPA', (103, 107))	('177Lu-MP-c', 'Chemical', '-', (29, 39))	('MP-p', 'Gene', '10200', (177, 181))	('177Lu-MP-c', 'Var', (29, 39))	('MP-p', 'Gene', (177, 181))	('177Lu', 'Chemical', 'MESH:C000615061', (29, 34))	('177Lu-MP-s', 'Chemical', '-', (156, 166))	('177Lu', 'Chemical', 'MESH:C000615061', (156, 161))	('better', 'PosReg', (69, 75))	('177Lu', 'Chemical', 'MESH:C000615061', (171, 176))	('clearance', 'MPA', (76, 85))
24758	27372424	The divergence in blood clearance substantially increased overtime with 177Lu-MP-c having 0.55 +- 0.10 %ID/g which was 2.8 and 5.3 fold lower than 177Lu-MP-s and 177Lu-MP-p at 144 h p.i..	('lower', 'NegReg', (136, 141))	('increased', 'PosReg', (48, 57))	('177Lu', 'Chemical', 'MESH:C000615061', (147, 152))	('177Lu', 'Chemical', 'MESH:C000615061', (72, 77))	('177Lu', 'Chemical', 'MESH:C000615061', (162, 167))	('MP-p', 'Gene', '10200', (168, 172))	('blood clearance', 'MPA', (18, 33))	('MP-p', 'Gene', (168, 172))	('177Lu-MP-c', 'Chemical', '-', (72, 82))	('177Lu-MP-c', 'Var', (72, 82))	('177Lu-MP-s', 'Chemical', '-', (147, 157))
24761	27372424	Insertion of a cathepsin S-cleavable linker into the multi-block HPMA copolymer was found to substantially reduce the liver and spleen retention over time.	('retention', 'biological_process', 'GO:0051235', ('135', '144'))	('cathepsin S', 'Gene', (15, 26))	('cathepsin S', 'Gene', '1520', (15, 26))	('reduce', 'NegReg', (107, 113))	('Insertion', 'Var', (0, 9))	('HPMA copolymer', 'Chemical', '-', (65, 79))
24762	27372424	For 177Lu-MP-c, the liver retention was 5.12 +- 0.56 %ID/g at 24 h p.i., but had substantially cleared to 1.47 +- 0.24 %ID/g by the 144 h time point.	('liver retention', 'Disease', (20, 35))	('177Lu-MP-c', 'Chemical', '-', (4, 14))	('retention', 'biological_process', 'GO:0051235', ('26', '35'))	('177Lu-MP-c', 'Var', (4, 14))	('liver retention', 'Disease', 'MESH:D016055', (20, 35))
24764	27372424	By the 144 h time point, the liver retention of 177Lu-MP-c was found to be 2.0 and 2.6 fold lower than the scrambled and non-cleavable controls, respectively.	('liver retention', 'Disease', (29, 44))	('liver retention', 'Disease', 'MESH:D016055', (29, 44))	('retention', 'biological_process', 'GO:0051235', ('35', '44'))	('177Lu-MP-c', 'Chemical', '-', (48, 58))	('177Lu-MP-c', 'Var', (48, 58))	('lower', 'NegReg', (92, 97))
24767	27372424	Comparison amongst the 177Lu-MPs found that the spleen retention of 177Lu-MP-c was 2.2 and 3.2 fold lower than 177Lu-MP-s and 177Lu-MP-p, correspondingly, at the 144 h time point.	('retention', 'biological_process', 'GO:0051235', ('55', '64'))	('177Lu-MPs', 'Chemical', '-', (23, 32))	('177Lu-MP-s', 'Chemical', '-', (111, 121))	('177Lu', 'Chemical', 'MESH:C000615061', (111, 116))	('lower', 'NegReg', (100, 105))	('177Lu-MP-c', 'Chemical', '-', (68, 78))	('177Lu', 'Chemical', 'MESH:C000615061', (23, 28))	('MP-p', 'Gene', '10200', (132, 136))	('177Lu-MP-c', 'Var', (68, 78))	('177Lu', 'Chemical', 'MESH:C000615061', (126, 131))	('177Lu', 'Chemical', 'MESH:C000615061', (68, 73))	('MP-p', 'Gene', (132, 136))	('spleen retention', 'MPA', (48, 64))
24768	27372424	Undoubtedly, the more rapid blood clearance of 177Lu-MP-c contributed to the lower retention observed in the liver, spleen and other non-target tissues, particularly at early time points (i.e., 4 and 24 h).	('lower', 'NegReg', (77, 82))	('177Lu-MP-c', 'Var', (47, 57))	('177Lu-MP-c', 'Chemical', '-', (47, 57))	('blood clearance', 'MPA', (28, 43))	('retention', 'biological_process', 'GO:0051235', ('83', '92'))	('retention', 'MPA', (83, 92))
24770	27372424	The liver and spleen retention of 177Lu-MP-c over the same time period was substantially higher (e.g., at 144 h, liver and spleen retention was 28 and 21 % of the 4 h time point).	('retention', 'biological_process', 'GO:0051235', ('21', '30'))	('retention', 'biological_process', 'GO:0051235', ('130', '139'))	('177Lu-MP-c', 'Chemical', '-', (34, 44))	('higher', 'PosReg', (89, 95))	('177Lu-MP-c', 'Var', (34, 44))	('liver', 'MPA', (4, 9))	('liver', 'MPA', (113, 118))
24771	27372424	Therefore, this suggests that at 72 and 144 h, declines in tissue retention for 177Lu-MP-c largely reflects processing of the cathepsin S-cleavable copolymer by the tissue and not merely a matter of reduced blood retention.	('177Lu-MP-c', 'Var', (80, 90))	('retention', 'biological_process', 'GO:0051235', ('213', '222'))	('retention', 'biological_process', 'GO:0051235', ('66', '75'))	('declines', 'Disease', 'MESH:D060825', (47, 55))	('copolymer', 'Chemical', '-', (148, 157))	('cathepsin S', 'Gene', (126, 137))	('tissue retention', 'MPA', (59, 75))	('declines', 'Disease', (47, 55))	('177Lu-MP-c', 'Chemical', '-', (80, 90))	('cathepsin S', 'Gene', '1520', (126, 137))	('blood retention', 'Phenotype', 'HP:0000969', (207, 222))
24776	27372424	Additionally, the statistically identical tumor retention of 177Lu-MP-c relative to the scramble and non-cleavable controls strongly implies that cleavage of the cathepsin S-susceptible linker in the tumor is limited and/or clearance of the resulting single block copolymers from the tumor is ineffective.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', (42, 47))	('cathepsin S', 'Gene', (162, 173))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('177Lu-MP-c', 'Var', (61, 71))	('cathepsin S', 'Gene', '1520', (162, 173))	('177Lu-MP-c', 'Chemical', '-', (61, 71))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('retention', 'biological_process', 'GO:0051235', ('48', '57'))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('cleavage', 'MPA', (146, 154))	('copolymers', 'Chemical', '-', (264, 274))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', (284, 289))
24777	27372424	As a result of the substantial tumor retention and non-target clearance, 177Lu-MP-c demonstrated significantly higher (p < 0.05) T/NT ratios, given in Table 4, in the blood, liver and spleen at 72 p.i..	('177Lu-MP-c', 'Chemical', '-', (73, 83))	('T/NT ratios', 'MPA', (129, 140))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('177Lu-MP-c', 'Var', (73, 83))	('tumor', 'Disease', (31, 36))	('retention', 'biological_process', 'GO:0051235', ('37', '46'))	('higher', 'PosReg', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
24779	27372424	when 177Lu-MP-c provided significantly higher contrast in all selected organs (p < 0.05) relative to the other copolymers.	('copolymers', 'Chemical', '-', (111, 121))	('higher', 'PosReg', (39, 45))	('177Lu-MP-c', 'Chemical', '-', (5, 15))	('contrast', 'MPA', (46, 54))	('177Lu-MP-c', 'Var', (5, 15))
24780	27372424	The mean T/NT ratios for 177Lu-MP-c were also found to be higher than that of copolymer 177Lu-1 in our first generation copolymers at 72 h (blood (p < 0.02), liver (p < 0.07) and kidney (p < 0.03)) and 144 h (blood (p < 0.05), liver (p < 0.02).	('copolymer', 'Chemical', '-', (120, 129))	('177Lu', 'Chemical', 'MESH:C000615061', (25, 30))	('177Lu-MP-c', 'Chemical', '-', (25, 35))	('177Lu', 'Chemical', 'MESH:C000615061', (88, 93))	('copolymers', 'Chemical', '-', (120, 130))	('177Lu-MP-c', 'Var', (25, 35))	('higher', 'PosReg', (58, 64))	('copolymer', 'Chemical', '-', (78, 87))	('T/NT ratios', 'MPA', (9, 20))
24784	27372424	For all 177Lu-MPs, tumors were visualized at 24 h p.i.	('tumors', 'Disease', (19, 25))	('177Lu-MPs', 'Chemical', '-', (8, 17))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('177Lu-MPs', 'Var', (8, 17))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
24789	27372424	In the small-animal SPECT/CT imaging studies, pronounced accumulation of the 177Lu-MPs in the thoracic and abdominal regions was observed at 24 h, likely due to retention in the liver, spleen, lungs and heart (blood).	('accumulation', 'PosReg', (57, 69))	('177Lu-MPs', 'Var', (77, 86))	('retention', 'biological_process', 'GO:0051235', ('161', '170'))	('177Lu-MPs', 'Chemical', '-', (77, 86))
24790	27372424	For 177Lu-MP-c, the clearance of radioactivity from these non-target tissues outpaced that of the scrambled (177Lu-MP-s) and non-cleavable (177Lu-MP-p) multi-block HPMA copolymers.	('HPMA copolymers', 'Chemical', '-', (164, 179))	('clearance', 'MPA', (20, 29))	('MP-p', 'Gene', '10200', (146, 150))	('177Lu-MP-c', 'Chemical', '-', (4, 14))	('177Lu-MP-s', 'Chemical', '-', (109, 119))	('177Lu', 'Chemical', 'MESH:C000615061', (109, 114))	('177Lu', 'Chemical', 'MESH:C000615061', (140, 145))	('177Lu', 'Chemical', 'MESH:C000615061', (4, 9))	('177Lu-MP-c', 'Var', (4, 14))	('MP-p', 'Gene', (146, 150))
24791	27372424	This leads to 72 h and 144 h images of 177Lu-MP-c with superior tumor contrasting.	('tumor', 'Disease', (64, 69))	('177Lu-MP-c', 'Chemical', '-', (39, 49))	('177Lu-MP-c', 'Var', (39, 49))	('to 7', 'Species', '1214577', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
24795	27372424	Relative to controls, 177Lu-MP-c demonstrated substantially higher non-target clearance from MPS-associated tissues without, importantly, affecting the HPAC tumor targeting and retention capabilities of the copolymers.	('tumor', 'Disease', (157, 162))	('177Lu-MP-c', 'Chemical', '-', (22, 32))	('retention', 'biological_process', 'GO:0051235', ('177', '186'))	('higher', 'PosReg', (60, 66))	('177Lu-MP-c', 'Var', (22, 32))	('MPS', 'Disease', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('non-target clearance', 'MPA', (67, 87))	('copolymers', 'Chemical', '-', (207, 217))	('HPAC', 'Chemical', '-', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('MPS', 'Disease', 'MESH:D009084', (93, 96))
24846	26062664	Primer pairs against Homo sapiens gene SNAI1 (HP208950) and GAPDH (HP205798) were purchased from OriGene (Beijing, China).	('HP205798', 'Var', (67, 75))	('SNAI1', 'Gene', '6615', (39, 44))	('SNAI1', 'Gene', (39, 44))	('HP208950', 'Var', (46, 54))	('Homo sapiens', 'Species', '9606', (21, 33))	('GAPDH', 'Gene', (60, 65))	('GAPDH', 'Gene', '2597', (60, 65))
24850	26062664	The primary antibodies used in the immunoblotting assays were: SNAI1 (ab117866; Abcam) and GAPDH (G8140; United States Biological, Swampscott, MA, USA).	('SNAI1', 'Gene', '6615', (63, 68))	('G8140;', 'Var', (98, 104))	('GAPDH', 'Gene', '2597', (91, 96))	('SNAI1', 'Gene', (63, 68))	('GAPDH', 'Gene', (91, 96))
24856	26062664	These constructs were designated as wild-type (wt) SNAI1-3'-UTR or mutant (mt) SNAI1-3'-UTR, respectively.	('SNAI1', 'Gene', (51, 56))	('SNAI1', 'Gene', '6615', (79, 84))	('SNAI1', 'Gene', (79, 84))	('mutant', 'Var', (67, 73))	('SNAI1', 'Gene', '6615', (51, 56))
24887	26062664	When anti-miR-153 was transfected, an increase in luciferase activity of wt SNAI1 3'-UTR was observed.	('SNAI1', 'Gene', '6615', (76, 81))	('SNAI1', 'Gene', (76, 81))	('increase', 'PosReg', (38, 46))	('luciferase activity', 'molecular_function', 'GO:0047077', ('50', '69'))	('luciferase', 'Enzyme', (50, 60))	('miR', 'Gene', '220972', (10, 13))	('miR', 'Gene', (10, 13))	('luciferase activity', 'molecular_function', 'GO:0045289', ('50', '69'))	('transfected', 'Var', (22, 33))	('luciferase activity', 'molecular_function', 'GO:0047712', ('50', '69'))	('activity', 'MPA', (61, 69))	('luciferase activity', 'molecular_function', 'GO:0050397', ('50', '69'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('50', '69'))
24902	26062664	Statistical analysis indicated that miR-153 was expressed at significantly lower levels in PDAC patients with lymph node metastasis, poor tumor differentiation, tumor recurrence and advanced TNM tumor stage.	('TNM tumor', 'Disease', (191, 200))	('lymph', 'Disease', (110, 115))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', (138, 143))	('PDAC', 'Disease', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (161, 166))	('miR', 'Gene', (36, 39))	('lower', 'NegReg', (75, 80))	('poor', 'Var', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('PDAC', 'Chemical', '-', (91, 95))	('TNM tumor', 'Disease', 'MESH:D009369', (191, 200))	('PDAC', 'Phenotype', 'HP:0006725', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('patients', 'Species', '9606', (96, 104))	('miR', 'Gene', '220972', (36, 39))
24934	25879528	Cytoplasmic Keap1 immunostaining associated with N0-staging (p = 0.0009) and the absence of distant metastases (p = 0.018).	('metastases', 'Disease', (100, 110))	('N0-staging', 'CPA', (49, 59))	('metastases', 'Disease', 'MESH:D009362', (100, 110))	('Cytoplasmic', 'Var', (0, 11))	('associated', 'Reg', (33, 43))
24935	25879528	Membranous Keap1 associated with longer relapse-free survival (p = 0.041) and pancreatic cancer-specific survival (median survival 14 vs. 32 months; p = 0.029) and was in multivariate analysis an independent prognostic factor of pancreatic cancer-related death (HR 2.66, 95%CI 1.23-5.75).	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (229, 246))	('Membranous Keap1', 'Var', (0, 16))	('relapse-free survival', 'CPA', (40, 61))	('pancreatic cancer', 'Disease', (229, 246))	('pancreatic cancer', 'Disease', 'MESH:D010190', (229, 246))	('pancreatic cancer', 'Disease', (78, 95))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))	('longer', 'PosReg', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
24936	25879528	Oxidative stress and main redox regulators may participate in pancreatic carcinogenesis and Keap1 appears as a promising prognostic factor in pancreatic cancer.	('pancreatic cancer', 'Disease', (142, 159))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('pancreatic carcinogenesis', 'Disease', (62, 87))	('pancreatic cancer', 'Disease', 'MESH:D010190', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Oxidative stress', 'MPA', (0, 16))	('participate', 'Reg', (47, 58))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (62, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (142, 159))	('Keap1', 'Var', (92, 97))
24943	25879528	An expanding amount of literature from in vitro experiments suggests that ROS have a substantial effect on pancreatic carcinogenesis.	('ROS', 'Var', (74, 77))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (107, 132))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))	('pancreatic carcinogenesis', 'Disease', (107, 132))
24983	25879528	The alterations in the repressor of Nrf2, Keap1 may activate Nrf2-regulated antioxidant response pathway at least 1) by achievement of somatic Keap1 mutations to disturb Nrf2/Keap1 interaction 2) by epigenetic silencing via methylation of Keap1 resulting in nuclear accumulation of Nrf2 3) by cysteine residual modifications of Keap1.	('disturb', 'NegReg', (162, 169))	('alterations', 'Var', (4, 15))	('epigenetic silencing', 'Var', (199, 219))	('mutations', 'Var', (149, 158))	('nuclear accumulation', 'MPA', (258, 278))	('interaction', 'Interaction', (181, 192))	('Keap1', 'Gene', (143, 148))	('cysteine', 'Chemical', 'MESH:D003545', (293, 301))	('activate', 'PosReg', (52, 60))	('methylation', 'biological_process', 'GO:0032259', ('224', '235'))	('Nrf2-regulated antioxidant response pathway', 'Pathway', (61, 104))	('Nrf2', 'Gene', (282, 286))	('Nrf2/Keap1', 'Gene', (170, 180))
24985	25879528	In pancreatic carcinomas only synonymous mutations of Keap1 have been reported but interestingly in the context of pancreatic cancer biology, Keap1 mutations in other cancers seem to be more considerably prevalent in adenocarcinomas and in patients with smoking history.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('Keap1', 'Gene', (142, 147))	('pancreatic carcinomas', 'Disease', (3, 24))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('adenocarcinomas', 'Disease', 'MESH:D000230', (217, 232))	('adenocarcinomas', 'Disease', (217, 232))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (222, 232))	('cancers', 'Disease', (167, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutations', 'Var', (148, 157))	('prevalent', 'Reg', (204, 213))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (3, 24))	('pancreatic cancer', 'Disease', (115, 132))	('patients', 'Species', '9606', (240, 248))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('cancers', 'Disease', 'MESH:D009369', (167, 174))
24987	25879528	In the present study cytoplasmic Keap1 expression was tightly connected to reduced metastatic tendency, both to lymph nodes and to distant sites.	('metastatic tendency', 'CPA', (83, 102))	('lymph nodes', 'Disease', 'MESH:D000072717', (112, 123))	('reduced', 'NegReg', (75, 82))	('lymph nodes', 'Disease', (112, 123))	('cytoplasmic', 'Var', (21, 32))
24991	25879528	There were no long-time survivors in patients with negative membranous Keap1 immunostaining, whereas in those with Keap1 expression there was a plateau in survival curve during five follow-up years.	('Keap1', 'Var', (115, 120))	('negative', 'NegReg', (51, 59))	('patients', 'Species', '9606', (37, 45))
24994	25879528	In contrast, we and others have previously shown that there is aberrant Keap1 methylation in triple-negative breast cancer (TNBC) and Keap1 overexpression is associated with poor prognosis in TNBC.	('Keap1', 'Var', (134, 139))	('methylation', 'Var', (78, 89))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('TNBC', 'Disease', (124, 128))	('Keap1', 'Gene', (72, 77))	('aberrant', 'Var', (63, 71))	('overexpression', 'PosReg', (140, 154))	('methylation', 'biological_process', 'GO:0032259', ('78', '89'))	('TNBC', 'Disease', 'None', (192, 196))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TNBC', 'Disease', (192, 196))	('TNBC', 'Disease', 'None', (124, 128))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
24998	25879528	We found no association between 8-OHdG expression and either RFS or PCSS, but the presence of nuclear 8-OHdG was connected to smaller primary tumor size and the absence of lymph node metastases.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('8-OHdG', 'Chemical', 'MESH:C067134', (32, 38))	('RFS', 'Disease', (61, 64))	('smaller', 'NegReg', (126, 133))	('tumor', 'Disease', (142, 147))	('RFS', 'Disease', 'MESH:D005198', (61, 64))	('8-OHdG', 'Chemical', 'MESH:C067134', (102, 108))	('presence', 'Var', (82, 90))	('8-OHdG', 'Var', (102, 108))	('lymph node metastases', 'Disease', 'MESH:D009362', (172, 193))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('lymph node metastases', 'Disease', (172, 193))
25026	25635996	Our findings suggest that miR-1178 expression accelerates pancreatic tumorigenesis by the direct inhibition of CHIP expression.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('accelerates', 'PosReg', (46, 57))	('miR-1178', 'Gene', '100302274', (26, 34))	('tumor', 'Disease', (69, 74))	('inhibition', 'NegReg', (97, 107))	('CHIP expression', 'MPA', (111, 126))	('miR-1178', 'Gene', (26, 34))	('pancreatic', 'Disease', 'MESH:D010195', (58, 68))	('pancreatic', 'Disease', (58, 68))	('expression', 'Var', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
25045	25635996	PANC-1 cells were seeded into 12-well plates (1x105 cells/well) and co-transfected with the wild-type or mutant vector and 50 nM miR-1178 mimics or NC mimics using Lipofectamine 2000.	('miR-1178', 'Gene', '100302274', (129, 137))	('miR-1178', 'Gene', (129, 137))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (164, 182))	('mutant', 'Var', (105, 111))	('PANC-1', 'CellLine', 'CVCL:0480', (0, 6))
25049	25635996	To determine whether CHIP is a direct target of miR-1178, the 3'-UTR of CHIP with wild-type or mutant seed sequence recognition sites was cloned into a dual-luciferase reporter (Fig.	('miR-1178', 'Gene', '100302274', (48, 56))	('miR-1178', 'Gene', (48, 56))	('mutant', 'Var', (95, 101))
25050	25635996	We found that luciferase activity was decreased after co-transfection of the miR-1178 mimics with the wild-type vector, compared with co-transfection of the miR-1178 mimics with the mutant vector (P < 0.05) (Fig.	('decreased', 'NegReg', (38, 47))	('luciferase activity', 'molecular_function', 'GO:0050397', ('14', '33'))	('miR-1178', 'Gene', '100302274', (157, 165))	('luciferase activity', 'molecular_function', 'GO:0045289', ('14', '33'))	('miR-1178', 'Gene', '100302274', (77, 85))	('luciferase activity', 'molecular_function', 'GO:0050248', ('14', '33'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('14', '33'))	('miR-1178', 'Gene', (77, 85))	('miR-1178', 'Gene', (157, 165))	('mimics', 'Var', (86, 92))	('activity', 'MPA', (25, 33))	('luciferase activity', 'molecular_function', 'GO:0047077', ('14', '33'))	('luciferase', 'Enzyme', (14, 24))
25064	25635996	In agreement with this finding, the migratory abilities of these two cell lines were also enhanced after the cells were treated with the miR-1178 mimics, while the opposite results were observed when the cells were treated with the miR-1178 inhibitor (Fig.	('migratory abilities of', 'CPA', (36, 58))	('miR-1178', 'Gene', '100302274', (232, 240))	('miR-1178', 'Gene', '100302274', (137, 145))	('miR-1178', 'Gene', (137, 145))	('miR-1178', 'Gene', (232, 240))	('enhanced', 'PosReg', (90, 98))	('mimics', 'Var', (146, 152))
25074	25635996	In agreement with the inactivation of EGFR and its downstream pathways, cell invasion, migration (Fig.	('inactivation', 'Var', (22, 34))	('EGFR', 'Gene', '1956', (38, 42))	('migration', 'CPA', (87, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('EGFR', 'Gene', (38, 42))	('cell invasion', 'CPA', (72, 85))
25088	25635996	We found that luciferase activity was dramatically decreased after co-transfection of the miR-1178 mimics with the vector expressing wild-type CHIP 3'-UTR, compared with co-transfection of the mimics with the vector expressing a mutated CHIP 3'-UTR.	('luciferase activity', 'molecular_function', 'GO:0050397', ('14', '33'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('14', '33'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('14', '33'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('14', '33'))	('decreased', 'NegReg', (51, 60))	('luciferase', 'Enzyme', (14, 24))	('luciferase activity', 'molecular_function', 'GO:0047077', ('14', '33'))	('activity', 'MPA', (25, 33))	('miR-1178', 'Gene', '100302274', (90, 98))	('miR-1178', 'Gene', (90, 98))	('mimics', 'Var', (99, 105))
25111	25635996	In accordance with the inactivation of EGFR and its downstream pathways, cell proliferation, G1/S transition, migration and invasion were also decreased.	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('decreased', 'NegReg', (143, 152))	('G1/S transition', 'CPA', (93, 108))	('cell proliferation', 'CPA', (73, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('invasion', 'CPA', (124, 132))	('inactivation', 'Var', (23, 35))
25120	24388967	KRAS: feeding pancreatic cancer proliferation Oncogenic KRAS mutation is the signature genetic event in the progression and growth of pancreatic ductal adenocarcinoma (PDAC), an almost universally fatal disease.	('pancreatic cancer', 'Disease', (14, 31))	('PDAC', 'Chemical', '-', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('pancreatic cancer', 'Disease', 'MESH:D010190', (14, 31))	('KRAS', 'Gene', (56, 60))	('mutation', 'Var', (61, 69))	('pancreatic ductal adenocarcinoma', 'Disease', (134, 166))	('KRAS', 'Gene', '3845', (56, 60))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (134, 166))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (134, 166))	('PDAC', 'Phenotype', 'HP:0006725', (168, 172))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (14, 31))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
25121	24388967	Although it has been appreciated for some time that nearly 95% of PDAC harbor mutationally activated KRAS, to date no effective treatments that target this mutant protein have reached the clinic.	('hat', 'Gene', (140, 143))	('hat', 'Gene', (48, 51))	('PDAC', 'Chemical', '-', (66, 70))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('KRAS', 'Gene', (101, 105))	('hat', 'Gene', '9407', (140, 143))	('hat', 'Gene', '9407', (48, 51))	('mutationally', 'Var', (78, 90))	('PDAC', 'Phenotype', 'HP:0006725', (66, 70))	('PDAC', 'Disease', (66, 70))	('activated', 'Reg', (91, 100))
25122	24388967	A number of studies have shown that oncogenic KRAS plays a central role in controlling tumor metabolism by orchestrating multiple metabolic changes including stimulation of glucose uptake, differential channeling of glucose intermediates, reprogrammed glutamine metabolism, increased autophagy, and macropinocytosis.	('oncogenic', 'Var', (36, 45))	('glucose', 'Chemical', 'MESH:D005947', (173, 180))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('252', '272'))	('autophagy', 'CPA', (284, 293))	('glucose', 'MPA', (173, 180))	('differential channeling of glucose intermediates', 'MPA', (189, 237))	('stimulation', 'PosReg', (158, 169))	('macropinocytosis', 'biological_process', 'GO:0044351', ('299', '315'))	('increased', 'PosReg', (274, 283))	('macropinocytosis', 'CPA', (299, 315))	('autophagy', 'biological_process', 'GO:0016236', ('284', '293'))	('tumor', 'Disease', (87, 92))	('metabolism', 'biological_process', 'GO:0008152', ('93', '103'))	('hat', 'Gene', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('glucose uptake', 'biological_process', 'GO:0046323', ('173', '187'))	('glucose', 'Chemical', 'MESH:D005947', (216, 223))	('glutamine', 'Chemical', 'MESH:D005973', (252, 261))	('autophagy', 'biological_process', 'GO:0006914', ('284', '293'))	('hat', 'Gene', '9407', (32, 35))	('reprogrammed glutamine metabolism', 'MPA', (239, 272))
25127	24388967	Aside from a few rare exceptions, mutationally activated Ras proteins found in human cancers result predominantly from one of three single point mutations at residues G12, G13 or Q61.	('Ras proteins', 'Protein', (57, 69))	('G13', 'Var', (172, 175))	('mutationally', 'Var', (34, 46))	('human', 'Species', '9606', (79, 84))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('Q61', 'Var', (179, 182))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('result', 'Reg', (93, 99))
25128	24388967	Oncogenic substitution of G12 or G13 leads to constitutive activation of Ras by creating steric hindrance that prevents the formation of van der Waals interactions between Ras and RasGAPS, whereas substitutions of Q61 interfere with the coordination of a water molecule necessary for GTP-hydrolysis.	('steric hindrance', 'MPA', (89, 105))	('van der Waals interactions', 'MPA', (137, 163))	('interfere', 'NegReg', (218, 227))	('G13', 'Gene', (33, 36))	('GTP-hydrolysis', 'biological_process', 'GO:0006184', ('284', '298'))	('formation', 'biological_process', 'GO:0009058', ('124', '133'))	('GTP', 'Chemical', 'MESH:D006160', (284, 287))	('coordination of a water molecule', 'MPA', (237, 269))	('hat', 'Gene', (107, 110))	('hat', 'Gene', '9407', (107, 110))	('G12', 'Gene', (26, 29))	('substitution', 'Var', (10, 22))	('formation', 'MPA', (124, 133))	('water', 'Chemical', 'MESH:D014867', (255, 260))	('activation', 'PosReg', (59, 69))	('prevents', 'NegReg', (111, 119))
25131	24388967	There is nearly exclusive mutation of KRAS in pancreatic, colon, and lung cancer; whereas HRAS mutations are associated with skin (keratinocyte), head and neck, and bladder tumors; and NRAS mutations are present in haematopoietic and skin (melanocyte) malignancies.	('pancreatic', 'Disease', (46, 56))	('HRAS', 'Disease', 'None', (90, 94))	('bladder tumors', 'Disease', 'MESH:D001749', (165, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('NRAS', 'Gene', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('colon', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('lung cancer', 'Disease', (69, 80))	('mutations', 'Var', (95, 104))	('bladder tumors', 'Disease', (165, 179))	('associated', 'Reg', (109, 119))	('mutation', 'Var', (26, 34))	('HRAS', 'Disease', (90, 94))	('bladder tumors', 'Phenotype', 'HP:0009725', (165, 179))	('malignancies', 'Disease', 'MESH:D009369', (252, 264))	('pancreatic', 'Disease', 'MESH:D010195', (46, 56))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('malignancies', 'Disease', (252, 264))	('neck', 'cellular_component', 'GO:0044326', ('155', '159'))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('KRAS', 'Gene', (38, 42))
25132	24388967	In terms of the distribution of missense RAS mutations across the entire cancer genomic landscape, mutation of KRAS occurs most frequently, accounting for 85% of RAS mutations, followed by NRAS (12%), with HRAS mutations relatively rare (3%).	('HRAS', 'Disease', (206, 210))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('HRAS', 'Disease', 'None', (206, 210))	('mutations', 'Var', (166, 175))	('KRAS', 'Gene', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutation', 'Var', (99, 107))	('RAS', 'Gene', (162, 165))
25134	24388967	The frequency and specific substitutions show cancer type differences, with 98% of KRAS mutations in PDAC occurring at position G12 (Figure 2).	('PDAC', 'Phenotype', 'HP:0006725', (101, 105))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('KRAS mutations', 'Var', (83, 97))	('cancer', 'Disease', (46, 52))	('PDAC', 'Chemical', '-', (101, 105))	('PDAC', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
25136	24388967	In PDAC, KRAS mutation is an early and initiating event as it has been shown that over 90% of low-grade pancreatic intraepithelial neoplasia (PanIN) lesions (Figure 3) harbor oncogenic KRAS mutations.	('hat', 'Gene', '9407', (78, 81))	('PDAC', 'Chemical', '-', (3, 7))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (115, 140))	('mutations', 'Var', (190, 199))	('neoplasia', 'Phenotype', 'HP:0002664', (131, 140))	('PDAC', 'Phenotype', 'HP:0006725', (3, 7))	('oncogenic', 'Reg', (175, 184))	('pancreatic intraepithelial neoplasia (PanIN) lesions', 'Disease', 'MESH:D018290', (104, 156))	('hat', 'Gene', (78, 81))	('KRAS', 'Gene', (185, 189))
25137	24388967	PanINs are graded from stage I to III, and along this continuum they display increasing disorganization and nuclear abnormalities, with high-grade PanINs ultimately transforming into true PDAC.	('PanINs', 'Var', (147, 153))	('true PDAC', 'Disease', (183, 192))	('disorganization', 'CPA', (88, 103))	('PDAC', 'Phenotype', 'HP:0006725', (188, 192))	('transforming', 'Reg', (165, 177))	('nuclear abnormalities', 'CPA', (108, 129))	('PDAC', 'Chemical', '-', (188, 192))
25138	24388967	Molecular profiling studies have reinforced the PanIN-to-PDAC progression by demonstrating that KRAS mutation is followed by subsequent inactivation of the tumor suppressor gene CDKN2A (or INK4A/ARF, which encodes p14/Arf and p16/INK4A), followed by inactivation of two other tumor suppressor genes TP53 and SMAD4 (Figure 3).	('INK4', 'Gene', '1029', (230, 234))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('SMAD4', 'Gene', (308, 313))	('CDKN2', 'Gene', '1029', (178, 183))	('ARF', 'Disease', 'MESH:D058186', (195, 198))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('156', '172'))	('tumor', 'Disease', (156, 161))	('hat', 'Gene', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('INK4', 'Gene', (230, 234))	('INK4', 'Gene', '1029', (189, 193))	('tumor suppressor', 'biological_process', 'GO:0051726', ('156', '172'))	('SMAD4', 'Gene', '4089', (308, 313))	('KRAS', 'Gene', (96, 100))	('inactivation', 'NegReg', (136, 148))	('hat', 'Gene', '9407', (92, 95))	('INK4', 'Gene', (189, 193))	('CDKN2', 'Gene', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (276, 281))	('PDAC', 'Chemical', '-', (57, 61))	('ARF', 'Disease', (195, 198))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('276', '292'))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('PDAC', 'Phenotype', 'HP:0006725', (57, 61))	('tumor suppressor', 'biological_process', 'GO:0051726', ('276', '292'))	('mutation', 'Var', (101, 109))
25139	24388967	Comprehensive genetic analysis has revealed that PDAC is an extremely complex and heterogeneous disease, and throughout the progressive accumulation of mutations, KRAS continues to drive PDAC development by contributing to tumor maintenance.	('PDAC', 'Phenotype', 'HP:0006725', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('hat', 'Gene', (45, 48))	('mutations', 'Var', (152, 161))	('PDAC', 'Chemical', '-', (49, 53))	('drive', 'PosReg', (181, 186))	('KRAS', 'Gene', (163, 167))	('contributing', 'Reg', (207, 219))	('hat', 'Gene', '9407', (45, 48))	('PDAC', 'Chemical', '-', (187, 191))	('PDAC', 'Disease', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('PDAC', 'Phenotype', 'HP:0006725', (49, 53))	('PDAC', 'Disease', (187, 191))
25141	24388967	The considerable experimental evidence for the role of mutant KRAS as a driver of cancer development and growth has prompted an intensive effort to identify pharmacologic approaches to block aberrant Ras function for cancer treatment (Figure 4).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('KRAS', 'Gene', (62, 66))	('mutant', 'Var', (55, 61))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
25144	24388967	Despite promising preclinical results, clinical trials with FTIs were disappointing as, although FTIs blocked the association of H-Ras with the plasma membrane, they lacked antitumor activity in cancers involving mutant K-Ras and N-Ras due to the unforeseen compensatory activity of the FTase-related enzyme geranylgeranyltransferase-I, which modifies RAS with a geranylgeranyl, rather than a farnesyl group.	('plasma membrane', 'cellular_component', 'GO:0005886', ('144', '159'))	('cancers', 'Disease', (195, 202))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('K-Ras', 'Protein', (220, 225))	('H-Ras', 'Protein', (129, 134))	('association', 'Interaction', (114, 125))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('blocked', 'NegReg', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('lacked', 'NegReg', (166, 172))	('tumor', 'Disease', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('mutant', 'Var', (213, 219))
25146	24388967	The identification of synthetic lethal partners of mutant KRAS generated considerable excitement for novel anti-Ras strategies that was then quickly dampened by concerns about the robustness of some of the identified hits.	('KRAS', 'Gene', (58, 62))	('mutant', 'Var', (51, 57))	('anti-Ras', 'CPA', (107, 115))	('hat', 'Gene', (128, 131))	('hat', 'Gene', '9407', (128, 131))
25147	24388967	Recently, both mouse genetic and in vitro experiments have implicated KRAS, TP53, MYC, and LKB1 not only in increased PDAC proliferation, but also in the alteration of glucose and glutamine utilization and metabolism.	('LKB1', 'Gene', (91, 95))	('PDAC', 'Phenotype', 'HP:0006725', (118, 122))	('glutamine', 'Chemical', 'MESH:D005973', (180, 189))	('PDAC proliferation', 'CPA', (118, 136))	('KRAS', 'Var', (70, 74))	('increased', 'PosReg', (108, 117))	('metabolism', 'biological_process', 'GO:0008152', ('206', '216'))	('MYC,', 'Gene', '17869', (82, 86))	('alteration', 'Reg', (154, 164))	('TP53', 'Gene', (76, 80))	('mouse', 'Species', '10090', (15, 20))	('PDAC', 'Chemical', '-', (118, 122))	('glucose', 'Chemical', 'MESH:D005947', (168, 175))
25148	24388967	Herein, we will specifically review papers describing oncogenic KRAS-driven metabolic variations that contribute to PDAC progression and indicate the potential ways these pathways could be targeted therapeutically.	('hat', 'Gene', '9407', (98, 101))	('PDAC', 'Phenotype', 'HP:0006725', (116, 120))	('variations', 'Var', (86, 96))	('PDAC', 'Disease', (116, 120))	('contribute', 'Reg', (102, 112))	('hat', 'Gene', (98, 101))	('PDAC', 'Chemical', '-', (116, 120))
25149	24388967	Aberrant metabolism is now considered one of the hallmarks of cancer.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('metabolism', 'biological_process', 'GO:0008152', ('9', '19'))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
25160	24388967	This metabolic alteration provides a distinct survival advantage as it has been shown that cell lines harboring oncogenic KRAS were able to survive long-term culture in a low glucose environment.	('oncogenic KRAS', 'Var', (112, 126))	('hat', 'Gene', (87, 90))	('hat', 'Gene', '9407', (87, 90))	('survival advantage', 'CPA', (46, 64))	('KRAS', 'Var', (122, 126))	('glucose', 'Chemical', 'MESH:D005947', (175, 182))
25162	24388967	Recently, it was demonstrated that mutant KRAS enhances expression of GLUT1 and several other genes encoding rate-limiting glycolytic enzymes, including hexokinase 1 and 2 (Hk1, Hk2), and phosphofructokinase-1 (Pfkl), as well as lactate dehydrogenase A (Ldha), the enzyme responsible for converting pyruvate to lactate (Figure 5).	('2 (Hk1', 'Gene', '3098', (170, 176))	('mutant', 'Var', (35, 41))	('hexokinase 1', 'Gene', '3098', (153, 165))	('hat', 'Gene', '9407', (31, 34))	('phosphofructokinase-1', 'molecular_function', 'GO:0008662', ('188', '209'))	('hexokinase 1', 'Gene', (153, 165))	('lactate', 'Chemical', 'MESH:D019344', (229, 236))	('Hk1', 'molecular_function', 'GO:0004673', ('173', '176'))	('expression', 'MPA', (56, 66))	('Ldha', 'Gene', (254, 258))	('KRAS', 'Gene', (42, 46))	('enhances', 'PosReg', (47, 55))	('(Pfkl)', 'Gene', '5211', (210, 216))	('Pfkl', 'Gene', (211, 215))	('hat', 'Gene', (31, 34))	('pyruvate', 'Chemical', 'MESH:D019289', (299, 307))	('lactate', 'Chemical', 'MESH:D019344', (311, 318))	('GLUT1', 'Gene', (70, 75))	('Hk2', 'molecular_function', 'GO:0008256', ('178', '181'))	('(Ldha)', 'Gene', '3939', (253, 259))
25163	24388967	Additionally, through the upregulation of other rate-limiting enzymes, mutant K-Ras leads to a shunting of glycolytic intermediates into anabolic pathways including the hexosamine biosynthesis pathway (HBP) and the non-oxidative arm of the pentose phosphate pathway (PPP) (Figure 5).	('anabolic pathways', 'MPA', (137, 154))	('hexosamine biosynthesis', 'MPA', (169, 192))	('pentose phosphate', 'Chemical', 'MESH:D010428', (240, 257))	('K-Ras', 'Gene', (78, 83))	('hexosamine', 'Chemical', 'MESH:D006595', (169, 179))	('shunting of glycolytic intermediates', 'MPA', (95, 131))	('biosynthesis', 'biological_process', 'GO:0009058', ('180', '192'))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('240', '265'))	('mutant', 'Var', (71, 77))	('upregulation', 'PosReg', (26, 38))
25168	24388967	Likewise, it has been demonstrated in lung cancer lines that Pfk1, a key glycolytic enzyme, was inactivated due to O-GlcNAcylation, resulting in the redirection of glycolytic flux through the PPP.	('lung cancer', 'Disease', (38, 49))	('redirection', 'PosReg', (149, 160))	('hat', 'Gene', '9407', (57, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('O-GlcNAcylation', 'Var', (115, 130))	('inactivated', 'NegReg', (96, 107))	('Pfk1', 'Gene', (61, 65))	('O-GlcNAcylation', 'Chemical', '-', (115, 130))	('glycolytic flux', 'MPA', (164, 179))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('hat', 'Gene', (57, 60))	('Pfk', 'molecular_function', 'GO:0003872', ('61', '64'))
25182	24388967	However, it appears that in the context of PDAC, oncogenic K-Ras expression directs the metabolism of glutamine through a different pathway.	('hat', 'Gene', (21, 24))	('hat', 'Gene', '9407', (21, 24))	('PDAC', 'Phenotype', 'HP:0006725', (43, 47))	('directs', 'Reg', (76, 83))	('K-Ras', 'Gene', (59, 64))	('glutamine', 'Chemical', 'MESH:D005973', (102, 111))	('PDAC', 'Chemical', '-', (43, 47))	('metabolism', 'biological_process', 'GO:0008152', ('88', '98'))	('oncogenic', 'Var', (49, 58))	('metabolism of glutamine', 'MPA', (88, 111))
25183	24388967	A recent report showed that KRAS mutant PDAC uses a unique form of glutamine metabolism to regulate redox balance.	('regulate', 'Reg', (91, 99))	('PDAC', 'Phenotype', 'HP:0006725', (40, 44))	('hat', 'Gene', (24, 27))	('glutamine metabolism', 'MPA', (67, 87))	('hat', 'Gene', '9407', (24, 27))	('glutamine', 'Chemical', 'MESH:D005973', (67, 76))	('PDAC', 'Chemical', '-', (40, 44))	('KRAS mutant', 'Var', (28, 39))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('67', '87'))	('redox balance', 'MPA', (100, 113))	('PDAC', 'Gene', (40, 44))
25185	24388967	The conversion of malate to pyruvate by ME1 results in an increased NADPH/NADP+ ratio in the cell, which maintains the cellular redox state (Figure 5).	('ME1', 'Var', (40, 43))	('malate', 'Chemical', 'MESH:C030298', (18, 24))	('ME1', 'Chemical', '-', (40, 43))	('increased', 'PosReg', (58, 67))	('NADPH', 'Chemical', 'MESH:D009249', (68, 73))	('pyruvate', 'Chemical', 'MESH:D019289', (28, 36))	('maintains', 'Reg', (105, 114))	('cellular redox state', 'MPA', (119, 139))	('malate', 'MPA', (18, 24))	('NADP+', 'Chemical', 'MESH:D009249', (74, 79))	('conversion', 'MPA', (4, 14))	('NADPH/NADP+ ratio', 'MPA', (68, 85))
25186	24388967	Proteomic analysis supports this unique pattern of protein upregulation in PDAC, and mutant K-Ras drives this metabolic reprogramming via increasing GOT1 and decreasing GLUD1 gene expression, resulting in increased flux through the GOT1-dependent pathway.	('GOT1', 'Gene', (149, 153))	('K-Ras', 'Gene', (92, 97))	('protein', 'Protein', (51, 58))	('GLUD1 gene expression', 'MPA', (169, 190))	('PDAC', 'Disease', (75, 79))	('PDAC', 'Phenotype', 'HP:0006725', (75, 79))	('PDAC', 'Chemical', '-', (75, 79))	('gene expression', 'biological_process', 'GO:0010467', ('175', '190'))	('flux', 'MPA', (215, 219))	('increased', 'PosReg', (205, 214))	('decreasing', 'NegReg', (158, 168))	('upregulation', 'PosReg', (59, 71))	('mutant', 'Var', (85, 91))	('increasing', 'PosReg', (138, 148))	('GOT1-dependent pathway', 'Pathway', (232, 254))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
25191	24388967	This apparent discrepancy could be rationalized based on the dual nature of ROS, where low levels of ROS may be growth promoting but high levels are cytotoxic.	('ROS', 'Var', (101, 104))	('ROS', 'Chemical', '-', (101, 104))	('ROS', 'Chemical', '-', (76, 79))	('growth', 'MPA', (112, 118))
25198	24388967	A clinicopathological study of samples from 71 different PDAC patients revealed that PDAC exhibited activated autophagy and that high LC3 protein (a component of autophagosome formation) expression correlated with poor patient outcome.	('autophagosome formation', 'biological_process', 'GO:0000045', ('162', '185'))	('LC3 protein', 'Protein', (134, 145))	('hat', 'Gene', (125, 128))	('patients', 'Species', '9606', (62, 70))	('activated', 'PosReg', (100, 109))	('PDAC', 'Chemical', '-', (85, 89))	('autophagy', 'CPA', (110, 119))	('patient', 'Species', '9606', (62, 69))	('PDAC', 'Phenotype', 'HP:0006725', (85, 89))	('autophagy', 'biological_process', 'GO:0016236', ('110', '119'))	('hat', 'Gene', '9407', (125, 128))	('hat', 'Gene', (81, 84))	('patient', 'Species', '9606', (219, 226))	('autophagosome', 'cellular_component', 'GO:0005776', ('162', '175'))	('PDAC', 'Chemical', '-', (57, 61))	('autophagy', 'biological_process', 'GO:0006914', ('110', '119'))	('hat', 'Gene', '9407', (81, 84))	('high', 'Var', (129, 133))	('PDAC', 'Phenotype', 'HP:0006725', (57, 61))	('PDAC', 'Disease', (85, 89))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))
25200	24388967	Correspondingly, genetic depletion of ATG5 or pharmacological inhibition of autophagy with chloroquine suppressed PDAC cell line growth in vitro and tumorigencity in vivo.	('PDAC', 'Disease', (114, 118))	('PDAC', 'Phenotype', 'HP:0006725', (114, 118))	('ATG5', 'Gene', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('autophagy', 'CPA', (76, 85))	('genetic depletion', 'Var', (17, 34))	('autophagy', 'biological_process', 'GO:0016236', ('76', '85'))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('autophagy', 'biological_process', 'GO:0006914', ('76', '85'))	('suppressed', 'NegReg', (103, 113))	('tumor', 'Disease', (149, 154))	('PDAC', 'Chemical', '-', (114, 118))	('chloroquine', 'Chemical', 'MESH:D002738', (91, 102))
25203	24388967	Similar analyses in the pancreatic cancer cell line PANC-1 and other RAS mutant human tumor cell lines showed that high basal autophagy is necessary for the growth and survival of these cell lines.	('pancreatic cancer', 'Disease', (24, 41))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (24, 41))	('tumor', 'Disease', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('autophagy', 'biological_process', 'GO:0016236', ('126', '135'))	('autophagy', 'biological_process', 'GO:0006914', ('126', '135'))	('hat', 'Gene', (111, 114))	('mutant', 'Var', (73, 79))	('human', 'Species', '9606', (80, 85))	('hat', 'Gene', '9407', (111, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (24, 41))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('PANC-1', 'CellLine', 'CVCL:0480', (52, 58))
25210	24388967	While the details diverge in these studies, the unifying reliance upon autophagy in PDAC and other RAS mutant tumors to meet metabolic demand is striking.	('PDAC', 'Disease', (84, 88))	('PDAC', 'Phenotype', 'HP:0006725', (84, 88))	('autophagy', 'biological_process', 'GO:0006914', ('71', '80'))	('mutant', 'Var', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('PDAC', 'Chemical', '-', (84, 88))	('autophagy', 'biological_process', 'GO:0016236', ('71', '80'))
25218	24388967	A recent report demonstrated that PDAC cells expressing oncogenic KRAS utilized macropinocytosis to transport extracellular protein into the cell and that this endocytosed protein served as a source of glutamine.	('hat', 'Gene', (151, 154))	('hat', 'Gene', '9407', (30, 33))	('transport', 'biological_process', 'GO:0006810', ('100', '109'))	('PDAC', 'Chemical', '-', (34, 38))	('macropinocytosis', 'biological_process', 'GO:0044351', ('80', '96'))	('KRAS', 'Var', (66, 70))	('hat', 'Gene', '9407', (151, 154))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('transport extracellular protein into the cell', 'MPA', (100, 145))	('PDAC', 'Phenotype', 'HP:0006725', (34, 38))	('hat', 'Gene', (30, 33))	('macropinocytosis', 'MPA', (80, 96))	('oncogenic KRAS', 'Var', (56, 70))	('extracellular', 'cellular_component', 'GO:0005576', ('110', '123'))	('glutamine', 'Chemical', 'MESH:D005973', (202, 211))
25224	24388967	RNAi silencing of CD147 expression, required for the function and expression of the MCT1 and MCT4 lactate transporters that remove intracellular lactate, inhibited pancreatic cell proliferation and suppressed PDAC cell line xenograft growth in mice.	('MCT', 'biological_process', 'GO:0120197', ('84', '87'))	('mice', 'Species', '10090', (244, 248))	('hat', 'Gene', '9407', (120, 123))	('PDAC cell line xenograft growth in', 'CPA', (209, 243))	('cell proliferation', 'biological_process', 'GO:0008283', ('175', '193'))	('pancreatic', 'Disease', (164, 174))	('suppressed', 'NegReg', (198, 208))	('MCT1', 'Gene', '17236', (84, 88))	('silencing', 'Var', (5, 14))	('inhibited', 'NegReg', (154, 163))	('CD147', 'Gene', (18, 23))	('intracellular', 'cellular_component', 'GO:0005622', ('131', '144'))	('MCT4', 'Gene', (93, 97))	('PDAC', 'Chemical', '-', (209, 213))	('PDAC', 'Phenotype', 'HP:0006725', (209, 213))	('lactate', 'Chemical', 'MESH:D019344', (145, 152))	('hat', 'Gene', (120, 123))	('lactate', 'Chemical', 'MESH:D019344', (98, 105))	('remove intracellular lactate', 'MPA', (124, 152))	('MCT4', 'Gene', '80879', (93, 97))	('pancreatic', 'Disease', 'MESH:D010195', (164, 174))	('RNAi', 'biological_process', 'GO:0016246', ('0', '4'))	('MCT1', 'Gene', (84, 88))	('MCT', 'biological_process', 'GO:0120197', ('93', '96'))
25226	24388967	Aside from upregulating LDHA expression, K-Ras(G12D) expression in PDAC also preferentially induces flux through the nonoxidative PPP and if this pathway is blocked, tumorigenic activity is suppressed.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('PDAC', 'Phenotype', 'HP:0006725', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('flux through the nonoxidative PPP', 'MPA', (100, 133))	('tumor', 'Disease', (166, 171))	('K-Ras(G12D) expression', 'Var', (41, 63))	('preferentially', 'PosReg', (77, 91))	('upregulating', 'PosReg', (11, 23))	('G12D', 'Mutation', 'rs121913529', (47, 51))	('PDAC', 'Chemical', '-', (67, 71))	('induces', 'PosReg', (92, 99))	('LDHA expression', 'MPA', (24, 39))	('PDAC', 'Gene', (67, 71))
25228	24388967	Furthermore, Hk2 has been identified as an attractive target for KRAS-driven lung cancers, as systemic whole-body deletion of HK2 in the mouse selectively targets cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('HK2', 'molecular_function', 'GO:0008256', ('126', '129'))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('mouse', 'Species', '10090', (137, 142))	('lung cancers', 'Disease', 'MESH:D008175', (77, 89))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('lung cancers', 'Phenotype', 'HP:0100526', (77, 89))	('Hk2', 'molecular_function', 'GO:0008256', ('13', '16'))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('HK2', 'Gene', (126, 129))	('lung cancers', 'Disease', (77, 89))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('deletion', 'Var', (114, 122))
25229	24388967	Based on the finding that mutant KRAS enhances expression of HK2, it is possible that it may be an attractive target for pancreatic cancers as well.	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('hat', 'Gene', '9407', (82, 85))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (121, 139))	('HK2', 'molecular_function', 'GO:0008256', ('61', '64'))	('KRAS', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('expression', 'MPA', (47, 57))	('hat', 'Gene', (22, 25))	('hat', 'Gene', '9407', (22, 25))	('enhances', 'PosReg', (38, 46))	('mutant', 'Var', (26, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (121, 138))	('HK2', 'Protein', (61, 64))	('hat', 'Gene', (82, 85))	('pancreatic cancers', 'Disease', 'MESH:D010190', (121, 139))	('pancreatic cancers', 'Disease', (121, 139))
25239	24388967	The finding that RAS-transformed cells depend on autophagy for survival, suggests that cancers with high levels of mutant Ras proteins will be particularly susceptible to autophagy inhibition.	('proteins', 'Protein', (126, 134))	('cancers', 'Disease', (87, 94))	('autophagy', 'biological_process', 'GO:0016236', ('49', '58'))	('autophagy', 'biological_process', 'GO:0016236', ('171', '180'))	('hat', 'Gene', '9407', (13, 16))	('autophagy', 'biological_process', 'GO:0006914', ('49', '58'))	('hat', 'Gene', (83, 86))	('mutant', 'Var', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('autophagy', 'biological_process', 'GO:0006914', ('171', '180'))	('hat', 'Gene', '9407', (83, 86))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('hat', 'Gene', (13, 16))	('Ras', 'Gene', (122, 125))	('autophagy', 'CPA', (171, 180))
25242	24388967	There are multiple early phase studies exploring the use of HCQ in pancreatic cancer in various therapeutic combinations and in various stages of the disease (NCT01128296, NCT01506973, NCT01494155, NCT01273805).	('NCT01273805', 'Var', (198, 209))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (67, 84))	('HCQ', 'Chemical', 'MESH:D006886', (60, 63))	('NCT01128296', 'Var', (159, 170))	('NCT01506973', 'Var', (172, 183))	('pancreatic cancer', 'Disease', 'MESH:D010190', (67, 84))	('pancreatic cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('NCT01494155', 'Var', (185, 196))
25246	24388967	We have summarized and highlighted the recently defined role of oncogenic KRAS in the regulation of altered metabolic signaling pathways in PDAC, a clinically challenging disease in dire need of new treatments.	('PDAC', 'Chemical', '-', (140, 144))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('KRAS', 'Var', (74, 78))	('PDAC', 'Phenotype', 'HP:0006725', (140, 144))	('PDAC', 'Disease', (140, 144))	('signaling', 'biological_process', 'GO:0023052', ('118', '127'))
25250	24388967	To maintain redox balance, mutant KRAS alters glutamine utilization by increasing transcription of transaminases, which send the glutamine carbon skeleton down a metabolic pathway that fuels NADPH production.	('transcription', 'MPA', (82, 95))	('alters', 'Reg', (39, 45))	('increasing', 'PosReg', (71, 81))	('hat', 'Gene', (181, 184))	('glutamine carbon skeleton', 'MPA', (129, 154))	('mutant', 'Var', (27, 33))	('glutamine', 'Chemical', 'MESH:D005973', (129, 138))	('hat', 'Gene', '9407', (181, 184))	('glutamine', 'Chemical', 'MESH:D005973', (46, 55))	('transaminases', 'Enzyme', (99, 112))	('carbon', 'Chemical', 'MESH:D002244', (139, 145))	('transcription', 'biological_process', 'GO:0006351', ('82', '95'))	('glutamine utilization', 'MPA', (46, 67))	('NADPH', 'Chemical', 'MESH:D009249', (191, 196))
25251	24388967	To supply cells with as much glutamine and other amino acids as possible, oncogenic KRAS also drives macropinocytosis of extracellular fluids in PDAC cells.	('drives', 'Reg', (94, 100))	('oncogenic', 'Var', (74, 83))	('macropinocytosis of extracellular fluids', 'MPA', (101, 141))	('glutamine', 'Chemical', 'MESH:D005973', (29, 38))	('KRAS', 'Gene', (84, 88))	('PDAC', 'Chemical', '-', (145, 149))	('extracellular', 'cellular_component', 'GO:0005576', ('121', '134'))	('macropinocytosis', 'biological_process', 'GO:0044351', ('101', '117'))	('PDAC', 'Phenotype', 'HP:0006725', (145, 149))
25252	24388967	Additionally, autophagy is upregulated by KRAS in PDAC to support cell survival, potentially by restraining oxidative damage and maintaining energy homeostasis.	('autophagy', 'CPA', (14, 23))	('KRAS', 'Var', (42, 46))	('PDAC', 'Phenotype', 'HP:0006725', (50, 54))	('autophagy', 'biological_process', 'GO:0006914', ('14', '23'))	('oxidative damage', 'MPA', (108, 124))	('cell survival', 'CPA', (66, 79))	('energy homeostasis', 'biological_process', 'GO:0097009', ('141', '159'))	('support', 'PosReg', (58, 65))	('upregulated', 'PosReg', (27, 38))	('maintaining', 'PosReg', (129, 140))	('PDAC', 'Chemical', '-', (50, 54))	('energy homeostasis', 'MPA', (141, 159))	('PDAC', 'Gene', (50, 54))	('autophagy', 'biological_process', 'GO:0016236', ('14', '23'))	('restraining', 'NegReg', (96, 107))
25256	24388967	Autophagy and macropinocytosis are upregulated by mutant KRAS to assist PDAC survival.	('Autophagy', 'biological_process', 'GO:0006914', ('0', '9'))	('macropinocytosis', 'biological_process', 'GO:0044351', ('14', '30'))	('Autophagy', 'biological_process', 'GO:0016236', ('0', '9'))	('PDAC', 'Chemical', '-', (72, 76))	('KRAS', 'Gene', (57, 61))	('upregulated', 'PosReg', (35, 46))	('mutant', 'Var', (50, 56))	('assist', 'PosReg', (65, 71))	('Autophagy', 'CPA', (0, 9))	('macropinocytosis', 'CPA', (14, 30))	('PDAC', 'Phenotype', 'HP:0006725', (72, 76))
25266	23622131	Progression requires specific genetic changes and, at least in pancreatic tumors, each stage seems to be associated with specific mutations.	('pancreatic tumors', 'Disease', (63, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (63, 80))	('mutations', 'Var', (130, 139))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (63, 79))	('associated', 'Reg', (105, 115))	('pancreatic tumors', 'Disease', 'MESH:D010190', (63, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
25267	23622131	Oncogenic KRAS was first associated with pancreatic cancer at least 24 years ago.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('associated', 'Reg', (25, 35))	('KRAS', 'Gene', (10, 14))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (41, 58))	('pancreatic cancer', 'Disease', (41, 58))	('Oncogenic', 'Var', (0, 9))	('pancreatic cancer', 'Disease', 'MESH:D010190', (41, 58))
25268	23622131	At that time, Kras was shown to be mutated to an oncogenic form, most commonly KrasG12D, in most pancreatic tumors.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('KrasG12D', 'Var', (79, 87))	('pancreatic tumors', 'Disease', 'MESH:D010190', (97, 114))	('pancreatic tumors', 'Disease', (97, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (97, 114))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (97, 113))
25272	23622131	One limitation is that they express oncogenic KRAS in all the cells of the pancreas, unlike human pancreatic tumors.	('pancreatic tumors', 'Phenotype', 'HP:0002894', (98, 115))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (98, 114))	('KRAS', 'Var', (46, 50))	('pancreatic tumors', 'Disease', 'MESH:D010190', (98, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('pancreatic tumors', 'Disease', (98, 115))	('human', 'Species', '9606', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
25273	23622131	Another is the concurrent, rather than sequential, introduction of the genetic alterations associated with each stage of spontaneous tumor development.	('genetic alterations', 'Var', (71, 90))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (133, 138))
25282	23622131	Specific point mutations in KRAS (primarily those that affect KRAS-GTPase-activating protein interactions) reduce GTP hydrolysis and thereby cause KRAS to remain active.	('KRAS', 'Gene', (28, 32))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('114', '128'))	('affect', 'Reg', (55, 61))	('GTP', 'Chemical', 'MESH:D006160', (114, 117))	('KRAS-GTPase-activating protein interactions', 'Gene', (62, 105))	('reduce', 'NegReg', (107, 113))	('GTP hydrolysis', 'MPA', (114, 128))	('cause', 'Reg', (141, 146))	('GTP', 'Chemical', 'MESH:D006160', (67, 70))	('KRAS-GTPase-activating protein interactions', 'Gene', '16653', (62, 105))	('point mutations', 'Var', (9, 24))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
25283	23622131	They are considered to be oncogenic because when they were first investigated, they were observed to transform cells in the absence of other manipulations, and cells that expressed these mutant forms of KRAS formed tumors in vivo.	('KRAS', 'Gene', (203, 207))	('formed', 'Reg', (208, 214))	('mutant', 'Var', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumors', 'Disease', (215, 221))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', 'MESH:D009369', (215, 221))
25284	23622131	It has been estimated that approximately 30% of all tumors have oncogenic mutations in RAS family members, HRAS, NRAS, and KRAS; oncogenic Kras is found in nearly every pancreatic tumor.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('HRAS', 'Gene', '15461', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('NRAS', 'Gene', '18176', (113, 117))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (169, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('mutations', 'Var', (74, 83))	('NRAS', 'Gene', (113, 117))	('tumors', 'Disease', (52, 58))	('RAS', 'Gene', (87, 90))	('pancreatic tumor', 'Disease', 'MESH:D010190', (169, 185))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('HRAS', 'Gene', (107, 111))	('KRAS', 'Gene', (123, 127))	('pancreatic tumor', 'Disease', (169, 185))
25288	23622131	When oncogenic Kras was evaluated as a biomarker, numerous studies reported that healthy people have cells with oncogenic Kras in different organs, including the pancreas, colon, and lungs, at rates far exceeding the rates of cancer development.	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('people', 'Species', '9606', (89, 95))	('Kras', 'Var', (122, 126))	('oncogenic Kras', 'Var', (112, 126))
25289	23622131	More recently, mice that express oncogenic Kras, either in the whole body or in specific organs, develop cancers from only a small fraction of the cells that contain the oncogenic Kras, It can therefore be assumed that other, genetic or epigenetic, factors are required to initiate carcinogenesis, even when a mutation in the Kras oncogene has been acquired.	('initiate carcinogenesis', 'Disease', (273, 296))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mice', 'Species', '10090', (15, 19))	('Kras', 'Var', (43, 47))	('initiate carcinogenesis', 'Disease', 'MESH:D063646', (273, 296))
25294	23622131	In this light, it is noteworthy that many reagents shown to accelerate formation of pancreatic ductal adenocarcinomas (PDACs) in mice that express oncogenic Kras, also directly or indirectly activate KRAS.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('Kras', 'Var', (157, 161))	('accelerate', 'PosReg', (60, 70))	('KRAS', 'Gene', (200, 204))	('oncogenic Kras', 'Var', (147, 161))	('PDACs', 'Chemical', '-', (119, 124))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (84, 116))	('pancreatic ductal adenocarcinomas', 'Disease', (84, 117))	('activate', 'PosReg', (191, 199))	('formation', 'biological_process', 'GO:0009058', ('71', '80'))	('mice', 'Species', '10090', (129, 133))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (84, 117))
25296	23622131	It is conceivable that the oncogenic stress associated with expression of oncogenic Kras might result in apoptosis or senescence, and factors that allow cells to overcome the senescence barrier, such as inflammation or loss of tumor suppressor genes, such as p16 or p53, allow the transformation process.	('p16', 'Gene', (259, 262))	('tumor', 'Disease', (227, 232))	('inflammation', 'biological_process', 'GO:0006954', ('203', '215'))	('inflammation', 'Disease', 'MESH:D007249', (203, 215))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('loss', 'NegReg', (219, 223))	('apoptosis', 'biological_process', 'GO:0097194', ('105', '114'))	('senescence', 'CPA', (118, 128))	('expression', 'Var', (60, 70))	('apoptosis', 'biological_process', 'GO:0006915', ('105', '114'))	('p53', 'Gene', '22059', (266, 269))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('inflammation', 'Disease', (203, 215))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('227', '243'))	('senescence', 'biological_process', 'GO:0010149', ('118', '128'))	('Kras', 'Gene', (84, 88))	('apoptosis', 'CPA', (105, 114))	('tumor suppressor', 'biological_process', 'GO:0051726', ('227', '243'))	('result in', 'Reg', (95, 104))	('p53', 'Gene', (266, 269))	('senescence', 'biological_process', 'GO:0010149', ('175', '185'))
25302	23622131	Therefore, the mechanisms that increase the levels of oncogenic Kras in cells contribute to transformation and cancer development.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('contribute', 'Reg', (78, 88))	('transformation', 'CPA', (92, 106))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('Kras', 'Var', (64, 68))
25303	23622131	People acquire oncogenic mutations in Kras in lung, pancreas, colon, and other tissues as they age.	('oncogenic', 'Reg', (15, 24))	('mutations', 'Var', (25, 34))	('People', 'Species', '9606', (0, 6))	('Kras', 'Gene', (38, 42))
25307	23622131	However, oncogenic KRAS has slower kinetics of return to its guanosine diphosphate-bound status than nononcogenic forms.	('return to', 'MPA', (47, 56))	('oncogenic', 'Var', (9, 18))	('slower', 'NegReg', (28, 34))	('guanosine diphosphate', 'Chemical', 'MESH:D006153', (61, 82))
25312	23622131	This concept also indicates that attempting to block cancer initiation downstream of KRAS will be a challenge because many effectors are activated by KRAS (Figure 1).	('block cancer', 'Disease', 'MESH:D009369', (47, 59))	('activated', 'PosReg', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('block cancer', 'Disease', (47, 59))	('KRAS', 'Var', (150, 154))
25315	23622131	Increased Kras activity is required for development of hepatocellular carcinoma, via alterations in GTPase-activating proteins, instead of oncogenic mutations.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (55, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('hepatocellular carcinoma', 'Disease', (55, 79))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (55, 79))	('GTP', 'Chemical', 'MESH:D006160', (100, 103))	('GTPase-activating proteins', 'Protein', (100, 126))	('alterations', 'Var', (85, 96))
25330	23622131	However, progression requires inactivation of tumor suppressors, such as p16.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('inactivation', 'Var', (30, 42))	('tumor', 'Disease', (46, 51))	('p16', 'Gene', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
25331	23622131	In humans, sporadic mutations in Kras might occur, and in most cases be cleared from the tissue by cell senescence.	('humans', 'Species', '9606', (3, 9))	('Kras', 'Gene', (33, 37))	('mutations', 'Var', (20, 29))	('senescence', 'biological_process', 'GO:0010149', ('104', '114'))
25346	23622131	Inactivation in low-grade PanIN lesions results in most cells that line the dysplastic ducts to activate expression of genes of the acinar lineage, and inactivate ductal genes, in a process that is the opposite of acinar to ductal metaplasia.	('metaplasia', 'biological_process', 'GO:0036074', ('231', '241'))	('inactivate', 'NegReg', (152, 162))	('activate', 'PosReg', (96, 104))	('genes', 'Gene', (119, 124))	('dysplastic', 'Disease', (76, 86))	('dysplastic', 'Disease', 'MESH:D004416', (76, 86))	('ductal metaplasia', 'Disease', 'MESH:D008679', (224, 241))	('ductal genes', 'Gene', (163, 175))	('ductal metaplasia', 'Disease', (224, 241))	('lesions', 'Var', (32, 39))	('PanIN', 'Gene', (26, 31))	('expression', 'MPA', (105, 115))	('Inactivation', 'Var', (0, 12))
25351	23622131	Loss, inactivation, or mutation of multiple tumor suppressors (such as Tp53 and p16) is commonly detected in human pancreatic tumors.	('human', 'Species', '9606', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('mutation', 'Var', (23, 31))	('inactivation', 'Var', (6, 18))	('pancreatic tumors', 'Disease', 'MESH:D010190', (115, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('Loss', 'NegReg', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('pancreatic tumors', 'Disease', (115, 132))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('p16', 'Gene', (80, 83))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (115, 132))	('Tp53', 'Gene', (71, 75))	('tumor', 'Disease', (44, 49))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (115, 131))	('tumor', 'Disease', (126, 131))
25353	23622131	For example, in KC mice, which express endogenous levels of oncogenic Kras, the tumor suppressor Tp53 tends to be mutated or lost at late stages of tumor development.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutated', 'Var', (114, 121))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (80, 85))	('Tp53', 'Gene', (97, 101))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('lost', 'NegReg', (125, 129))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('mice', 'Species', '10090', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
25357	23622131	To speed cancer development in models with low Kras activity, mutant alleles of tumor suppressors can be introduced, which would resemble development of pancreatic cancer in humans.	('cancer', 'Disease', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('mutant', 'Var', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (153, 170))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (80, 85))	('pancreatic cancer', 'Disease', (153, 170))	('humans', 'Species', '9606', (174, 180))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('pancreatic cancer', 'Disease', 'MESH:D010190', (153, 170))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
25358	23622131	iKras mice carrying a loss-of-function allele in p53 (called iKras*p53 mice) rapidly develop pancreatic adenocarcinoma with high penetrance, and can be used to determine the effects of Kras inactivation in invasive tumors.	('mice', 'Species', '10090', (71, 75))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '22059', (49, 52))	('invasive tumors', 'Disease', 'MESH:D009369', (206, 221))	('allele', 'Var', (39, 45))	('mice', 'Species', '10090', (6, 10))	('p53', 'Gene', (67, 70))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (93, 118))	('p53', 'Gene', '22059', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('pancreatic adenocarcinoma', 'Disease', (93, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('invasive tumors', 'Disease', (206, 221))	('loss-of-function', 'NegReg', (22, 38))	('develop', 'PosReg', (85, 92))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (93, 118))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
25359	23622131	Studies with these mice have shown that inactivation of Kras leads to rapid tumor regression through loss of tumor cell proliferation and viability.	('loss', 'NegReg', (101, 105))	('cell proliferation', 'biological_process', 'GO:0008283', ('115', '133'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('Kras', 'Gene', (56, 60))	('mice', 'Species', '10090', (19, 23))	('inactivation', 'Var', (40, 52))	('tumor', 'Disease', (109, 114))
25361	23622131	In vivo imaging studies showed rapid regression of the primary tumor and liver metastases on Kras inactivation.	('tumor', 'Disease', (63, 68))	('inactivation', 'Var', (98, 110))	('metastases', 'Disease', 'MESH:D009362', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('metastases', 'Disease', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Kras', 'Gene', (93, 97))
25371	23622131	Inactivation of Kras also leads to resolution of the chronic inflammation associated with pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('inflammation', 'biological_process', 'GO:0006954', ('61', '73'))	('Kras', 'Gene', (16, 20))	('pancreatic cancer', 'Disease', (90, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Inactivation', 'Var', (0, 12))	('resolution', 'MPA', (35, 45))
25394	23622131	Interestingly, in vitro studies using cell lines with the characteristics of classic and quasi-mesenchymal subtypes showed that classic PDACs depend on Kras, whereas those of the mesenchymal subtype are not.	('PDACs', 'Chemical', '-', (136, 141))	('depend', 'Reg', (142, 148))	('Kras', 'Var', (152, 156))
25405	23622131	In addition, expression of BRAFV600E, but not PI3CAH1047R, in combination with a cancer-associated mutant form of p53 (TP53R270H), led to development of lethal PDACs in mice.	('p53', 'Gene', (114, 117))	('p53', 'Gene', '22059', (114, 117))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('BRAFV600E', 'Var', (27, 36))	('led to', 'Reg', (131, 137))	('PDACs', 'Chemical', '-', (160, 165))	('lethal PDACs', 'CPA', (153, 165))	('cancer', 'Disease', (81, 87))	('BRAFV600E', 'Mutation', 'rs113488022', (27, 36))	('mice', 'Species', '10090', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('development', 'CPA', (138, 149))
25409	23622131	Inhibition of the MAPK signaling with the inhibitor PD325901 had a cytostatic effect on KPC tumors, orthotopically implanted in immune-competent, syngeneic mice.	('MAPK signaling', 'biological_process', 'GO:0000165', ('18', '32'))	('MAPK signaling', 'Pathway', (18, 32))	('Inhibition', 'NegReg', (0, 10))	('KPC tumors', 'Disease', (88, 98))	('PD325901', 'Var', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mice', 'Species', '10090', (156, 160))	('KPC tumors', 'Disease', 'MESH:C565455', (88, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('PD325901', 'Chemical', 'MESH:C506614', (52, 60))	('cytostatic', 'MPA', (67, 77))	('MAPK', 'molecular_function', 'GO:0004707', ('18', '22'))
25411	23622131	This finding contrasts, at least in part, with the observation that Kras inactivation in tumors affects cell survival in iKras* mice.	('tumors', 'Disease', (89, 95))	('Kras*', 'Gene', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('Kras', 'Gene', (68, 72))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('inactivation', 'Var', (73, 85))	('cell survival', 'CPA', (104, 117))	('mice', 'Species', '10090', (128, 132))	('Kras*', 'Gene', '16653', (122, 127))	('affects', 'Reg', (96, 103))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
25414	23622131	Similar results were obtained with the MEK and AKT inhibitors GDC0941 and AZD6244, respectively.	('GDC0941', 'Var', (62, 69))	('GDC0941', 'Chemical', 'MESH:C532162', (62, 69))	('AKT', 'Pathway', (47, 50))	('AZD6244', 'Chemical', 'MESH:C517975', (74, 81))	('MEK', 'Gene', (39, 42))	('MEK', 'Gene', '5609', (39, 42))
25418	23622131	Inhibitors of cyclin-dependent kinase-5 have been shown to suppress KRAS-Ral signaling and block pancreatic tumor formation and progression in mice.	('cyclin', 'molecular_function', 'GO:0016538', ('14', '20'))	('pancreatic tumor', 'Disease', (97, 113))	('cyclin-dependent kinase-5', 'Gene', '12568', (14, 39))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Ral', 'Gene', '56044', (73, 76))	('Inhibitors', 'Var', (0, 10))	('pancreatic tumor', 'Disease', 'MESH:D010190', (97, 113))	('Ral', 'Gene', (73, 76))	('cyclin-dependent kinase-5', 'Gene', (14, 39))	('block', 'NegReg', (91, 96))	('suppress', 'NegReg', (59, 67))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (97, 113))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))	('formation', 'biological_process', 'GO:0009058', ('114', '123'))	('mice', 'Species', '10090', (143, 147))
25423	23622131	Nuclear factor-kappaB and signal transducer and activator of transcription 3 signaling are regulated by Kras, and can be targeted with specific inhibitors.	('transcription', 'biological_process', 'GO:0006351', ('61', '74'))	('Kras', 'Var', (104, 108))	('Nuclear factor-kappaB', 'MPA', (0, 21))	('regulated', 'Reg', (91, 100))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))	('signal transducer and activator of transcription 3', 'Gene', '20848', (26, 76))
25427	23622131	Experimental inhibition of Kras activity slows growth or even causes regression of pancreatic tumors in mice.	('pancreatic tumors', 'Disease', 'MESH:D010190', (83, 100))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('pancreatic tumors', 'Disease', (83, 100))	('slows growth', 'Phenotype', 'HP:0001510', (41, 53))	('growth', 'MPA', (47, 53))	('slows', 'NegReg', (41, 46))	('inhibition', 'Var', (13, 23))	('mice', 'Species', '10090', (104, 108))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (83, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (83, 99))	('Kras', 'Protein', (27, 31))	('regression', 'NegReg', (69, 79))
25429	23622131	But will inhibiting oncogenic KRAS be sufficient to cure patients with pancreatic cancer?	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('patients', 'Species', '9606', (57, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('inhibiting', 'Var', (9, 19))	('pancreatic cancer', 'Disease', (71, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (71, 88))
25430	23622131	In mice, inactivation of Kras leads to tumor regression, and the animals remain healthy, with no evidence of relapse, for a relatively long time.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mice', 'Species', '10090', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Kras', 'Gene', (25, 29))	('inactivation', 'Var', (9, 21))	('tumor', 'Disease', (39, 44))
25432	23622131	However, individual tumor cells survive inactivation of Kras, presumably by maintaining a dormant state.	('dormant', 'MPA', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('Kras', 'Gene', (56, 60))	('inactivation', 'Var', (40, 52))	('tumor', 'Disease', (20, 25))
25435	23622131	Full tumor eradication will require identification of the mechanisms that allow a subset of tumor cells to survive Kras inactivation, and development of methods to target them.	('Kras', 'Gene', (115, 119))	('inactivation', 'Var', (120, 132))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', (92, 97))
25440	23622131	Whether the expression of an oncogenic form of Kras is sufficient to obtain these high levels of activation in tumor cells, or whether mutant RAS requires further activation by upstream signals to achieve its fully active GTP-bound state to drive cancer growth remains an unresolved issue.	('GTP', 'Chemical', 'MESH:D006160', (222, 225))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('RAS', 'Gene', (142, 145))	('mutant', 'Var', (135, 141))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('tumor', 'Disease', (111, 116))
25444	23622131	Recent studies in mouse models indicate that KRAS activity leads to inflammation and changes in the stroma.	('inflammation', 'biological_process', 'GO:0006954', ('68', '80'))	('changes', 'Reg', (85, 92))	('mouse', 'Species', '10090', (18, 23))	('leads to', 'Reg', (59, 67))	('inflammation', 'Disease', 'MESH:D007249', (68, 80))	('inflammation', 'Disease', (68, 80))	('activity', 'Var', (50, 58))	('KRAS activity', 'Var', (45, 58))
25446	23622131	Experiments with Kras inactivation indicate that Kras activity is not only required for pancreatic tumor formation and development but, at least in mice, the requirement for Kras is continuous.	('inactivation', 'Var', (22, 34))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (88, 104))	('pancreatic tumor', 'Disease', (88, 104))	('formation', 'biological_process', 'GO:0009058', ('105', '114'))	('mice', 'Species', '10090', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('pancreatic tumor', 'Disease', 'MESH:D010190', (88, 104))
25466	23222481	I discuss below how familial cancer registries provide an important resource to aid the identification of cancer susceptibility genes, to characterize how mutations in these genes affect cancer risk and to provide a population for early detection studies using examples from familial pancreatic cancer.	('affect', 'Reg', (180, 186))	('cancer', 'Disease', (295, 301))	('cancer', 'Disease', (106, 112))	('familial cancer', 'Disease', 'MESH:D009369', (20, 35))	('familial pancreatic cancer', 'Disease', (275, 301))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (284, 301))	('familial cancer', 'Disease', (20, 35))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (275, 301))	('mutations', 'Var', (155, 164))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
25478	23222481	Furthermore, not all individuals who carry a mutation in a pancreatic cancer predisposition gene will have a family history of pancreatic cancer.	('pancreatic cancer', 'Disease', (127, 144))	('pancreatic cancer', 'Disease', 'MESH:D010190', (59, 76))	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('pancreatic cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutation', 'Var', (45, 53))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (59, 76))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))
25479	23222481	The use of a common definition across research studies facilitates the comparison of findings across studies, including gene discovery studies that aim to estimate the prevalence of pancreatic cancer gene mutations in familial pancreatic cancer kindreds and risk-quantification studies.	('familial pancreatic cancer', 'Disease', (218, 244))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (218, 244))	('pancreatic cancer', 'Disease', 'MESH:D010190', (182, 199))	('pancreatic cancer', 'Disease', (182, 199))	('pancreatic cancer', 'Disease', 'MESH:D010190', (227, 244))	('mutations', 'Var', (205, 214))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (182, 199))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (227, 244))
25487	23222481	A family history of pancreatic cancer is an imperfect surrogate of genetic risk because, although individuals are either born with an inherited mutation that predisposes to pancreatic cancer or not, the effect of family history changes over an individual's lifetime depending on whether additional family members develop the disease.	('pancreatic cancer', 'Disease', 'MESH:D010190', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (173, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutation', 'Var', (144, 152))	('pancreatic cancer', 'Disease', (173, 190))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('pancreatic cancer', 'Disease', 'MESH:D010190', (173, 190))	('changes', 'Reg', (228, 235))	('pancreatic cancer', 'Disease', (20, 37))
25510	23222481	Germline BRCA2 mutations were first described in patients with pancreatic cancer by Goggins et al., who reported that 7% (four of 41) of patients with pancreatic cancer carried BRCA2 mutations.	('pancreatic cancer', 'Disease', (63, 80))	('BRCA2', 'Gene', (9, 14))	('pancreatic cancer', 'Disease', 'MESH:D010190', (151, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (63, 80))	('mutations', 'Var', (183, 192))	('BRCA2', 'Gene', (177, 182))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (63, 80))	('BRCA2', 'Gene', '675', (9, 14))	('patients', 'Species', '9606', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('patients', 'Species', '9606', (49, 57))	('BRCA2', 'Gene', '675', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('pancreatic cancer', 'Disease', (151, 168))
25511	23222481	The mutation prevalence has been shown to be higher in familial pancreatic cancer kindreds : 16% in probands from families with three or more pancreatic cancers and 10-12% in families with two or more first-degree relatives with pancreatic cancer.	('pancreatic cancers', 'Disease', (142, 160))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (142, 159))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (229, 246))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('mutation', 'Var', (4, 12))	('pancreatic cancer', 'Disease', 'MESH:D010190', (142, 159))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (142, 160))	('pancreatic cancer', 'Disease', (229, 246))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('pancreatic cancer', 'Disease', 'MESH:D010190', (229, 246))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (55, 81))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('pancreatic cancer', 'Disease', 'MESH:D010190', (64, 81))	('higher', 'Reg', (45, 51))	('familial pancreatic cancer', 'Disease', (55, 81))	('pancreatic cancers', 'Disease', 'MESH:D010190', (142, 160))
25512	23222481	When evaluating pancreatic cancer kindreds, BRCA2 mutations cannot be ruled out by the lack of a family history of breast and/or ovarian cancer, as a substantial proportion of mutation-positive pancreatic cancer families report neither cancer.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (194, 211))	('breast and/or ovarian cancer', 'Disease', 'MESH:D010051', (115, 143))	('cancer', 'Disease', (137, 143))	('pancreatic cancer', 'Disease', (16, 33))	('BRCA2', 'Gene', '675', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast and/or ovarian cancer', 'Disease', (115, 143))	('pancreatic cancer', 'Disease', 'MESH:D010190', (194, 211))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', (236, 242))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (16, 33))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('pancreatic cancer', 'Disease', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('ovarian cancer', 'Phenotype', 'HP:0100615', (129, 143))	('mutations', 'Var', (50, 59))	('BRCA2', 'Gene', (44, 49))	('cancer', 'Disease', (27, 33))	('pancreatic cancer', 'Disease', 'MESH:D010190', (16, 33))
25513	23222481	Although the increased prevalence of BRCA2 mutations in patients with pancreatic cancer is clear, the evidence supporting a role for BRCA1 in pancreatic cancer has been mixed.	('patients', 'Species', '9606', (56, 64))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (142, 159))	('BRCA2', 'Gene', (37, 42))	('pancreatic cancer', 'Disease', (70, 87))	('pancreatic cancer', 'Disease', (142, 159))	('pancreatic cancer', 'Disease', 'MESH:D010190', (142, 159))	('pancreatic cancer', 'Disease', 'MESH:D010190', (70, 87))	('BRCA1', 'Gene', '672', (133, 138))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('BRCA2', 'Gene', '675', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (70, 87))	('BRCA1', 'Gene', (133, 138))
25514	23222481	Early studies suggested a 2.26-fold (95% CI = 1.26-4.06) increased risk of pancreatic cancer in BRCA1 mutation carriers, but other studies have reported no increase in the prevalence of BRCA1 mutations in patients with pancreatic cancer.	('patients', 'Species', '9606', (205, 213))	('pancreatic cancer', 'Disease', 'MESH:D010190', (219, 236))	('pancreatic cancer', 'Disease', (219, 236))	('mutation', 'Var', (102, 110))	('BRCA1', 'Gene', '672', (96, 101))	('BRCA1', 'Gene', '672', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (75, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (219, 236))	('BRCA1', 'Gene', (96, 101))	('BRCA1', 'Gene', (186, 191))	('pancreatic cancer', 'Disease', (75, 92))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (57, 92))	('pancreatic cancer', 'Disease', 'MESH:D010190', (75, 92))
25516	23222481	Germline mutations in the CDKN2A locus that encodes the tumour suppressors ARF and INK4A are associated with familial melanoma.	('ARF', 'Disease', 'MESH:D058186', (75, 78))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('INK4A', 'Gene', (83, 88))	('CDKN2A', 'Gene', (26, 32))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('CDKN2A', 'Gene', '1029', (26, 32))	('ARF', 'Disease', (75, 78))	('associated', 'Reg', (93, 103))	('Germline', 'Var', (0, 8))	('familial melanoma', 'Disease', (109, 126))	('familial melanoma', 'Disease', 'OMIM:155600', (109, 126))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('INK4A', 'Gene', '1029', (83, 88))	('tumour', 'Disease', (56, 62))
25517	23222481	People with these mutations also have a 38-fold increased risk of developing pancreatic cancer compared with the general population, so that their lifetime risk (by the age of 75) of developing pancreatic cancer is 17%.	('mutations', 'Var', (18, 27))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (194, 211))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('People', 'Species', '9606', (0, 6))	('pancreatic cancer', 'Disease', 'MESH:D010190', (194, 211))	('pancreatic cancer', 'Disease', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('pancreatic cancer', 'Disease', (77, 94))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
25518	23222481	Lynch syndrome mutation carriers have been estimated to have a 3.68% (95% CI = 1.45-5.88) lifetime (by the age of 70) risk of pancreatic cancer, and individuals with Peutz-Jeghers syndrome, which is caused by mutations in the STK11 (also known as LKB1) gene, have a 132-fold (95% CI = 44-261) increased risk of pancreatic cancer compared with the general population, and the lifetime risk of pancreatic cancer in these individuals has been estimated to be 11-32%.	('pancreatic cancer', 'Disease', 'MESH:D010190', (126, 143))	('STK11', 'Gene', (226, 231))	('LKB1', 'Gene', '6794', (247, 251))	('STK11', 'molecular_function', 'GO:0033868', ('226', '231'))	('pancreatic cancer', 'Disease', (311, 328))	('pancreatic cancer', 'Disease', (126, 143))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Peutz-Jeghers syndrome', 'Disease', (166, 188))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (311, 328))	('pancreatic cancer', 'Disease', 'MESH:D010190', (392, 409))	('STK11', 'Gene', '6794', (226, 231))	('caused by', 'Reg', (199, 208))	('LKB1', 'Gene', (247, 251))	('pancreatic cancer', 'Disease', (392, 409))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (126, 143))	('cancer', 'Phenotype', 'HP:0002664', (403, 409))	('Lynch syndrome', 'Disease', (0, 14))	('Peutz-Jeghers syndrome', 'Disease', 'MESH:D010580', (166, 188))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('pancreatic cancer', 'Disease', 'MESH:D010190', (311, 328))	('mutation', 'Var', (15, 23))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (293, 328))	('mutations', 'Var', (209, 218))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (392, 409))
25520	23222481	Germline mutations in PRSS1 and SPINK1 explain a proportion of hereditary pancreatitis families.	('Germline mutations', 'Var', (0, 18))	('explain', 'Reg', (39, 46))	('PRSS1', 'Gene', (22, 27))	('hereditary pancreatitis', 'Disease', 'MESH:C537262', (63, 86))	('pancreatitis', 'Phenotype', 'HP:0001733', (74, 86))	('hereditary pancreatitis', 'Disease', (63, 86))	('PRSS1', 'Gene', '5644', (22, 27))	('SPINK1', 'Gene', (32, 38))	('SPINK1', 'Gene', '6690', (32, 38))
25524	23222481	Active cigarette smoking has been shown to be associated with a 1.74-fold increased risk of pancreatic cancer (95% CI = 1.61-1.87).	('Active cigarette smoking', 'Var', (0, 24))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('pancreatic cancer', 'Disease', (92, 109))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 109))
25532	23222481	Many cancer susceptibility genes were found using linkage approaches; however, the lack of moderate to strong linkage genes for pancreatic cancer could be partly due to the fact that a mutation in one of several genes can lead to the same hereditary cancer phenotype.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('pancreatic cancer', 'Disease', 'MESH:D010190', (128, 145))	('lead to', 'Reg', (222, 229))	('pancreatic cancer', 'Disease', (128, 145))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('mutation', 'Var', (185, 193))	('hereditary cancer', 'Disease', 'MESH:D009369', (239, 256))	('hereditary cancer', 'Disease', (239, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('cancer', 'Disease', (139, 145))
25536	23222481	The germline and tumour DNA from a NFPTR patient with familial pancreatic cancer was sequenced, and more than 15,460 genetic variants that were not present in the human reference sequence were identified.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('familial pancreatic cancer', 'Disease', (54, 80))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (54, 80))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('variants', 'Var', (125, 133))	('patient', 'Species', '9606', (41, 48))	('human', 'Species', '9606', (163, 168))	('tumour', 'Disease', (17, 23))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
25537	23222481	The list of potential disease-causing mutations was narrowed using several criteria: the variant must cause premature inactivation or truncation of the protein; the gene must function as a tumour suppressor gene with a heterozygous germline variant coupled with a somatic mutation in the tumour; and the variant must not be present in control databases.	('cause', 'Reg', (102, 107))	('truncation', 'MPA', (134, 144))	('tumour', 'Disease', 'MESH:D009369', (288, 294))	('tumour', 'Phenotype', 'HP:0002664', (288, 294))	('tumour', 'Disease', (288, 294))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('premature inactivation', 'MPA', (108, 130))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('variant', 'Var', (89, 96))	('protein', 'Protein', (152, 159))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Disease', (189, 195))
25539	23222481	PALB2 is the binding partner of BRCA2, an established pancreatic cancer susceptibility gene, and, like BRCA2, mutations in PALB2 had previously been associated with familial breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('PALB2', 'Gene', '79728', (0, 5))	('pancreatic cancer', 'Disease', (54, 71))	('binding', 'molecular_function', 'GO:0005488', ('13', '20'))	('BRCA2', 'Gene', (103, 108))	('familial breast cancer', 'Disease', 'MESH:D001943', (165, 187))	('familial breast cancer', 'Disease', (165, 187))	('BRCA2', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (54, 71))	('mutations', 'Var', (110, 119))	('BRCA2', 'Gene', '675', (103, 108))	('associated with', 'Reg', (149, 164))	('PALB2', 'Gene', (123, 128))	('BRCA2', 'Gene', '675', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('PALB2', 'Gene', (0, 5))	('PALB2', 'Gene', '79728', (123, 128))	('pancreatic cancer', 'Disease', 'MESH:D010190', (54, 71))
25541	23222481	Although subsequent studies have validated the role of PALB2 mutation in familial pancreatic cancer, PALB2 mutations explain only a small proportion (1-3%) of familial pancreatic cancer kindreds.	('PALB2', 'Gene', (101, 106))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (159, 185))	('mutations', 'Var', (107, 116))	('PALB2', 'Gene', '79728', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (82, 99))	('mutation', 'Var', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (168, 185))	('familial pancreatic cancer', 'Disease', (159, 185))	('familial pancreatic cancer', 'Disease', (73, 99))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (73, 99))	('PALB2', 'Gene', (55, 60))	('PALB2', 'Gene', '79728', (55, 60))
25543	23222481	Candidate disease-associated changes were identified by excluding variants that already existed in single nucleotide polymorphism databases and by concentrating on variants that were rare in the population, were inactivating and heterozygous in the patient, and were shared among all affected pedigree members.	('patient', 'Species', '9606', (249, 256))	('variants', 'Var', (164, 172))	('variants', 'Var', (66, 74))
25544	23222481	After filtering, 156 variants remained, including mutations in the ataxia telangiectasia mutated (ATM) gene.	('ataxia telangiectasia mutated', 'Gene', (67, 96))	('ataxia telangiectasia mutated', 'Gene', '472', (67, 96))	('mutations', 'Var', (50, 59))	('ATM', 'Gene', (98, 101))	('telangiectasia', 'Phenotype', 'HP:0001009', (74, 88))	('ataxia', 'Phenotype', 'HP:0001251', (67, 73))	('ATM', 'Gene', '472', (98, 101))
25545	23222481	In two of the families, variants in ATM co-segregated with pancreatic cancer, and these variants had previously been reported in patients with ataxia telangiectasia.	('pancreatic cancer', 'Disease', 'MESH:D010190', (59, 76))	('ATM', 'Gene', (36, 39))	('pancreatic cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('variants', 'Var', (24, 32))	('ataxia telangiectasia', 'Disease', (143, 164))	('patients', 'Species', '9606', (129, 137))	('ataxia', 'Phenotype', 'HP:0001251', (143, 149))	('ATM', 'Gene', '472', (36, 39))	('telangiectasia', 'Phenotype', 'HP:0001009', (150, 164))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (59, 76))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (143, 164))
25547	23222481	Again, these variants had also previously been associated with ataxia telangiectasia.	('variants', 'Var', (13, 21))	('telangiectasia', 'Phenotype', 'HP:0001009', (70, 84))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (63, 84))	('ataxia', 'Phenotype', 'HP:0001251', (63, 69))	('ataxia telangiectasia', 'Disease', (63, 84))	('associated', 'Reg', (47, 57))
25550	23222481	Furthermore, many causative mutations, including those that lead to pancreatic cancer, are likely to be of only moderate penetrance.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lead to', 'Reg', (60, 67))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('pancreatic cancer', 'Disease', (68, 85))	('mutations', 'Var', (28, 37))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))
25552	23222481	Although these filters can be very powerful, the presence of phenocopies : sporadic cancers that occur in kindreds with familial cancer : can lead to the exclusion of disease-causing variants, as not all cancer cases in a kindred will necessarily carry the disease-causing mutation.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (84, 90))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('familial cancer', 'Disease', (120, 135))	('cancers', 'Disease', (84, 91))	('variants', 'Var', (183, 191))	('cancer', 'Disease', (129, 135))	('familial cancer', 'Disease', 'MESH:D009369', (120, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
25561	23222481	First, a model of inheritance for the genes underlying the aggregation of cancer in families is specified; and second, estimates of the prevalence of disease in mutation carriers and non-carries in conjunction with mutation frequency is estimated.	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('mutation', 'Var', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
25562	23222481	Using Bayes' rule, penetrance and prevalence estimates are converted to the probability of a phenotype given a particular genotype, and cancer risk is obtained through a weighted average of the penetrance in carriers and non-carriers, with weights derived from the probability that a given individual is a carrier or a non-carrier of the disease-causing mutation based on their family history data.	('carrier', 'molecular_function', 'GO:0005215', ('306', '313'))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('mutation', 'Var', (354, 362))	('carrier', 'molecular_function', 'GO:0005215', ('323', '330'))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
25583	23222481	This phase examined individuals from familial pancreatic cancer kindreds or individuals with a documented mutation in a pancreatic cancer predisposition gene.	('familial pancreatic cancer', 'Disease', (37, 63))	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (46, 63))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (37, 63))	('mutation', 'Var', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('pancreatic cancer', 'Disease', 'MESH:D010190', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('pancreatic cancer', 'Disease', (120, 137))
25590	23222481	Understanding the inherited genetic changes that can lead to the development of pancreatic cancer can have important therapeutic implications not only for familial cases but also for sporadic cases, as the same genes and pathways are often involved in both cases.	('changes', 'Var', (36, 43))	('pancreatic cancer', 'Disease', (80, 97))	('pancreatic cancer', 'Disease', 'MESH:D010190', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))
25603	23222481	For example, the probability of developing breast cancer given that one carries a mutation in BRCA1.	('breast cancer', 'Disease', (43, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('mutation', 'Var', (82, 90))	('BRCA1', 'Gene', '672', (94, 99))	('BRCA1', 'Gene', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))
25610	23222481	Mutations located in different alleles in the same gene that can cause a given genetic disease of phenotype.	('cause', 'Reg', (65, 70))	('genetic disease', 'Disease', (79, 94))	('Mutations', 'Var', (0, 9))	('genetic disease', 'Disease', 'MESH:D030342', (79, 94))
25612	23222481	An autosomal recessive condition caused mutations in the ATM gene.	('autosomal recessive condition', 'Disease', 'MESH:D019636', (3, 32))	('ATM', 'Gene', (57, 60))	('autosomal recessive condition', 'Disease', (3, 32))	('mutations', 'Var', (40, 49))	('caused', 'Reg', (33, 39))	('ATM', 'Gene', '472', (57, 60))
25650	21724610	This circumvents issues with a lack of statistical power in other conventional disparate-study analyses with lower sample numbers, to identify a set of genes that define a molecular signature capable of distinguishing benign tissue resected adjacent to cancer from malignant tissue.	('cancer', 'Disease', (253, 259))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('genes', 'Var', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
25693	21775419	While diverse in their tissues of origin, all cancers share the fundamental feature of propagated genetic mutations to daughter cells.	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Disease', (46, 53))	('genetic mutations', 'Var', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
25698	21775419	This review condenses the latest findings on the signaling pathways activated due to molecular crosstalk from Hh signaling in cancer and focuses on the hallmarks of malignancy.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('malignancy', 'Disease', 'MESH:D009369', (165, 175))	('molecular', 'Var', (85, 94))	('malignancy', 'Disease', (165, 175))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('signaling pathways', 'Pathway', (49, 67))
25716	21775419	Hh signaling can be constitutive due to (a) loss-of-function mutations in PTCH or (b) gain-of-function mutations in SMOH or (c) due to upregulated expression of the ligands or (d) due to dysregulated GLI expression.	('mutations', 'Var', (103, 112))	('GLI', 'Gene', (200, 203))	('PTCH', 'Gene', '5727', (74, 78))	('PTCH', 'Gene', (74, 78))	('expression', 'MPA', (147, 157))	('SMOH', 'Gene', (116, 120))	('mutations', 'Var', (61, 70))	('SMOH', 'Gene', '6608', (116, 120))	('GLI', 'Gene', '2735', (200, 203))	('gain-of-function', 'PosReg', (86, 102))	('signaling', 'biological_process', 'GO:0023052', ('3', '12'))	('Hh signaling', 'MPA', (0, 12))	('loss-of-function', 'NegReg', (44, 60))	('upregulated', 'PosReg', (135, 146))
25721	21775419	A few more hallmarks have recently emerged; these include genetic instability, metabolic flexibility, immune evasion, inflammation, and the tumor microenvironment.	('inflammation', 'Disease', 'MESH:D007249', (118, 130))	('genetic', 'Var', (58, 65))	('inflammation', 'Disease', (118, 130))	('immune evasion', 'biological_process', 'GO:0042783', ('102', '116'))	('metabolic flexibility', 'CPA', (79, 100))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('immune evasion', 'CPA', (102, 116))	('inflammation', 'biological_process', 'GO:0006954', ('118', '130'))	('immune evasion', 'biological_process', 'GO:0051842', ('102', '116'))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
25723	21775419	Since the Hh pathway is a key contributor to secreted molecules found in the extracellular matrix during fetal development, deregulated and/or constitutive activation of this pathway in cancer results in a rich microenvironment capable of potentiating malignant phenotypes in several types of transformed cells.	('activation', 'PosReg', (156, 166))	('malignant phenotypes', 'CPA', (252, 272))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('potentiating', 'PosReg', (239, 251))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('77', '97'))	('deregulated', 'Var', (124, 135))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
25728	21775419	While there are no reports thus far on the impact of Hh signaling on the length of telomeres or telomerase activity, a role for Hh signaling in promoting proliferation came about, through findings showing that inhibition of Hh signaling caused a decrease in the proliferative potential of cancer cells.	('telomerase activity', 'molecular_function', 'GO:0003720', ('96', '115'))	('decrease', 'NegReg', (246, 254))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('signaling', 'biological_process', 'GO:0023052', ('227', '236'))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))	('inhibition', 'Var', (210, 220))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('cancer', 'Disease', (289, 295))
25735	21775419	In fact, ablating Hh signaling causes a decrease in osteopontin expression simultaneous with a decrease in the proliferative capacity of the tumor cells, a property that was restored when osteopontin was re-expressed in the cells.	('decrease', 'NegReg', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('decrease', 'NegReg', (40, 48))	('expression', 'MPA', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('osteopontin', 'Gene', (52, 63))	('tumor', 'Disease', (141, 146))	('osteopontin', 'Gene', '6696', (188, 199))	('ablating', 'Var', (9, 17))	('osteopontin', 'Gene', (188, 199))	('signaling', 'biological_process', 'GO:0023052', ('21', '30'))	('osteopontin', 'Gene', '6696', (52, 63))
25736	21775419	Several leukemic cancers show deregulated Hh signaling that has been implicated to play a direct role in pro-survival phenotypes.	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('deregulated', 'Var', (30, 41))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('leukemic cancers', 'Disease', (8, 24))	('leukemic cancers', 'Disease', 'MESH:D007938', (8, 24))	('pro-survival', 'biological_process', 'GO:0043066', ('105', '117'))	('Hh signaling', 'MPA', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
25743	21775419	Gynecological cancers often present deregulated Hh signaling.	('cancers', 'Disease', (14, 21))	('deregulated', 'Var', (36, 47))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('Hh signaling', 'MPA', (48, 60))
25746	21775419	Overexpression of Hh signaling molecules is associated with increased proliferation of endometrial carcinoma cells and ovarian cancer systems characterized by downregulation of p21 and p27, potent inhibitors of cell cycle progression.	('cell cycle', 'biological_process', 'GO:0007049', ('211', '221'))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('endometrial carcinoma cells', 'Disease', (87, 114))	('ovarian cancer', 'Disease', 'MESH:D010051', (119, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (119, 133))	('p27', 'Gene', '3429', (185, 188))	('p21', 'Gene', (177, 180))	('proliferation', 'CPA', (70, 83))	('p27', 'Gene', (185, 188))	('p21', 'Gene', '644914', (177, 180))	('ovarian cancer', 'Disease', (119, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('Overexpression', 'Var', (0, 14))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (87, 108))	('downregulation', 'NegReg', (159, 173))	('endometrial carcinoma cells', 'Disease', 'MESH:D016889', (87, 114))	('signaling', 'biological_process', 'GO:0023052', ('21', '30'))	('increased', 'PosReg', (60, 69))
25759	21775419	Abolishing Hh signaling by silencing GLI1 reduced malignant properties characterized by slower tumor growth and decreased metastasis, concomitant with the reduced expression of osteopontin, suggesting that osteopontin mediates the pro-malignant effects of the Hh pathway on tumor cells.	('osteopontin', 'Gene', (206, 217))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (274, 279))	('decreased', 'NegReg', (112, 121))	('signaling', 'biological_process', 'GO:0023052', ('14', '23'))	('reduced', 'NegReg', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('slower', 'NegReg', (88, 94))	('osteopontin', 'Gene', '6696', (177, 188))	('malignant properties', 'CPA', (50, 70))	('osteopontin', 'Gene', (177, 188))	('GLI1', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('metastasis', 'CPA', (122, 132))	('tumor', 'Disease', (95, 100))	('silencing', 'Var', (27, 36))	('reduced', 'NegReg', (155, 162))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('expression', 'MPA', (163, 173))	('osteopontin', 'Gene', '6696', (206, 217))
25765	21775419	Failure to repair a double strand break can trigger cell death, whereas mis-repair of the break can lead to the generation of chromosomal translocations leading to tumor development and/or progression.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('Failure', 'Var', (0, 7))	('leading to', 'Reg', (153, 163))	('cell death', 'CPA', (52, 62))	('chromosomal translocations', 'Var', (126, 152))	('progression', 'CPA', (189, 200))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('lead to', 'Reg', (100, 107))	('cell death', 'biological_process', 'GO:0008219', ('52', '62'))	('mis-repair', 'Var', (72, 82))
25766	21775419	Double strand breaks in DNA can be induced following exposure to exogenous agents, such as ionizing radiation or radiomimetic chemicals, as well as naturally occurring intermediates of normal physiological processes.	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('Double strand breaks', 'Var', (0, 20))	('ionizing radiation', 'Disease', (91, 109))	('DNA', 'Gene', (24, 27))	('induced', 'Reg', (35, 42))	('ionizing radiation', 'Disease', 'MESH:D004194', (91, 109))
25767	21775419	When the ability to repair DNA damage due to double strand breaks was abolished in mice, Ptch1 function was specifically lost and was accompanied by an aberrant activation of Hh signaling.	('abolished', 'NegReg', (70, 79))	('mice', 'Species', '10090', (83, 87))	('Ptch1', 'Gene', '19206', (89, 94))	('Ptch1', 'Gene', (89, 94))	('lost', 'NegReg', (121, 125))	('double strand breaks', 'Var', (45, 65))	('Hh signaling', 'MPA', (175, 187))	('function', 'MPA', (95, 103))	('activation', 'PosReg', (161, 171))	('signaling', 'biological_process', 'GO:0023052', ('178', '187'))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))
25770	21775419	Thus, aberrant Hh signaling can promote tumorigenesis by disabling key signaling pathways that help maintain genomic stability and inhibit tumorigenesis.	('key signaling pathways', 'Pathway', (67, 89))	('signaling', 'biological_process', 'GO:0023052', ('71', '80'))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('inhibit', 'NegReg', (131, 138))	('aberrant', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('genomic stability', 'CPA', (109, 126))	('disabling', 'NegReg', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('promote', 'PosReg', (32, 39))
25810	21775419	SHH expression is elevated in several cirrhotic livers and may directly target fibroblastic hepatic stellate cells (fibroblasts) to survive and remodel liver stroma raising the possibility that the increased and sustained synthesis of SHH in the stromal compartment could actually be driving epithelial cell proliferation which may lead to genetic instability and accumulation of mutations.	('remodel liver stroma', 'Disease', (144, 164))	('epithelial', 'CPA', (292, 302))	('remodel liver stroma', 'Disease', 'MESH:D017093', (144, 164))	('SHH', 'Gene', (0, 3))	('cirrhotic livers', 'Phenotype', 'HP:0001394', (38, 54))	('SHH', 'Gene', '6469', (235, 238))	('epithelial cell proliferation', 'biological_process', 'GO:0050673', ('292', '321'))	('mutations', 'MPA', (380, 389))	('lead', 'Reg', (332, 336))	('SHH', 'Gene', '6469', (0, 3))	('synthesis', 'biological_process', 'GO:0009058', ('222', '231'))	('genetic instability', 'Var', (340, 359))	('SHH', 'Gene', (235, 238))	('elevated', 'PosReg', (18, 26))
25832	21775419	While CUR61414 (Curis/Genentech) failed a Phase I clinical trial, GDC-0449 (Genentech/Roche/Curis), a potent orally bioavailable SMO inhibitor is in Phase II trials, and has shown promising outcomes in basal cell carcinoma and medulloblastoma.	('medulloblastoma', 'Disease', 'MESH:D008527', (227, 242))	('GDC-0449', 'Gene', (66, 74))	('medulloblastoma', 'Disease', (227, 242))	('medulloblastoma', 'Phenotype', 'HP:0002885', (227, 242))	('SMO', 'Gene', '6608', (129, 132))	('CUR61414', 'Var', (6, 14))	('GDC-0449', 'Chemical', 'MESH:C538724', (66, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('SMO', 'Gene', (129, 132))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (202, 222))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (202, 222))	('basal cell carcinoma', 'Disease', (202, 222))
25834	21775419	BMS833923/XL139 (Bristol Myers Squibb/Exelixis) and LDE225 (Novartis), both orally bioavailable SMO antagonists, are also in clinical trials.	('SMO', 'Gene', '6608', (96, 99))	('LDE225', 'Gene', (52, 58))	('SMO', 'Gene', (96, 99))	('BMS833923/XL139', 'Var', (0, 15))
25842	21775419	The relevance of paracrine Hh signaling was highlighted further when inhibitors of this pathway had a more profound effect on the stromal cells rather than the tumor cells themselves in xenograft models.	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('signaling', 'biological_process', 'GO:0023052', ('30', '39'))	('effect', 'Reg', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('inhibitors', 'Var', (69, 79))	('tumor', 'Disease', (160, 165))
25846	21775419	This was exemplified by the dramatic initial response to GDC-0449, followed by recurrence of tumor in a patient with medulloblastoma (attributed to a mutation in the target molecule, SMO).	('GDC-0449', 'Chemical', 'MESH:C538724', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('GDC-0449', 'Var', (57, 65))	('SMO', 'Gene', '6608', (183, 186))	('SMO', 'Gene', (183, 186))	('mutation', 'Var', (150, 158))	('medulloblastoma', 'Disease', 'MESH:D008527', (117, 132))	('tumor', 'Disease', (93, 98))	('medulloblastoma', 'Phenotype', 'HP:0002885', (117, 132))	('patient', 'Species', '9606', (104, 111))	('medulloblastoma', 'Disease', (117, 132))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
25861	19549972	Overweight or obesity during early adulthood was associated with a greater risk of pancreatic cancer and a younger age of disease onset.	('pancreatic cancer', 'Disease', (83, 100))	('obesity', 'Phenotype', 'HP:0001513', (14, 21))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('Overweight', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('obesity', 'Disease', 'MESH:D009765', (14, 21))	('Overweight', 'Phenotype', 'HP:0025502', (0, 10))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))	('obesity', 'Disease', (14, 21))
25980	19549972	In clinical investigations, higher BMI has been related to reductions in both overall and recurrence-free survival, increased risk for secondary tumor, and tumor recurrence or progression in various types of cancer.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cancer', 'Disease', (208, 214))	('BMI', 'MPA', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('higher', 'Var', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', (156, 161))	('recurrence-free survival', 'CPA', (90, 114))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('reductions', 'NegReg', (59, 69))
26020	33782087	We orthotopically implanted 7940b cells into the pancreas and performed mass cytometry (CyTOF) analysis of the resulting tumors.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('7940b', 'Var', (28, 33))
26076	33782087	The iKras* mice represent an early lesion timepoint, whereas the iKras* p53* mice, which have a pancreas specific mutated p53, represent a late lesion timepoint, allowing us to evaluate Chil-TAMs and Cq-TAMs during progression of PDA.	('evaluate', 'Reg', (177, 185))	('mice', 'Species', '10090', (77, 81))	('p53', 'Gene', '22059', (122, 125))	('Kras', 'Gene', (5, 9))	('Kras', 'Gene', '16653', (5, 9))	('PDA', 'Phenotype', 'HP:0006725', (230, 233))	('Cq-TAMs', 'Chemical', '-', (200, 207))	('mutated', 'Var', (114, 121))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '22059', (72, 75))	('mice', 'Species', '10090', (11, 15))	('Chil-TAMs', 'Chemical', '-', (186, 195))	('Chil-TAMs', 'Phenotype', 'HP:0009710', (186, 195))	('Kras', 'Gene', (66, 70))	('PDA', 'Chemical', '-', (230, 233))	('Kras', 'Gene', '16653', (66, 70))	('Chil-', 'Phenotype', 'HP:0009710', (186, 191))	('p53', 'Gene', (122, 125))
26081	33782087	SAM 1 was defined by expression of C1qa, C1qb, and Trem2, whereas SAM 2 was defined by expression of Chil3, Plac8, and Ly6c2 (Fig 5C and D).	('Chil3', 'Gene', '12655', (101, 106))	('Trem2', 'Gene', (51, 56))	('Chil3', 'Gene', (101, 106))	('Ly6c2', 'Gene', '100041546', (119, 124))	('Plac8', 'Gene', (108, 113))	('Plac8', 'Gene', '231507', (108, 113))	('Ly6c2', 'Gene', (119, 124))	('C1qb', 'Var', (41, 45))	('C1qa', 'Var', (35, 39))
26104	33782087	We used a published dataset of single-cell RNA sequencing on PBMCs from healthy donors (n = 4) and PDA patients (n = 16) and queried it for the expression of our signature genes: C1QA, C1QB, and TREM2 (Fig S8A).	('PDA', 'Phenotype', 'HP:0006725', (99, 102))	('RNA', 'cellular_component', 'GO:0005562', ('43', '46'))	('TREM2', 'Gene', (195, 200))	('PDA', 'Chemical', '-', (99, 102))	('patients', 'Species', '9606', (103, 111))	('C1QA', 'Var', (179, 183))	('C1QB', 'Var', (185, 189))
26131	33782087	The authors reported a population of inflammatory macrophages defined by high expression of Ly6c, Plac8, and Chil3 and a resident macrophage subset defined by high expression of Cd81, C1qa, C1qb, and C1qc.	('C1qa', 'Var', (184, 188))	('C1qb', 'Var', (190, 194))	('C1qc', 'Gene', '12262', (200, 204))	('Cd81', 'Var', (178, 182))	('Chil3', 'Gene', (109, 114))	('Ly6c', 'Gene', '17067', (92, 96))	('Ly6c', 'Gene', (92, 96))	('Chil3', 'Gene', '12655', (109, 114))	('Plac8', 'Gene', (98, 103))	('Plac8', 'Gene', '231507', (98, 103))	('C1qc', 'Gene', (200, 204))
26278	33627631	There are three common processes of circRNA reverse splicing: exon skipping, intron pairing, and RNA-binding-protein-driven circularization.	('RNA-binding-protein', 'Gene', (97, 116))	('exon skipping', 'Var', (62, 75))	('RNA-binding-protein', 'Gene', '84549', (97, 116))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('intron pairing', 'Var', (77, 91))	('RNA', 'cellular_component', 'GO:0005562', ('97', '100'))	('splicing', 'biological_process', 'GO:0045292', ('52', '60'))	('RNA-binding', 'molecular_function', 'GO:0003723', ('97', '108'))
26280	33627631	For example, circ_0055625, which is highly expressed in colon cancer, acts as a "sponge" for miR-106b to further promote the development of the disease.	('miR-106b', 'Gene', '406900', (93, 101))	('colon cancer', 'Disease', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('promote', 'PosReg', (113, 120))	('circ_0055625', 'Var', (13, 25))	('miR-106b', 'Gene', (93, 101))	('colon cancer', 'Phenotype', 'HP:0003003', (56, 68))	('colon cancer', 'Disease', 'MESH:D015179', (56, 68))	('development', 'CPA', (125, 136))
26298	33627631	The expression level of Circ_100876 in ESCC was found to be significantly increased; furthermore, its expression level was strongly correlated with the depth of invasion, lymph node metastasis, and vascular invasion of esophageal cancer cells, and the survival time of patients with high expression of Circ_100876 was significantly shortened.	('expression level', 'MPA', (4, 20))	('shortened', 'NegReg', (332, 341))	('Circ_100876', 'Var', (302, 313))	('Circ_100876', 'Var', (24, 35))	('esophageal cancer', 'Disease', (219, 236))	('correlated', 'Reg', (132, 142))	('ESCC', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('esophageal cancer', 'Disease', 'MESH:D004938', (219, 236))	('lymph node metastasis', 'CPA', (171, 192))	('increased', 'PosReg', (74, 83))	('depth of invasion', 'CPA', (152, 169))	('vascular invasion', 'CPA', (198, 215))	('expression level', 'MPA', (102, 118))	('patients', 'Species', '9606', (269, 277))	('survival time', 'CPA', (252, 265))
26299	33627631	In addition, after the knockout of Circ_100876, the proliferation level of tumor cells decreased significantly (resulting in G2/M-phase cell cycle arrest and the occurrence of apoptosis in vitro), and the occurrence of cell metastasis, invasion, and epithelial mesenchymal transformation (EMT) was inhibited, which clearly indicated that Circ_100876 was closely related to the proliferation, metastasis, and invasion of esophageal cancer, such that it can be used as a marker to detect esophageal cancer.	('invasion', 'CPA', (236, 244))	('M-phase', 'biological_process', 'GO:0000279', ('128', '135'))	('cancer', 'Phenotype', 'HP:0002664', (431, 437))	('proliferation level', 'CPA', (52, 71))	('tumor', 'Disease', (75, 80))	('apoptosis', 'biological_process', 'GO:0097194', ('176', '185'))	('apoptosis', 'biological_process', 'GO:0006915', ('176', '185'))	('decreased', 'NegReg', (87, 96))	('inhibited', 'NegReg', (298, 307))	('epithelial mesenchymal transformation', 'CPA', (250, 287))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (486, 503))	('arrest', 'Disease', (147, 153))	('Circ_100876', 'Var', (35, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (420, 437))	('cancer', 'Phenotype', 'HP:0002664', (497, 503))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('apoptosis', 'CPA', (176, 185))	('esophageal cancer', 'Disease', (486, 503))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('136', '153'))	('knockout', 'Var', (23, 31))	('esophageal cancer', 'Disease', (420, 437))	('cell metastasis', 'CPA', (219, 234))	('EMT', 'biological_process', 'GO:0001837', ('289', '292'))	('arrest', 'Disease', 'MESH:D006323', (147, 153))
26306	33627631	In ESCC, miR-3680-3p is expressed at a low level and plays a role in inhibiting tumor growth, while circ-PRKCI can bind to miR-3680-3p and reverse its regulatory effect.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('miR-3680-3p', 'Var', (9, 20))	('regulatory effect', 'MPA', (151, 168))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PRKCI', 'Gene', '5584', (105, 110))	('bind', 'Interaction', (115, 119))	('PRKCI', 'Gene', (105, 110))	('tumor', 'Disease', (80, 85))	('miR-3680-3p', 'Var', (123, 134))	('reverse', 'NegReg', (139, 146))	('inhibiting', 'NegReg', (69, 79))
26307	33627631	In addition, some overexpressed circRNAs regulate biological processes in tumors through their own pathways; for example, circ_0003340 is overexpressed in ESCC and promotes tumor development through the miR-564/TPX2 pathway.	('circ_0003340', 'Var', (122, 134))	('TPX2', 'Gene', (211, 215))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('miR-564', 'Gene', '693149', (203, 210))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('regulate', 'Reg', (41, 49))	('promotes', 'PosReg', (164, 172))	('TPX2', 'Gene', '22974', (211, 215))	('tumor', 'Disease', (173, 178))	('miR-564', 'Gene', (203, 210))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('ESCC', 'Disease', (155, 159))	('tumors', 'Disease', (74, 80))
26309	33627631	The expression of hsa_circ_0012563 in ESCC was significantly upregulated, while hsa_circ_0012563 knockout inhibited the XRCC1-mediated EMT pathway, which, in turn, inhibited cell migration and invasion.	('upregulated', 'PosReg', (61, 72))	('EMT', 'biological_process', 'GO:0001837', ('135', '138'))	('XRCC1', 'Gene', (120, 125))	('inhibited', 'NegReg', (106, 115))	('expression', 'MPA', (4, 14))	('hsa_circ_0012563', 'Var', (18, 34))	('hsa_circ_0012563', 'Var', (80, 96))	('inhibited', 'NegReg', (164, 173))	('XRCC1', 'Gene', '7515', (120, 125))	('cell migration', 'biological_process', 'GO:0016477', ('174', '188'))
26310	33627631	Hsa_circ_0004771 is significantly upregulated in ESCC, and, by acting as a molecular sponge of miR-339-5p, it positively regulates CDC25A to promote the proliferation of ESCC.	('ESCC', 'CPA', (170, 174))	('upregulated', 'PosReg', (34, 45))	('Hsa_circ_0004771', 'Var', (0, 16))	('proliferation', 'CPA', (153, 166))	('promote', 'PosReg', (141, 148))	('regulates', 'Reg', (121, 130))	('ESCC', 'Disease', (49, 53))	('CDC25A', 'Gene', (131, 137))	('CDC25A', 'Gene', '993', (131, 137))
26311	33627631	Hsa_circ_0006948, which is overexpressed in ESCC tissue, can induce EMT and promote tumor progression by acting as a sponge for miR490-3p.	('promote', 'PosReg', (76, 83))	('induce', 'PosReg', (61, 67))	('Hsa_circ_0006948', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('EMT', 'biological_process', 'GO:0001837', ('68', '71'))	('tumor', 'Disease', (84, 89))	('EMT', 'CPA', (68, 71))
26329	33627631	On the other hand, circRNA_001569 interacts with miR-145, inhibits the biological activity of this miRNA, and further inhibits the expression of NR4A2, the downstream target of miR-145; thus, it significantly improves the vitality of GC cells, promotes proliferation and reduces apoptosis.	('inhibits', 'NegReg', (118, 126))	('interacts', 'Interaction', (34, 43))	('promotes', 'PosReg', (244, 252))	('proliferation', 'CPA', (253, 266))	('NR4A2', 'Gene', '4929', (145, 150))	('reduces', 'NegReg', (271, 278))	('apoptosis', 'biological_process', 'GO:0097194', ('279', '288'))	('apoptosis', 'biological_process', 'GO:0006915', ('279', '288'))	('vitality', 'CPA', (222, 230))	('miR-145', 'Gene', '406937', (177, 184))	('NR4A2', 'Gene', (145, 150))	('improves', 'PosReg', (209, 217))	('miR-145', 'Gene', '406937', (49, 56))	('miR-145', 'Gene', (177, 184))	('inhibits', 'NegReg', (58, 66))	('biological activity of this miRNA', 'MPA', (71, 104))	('expression', 'MPA', (131, 141))	('apoptosis', 'CPA', (279, 288))	('miR-145', 'Gene', (49, 56))	('circRNA_001569', 'Var', (19, 33))
26334	33627631	), circRNA_100269, circYAP1, CircLARP4, circ-ZFR, circFAT1 (e2), and circ_0027599 (ref. )	('CircLARP4', 'Gene', '113251', (29, 38))	('YAP1', 'Gene', (23, 27))	('CircLARP4', 'Gene', (29, 38))	('circ_0027599', 'Var', (69, 81))	('YAP1', 'Gene', '10413', (23, 27))
26341	33627631	Its abnormal expression affects the proliferation of tumor cells and the development of PDAC.	('abnormal', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('affects', 'Reg', (24, 31))	('tumor', 'Disease', (53, 58))	('development of PDAC', 'CPA', (73, 92))
26342	33627631	Studies have shown that the expression of circRNA_100782 in PDAC tissue is significantly upregulated and plays a positive role in regulating the proliferation of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('regulating', 'Reg', (130, 140))	('positive', 'PosReg', (113, 121))	('upregulated', 'PosReg', (89, 100))	('tumor', 'Disease', (162, 167))	('expression', 'MPA', (28, 38))	('circRNA_100782', 'Var', (42, 56))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
26343	33627631	found that circRNA_100782 inhibits the biological activity of miR-124 and further activates its downstream targets, interleukin-6 receptor (IL6R) and signal transducer and activator of transcription 3 (STAT3), by acting as a sponge for miR-124, thus enabling cell proliferation to be promoted.	('biological activity', 'MPA', (39, 58))	('inhibits', 'NegReg', (26, 34))	('STAT3', 'Gene', (202, 207))	('promoted', 'PosReg', (284, 292))	('transcription', 'biological_process', 'GO:0006351', ('185', '198'))	('cell proliferation', 'biological_process', 'GO:0008283', ('259', '277'))	('miR-124', 'Gene', (62, 69))	('IL6R', 'Gene', (140, 144))	('interleukin-6 receptor', 'Gene', (116, 138))	('activates', 'PosReg', (82, 91))	('IL6R', 'molecular_function', 'GO:0004915', ('140', '144'))	('signal transducer and activator of transcription 3', 'Gene', '6774', (150, 200))	('enabling', 'PosReg', (250, 258))	('interleukin-6 receptor', 'Gene', '3570', (116, 138))	('cell proliferation', 'CPA', (259, 277))	('IL6R', 'Gene', '3570', (140, 144))	('STAT3', 'Gene', '6774', (202, 207))	('circRNA_100782', 'Var', (11, 25))
26346	33627631	In addition, circRNA_0007534 and ciRS-7 are also highly expressed in PDAC tissues; circRNA_0007534 regulates miR-625 and miR-892b, increasing the carcinogenicity of PDAC, while ciRS-7 targets miR-7 and regulates the EGFR/STAT3 signal pathway, thus playing a carcinogenic role.	('STAT3', 'Gene', (221, 226))	('carcinogenic', 'Disease', (258, 270))	('EGFR', 'molecular_function', 'GO:0005006', ('216', '220'))	('carcinogenic', 'Disease', (146, 158))	('STAT3', 'Gene', '6774', (221, 226))	('EGFR', 'Gene', (216, 220))	('miR-7', 'Gene', '10859', (192, 197))	('regulates', 'Reg', (99, 108))	('ciRS-7', 'Gene', '103611090', (177, 183))	('ciRS-7', 'Gene', '103611090', (33, 39))	('regulates', 'Reg', (202, 211))	('carcinogenic', 'Disease', 'MESH:D063646', (258, 270))	('carcinogenic', 'Disease', 'MESH:D063646', (146, 158))	('increasing', 'PosReg', (131, 141))	('miR-625', 'Gene', (109, 116))	('ciRS-7', 'Gene', (177, 183))	('ciRS-7', 'Gene', (33, 39))	('miR-892b', 'Gene', '100126307', (121, 129))	('circRNA_0007534', 'Var', (83, 98))	('EGFR', 'Gene', '1956', (216, 220))	('miR-625', 'Gene', '693210', (109, 116))	('miR-892b', 'Gene', (121, 129))	('miR-7', 'Gene', (192, 197))
26352	33627631	The expression level of hsa_circ_100338 in HC is closely related to tumor metastasis and the rate of patient survival.	('expression level', 'MPA', (4, 20))	('hsa_circ_100338', 'Var', (24, 39))	('tumor metastasis', 'Disease', 'MESH:D009362', (68, 84))	('tumor metastasis', 'Disease', (68, 84))	('related', 'Reg', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('patient', 'Species', '9606', (101, 108))
26353	33627631	In addition, the study found that an increase in hsa_circ_100338 can also activate the mTOR signaling pathway in HC through the circRNA_100338/miR141-3p/RHEB axis and is related to poor prognosis in patients with hepatitis B-related HC.	('mTOR', 'Gene', '2475', (87, 91))	('hsa_circ_100338', 'Var', (49, 64))	('hepatitis', 'Phenotype', 'HP:0012115', (213, 222))	('hepatitis B-related HC', 'Disease', 'MESH:D006509', (213, 235))	('hepatitis B-related HC', 'Disease', (213, 235))	('signaling pathway', 'biological_process', 'GO:0007165', ('92', '109'))	('increase', 'PosReg', (37, 45))	('patients', 'Species', '9606', (199, 207))	('RHEB', 'Gene', (153, 157))	('activate', 'PosReg', (74, 82))	('RHEB', 'Gene', '6009', (153, 157))	('mTOR', 'Gene', (87, 91))
26354	33627631	found that circ_104075 is abundant in liver cancer tumor tissues, cells, and patient serum and can act as a sponge for miR-582-3p to upregulate the expression of the downstream target YAP.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('liver cancer tumor', 'Disease', 'MESH:D006528', (38, 56))	('liver cancer', 'Phenotype', 'HP:0002896', (38, 50))	('YAP', 'Gene', '10413', (184, 187))	('miR-582-3p', 'Var', (119, 129))	('upregulate', 'PosReg', (133, 143))	('YAP', 'Gene', (184, 187))	('circ_104075', 'Var', (11, 22))	('expression', 'MPA', (148, 158))	('patient', 'Species', '9606', (77, 84))	('liver cancer tumor', 'Disease', (38, 56))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
26357	33627631	Circ_0067934 is also upregulated in HC tissues and cell lines, while knockout of the circ_0067934 gene can inhibit proliferation, migration, invasion, and apoptosis in Hep3B and Huh7 cells.	('inhibit', 'NegReg', (107, 114))	('invasion', 'CPA', (141, 149))	('Hep3B', 'CellLine', 'CVCL:0326', (168, 173))	('apoptosis', 'biological_process', 'GO:0006915', ('155', '164'))	('Huh7', 'CellLine', 'CVCL:0336', (178, 182))	('proliferation', 'CPA', (115, 128))	('migration', 'CPA', (130, 139))	('knockout', 'Var', (69, 77))	('apoptosis', 'CPA', (155, 164))	('circ_0067934', 'Gene', (85, 97))	('apoptosis', 'biological_process', 'GO:0097194', ('155', '164'))
26360	33627631	In HCC patients with high body fat percentages, the expression of circ-DB is upregulated, and circ-DB downregulates the expression of miR-34a by acting as a miRNA sponge, thus activating USP7, which can promote tumor growth and metastasis by reducing the ubiquitination of Cyclin A2 and many other proteins.	('upregulated', 'PosReg', (77, 88))	('USP7', 'Gene', '7874', (187, 191))	('Cyclin', 'molecular_function', 'GO:0016538', ('273', '279'))	('tumor', 'Disease', (211, 216))	('patients', 'Species', '9606', (7, 15))	('expression', 'MPA', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('metastasis', 'CPA', (228, 238))	('circ-DB', 'Gene', (66, 73))	('Cyclin A2', 'Gene', '890', (273, 282))	('reducing', 'NegReg', (242, 250))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('miR-34a', 'Gene', (134, 141))	('Cyclin A2', 'Gene', (273, 282))	('USP7', 'Gene', (187, 191))	('USP', 'molecular_function', 'GO:0051748', ('187', '190'))	('downregulates', 'NegReg', (102, 115))	('miR-34a', 'Gene', '407040', (134, 141))	('expression', 'MPA', (52, 62))	('activating', 'PosReg', (176, 186))	('promote', 'PosReg', (203, 210))	('circ-DB', 'Var', (94, 101))
26365	33627631	It can mediate sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1, and N-methylated CircRNA-SORE can also maintain sorafenib resistance through beta-catenin signaling.	('stabilizing', 'NegReg', (67, 78))	('YBX1', 'Gene', (79, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('mediate', 'Reg', (7, 14))	('beta-catenin', 'Gene', (162, 174))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('sorafenib resistance', 'MPA', (133, 153))	('hepatocellular carcinoma', 'Disease', (39, 63))	('sorafenib', 'Chemical', 'MESH:D000077157', (15, 24))	('beta-catenin', 'Gene', '1499', (162, 174))	('YBX1', 'Gene', '4904', (79, 83))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (39, 63))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (39, 63))	('sorafenib', 'Chemical', 'MESH:D000077157', (133, 142))	('maintain', 'Reg', (124, 132))	('N-methylated', 'Var', (89, 101))
26374	33627631	The overall survival rate of CCA patients with high expression of CDR1as is significantly lower than that of CCA patients with low expression of CDR1as.	('CDR1as', 'Gene', (145, 151))	('patients', 'Species', '9606', (33, 41))	('CDR1as', 'Gene', '103611090', (66, 72))	('CDR1as', 'Gene', '103611090', (145, 151))	('patients', 'Species', '9606', (113, 121))	('CCA', 'Disease', (29, 32))	('high expression', 'Var', (47, 62))	('lower', 'NegReg', (90, 95))	('CDR1as', 'Gene', (66, 72))
26377	33627631	found that circ_0005230 is highly expressed in CCA, playing a carcinogenic role by acting as a sponge for miR-1238 and miR-1299, and is positively correlated with clinical severity.	('miR-1238', 'Gene', (106, 114))	('miR-1299', 'Gene', (119, 127))	('miR-1238', 'Gene', '100302226', (106, 114))	('miR-1299', 'Gene', '100302167', (119, 127))	('circ_0005230', 'Var', (11, 23))	('CCA', 'Disease', (47, 50))	('carcinogenic', 'Disease', 'MESH:D063646', (62, 74))	('carcinogenic', 'Disease', (62, 74))	('correlated', 'Reg', (147, 157))
26378	33627631	The other circRNA, hsa_circ_0001649, is scarce in CCA tissues and cells, while high levels of hsa_circ_0001649 can inhibit the proliferation, migration, and invasion of CCA cells and induce cell apoptosis to exert a tumor suppressor effect.	('cell apoptosis', 'CPA', (190, 204))	('tumor', 'Disease', (216, 221))	('CCA', 'Disease', (169, 172))	('proliferation', 'CPA', (127, 140))	('inhibit', 'NegReg', (115, 122))	('migration', 'CPA', (142, 151))	('hsa_circ_0001649', 'Var', (94, 110))	('tumor suppressor', 'biological_process', 'GO:0051726', ('216', '232'))	('apoptosis', 'biological_process', 'GO:0006915', ('195', '204'))	('invasion', 'CPA', (157, 165))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('216', '232'))	('induce', 'Reg', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('apoptosis', 'biological_process', 'GO:0097194', ('195', '204'))
26390	33627631	The mechanism may be that circRNA100290 binds to miR-516b, which affects the activity of its downstream target FZD4, thus activating the Wnt/beta-catenin signaling pathway to affect the proliferation, migration, and invasiveness of tumor cells.	('FZD4', 'Gene', (111, 115))	('miR-516b', 'Gene', (49, 57))	('invasiveness of tumor', 'Disease', 'MESH:D009361', (216, 237))	('migration', 'CPA', (201, 210))	('circRNA100290', 'Var', (26, 39))	('signaling pathway', 'biological_process', 'GO:0007165', ('154', '171'))	('proliferation', 'CPA', (186, 199))	('beta-catenin', 'Gene', (141, 153))	('invasiveness of tumor', 'Disease', (216, 237))	('affects', 'Reg', (65, 72))	('beta-catenin', 'Gene', '1499', (141, 153))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('activity', 'MPA', (77, 85))	('affect', 'Reg', (175, 181))	('FZD4', 'Gene', '8322', (111, 115))	('miR-516b', 'Chemical', '-', (49, 57))	('activating', 'Reg', (122, 132))
26396	33627631	In addition, hsa_circ_0004585, hsa_circRNA_102958, circRNA_101951, circ_0060745, circ_0001946, circRNA_0000392, and circRNA_100876 are highly expressed in CRC and regulate tumor growth through their own pathways.	('regulate', 'Reg', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('circ_0060745', 'Var', (67, 79))	('CRC', 'Phenotype', 'HP:0003003', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('circRNA_101951', 'Var', (51, 65))	('circRNA_0000392', 'Var', (95, 110))	('circ_0001946', 'Var', (81, 93))	('circRNA_100876', 'Var', (116, 130))	('CRC', 'Disease', (155, 158))
26397	33627631	Other circRNAs play inhibitory roles in CRC: hsa_circRNA_103809 is expressed at low levels in CRC, and as a tumor suppressor gene, it regulates tumor cell proliferation and migration through the miR-532-3p/FOXO4 axis; circRNA_0026344 also acts as a tumor suppressor gene to affect the occurrence and development of tumors.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('249', '265'))	('circRNA_0026344', 'Var', (218, 233))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('tumor', 'Disease', (249, 254))	('cell proliferation', 'biological_process', 'GO:0008283', ('150', '168'))	('occurrence', 'CPA', (285, 295))	('tumor suppressor', 'biological_process', 'GO:0051726', ('249', '265'))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('FOXO4', 'Gene', '4303', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('migration', 'CPA', (173, 182))	('affect', 'Reg', (274, 280))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumor', 'Disease', (144, 149))	('tumors', 'Disease', (315, 321))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('108', '124'))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('CRC', 'Phenotype', 'HP:0003003', (40, 43))	('tumors', 'Disease', 'MESH:D009369', (315, 321))	('tumor suppressor', 'biological_process', 'GO:0051726', ('108', '124'))	('regulates', 'Reg', (134, 143))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('FOXO4', 'Gene', (206, 211))	('tumor', 'Disease', (315, 320))
26398	33627631	The expression of circRNA_0026344 in CRC is significantly downregulated, and it functions as a sponge for miR-21/miR-31.	('miR-21', 'Gene', (106, 112))	('miR-31', 'Gene', '407035', (113, 119))	('expression', 'MPA', (4, 14))	('circRNA_0026344', 'Var', (18, 33))	('downregulated', 'NegReg', (58, 71))	('miR-21', 'Gene', '406991', (106, 112))	('CRC', 'Phenotype', 'HP:0003003', (37, 40))	('miR-31', 'Gene', (113, 119))
26399	33627631	The downregulation of circRNA_0026344 levels will lead to an increase in CRC progression and lymph node metastasis; therefore, low expression of circRNA_0026344 may predict a poor prognosis in CRC patients.	('CRC', 'Disease', (73, 76))	('patients', 'Species', '9606', (197, 205))	('CRC', 'Disease', (193, 196))	('CRC', 'Phenotype', 'HP:0003003', (73, 76))	('circRNA_0026344', 'Var', (145, 160))	('expression', 'MPA', (131, 141))	('CRC', 'Phenotype', 'HP:0003003', (193, 196))	('downregulation', 'NegReg', (4, 18))	('increase', 'PosReg', (61, 69))	('lymph node metastasis', 'CPA', (93, 114))
26422	32700262	We observed a significant decrease in N-cadherin expression in pancreatic cancer cells in response to ERas gene silencing by immunofluorescence assay and western blot.	('pancreatic cancer', 'Disease', (63, 80))	('gene silencing', 'biological_process', 'GO:0016458', ('107', '121'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (63, 80))	('decrease', 'NegReg', (26, 34))	('ERas', 'Gene', (102, 106))	('expression', 'MPA', (49, 59))	('N-cadherin', 'Protein', (38, 48))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (63, 80))	('gene silencing', 'Var', (107, 121))	('cadherin', 'molecular_function', 'GO:0008014', ('40', '48'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
26424	32700262	We further investigated the regulatory mechanisms of ERas in pancreatic cancer and found that ERas may activate the Erk/Akt signaling pathway.	('Akt signaling', 'biological_process', 'GO:0043491', ('120', '133'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('Erk', 'Gene', '2048', (116, 119))	('Akt', 'Gene', '207', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('signaling pathway', 'biological_process', 'GO:0007165', ('124', '141'))	('Erk', 'molecular_function', 'GO:0004707', ('116', '119'))	('ERas', 'Var', (94, 98))	('activate', 'PosReg', (103, 111))	('Erk', 'Gene', (116, 119))	('Akt', 'Gene', (120, 123))	('pancreatic cancer', 'Disease', (61, 78))
26447	32700262	The Erk inhibitor SCH772984 was obtained from Selleck Chemicals (Houston, TX, USA) and dissolved in 100% dimethyl sulfoxide (DMSO) at a concentration of 10 mM.	('Erk', 'molecular_function', 'GO:0004707', ('4', '7'))	('SCH772984', 'Var', (18, 27))	('Erk', 'Gene', '2048', (4, 7))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (105, 123))	('DMSO', 'Chemical', 'MESH:D004121', (125, 129))	('SCH772984', 'Chemical', 'MESH:C587178', (18, 27))	('Erk', 'Gene', (4, 7))
26453	32700262	The primary antibodies were anti-ERas antibody (1:1000; Abgent), anti-E-cadherin antibody (1:1000; #14472; Cell Signaling Technology), anti-N-cadherin antibody (1:1000; #13116; Cell Signaling Technology), anti-Erk (1:1000; #4695; Cell Signaling Technology), anti-phospho-ErkThr202/Tyr204 (1:1000; #9101; Cell Signaling Technology), anti-Akt (1:1000; #4691; Cell Signaling Technology), anti-phospho-AktSer473 (1:1000; #4060; Cell Signaling Technology), and rabbit anti-beta-actin (1:5000; Abcam).	('antibody', 'cellular_component', 'GO:0019815', ('38', '46'))	('antibody', 'cellular_component', 'GO:0019815', ('151', '159'))	('antibody', 'cellular_component', 'GO:0019815', ('81', '89'))	('Signaling', 'biological_process', 'GO:0023052', ('182', '191'))	('cadherin', 'molecular_function', 'GO:0008014', ('142', '150'))	('anti-N-cadherin', 'Var', (135, 150))	('1:1000; #4691', 'Var', (342, 355))	('Signaling', 'biological_process', 'GO:0023052', ('429', '438'))	('Erk', 'Gene', (271, 274))	('Signaling', 'biological_process', 'GO:0023052', ('235', '244'))	('antibody', 'cellular_component', 'GO:0019814', ('38', '46'))	('Signaling', 'biological_process', 'GO:0023052', ('309', '318'))	('antibody', 'cellular_component', 'GO:0019814', ('151', '159'))	('antibody', 'cellular_component', 'GO:0019814', ('81', '89'))	('cadherin', 'molecular_function', 'GO:0008014', ('72', '80'))	('beta-actin', 'Gene', '728378', (468, 478))	('Tyr204', 'Chemical', '-', (281, 287))	('Akt', 'Gene', (337, 340))	('Erk', 'Gene', '2048', (210, 213))	('antibody', 'molecular_function', 'GO:0003823', ('38', '46'))	('antibody', 'molecular_function', 'GO:0003823', ('81', '89'))	('Akt', 'Gene', '207', (337, 340))	('antibody', 'molecular_function', 'GO:0003823', ('151', '159'))	('Signaling', 'biological_process', 'GO:0023052', ('112', '121'))	('Akt', 'Gene', (398, 401))	('antibody', 'cellular_component', 'GO:0042571', ('38', '46'))	('antibody', 'cellular_component', 'GO:0042571', ('81', '89'))	('antibody', 'cellular_component', 'GO:0042571', ('151', '159'))	('Akt', 'Gene', '207', (398, 401))	('Erk', 'Gene', '2048', (271, 274))	('Signaling', 'biological_process', 'GO:0023052', ('362', '371'))	('Erk (1', 'molecular_function', 'GO:0004707', ('210', '216'))	('beta-actin', 'Gene', (468, 478))	('Erk', 'Gene', (210, 213))
26489	32700262	Our results showed that both SW1990 and Panc-1 exhibit high endogenous expression of ERas, and thus SW1990 and Panc-1 were used for subsequent functional assays.	('Panc-1', 'Gene', (40, 46))	('Panc-1', 'CellLine', 'CVCL:0480', (40, 46))	('ERas', 'Gene', (85, 89))	('Panc-1', 'CellLine', 'CVCL:0480', (111, 117))	('endogenous expression', 'MPA', (60, 81))	('SW1990', 'Var', (29, 35))	('SW1990', 'CellLine', 'CVCL:1723', (100, 106))	('SW1990', 'CellLine', 'CVCL:1723', (29, 35))
26490	32700262	We downregulated the expression of ERas in the cell lines using two siRNAs (siRNA30 and siRNA32) and confirmed that the expression levels of ERas were markedly decreased in both SW1990 and Panc-1 cells after siRNA30 and siRNA32 transfection compared with cells transfected with control siRNA (Fig.	('transfection', 'Var', (228, 240))	('siRNA32 transfection', 'Var', (220, 240))	('Panc-1', 'CellLine', 'CVCL:0480', (189, 195))	('downregulated', 'NegReg', (3, 16))	('expression', 'MPA', (21, 31))	('SW1990', 'CellLine', 'CVCL:1723', (178, 184))	('decreased', 'NegReg', (160, 169))	('siRNA30', 'Var', (208, 215))	('expression levels', 'MPA', (120, 137))
26495	32700262	Flow cytometry assays showed that the apoptotic rate was significantly increased in ERas siRNA30-transfected cells compared with control cells (55.78% +- 6.21% vs. 28.21% +- 3.89% in SW1990, 52.19% +- 5.77% vs. 21.34% +- 4.85% in Panc-1, respectively; P < 0.01) (Fig.	('apoptotic rate', 'CPA', (38, 52))	('Panc-1', 'CellLine', 'CVCL:0480', (230, 236))	('SW1990', 'Var', (183, 189))	('increased', 'PosReg', (71, 80))	('ERas', 'Var', (84, 88))	('SW1990', 'CellLine', 'CVCL:1723', (183, 189))
26504	32700262	Decreased tumor volumes and weights were found in the ERas downregulation group compared with the control group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('Decreased tumor', 'Disease', (0, 15))	('ERas', 'Var', (54, 58))	('Decreased tumor', 'Disease', 'MESH:D002303', (0, 15))
26513	32700262	We thus examined the role of Erk in pancreatic cell function using the Erk inhibitor SCH772984 and found the proliferation and colony formation of PCCs were inhibited by SCH772984 (Fig.	('Erk', 'Gene', '2048', (71, 74))	('SCH772984', 'Chemical', 'MESH:C587178', (170, 179))	('PCCs', 'Chemical', '-', (147, 151))	('inhibited', 'NegReg', (157, 166))	('formation', 'biological_process', 'GO:0009058', ('134', '143'))	('Erk', 'Gene', (71, 74))	('Erk', 'molecular_function', 'GO:0004707', ('71', '74'))	('Erk', 'molecular_function', 'GO:0004707', ('29', '32'))	('colony formation', 'CPA', (127, 143))	('SCH772984', 'Chemical', 'MESH:C587178', (85, 94))	('Erk', 'Gene', (29, 32))	('SCH772984', 'Var', (170, 179))	('proliferation', 'CPA', (109, 122))	('Erk', 'Gene', '2048', (29, 32))
26525	32700262	Importantly, subcutaneous tumor growth was inhibited in xenografts derived from cells with ERas knockdown.	('knockdown', 'Var', (96, 105))	('inhibited', 'NegReg', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (13, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
26526	32700262	Ki-67 immunohistochemical staining demonstrated significantly fewer proliferative cells in ERas knockdown xenograft tumors, indicating ERas enhances the proliferation of PCCs in tumors.	('tumors', 'Disease', (116, 122))	('fewer', 'NegReg', (62, 67))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('PCCs in', 'CPA', (170, 177))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('enhances', 'PosReg', (140, 148))	('proliferation', 'CPA', (153, 166))	('PCCs', 'Chemical', '-', (170, 174))	('ERas', 'Var', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('proliferative cells', 'CPA', (68, 87))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
26536	32700262	In addition, inhibition of the Erk pathway using the Erk inhibitor SCH772984 resulted in greatly decreased proliferation and colony formation of pancreatic cancer cells.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (145, 162))	('Erk', 'molecular_function', 'GO:0004707', ('31', '34'))	('Erk', 'Gene', '2048', (53, 56))	('Erk', 'Gene', (31, 34))	('colony formation', 'CPA', (125, 141))	('SCH772984', 'Chemical', 'MESH:C587178', (67, 76))	('proliferation', 'CPA', (107, 120))	('pancreatic cancer', 'Disease', (145, 162))	('pancreatic cancer', 'Disease', 'MESH:D010190', (145, 162))	('formation', 'biological_process', 'GO:0009058', ('132', '141'))	('Erk', 'Gene', '2048', (31, 34))	('decreased', 'NegReg', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('inhibition', 'NegReg', (13, 23))	('Erk', 'Gene', (53, 56))	('SCH772984', 'Var', (67, 76))	('Erk', 'molecular_function', 'GO:0004707', ('53', '56'))
26539	32700262	In addition, we revealed the biological role and potential signal pathways of ERas in pancreatic cancer progression.	('pancreatic cancer', 'Disease', (86, 103))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ERas', 'Var', (78, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
26541	32700262	Our results suggest that chemotherapy strategies using low-dose Erk inhibitor drugs might provide a beneficial therapeutic approach for the clinical application of pancreatic cancer.	('Erk', 'Gene', '2048', (64, 67))	('pancreatic cancer', 'Disease', (164, 181))	('low-dose', 'Var', (55, 63))	('pancreatic cancer', 'Disease', 'MESH:D010190', (164, 181))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (164, 181))	('Erk', 'Gene', (64, 67))	('Erk', 'molecular_function', 'GO:0004707', ('64', '67'))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
26542	32701143	Dipeptidyl peptidase like 6 promoter methylation is a potential prognostic biomarker for pancreatic ductal adenocarcinoma Background: Hypermethylation of gene promoters plays an important role in tumorigenesis.	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('tumor', 'Disease', (196, 201))	('Hypermethylation', 'Var', (134, 150))	('pancreatic ductal adenocarcinoma', 'Disease', (89, 121))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (89, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('Dipeptidyl peptidase like 6', 'Gene', (0, 27))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (89, 121))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('Dipeptidyl peptidase like 6', 'Gene', '1804', (0, 27))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
26547	32701143	Results: In GSE49149, the beta-value of the dipeptidyl peptidase like 6 (DPP6) promoter was significantly higher in tumor compared with normal samples (0.50 vs. 0.24, P<0.001).	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('beta-value', 'MPA', (26, 36))	('DPP6', 'Gene', '1804', (73, 77))	('higher', 'PosReg', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('GSE49149', 'Var', (12, 20))	('dipeptidyl peptidase like 6', 'Gene', '1804', (44, 71))	('tumor', 'Disease', (116, 121))	('DPP6', 'Gene', (73, 77))	('dipeptidyl peptidase like 6', 'Gene', (44, 71))
26549	32701143	In a multivariate Cox regression analysis, hypermethylation of the DPP6 promoter was an independent risk factor for PDAC (hazard ratio (HR) = 543.91, P=0.002).	('DPP6', 'Gene', '1804', (67, 71))	('PDAC', 'Phenotype', 'HP:0006725', (116, 120))	('DPP6', 'Gene', (67, 71))	('PDAC', 'Disease', (116, 120))	('hypermethylation', 'Var', (43, 59))	('PDAC', 'Chemical', '-', (116, 120))
26550	32701143	The results of BSP revealed that the number of methylated CG sites in the DPP6 promoter was greater in tumor samples than in normal samples (7.43 vs. 2.78, P<0.001).	('methylated', 'Var', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('BSP', 'Gene', (15, 18))	('tumor', 'Disease', (103, 108))	('BSP', 'Gene', '3381', (15, 18))	('DPP6', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('DPP6', 'Gene', '1804', (74, 78))
26552	32701143	Hypermethylation of the DPP6 promoter was associated with poor overall (HR = 3.61, P<0.001) and disease-free (HR = 2.01, P=0.016) survivals for PDAC patients.	('PDAC', 'Chemical', '-', (144, 148))	('patients', 'Species', '9606', (149, 157))	('disease-free', 'CPA', (96, 108))	('Hypermethylation', 'Var', (0, 16))	('DPP6', 'Gene', '1804', (24, 28))	('PDAC', 'Disease', (144, 148))	('PDAC', 'Phenotype', 'HP:0006725', (144, 148))	('poor', 'NegReg', (58, 62))	('DPP6', 'Gene', (24, 28))
26558	32701143	Recent studies indicated that during the pancreatic carcinogenesis, molecular epigenetic alterations are driving factors that have potential applications in early diagnosis and survival prediction.	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (41, 66))	('pancreatic carcinogenesis', 'Disease', (41, 66))	('molecular epigenetic alterations', 'Var', (68, 100))
26560	32701143	Genomic hypomethylation and promoter hypermethylation are typical epigenetic features during cancerization or aggression.	('aggression', 'Phenotype', 'HP:0000718', (110, 120))	('cancer', 'Disease', (93, 99))	('promoter', 'MPA', (28, 36))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('aggression', 'biological_process', 'GO:0002118', ('110', '120'))	('aggression', 'Disease', 'MESH:D001523', (110, 120))	('aggression', 'Disease', (110, 120))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Genomic hypomethylation', 'Var', (0, 23))
26561	32701143	In human malignancy, hypermethylation at promoter-associated CpG islands, which generally inhibits gene expression, has been proven to be a hallmark epigenetic alteration.	('hypermethylation', 'Var', (21, 37))	('gene expression', 'MPA', (99, 114))	('human', 'Species', '9606', (3, 8))	('malignancy', 'Disease', 'MESH:D009369', (9, 19))	('inhibits', 'NegReg', (90, 98))	('malignancy', 'Disease', (9, 19))	('gene expression', 'biological_process', 'GO:0010467', ('99', '114'))
26562	32701143	With regard to PDAC, aberrant methylation of gene promoters was found to be involved in oncogenesis and progression.	('PDAC', 'Phenotype', 'HP:0006725', (15, 19))	('oncogenesis', 'CPA', (88, 99))	('aberrant', 'Var', (21, 29))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('PDAC', 'Chemical', '-', (15, 19))	('progression', 'CPA', (104, 115))	('involved', 'Reg', (76, 84))	('oncogenesis', 'biological_process', 'GO:0007048', ('88', '99'))	('methylation', 'MPA', (30, 41))
26592	32701143	Of these, 367 were hypermethylated, and 39 were hypomethylated in tumor tissues compared with normal tissues (Figure 2A).	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('hypermethylated', 'Var', (19, 34))
26594	32701143	The probe IDs of TSS200, TSS1500, 5'UTR, and 1st exon for the 406 genes were mapped to the PDAC dataset of TCGA.	('TSS200', 'Gene', (17, 23))	('PDAC', 'Chemical', '-', (91, 95))	('TSS1500', 'Var', (25, 32))	('PDAC', 'Phenotype', 'HP:0006725', (91, 95))
26596	32701143	Among these genes, 49 hypermethylated genes and one hypomethylated gene were significantly associated with OS and were identified as PMDGs (Figure 2B and Supplementary Table S1).	('PMDGs', 'Chemical', '-', (133, 138))	('hypermethylated genes', 'Var', (22, 43))	('associated', 'Reg', (91, 101))
26603	32701143	In both the GSE49149 and PDAC cohort of TCGA, these seven genes showed similar methylation patterns in the promoter region: hypermethylation in tumor samples and hypomethylation in normal samples (Figure 4A,B).	('tumor', 'Disease', (144, 149))	('PDAC', 'Chemical', '-', (25, 29))	('hypermethylation', 'Var', (124, 140))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))	('hypomethylation', 'Var', (162, 177))	('PDAC', 'Phenotype', 'HP:0006725', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
26604	32701143	We integrated the above-mentioned seven genes and nine clinical factors into a multivariate Cox regression analysis, and found that chemotherapy and radiation were significant protective factors, while lymph node metastasis and promoter hypermethylation of DPP6 and HIST1H4E were significant risk factors for PDAC patients (Table 2).	('patients', 'Species', '9606', (314, 322))	('HIST1H4E', 'Gene', '8367', (266, 274))	('PDAC', 'Disease', (309, 313))	('promoter hypermethylation', 'Var', (228, 253))	('DPP6', 'Gene', '1804', (257, 261))	('PDAC', 'Chemical', '-', (309, 313))	('HIST1H4E', 'Gene', (266, 274))	('PDAC', 'Phenotype', 'HP:0006725', (309, 313))	('DPP6', 'Gene', (257, 261))
26608	32701143	The results confirmed that the numbers of methylated CG sites in DPP6 and MTMR7 in tumor tissues were significantly higher than in normal tissues (7.43 +- 6.12 vs. 2.78 +- 2.96, P<0.001; 45.95 +- 16.68 vs. 31.36 +- 16.90, P<0.001; Figure 5A,B).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('MTMR7', 'Gene', (74, 79))	('MTMR7', 'Gene', '9108', (74, 79))	('methylated', 'Var', (42, 52))	('tumor', 'Disease', (83, 88))	('higher', 'PosReg', (116, 122))	('DPP6', 'Gene', '1804', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('DPP6', 'Gene', (65, 69))
26611	32701143	The results showed that the methylated status of the DPP6 promoter had a moderate ability to distinguish tumor from normal tissues (AUC = 0.74, P<0.001; Figure 5E).	('DPP6', 'Gene', '1804', (53, 57))	('methylated', 'Var', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('DPP6', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
26612	32701143	The cut point was 4.5 methylated CG sites in the DPP6 promoter, with a specificity of 65% and a sensitivity of 78%.	('DPP6', 'Gene', (49, 53))	('methylated', 'Var', (22, 32))	('DPP6', 'Gene', '1804', (49, 53))
26615	32701143	Hypermethylation in gene promoters is a general epigenetic modification in cancer formation, especially for inhibition of tumor-suppressive genes such as PCDH10, DKK1, and KLF4.	('PCDH10', 'Gene', (154, 160))	('inhibition', 'NegReg', (108, 118))	('PCDH10', 'Gene', '57575', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Disease', (75, 81))	('KLF4', 'Gene', '9314', (172, 176))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('PC', 'Phenotype', 'HP:0002894', (154, 156))	('KLF4', 'Gene', (172, 176))	('DKK1', 'Gene', '22943', (162, 166))	('DKK1', 'Gene', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', (122, 127))	('formation', 'biological_process', 'GO:0009058', ('82', '91'))
26618	32701143	For certain genes such as CDO1, promoter methylation could be used as a diagnostic biomarker, and methylation of the ZNF671 promoter could predict survival.	('CDO1', 'Gene', '1036', (26, 30))	('survival', 'CPA', (147, 155))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('promoter', 'MPA', (32, 40))	('methylation', 'Var', (98, 109))	('predict', 'Reg', (139, 146))	('ZNF671', 'Gene', (117, 123))	('ZNF671', 'Gene', '79891', (117, 123))	('CDO1', 'Gene', (26, 30))
26625	32701143	Hypermethylation of GRM6 was detected in renal carcinoma, and LINGO3 was reported as one of the hub genes of metastatic melanoma.	('LINGO3', 'Gene', '645191', (62, 68))	('renal carcinoma', 'Disease', 'MESH:C538614', (41, 56))	('Hypermethylation', 'Var', (0, 16))	('GRM6', 'Gene', (20, 24))	('detected', 'Reg', (29, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('renal carcinoma', 'Disease', (41, 56))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('GRM6', 'Gene', '2916', (20, 24))	('renal carcinoma', 'Phenotype', 'HP:0005584', (41, 56))	('LINGO3', 'Gene', (62, 68))
26631	32701143	The results of the K-M survival analysis verified that hypermethylation of the DPP6 promoter was associated with poor OS and disease-free survival.	('hypermethylation', 'Var', (55, 71))	('DPP6', 'Gene', '1804', (79, 83))	('DPP6', 'Gene', (79, 83))	('poor OS', 'Disease', (113, 120))	('disease-free survival', 'CPA', (125, 146))
26632	32701143	Moreover, several malignant phenotypes, such as tumor size, lymph node invasion, and TNM stage, were related to hypermethylation of the DPP6 promoter.	('tumor', 'Disease', (48, 53))	('TNM', 'Gene', (85, 88))	('lymph node invasion', 'CPA', (60, 79))	('DPP6', 'Gene', '1804', (136, 140))	('TNM', 'Gene', '10178', (85, 88))	('DPP6', 'Gene', (136, 140))	('hypermethylation', 'Var', (112, 128))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('related', 'Reg', (101, 108))
26642	32701143	We studied the promoter methylation status across the whole genome through a series of bioinformatics analyses and identified that hypermethylation of the DPP6 promoter was an independent risk factor for PDAC.	('PDAC', 'Disease', (204, 208))	('PDAC', 'Phenotype', 'HP:0006725', (204, 208))	('risk', 'Reg', (188, 192))	('hypermethylation', 'Var', (131, 147))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('PDAC', 'Chemical', '-', (204, 208))	('DPP6', 'Gene', '1804', (155, 159))	('DPP6', 'Gene', (155, 159))
26654	32341770	Tissue-specific knockout of Dusp2 in mouse pancreas recapitulates PDAC phenotype and lymphovascular invasion.	('PDAC', 'Chemical', '-', (66, 70))	('Dusp2', 'Gene', (28, 33))	('knockout', 'Var', (16, 24))	('lymphovascular invasion', 'CPA', (85, 108))	('mouse', 'Species', '10090', (37, 42))	('PDAC', 'Disease', (66, 70))
26655	32341770	Collectively, these findings represent a conceptual advance in understanding pancreatic cancer lymphovascular invasion and suggest that loss-of-DUSP2-mediated VEGF-C processing may play important roles in early dissemination of pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (228, 245))	('pancreatic cancer lymphovascular invasion', 'Disease', (77, 118))	('pancreatic cancer lymphovascular invasion', 'Disease', 'MESH:D010190', (77, 118))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('pancreatic cancer', 'Disease', (228, 245))	('loss-of-DUSP2-mediated', 'Var', (136, 158))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('pancreatic cancer', 'Disease', 'MESH:D010190', (228, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
26656	32341770	Abbreviations: DUSP2: dual-specificity phosphatase-2; VEGF-C: vascular endothelial growth factor-C; EV: extracellular vesicles; PDAC: pancreatic ductal adenocarcinoma; KD: knockdown More than 90% of pancreatic cancers are originated from the exocrine ducts of the pancreas known as pancreatic ductal adenocarcinoma (PDAC).	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (282, 314))	('dual-specificity phosphatase-2', 'Gene', '1844', (22, 52))	('vascular endothelial growth factor-C', 'Gene', '7424', (62, 98))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('phosphatase', 'molecular_function', 'GO:0016791', ('39', '50'))	('PDAC', 'Chemical', '-', (316, 320))	('pancreatic cancers', 'Disease', 'MESH:D010190', (199, 217))	('knockdown', 'Var', (172, 181))	('pancreatic ductal adenocarcinoma', 'Disease', (282, 314))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('62', '96'))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (134, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (282, 314))	('PDAC', 'Chemical', '-', (128, 132))	('pancreatic ductal adenocarcinoma', 'Disease', (134, 166))	('vascular endothelial growth factor-C', 'Gene', (62, 98))	('extracellular', 'cellular_component', 'GO:0005576', ('104', '117'))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (199, 217))	('dual-specificity phosphatase-2', 'Gene', (22, 52))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (134, 166))	('pancreatic cancers', 'Disease', (199, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))
26663	32341770	Overexpression of VEGF-C in cancers has been tightly linked to lymphangiogenesis and is highly associated with lymphatic invasion and metastasis.	('cancers', 'Disease', (28, 35))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('63', '80'))	('lymphatic invasion', 'CPA', (111, 129))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('VEGF-C', 'Gene', (18, 24))	('linked', 'Reg', (53, 59))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('Overexpression', 'Var', (0, 14))	('associated with', 'Reg', (95, 110))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('lymphangiogenesis', 'CPA', (63, 80))
26675	32341770	In this study, we demonstrate that secreted VEGF-C is associated with EV and that loss-of-DUSP2 not only facilitates VEGF-C processing but also increases the production of EV-associated VEGF-C. Our findings point out the importance and novel regulation of DUSP2/VEGF-C axis in early pancreatic cancer progression.	('increases', 'PosReg', (144, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (283, 300))	('C axis', 'Species', '30531', (267, 273))	('loss-of-DUSP2', 'Gene', (82, 95))	('loss-of-DUSP2', 'Var', (82, 95))	('production', 'MPA', (158, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (283, 300))	('regulation', 'biological_process', 'GO:0065007', ('242', '252'))	('pancreatic cancer', 'Disease', (283, 300))	('rat', 'Species', '10116', (25, 28))	('VEGF-C processing', 'MPA', (117, 134))	('facilitates', 'PosReg', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))
26678	32341770	Stable knockdown of DUSP2 was achieved in PANC-1 cells using two different shRNAs (clone TRCN0000355667 and TRCN0000355666, RNAi core lab of Genomics Research Center, Academia Sinica, Taipei, Taiwan) and lentivirus delivery according to manufacturer's protocol.	('TRCN0000355666', 'Var', (108, 122))	('PANC-1', 'Gene', '104066', (42, 48))	('RNAi', 'biological_process', 'GO:0016246', ('124', '128'))	('core', 'cellular_component', 'GO:0019013', ('129', '133'))	('DUSP2', 'Gene', (20, 25))	('PANC-1', 'Gene', (42, 48))
26724	32341770	For orthotopic experiments, 1 x 106 PANC-1 with or without DUSP2 knockdown, suspended in 100 mul of RPMI medium were injected into the pancreas of mice.	('mice', 'Species', '10090', (147, 151))	('PANC-1', 'Gene', '104066', (36, 42))	('RPMI medium', 'Chemical', '-', (100, 111))	('PANC-1', 'Gene', (36, 42))	('knockdown', 'Var', (65, 74))	('DUSP2', 'Gene', (59, 64))
26725	32341770	For subcutaneous inoculation, 1 x 106 cells PANC-1 with or without DUSP2 knockdown suspended in 100 mul of RPMI medium were injected into the left and right flank of mice.	('RPMI medium', 'Chemical', '-', (107, 118))	('PANC-1', 'Gene', '104066', (44, 50))	('mice', 'Species', '10090', (166, 170))	('DUSP2', 'Gene', (67, 72))	('PANC-1', 'Gene', (44, 50))	('knockdown', 'Var', (73, 82))
26745	32341770	Taken all together, we provide evidence demonstrating that functional VEGF-C is associated with EV secretion in pancreatic cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('VEGF-C', 'Gene', (70, 76))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('functional', 'Var', (59, 69))	('rat', 'Species', '10116', (47, 50))	('associated', 'Reg', (80, 90))	('EV secretion', 'MPA', (96, 108))	('pancreatic cancer', 'Disease', (112, 129))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))	('secretion', 'biological_process', 'GO:0046903', ('99', '108'))
26754	32341770	To verify whether loss of DUSP2 affects VEGF-C expression, shRNAs targeting DUSP2 were used to knockdown DUSP2 in PANC-1 cells (which express higher levels of endogenous DUSP2).	('PANC-1', 'Gene', '104066', (114, 120))	('knockdown', 'Var', (95, 104))	('PANC-1', 'Gene', (114, 120))	('DUSP2', 'Gene', (105, 110))
26755	32341770	Results showed that knockdown of DUSP2 caused ERK phosphorylation (Figure 2(e)) and VEGF-C but did not cause VEGF-A overexpression (Figure 2(f)).	('ERK phosphorylation', 'MPA', (46, 65))	('DUSP2', 'Gene', (33, 38))	('knockdown', 'Var', (20, 29))	('phosphorylation', 'biological_process', 'GO:0016310', ('50', '65'))	('ERK', 'molecular_function', 'GO:0004707', ('46', '49'))	('VEGF-A', 'Gene', '7422', (109, 115))	('VEGF-C', 'MPA', (84, 90))	('VEGF-A', 'Gene', (109, 115))
26760	32341770	We then tested whether knockdown (KD) of DUSP2 in cancer cells promotes lymphangiogenesis.	('tested', 'Reg', (8, 14))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('lymphangiogenesis', 'CPA', (72, 89))	('DUSP2', 'Gene', (41, 46))	('knockdown', 'Var', (23, 32))	('promotes', 'PosReg', (63, 71))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('72', '89'))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
26763	32341770	Knockdown of DUSP2 led to larger tumour size and increased lymphangiogenesis in the xenograft animal model (Supplementary Figure 3).	('Knockdown', 'Var', (0, 9))	('tumour', 'Disease', (33, 39))	('increased', 'PosReg', (49, 58))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('59', '76'))	('larger', 'PosReg', (26, 32))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('DUSP2', 'Gene', (13, 18))	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('lymphangiogenesis', 'CPA', (59, 76))
26764	32341770	To further determine the in vivo effects of DUSP2-KD in pancreatic cancer progression, we performed orthotopic injection of control and DUSP2-KD PANC-1 cells into the pancreas of SCID mice.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (56, 73))	('PANC-1', 'Gene', (145, 151))	('pancreatic cancer', 'Disease', (56, 73))	('SCID', 'Disease', (179, 183))	('pancreatic cancer', 'Disease', 'MESH:D010190', (56, 73))	('DUSP2-KD', 'Var', (136, 144))	('SCID', 'Disease', 'MESH:D053632', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mice', 'Species', '10090', (184, 188))	('PANC-1', 'Gene', '104066', (145, 151))
26766	32341770	No obvious difference was observed in the size of primary tumours between control and DUSP2-KD tumours (Figure 3(c)).	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumours', 'Disease', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('tumours', 'Disease', (58, 65))	('DUSP2-KD', 'Var', (86, 94))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
26768	32341770	Intriguingly, there is a marked increase of lymphatic vessels (Lyve-1 positive) in DUSP2-KD tumours (Figure 2(d)) while the number of microvessels (CD31 positive) is low and no significant difference was observed.	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('lymphatic vessels', 'CPA', (44, 61))	('CD31', 'Gene', '5175', (148, 152))	('increase', 'PosReg', (32, 40))	('Lyve-1', 'Gene', (63, 69))	('DUSP2-KD', 'Var', (83, 91))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('Lyve-1', 'Gene', '10894', (63, 69))	('CD31', 'Gene', (148, 152))
26769	32341770	Evaluation of the primary tumours by histology examination led us to identify a significant increase in lymphovascular invasion (LVI) or nodal metastasis in DUSP2-KD tumours (88.8%) as compared to the control tumours (16.7%) (Figure 3(e)).	('tumours', 'Phenotype', 'HP:0002664', (209, 216))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('tumours', 'Disease', (166, 173))	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('tumours', 'Disease', (26, 33))	('DUSP2-KD', 'Var', (157, 165))	('tumours', 'Disease', 'MESH:D009369', (209, 216))	('tumours', 'Disease', (209, 216))	('increase', 'PosReg', (92, 100))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('nodal metastasis', 'CPA', (137, 153))	('tumours', 'Phenotype', 'HP:0002664', (166, 173))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('tumours', 'Disease', 'MESH:D009369', (166, 173))	('lymphovascular invasion', 'CPA', (104, 127))
26770	32341770	These data demonstrate that inhibition of DUSP2 promotes lymphangiogenesis and lymphovascular invasion ability of pancreatic cancer cells via VEGF-C dependent manner.	('rat', 'Species', '10116', (18, 21))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('57', '74'))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('inhibition', 'Var', (28, 38))	('lymphangiogenesis', 'CPA', (57, 74))	('promotes', 'PosReg', (48, 56))	('lymphovascular invasion ability of pancreatic cancer', 'Disease', 'MESH:D010190', (79, 131))	('DUSP2', 'Gene', (42, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))
26771	32341770	We generated Dusp2 conditional knockout (KO) in the mouse pancreas (Figure 3(f) top).	('Dusp2', 'Gene', (13, 18))	('mouse', 'Species', '10090', (52, 57))	('conditional knockout', 'Var', (19, 39))	('rat', 'Species', '10116', (7, 10))
26772	32341770	While Dusp2 KO alone is not sufficient to induce tumour formation, increased lymphangiogenesis (in the region of the intralobular duct) can be detected in the Dusp2 KO pancreas when compared to that in the wild type mouse (Figure 3(f) bottom).	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('77', '94'))	('mouse', 'Species', '10090', (216, 221))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('lymphangiogenesis', 'CPA', (77, 94))	('increased', 'PosReg', (67, 76))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('formation', 'biological_process', 'GO:0009058', ('56', '65'))	('Dusp2 KO', 'Var', (159, 167))	('tumour', 'Disease', (49, 55))
26774	32341770	At the 7th month, the KDC mice not only developed cancer in the pancreas but also significantly increased newly formed lymphatic vessels (Figure 3(g)), a phenomenon similar to what was observed in KPC mice.	('increased', 'PosReg', (96, 105))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('newly formed lymphatic vessels', 'CPA', (106, 136))	('mice', 'Species', '10090', (201, 205))	('mice', 'Species', '10090', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('KDC', 'Var', (22, 25))	('cancer in the pancreas', 'Phenotype', 'HP:0002894', (50, 72))	('developed', 'Reg', (40, 49))
26777	32341770	Since knockdown of DUSP2 makes the cells less adhesive to the neighbouring cells (Figure 4(a)), we thus investigated whether loss of DUSP2 affects the abilities of cell migration and invasion.	('cell migration', 'CPA', (164, 178))	('affects', 'Reg', (139, 146))	('loss', 'Var', (125, 129))	('investigated', 'Reg', (104, 116))	('cell migration', 'biological_process', 'GO:0016477', ('164', '178'))	('DUSP2', 'Gene', (19, 24))	('adhesive', 'MPA', (46, 54))	('DUSP2', 'Gene', (133, 138))	('rat', 'Species', '10116', (172, 175))	('less', 'NegReg', (41, 45))	('knockdown', 'Var', (6, 15))	('invasion', 'CPA', (183, 191))
26778	32341770	Indeed, wound healing migration and Transwell invasion assays demonstrated that DUSP2-KD enhanced cell migration and invasion (Figure 4(b,c)) and overexpression of DUSP2 decreased migration ability (Figure 4(d)).	('rat', 'Species', '10116', (183, 186))	('DUSP2-KD', 'Var', (80, 88))	('enhanced', 'PosReg', (89, 97))	('cell migration', 'biological_process', 'GO:0016477', ('98', '112'))	('wound healing', 'biological_process', 'GO:0042060', ('8', '21'))	('decreased', 'NegReg', (170, 179))	('migration ability', 'CPA', (180, 197))	('rat', 'Species', '10116', (25, 28))	('rat', 'Species', '10116', (106, 109))	('cell migration', 'CPA', (98, 112))	('rat', 'Species', '10116', (69, 72))	('invasion', 'CPA', (117, 125))
26780	32341770	Treatment with VEGF-C significantly increased PANC-1 migration while knockdown of VEGF-C significantly decreased pancreatic cancer cell migration without affecting its proliferation (Supplementary Figure 5).	('PANC-1', 'Gene', '104066', (46, 52))	('rat', 'Species', '10116', (56, 59))	('rat', 'Species', '10116', (139, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('cell migration', 'biological_process', 'GO:0016477', ('131', '145'))	('PANC-1', 'Gene', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('increased', 'PosReg', (36, 45))	('decreased pancreatic cancer', 'Disease', (103, 130))	('rat', 'Species', '10116', (175, 178))	('decreased pancreatic cancer', 'Disease', 'MESH:D010190', (103, 130))	('knockdown', 'Var', (69, 78))	('VEGF-C', 'Gene', (82, 88))
26781	32341770	Treatment with Lenvatinib or transient knockdown of VEGF-C abolished DUSP2-KD-promoted cell invasion (Figure 4(e,f)), indicating VEGF-C autocrine signalling mediates invasion in DUSP2-KD PANC-1 cells.	('Lenvatinib', 'Chemical', 'MESH:C531958', (15, 25))	('PANC-1', 'Gene', '104066', (187, 193))	('abolished', 'NegReg', (59, 68))	('autocrine signalling', 'biological_process', 'GO:0035425', ('136', '156'))	('knockdown', 'Var', (39, 48))	('PANC-1', 'Gene', (187, 193))	('cell invasion', 'CPA', (87, 100))	('DUSP2-KD-promoted', 'Gene', (69, 86))	('VEGF-C', 'Gene', (52, 58))
26783	32341770	We found that DUSP2-KD cells also showed enhanced transendothelial migration ability, which can be blocked by Lenvatinib (Figure 4(g)).	('rat', 'Species', '10116', (70, 73))	('enhanced', 'PosReg', (41, 49))	('transendothelial migration ability', 'CPA', (50, 84))	('DUSP2-KD', 'Var', (14, 22))	('Lenvatinib', 'Chemical', 'MESH:C531958', (110, 120))
26784	32341770	These data showed that DUSP2 knockdown resulted in increased malignant characteristics of pancreatic cancer cells, which, in conjunction with increased lymphangiogenesis, promotes early pancreatic cancer cell dissemination.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('promotes', 'PosReg', (171, 179))	('knockdown', 'Var', (29, 38))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (186, 203))	('increased', 'PosReg', (51, 60))	('early', 'CPA', (180, 185))	('pancreatic cancer', 'Disease', (90, 107))	('pancreatic cancer', 'Disease', (186, 203))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('DUSP2', 'Gene', (23, 28))	('pancreatic cancer', 'Disease', 'MESH:D010190', (186, 203))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('152', '169'))
26791	32341770	Isolation of EV from control and DUSP2-KD cells demonstrated that VEGF-C is increased in EV from DUSP2-KD cells (Figure 6(a)), which can be diminished by ERK inhibitor (Figure 6(b)).	('VEGF-C', 'Gene', (66, 72))	('increased', 'PosReg', (76, 85))	('ERK', 'molecular_function', 'GO:0004707', ('154', '157'))	('rat', 'Species', '10116', (55, 58))	('DUSP2-KD', 'Var', (97, 105))
26795	32341770	Our results indicated that DUSP2-KD PANC-1 cells have increased numbers of EVs ranging from 85 to 155 nm (Figure 6(e) left and middle), which can be diminished when treated with GW4869 (Figure 6(e) right).	('PANC-1', 'Gene', '104066', (36, 42))	('increased', 'PosReg', (54, 63))	('DUSP2-KD', 'Var', (27, 35))	('PANC-1', 'Gene', (36, 42))	('EVs ranging from 85 to 155 nm', 'MPA', (75, 104))	('GW4869', 'Chemical', 'MESH:C468773', (178, 184))
26798	32341770	CMV-driven VE-SNAP was stably expressed in the cells and proprotein convertase inhibitor was administered to dissect out the effect of DUSP2 in the secretion rate of EV-VEGF-C. Time course detection indicated that DUSP2-KD cells have an increased secretion rate of EV-VEGF-C as compared to control cells (Figure 6(g)).	('increased', 'PosReg', (237, 246))	('DUSP2-KD', 'Var', (214, 222))	('secretion rate', 'MPA', (247, 261))	('secretion', 'biological_process', 'GO:0046903', ('148', '157'))	('secretion', 'biological_process', 'GO:0046903', ('247', '256'))	('rat', 'Species', '10116', (158, 161))	('rat', 'Species', '10116', (257, 260))	('SNAP', 'molecular_function', 'GO:0005483', ('14', '18'))
26799	32341770	Last, we demonstrate that EV from DUSP2-KD cells promotes lymphangiogenesis in PANC-1 tumours compared to that treated with control PBS (Figure 6(h)).	('lymphangiogenesis', 'CPA', (58, 75))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('58', '75'))	('PANC-1', 'Gene', '104066', (79, 85))	('PANC-1', 'Gene', (79, 85))	('rat', 'Species', '10116', (16, 19))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('promotes', 'PosReg', (49, 57))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('DUSP2-KD', 'Var', (34, 42))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))	('PBS', 'Chemical', 'MESH:D007854', (132, 135))
26800	32341770	Together, we demonstrated that DUSP2 knockdown promotes the secretion of EV-VEGF-C. DUSP2 is a potent tumour suppressor that preferentially inactivates ERK; thus, loss of DUSP2 contributes to the activation of MAPK signalling, which results in accelerating cancer progression and malignancy.	('malignancy', 'Disease', (280, 290))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Disease', (102, 108))	('ERK', 'Protein', (152, 155))	('MAPK signalling', 'Pathway', (210, 225))	('inactivates', 'NegReg', (140, 151))	('DUSP2', 'Gene', (171, 176))	('MAPK', 'molecular_function', 'GO:0004707', ('210', '214'))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('ERK', 'molecular_function', 'GO:0004707', ('152', '155'))	('rat', 'Species', '10116', (250, 253))	('loss', 'Var', (163, 167))	('malignancy', 'Disease', 'MESH:D009369', (280, 290))	('rat', 'Species', '10116', (20, 23))	('secretion', 'MPA', (60, 69))	('accelerating', 'PosReg', (244, 256))	('activation', 'PosReg', (196, 206))	('MAPK signalling', 'biological_process', 'GO:0000165', ('210', '225'))	('cancer', 'Disease', (257, 263))	('secretion', 'biological_process', 'GO:0046903', ('60', '69'))
26802	32341770	We report here that loss-of-DUSP2 promotes early metastasis via increasing lymphovascular invasion in both orthotopic and genetic mouse models of PDAC.	('promotes', 'PosReg', (34, 42))	('early metastasis', 'CPA', (43, 59))	('loss-of-DUSP2', 'Gene', (20, 33))	('increasing', 'PosReg', (64, 74))	('PDAC', 'Chemical', '-', (146, 150))	('lymphovascular invasion', 'CPA', (75, 98))	('loss-of-DUSP2', 'Var', (20, 33))	('mouse', 'Species', '10090', (130, 135))
26803	32341770	Suppression of DUSP2 enhances lymphangiogenesis and cancer cell invasiveness via paracrine and autocrine effects of VEGF-C. As early dissemination is a unique feature that significantly increases the mortality rate of PDAC, this finding is of particular importance.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mortality', 'Disease', (200, 209))	('PDAC', 'Disease', (218, 222))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('30', '47'))	('Suppression', 'Var', (0, 11))	('PDAC', 'Chemical', '-', (218, 222))	('increases', 'PosReg', (186, 195))	('DUSP2', 'Gene', (15, 20))	('enhances', 'PosReg', (21, 29))	('mortality', 'Disease', 'MESH:D003643', (200, 209))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('rat', 'Species', '10116', (210, 213))	('lymphangiogenesis', 'CPA', (30, 47))
26806	32341770	As we showed in this study, knockdown of DUSP2 in pancreatic cancer cells increased the mature form of VEGF-C, which can enhance the lymphangiogenic properties of LECs.	('lymphangiogenic properties', 'CPA', (133, 159))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 67))	('DUSP2', 'Gene', (41, 46))	('pancreatic cancer', 'Disease', (50, 67))	('enhance', 'PosReg', (121, 128))	('increased', 'PosReg', (74, 83))	('pancreatic cancer', 'Disease', 'MESH:D010190', (50, 67))	('mature', 'MPA', (88, 94))	('knockdown', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('VEGF-C', 'Protein', (103, 109))
26815	32341770	Heparan sulphate proteoglycans (HSPGs) exist on cell-surface and in the extracellular matrix plays an important role in regulating growth factors action and distribution; thus, the presence of HSPGs on EVs may tether growth factors and mediate their function.	('tether', 'Interaction', (210, 216))	('growth', 'Protein', (217, 223))	('HSPGs', 'Protein', (193, 198))	('function', 'MPA', (250, 258))	('Heparan sulphate', 'Chemical', 'MESH:D006497', (0, 16))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('72', '92'))	('presence', 'Var', (181, 189))	('mediate', 'Reg', (236, 243))	('cell-surface', 'cellular_component', 'GO:0009986', ('48', '60'))
26819	32341770	By transmission electron microscopy and NTA analysis, we demonstrated that DUSP2-KD PANC-1 cells have increased numbers of EVs.	('PANC-1', 'Gene', '104066', (84, 90))	('DUSP2-KD', 'Var', (75, 83))	('PANC-1', 'Gene', (84, 90))	('rat', 'Species', '10116', (64, 67))	('EVs', 'MPA', (123, 126))	('NTA', 'Chemical', '-', (40, 43))	('increased', 'PosReg', (102, 111))
26820	32341770	Furthermore, 3D tracking for the fast-moving vesicles by inverted light sheet fluorescence microscopy provides evidence that vesicles' moving speed is accelerated in DUSP2-KD cells.	('rat', 'Species', '10116', (157, 160))	('accelerated', 'PosReg', (151, 162))	('moving', 'MPA', (135, 141))	('DUSP2-KD', 'Var', (166, 174))
26824	32341770	Therefore, it is likely that DUSP2 knockdown affects the cytoskeleton dynamics which results in enhancing migration ability and secretion of EVs.	('knockdown', 'Var', (35, 44))	('cytoskeleton', 'MPA', (57, 69))	('migration ability', 'CPA', (106, 123))	('enhancing', 'PosReg', (96, 105))	('secretion of EVs', 'MPA', (128, 144))	('rat', 'Species', '10116', (109, 112))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('57', '69'))	('DUSP2', 'Gene', (29, 34))	('secretion', 'biological_process', 'GO:0046903', ('128', '137'))	('affects', 'Reg', (45, 52))
26826	32341770	Downregulation of DUSP2 in pancreatic cancer cells increases VEGF-C mRNA transcription and enhances proprotein convertase activity, which promotes the production of the functional form of VEGF-C. DUSP2 downregulation also increases the amount and moving ability of EV-carried VEGF-C, which enhances the secretion of functional VEGF-C into the tumour microenvironment.	('moving ability', 'CPA', (247, 261))	('mRNA transcription', 'MPA', (68, 86))	('VEGF-C', 'Gene', (61, 67))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (27, 44))	('secretion', 'biological_process', 'GO:0046903', ('303', '312'))	('DUSP2', 'Gene', (196, 201))	('mRNA transcription', 'biological_process', 'GO:0009299', ('68', '86'))	('Downregulation', 'Var', (0, 14))	('increases', 'PosReg', (51, 60))	('tumour', 'Phenotype', 'HP:0002664', (343, 349))	('DUSP2', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (343, 349))	('pancreatic cancer', 'Disease', 'MESH:D010190', (27, 44))	('tumour', 'Disease', (343, 349))	('downregulation', 'NegReg', (202, 216))	('increases', 'PosReg', (222, 231))	('amount', 'MPA', (236, 242))	('proprotein', 'MPA', (100, 110))	('proprotein convertase activity', 'molecular_function', 'GO:0016808', ('100', '130'))	('pancreatic cancer', 'Disease', (27, 44))	('enhances', 'PosReg', (91, 99))	('enhances', 'PosReg', (290, 298))	('secretion', 'MPA', (303, 312))
26883	31874997	Protein expression of ABCC2 and SLC22A3 associates with prognosis of pancreatic adenocarcinoma ATP-binding cassette (ABC) and solute carrier (SLC) transporters translocate diverse substances across cellular membranes and their deregulation may cause drug resistance of cancers.	('ABCC2', 'Gene', (22, 27))	('carrier', 'molecular_function', 'GO:0005215', ('133', '140'))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (69, 94))	('SLC22A3', 'Gene', (32, 39))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (69, 94))	('drug resistance', 'Phenotype', 'HP:0020174', (250, 265))	('ABC', 'Gene', '10058', (22, 25))	('drug resistance', 'Disease', (250, 265))	('cause', 'Reg', (244, 249))	('ABC', 'Gene', (22, 25))	('ABC', 'Gene', '10058', (117, 120))	('ATP-binding cassette', 'Gene', (95, 115))	('cancers', 'Phenotype', 'HP:0002664', (269, 276))	('cancers', 'Disease', (269, 276))	('associates with', 'Reg', (40, 55))	('deregulation', 'Var', (227, 239))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('ABC', 'Gene', (117, 120))	('ATP-binding', 'molecular_function', 'GO:0005524', ('95', '106'))	('pancreatic adenocarcinoma', 'Disease', (69, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('ABCC2', 'Gene', '1244', (22, 27))	('drug resistance', 'biological_process', 'GO:0009315', ('250', '265'))	('drug resistance', 'biological_process', 'GO:0042493', ('250', '265'))	('SLC22A3', 'Gene', '6581', (32, 39))	('ATP-binding cassette', 'Gene', '10058', (95, 115))	('cancers', 'Disease', 'MESH:D009369', (269, 276))
26886	31874997	Negative SLC22A3 brush border staining in pancreatic tumors significantly increased the risk of both disease progression and patient s death in univariate analyses.	('pancreatic tumors', 'Disease', (42, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('increased', 'PosReg', (74, 83))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (42, 59))	('SLC22A3', 'Gene', (9, 16))	('brush border', 'cellular_component', 'GO:0005903', ('17', '29'))	('pancreatic tumors', 'Disease', 'MESH:D010190', (42, 59))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('patient', 'Species', '9606', (125, 132))	('death', 'Disease', 'MESH:D003643', (135, 140))	('death', 'Disease', (135, 140))	('Negative', 'Var', (0, 8))
26889	31874997	The combination of positive ABCC2 and negative SLC22A3 brush border staining predicted worst overall survival and patients with positive brush border staining of both proteins had best overall and progression-free survival.	('worst', 'NegReg', (87, 92))	('brush border', 'cellular_component', 'GO:0005903', ('55', '67'))	('overall survival', 'MPA', (93, 109))	('ABCC2', 'Gene', (28, 33))	('ABCC2', 'Gene', '1244', (28, 33))	('negative', 'NegReg', (38, 46))	('brush border', 'cellular_component', 'GO:0005903', ('137', '149'))	('patients', 'Species', '9606', (114, 122))	('progression-free', 'CPA', (197, 213))	('SLC22A3', 'Gene', (47, 54))	('positive', 'Var', (19, 27))
26893	31874997	Overexpression of ATP-binding cassette (ABC) transporters and downregulation of solute carrier (SLC) transporters is suspected to influence effective intracellular concentration of anticancer chemotherapeutics including some targeted agents.	('influence', 'Reg', (130, 139))	('ATP-binding cassette', 'Gene', '10058', (18, 38))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('effective intracellular concentration', 'MPA', (140, 177))	('intracellular', 'cellular_component', 'GO:0005622', ('150', '163'))	('ATP-binding', 'molecular_function', 'GO:0005524', ('18', '29'))	('ATP-binding cassette', 'Gene', (18, 38))	('downregulation', 'NegReg', (62, 76))	('ABC', 'Gene', (40, 43))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('carrier', 'molecular_function', 'GO:0005215', ('87', '94'))	('cancer', 'Disease', (185, 191))	('ABC', 'Gene', '10058', (40, 43))
26923	31874997	Patients with R1 resection had significantly worse PFS (P = 0.038, Log Rank) and OS (P = 0.001) than completely resected (R0) ones.	('worse', 'NegReg', (45, 50))	('Patients', 'Species', '9606', (0, 8))	('R1 resection', 'Var', (14, 26))	('PFS', 'CPA', (51, 54))
26931	31874997	The combination of positive ABCC2 and SLC22A3 brush border staining was also predictive of best OS, but additionally, patients with combination of positive ABCC2 and negative SLC22A3 intratumoral brush border staining had apparently the worst OS (P = 0.048, Log Rank and P = 0.013, Breslow; Fig.	('tumor', 'Disease', (188, 193))	('SLC22A3', 'Gene', (175, 182))	('ABCC2', 'Gene', (156, 161))	('brush border', 'cellular_component', 'GO:0005903', ('196', '208'))	('brush border', 'cellular_component', 'GO:0005903', ('46', '58'))	('ABCC2', 'Gene', (28, 33))	('positive', 'Var', (147, 155))	('ABCC2', 'Gene', '1244', (28, 33))	('negative', 'Var', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('patients', 'Species', '9606', (118, 126))	('ABCC2', 'Gene', '1244', (156, 161))
26934	31874997	Moreover, patients with apical SLC22A3 localization had significantly worse OS than those with basal localization (P = 0.021, Log Rank and P = 0.029, Breslow; Fig.	('SLC22A3', 'Gene', (31, 38))	('apical', 'Var', (24, 30))	('worse', 'NegReg', (70, 75))	('localization', 'biological_process', 'GO:0051179', ('39', '51'))	('localization', 'Var', (39, 51))	('patients', 'Species', '9606', (10, 18))	('localization', 'biological_process', 'GO:0051179', ('101', '113'))
26937	31874997	Our data clearly show that presence of SLC22A3 protein associates with prognosis of PDAC patients.	('protein', 'Protein', (47, 54))	('PDAC', 'Disease', (84, 88))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('patients', 'Species', '9606', (89, 97))	('associates with', 'Reg', (55, 70))	('SLC22A3', 'Gene', (39, 46))	('presence', 'Var', (27, 35))
26943	31874997	Specifically, genetic variability of SLC22A3 predisposes to colorectal and prostate cancer.	('colorectal and prostate cancer', 'Disease', 'MESH:D011471', (60, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (75, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('genetic variability', 'Var', (14, 33))	('SLC22A3', 'Gene', (37, 44))	('predisposes', 'Reg', (45, 56))
26944	31874997	Association of genetic variant rs2504938 in SLC22A3 with overall survival of pancreatic cancer patients was recently published.	('patients', 'Species', '9606', (95, 103))	('rs2504938', 'Var', (31, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('rs2504938', 'Mutation', 'rs2504938', (31, 40))	('Association', 'Reg', (0, 11))	('SLC22A3', 'Gene', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('pancreatic cancer', 'Disease', (77, 94))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
26949	31874997	Taken together previous studies suggested that genetic, epigenetic or phenotypic nature of SLC22A3 can serve as putative risk predictive or prognostic biomarker in cancer.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('genetic', 'Var', (47, 54))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('SLC22A3', 'Gene', (91, 98))	('epigenetic', 'Var', (56, 66))
26954	31874997	High SLC22A3 expression is being tested as a potential surrogate biomarker predicting response of several cancers to metformin.	('High', 'Var', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('SLC22A3', 'Gene', (5, 12))	('metformin', 'Chemical', 'MESH:D008687', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
26956	31874997	Recent genetic study reported that several polymorphisms in the ABCC2 gene (rs3740067, rs3740073 and rs717620) significantly associate with OS of PDAC patients in an early disease stage and may become prognostic biomarkers.	('rs3740067', 'Var', (76, 85))	('ABCC2', 'Gene', (64, 69))	('rs3740073', 'Var', (87, 96))	('rs717620', 'Var', (101, 109))	('associate with', 'Reg', (125, 139))	('patients', 'Species', '9606', (151, 159))	('ABCC2', 'Gene', '1244', (64, 69))	('rs717620', 'Mutation', 'rs717620', (101, 109))	('rs3740073', 'Mutation', 'rs3740073', (87, 96))	('PDAC', 'Disease', (146, 150))	('rs3740067', 'Mutation', 'rs3740067', (76, 85))
26957	31874997	This observation complements previous studies suggesting that ABCC2 polymorphism rs2273697 associates with poor OS and response to chemoradiotherapy of PDAC patients and upregulated ABCC2 protein expression leads to an altered sensitivity to gemcitabine and irinotecan in vitro.	('poor OS', 'MPA', (107, 114))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('rs2273697', 'Var', (81, 90))	('ABCC2', 'Gene', (182, 187))	('ABCC2', 'Gene', '1244', (182, 187))	('irinotecan', 'Chemical', 'MESH:D000077146', (258, 268))	('patients', 'Species', '9606', (157, 165))	('ABCC2', 'Gene', (62, 67))	('altered', 'Reg', (219, 226))	('gemcitabine', 'Chemical', 'MESH:C056507', (242, 253))	('ABCC2', 'Gene', '1244', (62, 67))	('rs2273697', 'Mutation', 'rs2273697', (81, 90))	('upregulated', 'PosReg', (170, 181))	('protein', 'Protein', (188, 195))
26958	31874997	Another study recently pointed out that silencing ABCC2 protein expression increases oxaliplatin accumulation and cytotoxicity in PANC-1 pancreatic cell line model in vitro.	('ABCC2', 'Gene', (50, 55))	('ABCC2', 'Gene', '1244', (50, 55))	('cytotoxicity', 'Disease', 'MESH:D064420', (114, 126))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('PANC-1', 'CellLine', 'CVCL:0480', (130, 136))	('protein', 'Protein', (56, 63))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (85, 96))	('silencing', 'Var', (40, 49))	('oxaliplatin accumulation', 'MPA', (85, 109))	('cytotoxicity', 'Disease', (114, 126))	('increases', 'PosReg', (75, 84))
26963	31874997	In fact, combination of positive ABCC2 and positive SLC22A3 predicted longest survival (both PFS and OS) suggesting that the extent of overall protein expression dysregulation is prognostic in this case.	('positive', 'Var', (43, 51))	('ABCC2', 'Gene', '1244', (33, 38))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('longest survival', 'CPA', (70, 86))	('SLC22A3', 'Gene', (52, 59))	('positive', 'Var', (24, 32))	('ABCC2', 'Gene', (33, 38))
27033	31506738	In stage III cancers, median survival times of 7.6 and 12.1 months were reached in patients treated with i. a. infusion and UAP-F, respectively.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('UAP-F', 'Var', (124, 129))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Disease', (13, 20))	('patients', 'Species', '9606', (83, 91))
27034	31506738	In stage IV cancers, median survival times of 6.6 and 8.7 months were reached in patients treated with i. a. infusion and UAP-F, respectively (Fig.	('UAP-F', 'Var', (122, 127))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', (12, 19))	('patients', 'Species', '9606', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
27065	31480737	The Use of Genetically Engineered Mouse Models for Studying the Function of Mutated Driver Genes in Pancreatic Cancer Pancreatic cancer is often treatment-resistant, with the emerging standard of care, gemcitabine, affording only a few months of incrementally-deteriorating survival.	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (118, 135))	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (100, 117))	('gemcitabine', 'Chemical', 'MESH:C056507', (202, 213))	('Mutated', 'Var', (76, 83))	('Pancreatic cancer', 'Disease', (118, 135))	('Pancreatic Cancer', 'Disease', (100, 117))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Mouse', 'Species', '10090', (34, 39))
27078	31480737	The second area of discovery is in the delineation of several key genetic alterations (signature lesions) that typify the development of most human PDACs.	('human', 'Species', '9606', (142, 147))	('alterations', 'Var', (74, 85))	('PDAC', 'Phenotype', 'HP:0006725', (148, 152))	('PDAC', 'Disease', 'MESH:D021441', (148, 152))	('genetic alterations', 'Var', (66, 85))	('PDAC', 'Disease', (148, 152))
27079	31480737	Pancreatic adenocarcinomas display a characteristic profile of genetic lesions, consisting of mutations in INK4A, KRAS, SMAD4/DPC4, and TP53 in a high proportion of tumors, and less frequent mutations in LKB1, APC, CTNNB1, ATM, BRCA2, ACVR1B, MKK4 (Ras downstream effector), and ARID1A.	('Pancreatic adenocarcinomas', 'Disease', 'MESH:D010195', (0, 26))	('MKK4', 'molecular_function', 'GO:0004708', ('243', '247'))	('LKB1', 'Gene', (204, 208))	('CTNNB1', 'Gene', '12387', (215, 221))	('Pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (0, 26))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('ACVR1B', 'Gene', '11479', (235, 241))	('APC', 'cellular_component', 'GO:0005680', ('210', '213'))	('INK4A', 'Gene', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (16, 26))	('ARID1A', 'Gene', (279, 285))	('ATM', 'Gene', (223, 226))	('ARID1A', 'Gene', '93760', (279, 285))	('SMAD4', 'Gene', '17128', (120, 125))	('DPC4', 'Gene', (126, 130))	('MKK4', 'Gene', (243, 247))	('mutations', 'Var', (94, 103))	('tumors', 'Disease', (165, 171))	('Pancreatic adenocarcinomas', 'Disease', (0, 26))	('APC', 'Disease', 'MESH:D011125', (210, 213))	('BRCA2', 'Gene', (228, 233))	('KRAS', 'Gene', (114, 118))	('mutations', 'Reg', (191, 200))	('APC', 'Disease', (210, 213))	('ACVR1B', 'Gene', (235, 241))	('MKK4', 'Gene', '26398', (243, 247))	('TP53', 'Gene', (136, 140))	('CTNNB1', 'Gene', (215, 221))	('KRAS', 'Gene', '16653', (114, 118))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('SMAD4', 'Gene', (120, 125))	('TP53', 'Gene', '22059', (136, 140))	('DPC4', 'Gene', '17128', (126, 130))
27080	31480737	Ongoing studies have been directed at determining the biological roles of these PDAC driver gene mutations, and in particular, relating those alterations to the processes of cancer initiation and progression (Figure 1).	('mutations', 'Var', (97, 106))	('cancer initiation', 'Disease', 'MESH:D009369', (174, 191))	('cancer initiation', 'Disease', (174, 191))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('PDAC', 'Disease', (80, 84))	('PDAC', 'Phenotype', 'HP:0006725', (80, 84))	('PDAC', 'Disease', 'MESH:D021441', (80, 84))
27089	31480737	These genetic lesions engage common oncogenic signaling pathways in the pathogenesis of the human disease, hence the mouse model should provide a relevant system for elucidating the molecular circuitry of human pancreatic adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (211, 236))	('genetic lesions', 'Var', (6, 21))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('engage', 'Reg', (22, 28))	('mouse', 'Species', '10090', (117, 122))	('oncogenic signaling pathways', 'Pathway', (36, 64))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010195', (211, 236))	('human', 'Species', '9606', (205, 210))	('pancreatic adenocarcinoma', 'Disease', (211, 236))	('human', 'Species', '9606', (92, 97))	('pathogenesis', 'biological_process', 'GO:0009405', ('72', '84'))
27094	31480737	Oncogenic KRAS mutations:at codons 12, 13 and 61:turn constitutively active KRAS forms, obviating the need for upstream inducing signals and rendering the protein insensitive to inhibition.	('KRAS', 'Gene', '16653', (76, 80))	('KRAS', 'Gene', (76, 80))	('mutations', 'Var', (15, 24))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('KRAS', 'Gene', '16653', (10, 14))	('KRAS', 'Gene', (10, 14))
27096	31480737	In addition to a role in tumor initiation, it appears that KRAS activation is required for maintenance of the tumorigenic growth of established PDAC, since disruption of KRAS activity:via RNA interference, antisense RNA, or expression of dominant-negative KRASN17:attenuates the tumorigenicity of PDAC cell lines.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('PDAC', 'Disease', 'MESH:D021441', (297, 301))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('PDAC', 'Disease', (297, 301))	('RNA', 'cellular_component', 'GO:0005562', ('188', '191'))	('KRAS', 'Gene', (59, 63))	('attenuates', 'NegReg', (264, 274))	('KRAS', 'Gene', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('PDAC', 'Disease', (144, 148))	('PDAC', 'Disease', 'MESH:D021441', (144, 148))	('KRAS', 'Gene', '16653', (59, 63))	('tumor initiation', 'Disease', 'MESH:D009369', (25, 41))	('RNA', 'cellular_component', 'GO:0005562', ('216', '219'))	('disruption', 'Var', (156, 166))	('PDAC', 'Phenotype', 'HP:0006725', (297, 301))	('tumor', 'Disease', (25, 30))	('tumor initiation', 'Disease', (25, 41))	('tumor', 'Disease', (279, 284))	('RNA interference', 'MPA', (188, 204))	('KRAS', 'Gene', '16653', (170, 174))	('KRAS', 'Gene', (256, 260))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('antisense RNA', 'molecular_function', 'GO:0009388', ('206', '219'))	('tumor', 'Disease', (110, 115))	('PDAC', 'Phenotype', 'HP:0006725', (144, 148))	('KRAS', 'Gene', '16653', (256, 260))	('RNA interference', 'biological_process', 'GO:0016246', ('188', '204'))	('antisense', 'Var', (206, 215))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
27102	31480737	Activating K-Ras mutations are the first genetic changes detected in the progression series present in about 30% of lesions showing the earliest stages of histological disturbance.	('Activating', 'PosReg', (0, 10))	('K-Ras', 'Gene', '16653', (11, 16))	('mutations', 'Var', (17, 26))	('K-Ras', 'Gene', (11, 16))
27103	31480737	Increasing in frequency with disease progression, K-Ras mutations are found in nearly 90% of PDACs, and thus this lesion appears to be a required event for this malignancy.	('mutations', 'Var', (56, 65))	('K-Ras', 'Gene', (50, 55))	('K-Ras', 'Gene', '16653', (50, 55))	('PDAC', 'Disease', (93, 97))	('PDAC', 'Phenotype', 'HP:0006725', (93, 97))	('PDAC', 'Disease', 'MESH:D021441', (93, 97))
27109	31480737	Thus, these data might imply that the acinar cells play an important role in response to oncogenic mutant KRAS mediated transformation in pancreas.	('mutant', 'Var', (99, 105))	('KRAS', 'Gene', (106, 110))	('KRAS', 'Gene', '16653', (106, 110))
27113	31480737	Thus, the cell population that is demonstrated to support PanIN formation following Kras activation can be tested for its ability to support PDAC development following the superimposed deletion of Ink4/Arf, p53, SMAD4, or other mutations within that compartment.	('Kras', 'Gene', (84, 88))	('PanIN', 'Disease', 'MESH:D002278', (58, 63))	('PanIN', 'Disease', (58, 63))	('Kras', 'Gene', '16653', (84, 88))	('SMAD4', 'Gene', (212, 217))	('p53', 'Gene', (207, 210))	('Arf', 'Gene', (202, 205))	('formation', 'biological_process', 'GO:0009058', ('64', '73'))	('deletion', 'Var', (185, 193))	('Arf', 'Gene', '12578', (202, 205))	('SMAD4', 'Gene', '17128', (212, 217))	('PDAC', 'Disease', (141, 145))	('PDAC', 'Phenotype', 'HP:0006725', (141, 145))	('PDAC', 'Disease', 'MESH:D021441', (141, 145))
27116	31480737	In vitro and xenograft studies have provided evidence that PI3K is critical for PDAC pathogenesis.	('PI3K', 'Var', (59, 63))	('pathogenesis', 'biological_process', 'GO:0009405', ('85', '97'))	('PDAC', 'Disease', (80, 84))	('PDAC', 'Phenotype', 'HP:0006725', (80, 84))	('PDAC', 'Disease', 'MESH:D021441', (80, 84))	('PI3K', 'molecular_function', 'GO:0016303', ('59', '63'))
27118	31480737	Along with chemical inhibitors or expression of dominant-negative AKT mutants, it interferes with cell growth, survival, and response to chemotherapy.	('response to chemotherapy', 'CPA', (125, 149))	('mutants', 'Var', (70, 77))	('AKT', 'Gene', (66, 69))	('cell growth', 'CPA', (98, 109))	('survival', 'CPA', (111, 119))	('AKT', 'Gene', '11651', (66, 69))	('cell growth', 'biological_process', 'GO:0016049', ('98', '109'))	('interferes', 'NegReg', (82, 92))
27119	31480737	The mutant activated KRAS, the defining mutation hot spot in PDAC, may activate the PI3K/AKT pathway directly, or through promoting autocrine EGFR signaling.	('activate', 'PosReg', (71, 79))	('mutant', 'Var', (4, 10))	('PDAC', 'Disease', (61, 65))	('KRAS', 'Gene', '16653', (21, 25))	('PDAC', 'Disease', 'MESH:D021441', (61, 65))	('PDAC', 'Phenotype', 'HP:0006725', (61, 65))	('AKT', 'Gene', '11651', (89, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('142', '146'))	('PI3K', 'molecular_function', 'GO:0016303', ('84', '88'))	('promoting', 'PosReg', (122, 131))	('KRAS', 'Gene', (21, 25))	('AKT', 'Gene', (89, 92))	('signaling', 'biological_process', 'GO:0023052', ('147', '156'))	('autocrine EGFR signaling', 'MPA', (132, 156))
27121	31480737	Notably, mutations in PTEN do not appear to contribute to AKT activation in PDAC, although some tumors may have reduced PTEN expression levels.	('PDAC', 'Disease', (76, 80))	('PDAC', 'Phenotype', 'HP:0006725', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mutations', 'Var', (9, 18))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('expression levels', 'MPA', (125, 142))	('PTEN', 'Gene', '19211', (22, 26))	('PTEN', 'Gene', (22, 26))	('PTEN', 'Gene', (120, 124))	('PTEN', 'Gene', '19211', (120, 124))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('reduced', 'NegReg', (112, 119))	('AKT', 'Gene', '11651', (58, 61))	('PDAC', 'Disease', 'MESH:D021441', (76, 80))	('AKT', 'Gene', (58, 61))
27122	31480737	In addition, amplification of regions of chromosome 19 spanning the AKT locus are detected in some PDAC cell lines and primary tumors, and correlate with high relative levels of AKT expression, suggesting that gene copy increases may contribute to elevated AKT activity in some PDACs.	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('primary tumors', 'Disease', 'MESH:D001932', (119, 133))	('PDAC', 'Disease', 'MESH:D021441', (99, 103))	('PDAC', 'Disease', (99, 103))	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))	('gene copy increases', 'Var', (210, 229))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('activity', 'MPA', (261, 269))	('PDAC', 'Disease', (278, 282))	('PDAC', 'Disease', 'MESH:D021441', (278, 282))	('elevated', 'PosReg', (248, 256))	('primary tumors', 'Disease', (119, 133))	('AKT', 'Gene', (68, 71))	('AKT', 'Gene', (178, 181))	('AKT', 'Gene', (257, 260))	('expression', 'MPA', (182, 192))	('PDAC', 'Phenotype', 'HP:0006725', (99, 103))	('AKT', 'Gene', '11651', (178, 181))	('AKT', 'Gene', '11651', (68, 71))	('PDAC', 'Phenotype', 'HP:0006725', (278, 282))	('AKT', 'Gene', '11651', (257, 260))
27125	31480737	Their results supported that p110alpha is also a target in p53 mutant PDAC.	('PDAC', 'Phenotype', 'HP:0006725', (70, 74))	('p53', 'Gene', (59, 62))	('mutant', 'Var', (63, 69))	('p110alpha', 'Gene', (29, 38))	('p110alpha', 'Gene', '18706', (29, 38))	('PDAC', 'Disease', 'MESH:D021441', (70, 74))	('PDAC', 'Disease', (70, 74))
27126	31480737	In contrast to EGFR deletion, deletion of p110alpha completely protects from oncogenic Kras and mutated p53-induced PDAC and lethality.	('mutated', 'Var', (96, 103))	('p110alpha', 'Gene', '18706', (42, 51))	('protects', 'NegReg', (63, 71))	('lethality', 'CPA', (125, 134))	('PDAC', 'Disease', 'MESH:D021441', (116, 120))	('PDAC', 'Phenotype', 'HP:0006725', (116, 120))	('PDAC', 'Disease', (116, 120))	('p53-induced', 'Gene', (104, 115))	('deletion', 'Var', (30, 38))	('Kras', 'Gene', (87, 91))	('Kras', 'Gene', '16653', (87, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('15', '19'))	('p110alpha', 'Gene', (42, 51))
27129	31480737	The EGFR pathway is also likely to contribute to the maintenance of established tumors, since disruption of EGFR signaling in human PDAC cells inhibits growth in vitro and tumorigenesis in xenografts.	('inhibits', 'NegReg', (143, 151))	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (172, 177))	('tumors', 'Disease', (80, 86))	('disruption', 'Var', (94, 104))	('PDAC', 'Phenotype', 'HP:0006725', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('growth', 'CPA', (152, 158))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('human', 'Species', '9606', (126, 131))	('tumor', 'Disease', (80, 85))	('EGFR signaling', 'Gene', (108, 122))	('PDAC', 'Disease', (132, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('4', '8'))	('PDAC', 'Disease', 'MESH:D021441', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))
27132	31480737	However, mouse models from others further indicated that aberrant activation of EGFR signaling in the pancreas produces metaplastic change of the pancreatic ducts, lesions that subsequently evolve into benign cystadenomas in the context of p53 and/or Ink4a/Arf loss.	('p53', 'Gene', (240, 243))	('Arf loss', 'Disease', (257, 265))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('mouse', 'Species', '10090', (9, 14))	('metaplastic change of', 'CPA', (120, 141))	('Ink4a/Arf', 'Gene', '12578', (251, 260))	('Ink4a/Arf', 'Gene', (251, 260))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('EGFR signaling', 'Gene', (80, 94))	('Arf loss', 'Disease', 'MESH:D016388', (257, 265))	('benign cystadenomas', 'Disease', (202, 221))	('benign cystadenomas', 'Disease', 'MESH:D003537', (202, 221))	('aberrant', 'Var', (57, 65))	('activation', 'PosReg', (66, 76))
27134	31480737	Aberrant activation of the PI3K-AKT pathway has been widely implicated in human cancers, including PDAC.	('PI3K', 'molecular_function', 'GO:0016303', ('27', '31'))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('AKT', 'Gene', '11651', (32, 35))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('PDAC', 'Disease', 'MESH:D021441', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('PDAC', 'Disease', (99, 103))	('PDAC', 'Phenotype', 'HP:0006725', (99, 103))	('AKT', 'Gene', (32, 35))	('implicated', 'Reg', (60, 70))	('human', 'Species', '9606', (74, 79))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
27136	31480737	While mutation of PTEN is not common in pancreatic cancer, a decrease or loss of PTEN expression has been reported in up to 60% of pancreatic cancer cell lines or tumor tissues.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PTEN', 'Gene', '19211', (81, 85))	('tumor', 'Disease', (163, 168))	('pancreatic cancer', 'Disease', (40, 57))	('decrease', 'NegReg', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('loss', 'NegReg', (73, 77))	('PTEN', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('expression', 'MPA', (86, 96))	('pancreatic cancer', 'Disease', (131, 148))	('PTEN', 'Gene', (81, 85))	('mutation', 'Var', (6, 14))	('PTEN', 'Gene', '19211', (18, 22))	('pancreatic cancer', 'Disease', 'MESH:D010190', (40, 57))
27139	31480737	A previous work with mice with only Pten deficiency in the pancreas revealed that loss of PTEN function in Pdx1-Cre, PtenLox/Lox mice led to a centroacinar cell that possessed adult stem cell properties, the expansion of which produced metaplasias similar to the phenotypes of Pdx1-Cre, KrasG12D/+, PtenLox/+ mice.	('Lox', 'Gene', (303, 306))	('PTEN', 'Gene', '19211', (90, 94))	('KrasG12D', 'Gene', (287, 295))	('Pdx1', 'Gene', (107, 111))	('Pten deficiency in the pancreas', 'Disease', (36, 67))	('produced', 'Reg', (227, 235))	('mice', 'Species', '10090', (21, 25))	('centroacinar cell', 'CPA', (143, 160))	('Pten deficiency in the pancreas', 'Disease', 'MESH:D010190', (36, 67))	('metaplasias', 'CPA', (236, 247))	('Lox', 'Gene', '16948', (125, 128))	('loss', 'NegReg', (82, 86))	('function', 'Var', (95, 103))	('mice', 'Species', '10090', (129, 133))	('Pdx1', 'Gene', '18609', (277, 281))	('adult stem cell properties', 'CPA', (176, 202))	('Lox', 'Gene', (125, 128))	('PTEN', 'Gene', (90, 94))	('Pdx1', 'Gene', (277, 281))	('KrasG12D', 'Gene', '16653', (287, 295))	('Lox', 'Gene', '16948', (121, 124))	('Lox', 'Gene', '16948', (303, 306))	('mice', 'Species', '10090', (309, 313))	('Pdx1', 'Gene', '18609', (107, 111))	('Lox', 'Gene', (121, 124))
27143	31480737	Inactivation or down regulation of LKB1 gene has been observed in a numerous of human cancers, including pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('observed', 'Reg', (54, 62))	('regulation', 'biological_process', 'GO:0065007', ('21', '31'))	('pancreatic cancer', 'Disease', (105, 122))	('down regulation', 'NegReg', (16, 31))	('LKB1', 'Gene', (35, 39))	('pancreatic cancer', 'Disease', 'MESH:D010190', (105, 122))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('Inactivation', 'Var', (0, 12))
27144	31480737	In addition, germline mutations in LKB1 have been associated with Peutz-Jeghers syndrome, which comprises gastrointestinal polyps and increases more than 100-fold, the risk of developing pancreatic cancer.	('gastrointestinal polyps', 'Disease', (106, 129))	('gastrointestinal polyps', 'Disease', 'MESH:D011127', (106, 129))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (187, 204))	('Peutz-Jeghers syndrome', 'Disease', 'MESH:D010580', (66, 88))	('pancreatic cancer', 'Disease', (187, 204))	('gastrointestinal polyps', 'Phenotype', 'HP:0200008', (106, 129))	('LKB1', 'Gene', (35, 39))	('germline mutations', 'Var', (13, 31))	('pancreatic cancer', 'Disease', 'MESH:D010190', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('associated', 'Reg', (50, 60))	('Peutz-Jeghers syndrome', 'Disease', (66, 88))
27145	31480737	Knockdown of LKB1 has been reported to increase cell growth, migration, invasion, and chemoresistance in PDAC.	('LKB1', 'Gene', (13, 17))	('PDAC', 'Disease', (105, 109))	('cell growth', 'CPA', (48, 59))	('PDAC', 'Disease', 'MESH:D021441', (105, 109))	('PDAC', 'Phenotype', 'HP:0006725', (105, 109))	('Knockdown', 'Var', (0, 9))	('increase', 'PosReg', (39, 47))	('migration', 'CPA', (61, 70))	('cell growth', 'biological_process', 'GO:0016049', ('48', '59'))	('invasion', 'CPA', (72, 80))	('chemoresistance', 'CPA', (86, 101))
27146	31480737	Moreover, as conventional knockout of Lkb1 in mice leads to embryonic lethality, conditional deletion of the LKB1 gene in the pancreas was generated and demonstrated the presence of cystic neoplasms that resemble human mucinous cystic neoplasms (MCNs).	('Lkb1', 'Gene', '20869', (38, 42))	('neoplasms', 'Phenotype', 'HP:0002664', (235, 244))	('neoplasm', 'Phenotype', 'HP:0002664', (189, 197))	('cystic neoplasms', 'Phenotype', 'HP:0010576', (228, 244))	('mucinous cystic neoplasms', 'Disease', 'MESH:D018297', (219, 244))	('cystic neoplasms', 'Disease', (182, 198))	('neoplasm', 'Phenotype', 'HP:0002664', (235, 243))	('cystic neoplasms', 'Disease', 'MESH:D052177', (182, 198))	('MCNs', 'Disease', (246, 250))	('deletion', 'Var', (93, 101))	('MCNs', 'Disease', 'MESH:D018297', (246, 250))	('embryonic lethality', 'Disease', (60, 79))	('human', 'Species', '9606', (213, 218))	('mucinous cystic neoplasms', 'Disease', (219, 244))	('Lkb1', 'Gene', (38, 42))	('cystic neoplasms', 'Phenotype', 'HP:0010576', (182, 198))	('cystic neoplasms', 'Disease', 'MESH:D052177', (228, 244))	('embryonic lethality', 'Disease', 'MESH:D020964', (60, 79))	('mice', 'Species', '10090', (46, 50))	('LKB1', 'Gene', (109, 113))	('neoplasms', 'Phenotype', 'HP:0002664', (189, 198))
27149	31480737	Loss of INK4A function, brought about by mutation, deletion, or promoter hypermethylation, occurs in 85%-90% of sporadic PDACs.	('function', 'MPA', (14, 22))	('INK4A', 'Gene', (8, 13))	('mutation', 'Var', (41, 49))	('Loss', 'NegReg', (0, 4))	('PDAC', 'Phenotype', 'HP:0006725', (121, 125))	('promoter', 'MPA', (64, 72))	('PDAC', 'Disease', (121, 125))	('deletion', 'Var', (51, 59))	('PDAC', 'Disease', 'MESH:D021441', (121, 125))
27153	31480737	In humans, INK4A appears to be the more important pancreatic cancer suppressor of this locus, as evidenced by germline and sporadic mutations that target INK4A but spare ARF.	('ARF', 'Gene', (170, 173))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 67))	('mutations', 'Var', (132, 141))	('pancreatic cancer', 'Disease', (50, 67))	('humans', 'Species', '9606', (3, 9))	('pancreatic cancer', 'Disease', 'MESH:D010190', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('INK4A', 'Gene', (154, 159))	('ARF', 'Gene', '12578', (170, 173))
27155	31480737	Nabeel and his colleagues investigated the role of the Ink4a/Arf locus in suppression of pancreatic ductal neoplasia in the mice and have found that Ink4a/Arf deletion alone does not give significant predisposition to PDAC but that, in the context of Kras activation, Ink4a/Arf deficiency leads to the rapid progression of PanIN to metastatic PDAC.	('PDAC', 'Disease', 'MESH:D021441', (218, 222))	('PDAC', 'Disease', (218, 222))	('PDAC', 'Disease', 'MESH:D021441', (343, 347))	('neoplasia', 'Phenotype', 'HP:0002664', (107, 116))	('PDAC', 'Disease', (343, 347))	('mice', 'Species', '10090', (124, 128))	('PanIN', 'Disease', 'MESH:D002278', (323, 328))	('Ink4a/Arf', 'Gene', (268, 277))	('Ink4a/Arf', 'Gene', (149, 158))	('Ink4a/Arf', 'Gene', (55, 64))	('Arf deficiency', 'Disease', (274, 288))	('pancreatic ductal neoplasia', 'Disease', 'MESH:D021441', (89, 116))	('PDAC', 'Phenotype', 'HP:0006725', (218, 222))	('PDAC', 'Phenotype', 'HP:0006725', (343, 347))	('Kras', 'Gene', (251, 255))	('Ink4a/Arf', 'Gene', '12578', (268, 277))	('Ink4a/Arf', 'Gene', '12578', (55, 64))	('Ink4a/Arf', 'Gene', '12578', (149, 158))	('Arf deficiency', 'Disease', 'None', (274, 288))	('Kras', 'Gene', '16653', (251, 255))	('PanIN', 'Disease', (323, 328))	('deletion', 'Var', (159, 167))	('pancreatic ductal neoplasia', 'Disease', (89, 116))
27159	31480737	In this model, LSL-KrasG12D, Pdx1-Cre, Ink4a/ArfLoxp/Loxp mice with documented efficient deletion of the Ink4a/Arf in the pancreas developed weight loss, ascites, jaundice, and a palpable abdominal mass between seven and 11 weeks of age.	('Lox', 'Gene', '16948', (48, 51))	('Ink4a/Arf', 'Gene', (105, 114))	('ascites', 'Disease', (154, 161))	('deletion', 'Var', (89, 97))	('Lox', 'Gene', (48, 51))	('Ink4a/Arf', 'Gene', '12578', (105, 114))	('Ink4a/Arf', 'Gene', (39, 48))	('jaundice', 'Phenotype', 'HP:0000952', (163, 171))	('ascites', 'Disease', 'MESH:D001201', (154, 161))	('abdominal mass', 'Phenotype', 'HP:0031500', (188, 202))	('palpable abdominal mass', 'CPA', (179, 202))	('KrasG12D', 'Gene', '16653', (19, 27))	('Lox', 'Gene', '16948', (53, 56))	('Ink4a/Arf', 'Gene', '12578', (39, 48))	('weight loss', 'Disease', 'MESH:D015431', (141, 152))	('jaundice', 'Disease', (163, 171))	('ascites', 'Phenotype', 'HP:0001541', (154, 161))	('Lox', 'Gene', (53, 56))	('mice', 'Species', '10090', (58, 62))	('weight loss', 'Phenotype', 'HP:0001824', (141, 152))	('Pdx1', 'Gene', '18609', (29, 33))	('jaundice', 'Disease', 'MESH:D007565', (163, 171))	('KrasG12D', 'Gene', (19, 27))	('Pdx1', 'Gene', (29, 33))	('weight loss', 'Disease', (141, 152))
27165	31480737	The tumor suppressor role of TGFbeta signaling is underscored by presence of inactivating TGFbeta receptor mutations in a number of cancers.	('tumor', 'Disease', (4, 9))	('cancers', 'Disease', (132, 139))	('TGFbeta', 'Gene', (29, 36))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('mutations', 'Var', (107, 116))	('TGFbeta', 'Gene', '21803', (90, 97))	('inactivating', 'NegReg', (77, 89))	('TGFbeta', 'Gene', '21803', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor suppressor', 'biological_process', 'GO:0051726', ('4', '20'))	('TGFbeta', 'Gene', (90, 97))	('signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('4', '20'))
27166	31480737	Significantly the role of TGFbeta in blocking cancer development also involves control of epithelial cell/tissue microenvironment interactions, as demonstrated by the development of epithelial cancers in mice with T-cell specific Smad4 deletion and fibroblast-specific TGFbetaRII deletion.	('TGFbeta', 'Gene', (26, 33))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('TGFbeta', 'Gene', '21803', (269, 276))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('epithelial cancers', 'Disease', 'MESH:D009369', (182, 200))	('cancer', 'Disease', (193, 199))	('deletion', 'Var', (280, 288))	('deletion', 'Var', (236, 244))	('cancer', 'Disease', (46, 52))	('TGFbeta', 'Gene', '21803', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('epithelial cancers', 'Disease', (182, 200))	('TGFbeta', 'Gene', (269, 276))	('mice', 'Species', '10090', (204, 208))	('Smad4', 'Gene', (230, 235))
27167	31480737	Finally, it should be noted that inactivation of BMP and Activin signaling are also implicated in cancer development, hence the tumor suppressor function of Smad4 may also involve a requirement in mediating signaling from these receptors (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Activin', 'molecular_function', 'GO:0005160', ('57', '64'))	('cancer', 'Disease', (98, 104))	('Activin', 'Gene', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Activin', 'molecular_function', 'GO:0016915', ('57', '64'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('128', '144'))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))	('BMP', 'MPA', (49, 52))	('signaling', 'biological_process', 'GO:0023052', ('207', '216'))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor suppressor', 'biological_process', 'GO:0051726', ('128', '144'))	('tumor', 'Disease', (128, 133))	('inactivation', 'Var', (33, 45))	('mediating', 'MPA', (197, 206))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('implicated', 'Reg', (84, 94))	('Activin', 'Gene', '83729', (57, 64))	('Smad4', 'Gene', (157, 162))
27174	31480737	This gene maps to human chromosome 18q21, a region that sustains deletion in approximately 30% of PDAC cases.	('PDAC', 'Disease', 'MESH:D021441', (98, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('24', '34'))	('human', 'Species', '9606', (18, 23))	('PDAC', 'Disease', (98, 102))	('PDAC', 'Phenotype', 'HP:0006725', (98, 102))	('deletion', 'Var', (65, 73))
27175	31480737	Inactivating mutations in Smad4 are far more common in PDAC than in any other cancer type.	('common', 'Reg', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PDAC', 'Phenotype', 'HP:0006725', (55, 59))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('Inactivating mutations', 'Var', (0, 22))	('Smad4', 'Gene', (26, 31))	('PDAC', 'Disease', (55, 59))	('PDAC', 'Disease', 'MESH:D021441', (55, 59))
27176	31480737	The biological role of Smad4 mutations in human PDAC progression is an area of active investigation, often with contrasting observation.	('human', 'Species', '9606', (42, 47))	('mutations', 'Var', (29, 38))	('Smad4', 'Gene', (23, 28))	('PDAC progression', 'Disease', 'MESH:D021441', (48, 64))	('PDAC', 'Phenotype', 'HP:0006725', (48, 52))	('PDAC progression', 'Disease', (48, 64))
27184	31480737	While KrasG12D alone initiated PanIN development that progressed slowly to PDAC, the combination of mutant KrasG12D and SMAD4 deficiency in the mouse pancreas resulted in the development of tumors resembling human intraductal papillary mucinous neoplasia (IPMN).	('KrasG12D', 'Gene', '16653', (6, 14))	('mouse', 'Species', '10090', (144, 149))	('PDAC', 'Disease', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('PDAC', 'Disease', 'MESH:D021441', (75, 79))	('PanIN', 'Disease', 'MESH:D002278', (31, 36))	('development', 'Reg', (175, 186))	('tumors', 'Disease', (190, 196))	('human', 'Species', '9606', (208, 213))	('SMAD4 deficiency', 'Disease', 'MESH:C537702', (120, 136))	('intraductal papillary mucinous neoplasia', 'Disease', (214, 254))	('KrasG12D', 'Gene', '16653', (107, 115))	('KrasG12D', 'Gene', (6, 14))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('SMAD4 deficiency', 'Disease', (120, 136))	('mucinous neoplasia', 'Phenotype', 'HP:0031495', (236, 254))	('PDAC', 'Phenotype', 'HP:0006725', (75, 79))	('neoplasia', 'Phenotype', 'HP:0002664', (245, 254))	('IPMN', 'Disease', (256, 260))	('KrasG12D', 'Gene', (107, 115))	('IPMN', 'Disease', 'MESH:C565310', (256, 260))	('resulted in', 'Reg', (159, 170))	('intraductal papillary mucinous neoplasia', 'Disease', 'MESH:C565310', (214, 254))	('mutant', 'Var', (100, 106))	('PanIN', 'Disease', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
27186	31480737	TGFbeta is thought to promote PDAC desmoplasia (stromal proliferation), as well as contribute to the proliferation and invasion of the tumor cells in an autocrine manner; notably, the blockade of TGFbeta signaling attenuates tumorigenicity of some xenografts.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('signaling', 'biological_process', 'GO:0023052', ('204', '213'))	('promote', 'PosReg', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('PDAC', 'Disease', 'MESH:D021441', (30, 34))	('TGFbeta', 'Gene', (0, 7))	('tumor', 'Disease', (135, 140))	('TGFbeta', 'Gene', (196, 203))	('tumor', 'Disease', (225, 230))	('PDAC', 'Disease', (30, 34))	('blockade', 'Var', (184, 192))	('PDAC', 'Phenotype', 'HP:0006725', (30, 34))	('attenuates', 'NegReg', (214, 224))	('TGFbeta', 'Gene', '21803', (0, 7))	('TGFbeta', 'Gene', '21803', (196, 203))	('contribute', 'Reg', (83, 93))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
27187	31480737	In contrast, the tumor suppressor role of TGFbeta signaling is underscored by presence of inactivating TGFbeta receptor mutations in many different cancers, including colorectal and pancreatic cancer (Figure 3).	('tumor suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('mutations', 'Var', (120, 129))	('TGFbeta', 'Gene', (103, 110))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('tumor suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('tumor', 'Disease', (17, 22))	('inactivating', 'NegReg', (90, 102))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (182, 199))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('TGFbeta', 'Gene', '21803', (42, 49))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('cancers', 'Disease', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('colorectal and pancreatic cancer', 'Disease', 'MESH:D015179', (167, 199))	('TGFbeta', 'Gene', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('TGFbeta', 'Gene', '21803', (103, 110))
27188	31480737	Significantly, the role of TGFbeta in blocking cancer development also involves control of epithelial cell/tissue microenvironment interactions, as demonstrated by the development of epithelial cancers in mice with T-cell specific Smad4 deletion and fibroblast-specific TGFbetaRII deletion.	('cancer', 'Disease', (194, 200))	('TGFbeta', 'Gene', '21803', (27, 34))	('TGFbeta', 'Gene', (270, 277))	('epithelial cancers', 'Disease', (183, 201))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('cancer', 'Disease', (47, 53))	('Smad4', 'Gene', (231, 236))	('TGFbeta', 'Gene', '21803', (270, 277))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('TGFbeta', 'Gene', (27, 34))	('deletion', 'Var', (281, 289))	('mice', 'Species', '10090', (205, 209))	('epithelial cancers', 'Disease', 'MESH:D009369', (183, 201))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('deletion', 'Var', (237, 245))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
27193	31480737	TGFbeta signal is an important biological tumor suppressor program that is based on the prevalent genomic deletion of the TGF-beta superfamily gene in pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (151, 168))	('tumor', 'Disease', (42, 47))	('TGFbeta', 'Gene', (0, 7))	('TGF-beta', 'Gene', '21803', (122, 130))	('deletion', 'Var', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('TGFbeta', 'Gene', '21803', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('TGF-beta', 'Gene', (122, 130))	('pancreatic cancer', 'Disease', (151, 168))
27194	31480737	Recently, it has been identified that aberrations in the TGFbeta superfamily pathway, whether through the BMPs, Activin, or TGFbeta receptor of the pathway, can result in tumorigenesis and promote the tumor progression.	('TGFbeta', 'Gene', '21803', (124, 131))	('Activin', 'molecular_function', 'GO:0005160', ('112', '119'))	('TGFbeta', 'Gene', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (201, 206))	('Activin', 'Gene', '83729', (112, 119))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('promote', 'PosReg', (189, 196))	('Activin', 'molecular_function', 'GO:0016915', ('112', '119'))	('result in', 'Reg', (161, 170))	('TGFbeta', 'Gene', (124, 131))	('TGFbeta', 'Gene', '21803', (57, 64))	('aberrations', 'Var', (38, 49))	('Activin', 'Gene', (112, 119))
27196	31480737	Results from cancer genome-sequencing studies revealed that the activin A receptor Type 1B (ACVR1B) gene is mutated around 2% of PDAC samples, which may imply that ACVR1B could be a tumor suppressor gene in PDAC (Figure 3).	('PDAC', 'Disease', 'MESH:D021441', (129, 133))	('ACVR1B', 'Gene', '11479', (164, 170))	('PDAC', 'Disease', (129, 133))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('activin A receptor Type 1B', 'Gene', (64, 90))	('PDAC', 'Disease', 'MESH:D021441', (207, 211))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('PDAC', 'Disease', (207, 211))	('mutated', 'Var', (108, 115))	('activin', 'molecular_function', 'GO:0005160', ('64', '71'))	('ACVR1B', 'Gene', (92, 98))	('ACVR1B', 'Gene', (164, 170))	('PDAC', 'Phenotype', 'HP:0006725', (129, 133))	('activin', 'molecular_function', 'GO:0016915', ('64', '71'))	('cancer', 'Disease', (13, 19))	('activin A receptor Type 1B', 'Gene', '11479', (64, 90))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('182', '198'))	('PDAC', 'Phenotype', 'HP:0006725', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', (182, 187))	('tumor suppressor', 'biological_process', 'GO:0051726', ('182', '198'))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('ACVR1B', 'Gene', '11479', (92, 98))
27197	31480737	Meanwhile, Activin signaling alterations are also implicated in cancer development.	('Activin', 'Gene', (11, 18))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('implicated', 'Reg', (50, 60))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('alterations', 'Var', (29, 40))	('Activin', 'molecular_function', 'GO:0005160', ('11', '18'))	('Activin', 'Gene', '83729', (11, 18))	('Activin', 'molecular_function', 'GO:0016915', ('11', '18'))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
27201	31480737	Furthermore, a conditional knockout of ACVR1B in the pancreas increased the proliferation of pancreatic epithelial cells, promoted to the formation of ADM (acinar to ductal metaplasia), and induced pancreatic inflammation.	('increased', 'PosReg', (62, 71))	('induced', 'Reg', (190, 197))	('pancreatic inflammation', 'Disease', 'MESH:D007249', (198, 221))	('pancreatic inflammation', 'Disease', (198, 221))	('inflammation', 'biological_process', 'GO:0006954', ('209', '221'))	('metaplasia', 'biological_process', 'GO:0036074', ('173', '183'))	('proliferation', 'CPA', (76, 89))	('promoted', 'PosReg', (122, 130))	('knockout', 'Var', (27, 35))	('formation', 'biological_process', 'GO:0009058', ('138', '147'))	('ACVR1B', 'Gene', (39, 45))	('ACVR1B', 'Gene', '11479', (39, 45))	('pancreatic inflammation', 'Phenotype', 'HP:0001733', (198, 221))
27202	31480737	Disruption of Acvr1b cooperating with Kras accelerated the development of cysts that resembled intraductal papillary mucinous neoplasm, but did not alter the growth of pancreatic intraepithelial neoplasias.	('intraductal papillary mucinous neoplasm', 'Disease', (95, 134))	('intraductal papillary mucinous neoplasm', 'Disease', 'MESH:D002285', (95, 134))	('Acvr1b', 'Gene', (14, 20))	('neoplasias', 'Phenotype', 'HP:0002664', (195, 205))	('mucinous neoplasm', 'Phenotype', 'HP:0031495', (117, 134))	('neoplasm', 'Phenotype', 'HP:0002664', (126, 134))	('accelerated', 'PosReg', (43, 54))	('development of cysts', 'CPA', (59, 79))	('Kras', 'Gene', (38, 42))	('Kras', 'Gene', '16653', (38, 42))	('pancreatic intraepithelial neoplasias', 'Disease', 'MESH:D018290', (168, 205))	('Acvr1b', 'Gene', '11479', (14, 20))	('pancreatic intraepithelial neoplasias', 'Disease', (168, 205))	('intraepithelial neoplasias', 'Phenotype', 'HP:0032187', (179, 205))	('neoplasia', 'Phenotype', 'HP:0002664', (195, 204))	('Disruption', 'Var', (0, 10))
27210	31480737	In our study, we showed that loss of KLF10 cooperates with KrasG12D leading to an invasive and widely metastatic phenotype of PDAC.	('KrasG12D', 'Gene', '16653', (59, 67))	('KLF10', 'Gene', (37, 42))	('KLF10', 'Gene', '21847', (37, 42))	('KrasG12D', 'Gene', (59, 67))	('PDAC', 'Disease', 'MESH:D021441', (126, 130))	('leading to', 'Reg', (68, 78))	('loss', 'Var', (29, 33))	('PDAC', 'Disease', (126, 130))	('PDAC', 'Phenotype', 'HP:0006725', (126, 130))
27211	31480737	Our studies further revealed that loss of KLF10 increased distant metastases and cancer stemness through activation of SDF-1/CXCR4 and AP-1 pathways in PDAC.	('metastases', 'Disease', 'MESH:D009362', (66, 76))	('AP-1', 'cellular_component', 'GO:0005907', ('135', '139'))	('CXCR4', 'Gene', '12767', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PDAC', 'Disease', 'MESH:D021441', (152, 156))	('metastases', 'Disease', (66, 76))	('PDAC', 'Disease', (152, 156))	('CXCR4', 'Gene', (125, 130))	('activation', 'PosReg', (105, 115))	('KLF10', 'Gene', (42, 47))	('AP-1 pathways', 'Pathway', (135, 148))	('cancer stemness', 'Disease', 'MESH:D009369', (81, 96))	('SDF-1', 'Gene', (119, 124))	('SDF-1', 'Gene', '20315', (119, 124))	('KLF10', 'Gene', '21847', (42, 47))	('increased', 'PosReg', (48, 57))	('PDAC', 'Phenotype', 'HP:0006725', (152, 156))	('loss', 'Var', (34, 38))	('cancer stemness', 'Disease', (81, 96))	('CXCR4', 'molecular_function', 'GO:0038147', ('125', '130'))
27218	31480737	Notably, loss of TGIF1 combined with KrasG12D promoted shorter latency PDAC and a greater propensity for distant metastases.	('KrasG12D', 'Gene', (37, 45))	('TGIF1', 'Gene', (17, 22))	('PDAC', 'Disease', (71, 75))	('TGIF1', 'Gene', '21815', (17, 22))	('PDAC', 'Disease', 'MESH:D021441', (71, 75))	('PDAC', 'Phenotype', 'HP:0006725', (71, 75))	('shorter', 'NegReg', (55, 62))	('loss', 'Var', (9, 13))	('metastases', 'Disease', (113, 123))	('KrasG12D', 'Gene', '16653', (37, 45))	('metastases', 'Disease', 'MESH:D009362', (113, 123))
27223	31480737	Apc modulates the canonical Wnt signaling pathway through mediating beta-catenin degradation, thus inactivation of APC creates a permissive condition, whereby free unphosphorylated beta-catenin is significantly more stable, and translocates into the nucleus to active Wnt signaling.	('canonical Wnt signaling pathway', 'biological_process', 'GO:0060070', ('18', '49'))	('Wnt', 'Gene', (268, 271))	('inactivation', 'Var', (99, 111))	('Wnt', 'Gene', '22408', (268, 271))	('Wnt', 'Gene', (28, 31))	('Apc', 'cellular_component', 'GO:0005680', ('0', '3'))	('Wnt', 'Gene', '22408', (28, 31))	('beta-catenin', 'MPA', (68, 80))	('modulates', 'Reg', (4, 13))	('Apc', 'Gene', (0, 3))	('APC', 'Disease', 'MESH:D011125', (115, 118))	('more', 'PosReg', (211, 215))	('Apc', 'Gene', '11789', (0, 3))	('APC', 'Disease', (115, 118))	('degradation', 'biological_process', 'GO:0009056', ('81', '92'))	('APC', 'cellular_component', 'GO:0005680', ('115', '118'))	('translocates', 'MPA', (228, 240))	('signaling', 'biological_process', 'GO:0023052', ('272', '281'))	('nucleus', 'cellular_component', 'GO:0005634', ('250', '257'))
27226	31480737	Additionally, ectopic activation of Wnt signaling at early stages of pancreas organogenesis may regulate the increases of Hedgehog activity, while Hedgehog signaling is known to active embryonic activity in many endodermal organs.	('Wnt', 'Gene', (36, 39))	('Wnt', 'Gene', '22408', (36, 39))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('ectopic', 'Var', (14, 21))	('increases', 'PosReg', (109, 118))	('Hedgehog activity', 'MPA', (122, 139))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('organogenesis', 'biological_process', 'GO:0048513', ('78', '91'))
27227	31480737	Further, upregulation of Wnt signaling could be induced via specific mutations in the APC, beta-catenin, or Axin genes, which are thought to play some crucial roles in the development of human gastrointestinal tumors.	('gastrointestinal tumors', 'Disease', (193, 216))	('mutations', 'Var', (69, 78))	('Axin', 'Gene', '8312', (108, 112))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (193, 216))	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('upregulation', 'PosReg', (9, 21))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('gastrointestinal tumors', 'Disease', 'MESH:D005770', (193, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('beta-catenin', 'Gene', (91, 103))	('Axin', 'Gene', (108, 112))	('APC', 'Disease', 'MESH:D011125', (86, 89))	('Wnt', 'Gene', (25, 28))	('APC', 'Disease', (86, 89))	('human', 'Species', '9606', (187, 192))	('Wnt', 'Gene', '22408', (25, 28))	('APC', 'cellular_component', 'GO:0005680', ('86', '89'))
27228	31480737	Mutations in either APC or beta-catenin are commonly found in other gastrointestinal cancer, including PDAC.	('found', 'Reg', (53, 58))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (68, 91))	('APC', 'Disease', 'MESH:D011125', (20, 23))	('gastrointestinal cancer', 'Disease', (68, 91))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (68, 91))	('Mutations', 'Var', (0, 9))	('PDAC', 'Disease', 'MESH:D021441', (103, 107))	('APC', 'Disease', (20, 23))	('beta-catenin', 'Protein', (27, 39))	('PDAC', 'Disease', (103, 107))	('PDAC', 'Phenotype', 'HP:0006725', (103, 107))	('APC', 'cellular_component', 'GO:0005680', ('20', '23'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
27233	31480737	From our previous study, attempting to study the deletion of APC in the pancreas, we observed that APC haploinsufficiency corresponded with KrasG12D mutation and P53 loss in mice, leading to rapidly increased development of metastatic PDAC when compared with Pdx1-cre, KrasG12D, P53Lox/+ mice That evidence indicated a critical tumor suppressor role of APC in pancreatic cancer progression.	('mice', 'Species', '10090', (174, 178))	('KrasG12D', 'Gene', '16653', (269, 277))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (360, 377))	('APC haploinsufficiency', 'Disease', (99, 121))	('KrasG12D', 'Gene', '16653', (140, 148))	('tumor', 'Disease', (328, 333))	('APC', 'cellular_component', 'GO:0005680', ('353', '356'))	('PDAC', 'Phenotype', 'HP:0006725', (235, 239))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('mice', 'Species', '10090', (288, 292))	('KrasG12D', 'Gene', (269, 277))	('APC', 'Disease', 'MESH:D011125', (99, 102))	('APC haploinsufficiency', 'Disease', 'MESH:D058495', (99, 121))	('APC', 'Disease', 'MESH:D011125', (61, 64))	('pancreatic cancer', 'Disease', 'MESH:D010190', (360, 377))	('APC', 'Disease', 'MESH:D011125', (353, 356))	('APC', 'Disease', (99, 102))	('APC', 'Disease', (353, 356))	('APC', 'Disease', (61, 64))	('APC', 'cellular_component', 'GO:0005680', ('61', '64'))	('KrasG12D', 'Gene', (140, 148))	('Pdx1', 'Gene', '18609', (259, 263))	('APC', 'cellular_component', 'GO:0005680', ('99', '102'))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('P53', 'Gene', (162, 165))	('increased', 'PosReg', (199, 208))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('328', '344'))	('pancreatic cancer', 'Disease', (360, 377))	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('PDAC', 'Disease', 'MESH:D021441', (235, 239))	('P53', 'Gene', '22059', (162, 165))	('PDAC', 'Disease', (235, 239))	('loss', 'NegReg', (166, 170))	('Pdx1', 'Gene', (259, 263))	('tumor suppressor', 'biological_process', 'GO:0051726', ('328', '344'))	('P53', 'Gene', (279, 282))	('P53', 'Gene', '22059', (279, 282))	('mutation', 'Var', (149, 157))
27239	31480737	Human SWI/SNF complexes contain either of two alternative catalytic (ATPase) subunits, SMARCA4 (BRG1) or SMARCA2 (BRM), as well as 8-10 other subunits.	('Human', 'Species', '9606', (0, 5))	('SMARCA2', 'Gene', (105, 112))	('SMARCA2', 'Gene', '6595', (105, 112))	('SMARCA4', 'Var', (87, 94))	('ATP', 'Chemical', 'MESH:D000255', (69, 72))	('BRM', 'Gene', (114, 117))	('BRM', 'Gene', '6595', (114, 117))
27243	31480737	In addition, ARID1A is one of the most frequently deleted genes in a variety of tumor types, and knockdown of ARID1A leads to a failure of cell cycle arrest.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('ARID1A', 'Gene', '93760', (110, 116))	('knockdown', 'Var', (97, 106))	('failure', 'NegReg', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ARID1A', 'Gene', (13, 19))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('139', '156'))	('tumor', 'Disease', (80, 85))	('ARID1A', 'Gene', '93760', (13, 19))	('ARID1A', 'Gene', (110, 116))	('cell cycle arrest', 'CPA', (139, 156))	('failure of cell cycle arrest', 'Phenotype', 'HP:0011018', (128, 156))
27246	31480737	Deletion of ATM function in mammal cells causes impairment in DNA repair functions and cell cycle checkpoint control.	('ATM', 'Gene', (12, 15))	('impairment', 'NegReg', (48, 58))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('mammal', 'Species', '9606', (28, 34))	('DNA repair', 'MPA', (62, 72))	('DNA repair', 'biological_process', 'GO:0006281', ('62', '72'))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('87', '108'))	('cell cycle checkpoint control', 'CPA', (87, 116))	('Deletion', 'Var', (0, 8))
27249	31480737	Meanwhile, germline mutations in BRCA1 and BRCA2 confer increased risks to hereditary breast and ovarian cancer syndrome.	('BRCA2', 'Gene', (43, 48))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('germline mutations', 'Var', (11, 29))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('hereditary breast and ovarian cancer syndrome', 'Disease', 'MESH:D061325', (75, 120))	('BRCA1', 'Gene', (33, 38))	('risks', 'Reg', (66, 71))
27250	31480737	A number of studies have shown that pedigrees with germline mutations in ATM, BRCA1, and BRCA2 also have an increased lifetime risk of pancreatic cancer in familial pancreatic cancer (FPC) kindreds.	('ATM', 'Gene', (73, 76))	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (135, 152))	('familial pancreatic cancer', 'Disease', (156, 182))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (156, 182))	('pancreatic cancer', 'Disease', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('pancreatic cancer', 'Disease', 'MESH:D010190', (135, 152))	('FPC', 'Disease', 'MESH:D010190', (184, 187))	('FPC', 'cellular_component', 'GO:1990900', ('184', '187'))	('BRCA2', 'Gene', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('FPC', 'Disease', (184, 187))	('BRCA1', 'Gene', (78, 83))	('germline mutations', 'Var', (51, 69))
27255	31480737	One study found that mice with conditional germline homozygosity for Brca2 truncating mutations led to developing PanINs at five months of age, and 15% of the mutant mice progressed to pancreatic cancer at 15 months of age without Kras activation.	('pancreatic cancer', 'Disease', (185, 202))	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('pancreatic cancer', 'Disease', 'MESH:D010190', (185, 202))	('Kras', 'Gene', '16653', (231, 235))	('mice', 'Species', '10090', (21, 25))	('mutant', 'Var', (159, 165))	('progressed', 'Reg', (171, 181))	('mice', 'Species', '10090', (166, 170))	('PanIN', 'Disease', 'MESH:D002278', (114, 119))	('PanIN', 'Disease', (114, 119))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (185, 202))	('Brca2', 'Gene', (69, 74))	('Kras', 'Gene', (231, 235))
27256	31480737	Furthermore, it has been reported that germline heterozygosity for BRCA2 and K-rasG12D cooperate to promote PDAC progression and systemic metastasis in mice.	('systemic metastasis', 'CPA', (129, 148))	('BRCA2', 'Gene', (67, 72))	('mice', 'Species', '10090', (152, 156))	('K-rasG12D', 'Gene', (77, 86))	('PDAC', 'Phenotype', 'HP:0006725', (108, 112))	('promote', 'PosReg', (100, 107))	('PDAC progression', 'Disease', (108, 124))	('PDAC progression', 'Disease', 'MESH:D021441', (108, 124))	('germline heterozygosity', 'Var', (39, 62))
27257	31480737	In this report, tumor growth and survival time were observed and compared in mice with Pdx1-Cre, LSL-K-rasG12D and a germline heterozygosity for Brca2 Tr/Delta11 background, and Pdx1-Cre, LSL-K-rasG12D mutant mice, and they found that the median survival for Pdx1-Cre, LSL-K-rasG12D, Brca2 Tr/Delta11 mice is significantly shorter by approximately 5 months.	('Pdx1', 'Gene', (87, 91))	('mice', 'Species', '10090', (77, 81))	('mice', 'Species', '10090', (209, 213))	('Pdx1', 'Gene', '18609', (178, 182))	('Pdx1', 'Gene', '18609', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('Pdx1', 'Gene', (259, 263))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('shorter', 'NegReg', (323, 330))	('Brca2', 'Gene', (284, 289))	('Delta11', 'Mutation', 'c.del11', (293, 300))	('Pdx1', 'Gene', '18609', (259, 263))	('tumor', 'Disease', (16, 21))	('Delta11', 'Mutation', 'c.del11', (154, 161))	('mice', 'Species', '10090', (301, 305))	('Pdx1', 'Gene', (178, 182))	('mutant', 'Var', (202, 208))
27258	31480737	In contrast, in another study to demonstrate the function of Brca2 in the progression of pancreatic cancer, the mouse models that combined pancreas specific KrasG12D activation and TP53 deletion with BRCA2 inactivation were generated.	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('TP53', 'Gene', (181, 185))	('deletion', 'Var', (186, 194))	('BRCA2', 'Gene', (200, 205))	('KrasG12D', 'Gene', (157, 165))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('mouse', 'Species', '10090', (112, 117))	('TP53', 'Gene', '22059', (181, 185))	('KrasG12D', 'Gene', '16653', (157, 165))	('pancreatic cancer', 'Disease', (89, 106))
27259	31480737	Unexpectedly, their results indicated that the mutant model of TP53 deletion and Brca2 inactivation promoted pancreatic cancer development, but the mouse model of KrasG12D combined with BRCA2 inactivation caused chromosomal instability and cell apoptosis, and resulted in the inhibition of tumors growth.	('tumors', 'Disease', 'MESH:D009369', (290, 296))	('pancreatic cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('245', '254'))	('inhibition', 'NegReg', (276, 286))	('mouse', 'Species', '10090', (148, 153))	('apoptosis', 'biological_process', 'GO:0006915', ('245', '254'))	('promoted', 'PosReg', (100, 108))	('KrasG12D', 'Gene', '16653', (163, 171))	('cell apoptosis', 'CPA', (240, 254))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('inactivation', 'Var', (192, 204))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('chromosomal instability', 'Phenotype', 'HP:0040012', (212, 235))	('deletion', 'Var', (68, 76))	('caused', 'Reg', (205, 211))	('chromosomal instability', 'CPA', (212, 235))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('KrasG12D', 'Gene', (163, 171))	('tumors', 'Disease', (290, 296))	('BRCA2', 'Gene', (186, 191))	('TP53', 'Gene', (63, 67))	('Brca2', 'Gene', (81, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('TP53', 'Gene', '22059', (63, 67))
27261	31480737	Germline mutations in ATM may cause increased risks in developing familial pancreatic cancer, and somatic mutations in ATM also have been reported in resected numerous sporadic human pancreatic cancer.	('Germline mutations', 'Var', (0, 18))	('ATM', 'Gene', (22, 25))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (183, 200))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('pancreatic cancer', 'Disease', 'MESH:D010190', (183, 200))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (66, 92))	('pancreatic cancer', 'Disease', (183, 200))	('familial pancreatic cancer', 'Disease', (66, 92))	('human', 'Species', '9606', (177, 182))	('pancreatic cancer', 'Disease', 'MESH:D010190', (75, 92))
27262	31480737	To study the loss of ATM associated with the genome integrity during PDAC progression, a recent report demonstrated the potential effects of Atm deletion in the pancreatic cancer mouse model.	('mouse', 'Species', '10090', (179, 184))	('pancreatic cancer', 'Disease', 'MESH:D010190', (161, 178))	('Atm', 'Gene', '11920', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Atm', 'Gene', (141, 144))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (161, 178))	('PDAC', 'Phenotype', 'HP:0006725', (69, 73))	('PDAC progression', 'Disease', (69, 85))	('PDAC progression', 'Disease', 'MESH:D021441', (69, 85))	('pancreatic cancer', 'Disease', (161, 178))	('deletion', 'Var', (145, 153))
27265	31480737	On the other hand, other studies indicated that ATM deficiency increases the proportion of chromosomal alterations in pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('increases', 'PosReg', (63, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (118, 135))	('chromosomal', 'Var', (91, 102))	('deficiency', 'Var', (52, 62))	('pancreatic cancer', 'Disease', (118, 135))	('pancreatic cancer', 'Disease', 'MESH:D010190', (118, 135))	('ATM', 'Gene', (48, 51))
27269	31480737	Results of several recent studies revealed that mutations, translocations, and deletions of various subunits of the SWI/SNF complex occur in approximately 20% of human cancers, thus representing one of the most common altered molecular mechanisms in human cancers.	('SWI/SNF', 'Gene', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('116', '131'))	('cancers', 'Disease', 'MESH:D009369', (256, 263))	('cancers', 'Phenotype', 'HP:0002664', (256, 263))	('cancers', 'Disease', (256, 263))	('deletions', 'Var', (79, 88))	('human', 'Species', '9606', (162, 167))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('human', 'Species', '9606', (250, 255))	('mutations', 'Var', (48, 57))	('translocations', 'Var', (59, 73))
27270	31480737	Importantly, the AT-rich interactive domain 1A (ARID1A) gene which encodes the BAF250a protein, is the most frequently mutated of the SWI/SNF subunit, and has been reported to be mutated in nearly 20%-23% of pancreatic cancer cases.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (208, 225))	('BAF250a', 'Gene', (79, 86))	('AT-rich interactive domain 1A', 'Gene', '93760', (17, 46))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('ARID1A', 'Gene', (48, 54))	('pancreatic cancer', 'Disease', (208, 225))	('pancreatic cancer', 'Disease', 'MESH:D010190', (208, 225))	('ARID1A', 'Gene', '93760', (48, 54))	('mutated', 'Var', (119, 126))	('BAF250a', 'Gene', '93760', (79, 86))	('AT-rich interactive domain 1A', 'Gene', (17, 46))	('mutated', 'Var', (179, 186))
27274	31480737	One study done in GEM models revealed that conditional knockout of ARID1A induces inflammation, PanINs, and mucinous cysts.	('induces', 'Reg', (74, 81))	('ARID1A', 'Gene', '93760', (67, 73))	('PanIN', 'Disease', 'MESH:D002278', (96, 101))	('PanIN', 'Disease', (96, 101))	('mucinous cysts', 'Phenotype', 'HP:0200040', (108, 122))	('conditional knockout', 'Var', (43, 63))	('mucinous cysts', 'Disease', 'MESH:D002288', (108, 122))	('inflammation', 'Disease', 'MESH:D007249', (82, 94))	('mucinous cysts', 'Disease', (108, 122))	('inflammation', 'Disease', (82, 94))	('inflammation', 'biological_process', 'GO:0006954', ('82', '94'))	('ARID1A', 'Gene', (67, 73))
27280	31480737	In general, mutations in the SWI/SNF complex have now been found in about 20% of all human cancers.	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('mutations', 'Var', (12, 21))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('29', '44'))	('found', 'Reg', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('SWI/SNF', 'Gene', (29, 36))	('human', 'Species', '9606', (85, 90))
27281	31480737	Notably, one-third of pancreatic cancers harbor deletions or mutations in several subunits of the SWI/SNF complex.	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('pancreatic cancers', 'Disease', 'MESH:D010190', (22, 40))	('pancreatic cancers', 'Disease', (22, 40))	('mutations', 'Var', (61, 70))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (22, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('deletions', 'Var', (48, 57))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (22, 40))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('98', '113'))
27285	31480737	Meanwhile, results from genetically mouse models revealed that conditional deletion of BRG-1 in the pancreas from the mouse model of mutant KrasG12D induced PDAC resulted in the formation of MCNs or IPMNs, and some progress to PDAC.	('MCNs', 'Disease', (191, 195))	('formation', 'MPA', (178, 187))	('PDAC', 'Phenotype', 'HP:0006725', (157, 161))	('MCNs', 'Disease', 'MESH:D018297', (191, 195))	('formation', 'biological_process', 'GO:0009058', ('178', '187'))	('KrasG12D', 'Gene', '16653', (140, 148))	('mouse', 'Species', '10090', (118, 123))	('BRG-1', 'Gene', (87, 92))	('PDAC', 'Phenotype', 'HP:0006725', (227, 231))	('PDAC', 'Disease', (157, 161))	('KrasG12D', 'Gene', (140, 148))	('PDAC', 'Disease', 'MESH:D021441', (157, 161))	('mutant', 'Var', (133, 139))	('progress', 'PosReg', (215, 223))	('mouse', 'Species', '10090', (36, 41))	('IPMN', 'Disease', (199, 203))	('IPMN', 'Disease', 'MESH:C565310', (199, 203))	('PDAC', 'Disease', 'MESH:D021441', (227, 231))	('PDAC', 'Disease', (227, 231))
27286	31480737	In contrast, restoration of Brg1 expression leads to induce the mesenchymal phenotype in mouse and human BRG-1 null PDAC cells.	('Brg1', 'Gene', '20586', (28, 32))	('PDAC', 'Phenotype', 'HP:0006725', (116, 120))	('PDAC', 'Disease', 'MESH:D021441', (116, 120))	('PDAC', 'Disease', (116, 120))	('human', 'Species', '9606', (99, 104))	('mesenchymal phenotype', 'CPA', (64, 85))	('restoration', 'Var', (13, 24))	('Brg1', 'Gene', (28, 32))	('induce', 'PosReg', (53, 59))	('mouse', 'Species', '10090', (89, 94))
27290	31480737	Meanwhile, many studies have shown that P53 mutations appeared in advanced PanINs, consistent with a role in malignant PDAC progression.	('P53', 'Gene', (40, 43))	('PanIN', 'Disease', (75, 80))	('PDAC', 'Phenotype', 'HP:0006725', (119, 123))	('P53', 'Gene', '22059', (40, 43))	('PDAC progression', 'Disease', (119, 135))	('PDAC progression', 'Disease', 'MESH:D021441', (119, 135))	('mutations', 'Var', (44, 53))	('PanIN', 'Disease', 'MESH:D002278', (75, 80))	('appeared', 'Reg', (54, 62))
27293	31480737	Moreover, correlations have been reported in human PDAC between p53 mutations and enhanced VEGF expression, increased angiogenesis, and higher MVD, with all correlations to poor prognosis in human PDAC.	('enhanced', 'PosReg', (82, 90))	('MVD', 'MPA', (143, 146))	('VEGF', 'Gene', '7422', (91, 95))	('angiogenesis', 'biological_process', 'GO:0001525', ('118', '130'))	('PDAC', 'Phenotype', 'HP:0006725', (197, 201))	('increased', 'PosReg', (108, 117))	('expression', 'MPA', (96, 106))	('VEGF', 'Gene', (91, 95))	('PDAC', 'Phenotype', 'HP:0006725', (51, 55))	('human', 'Species', '9606', (191, 196))	('p53', 'Gene', (64, 67))	('angiogenesis', 'CPA', (118, 130))	('PDAC', 'Disease', 'MESH:D021441', (197, 201))	('higher', 'PosReg', (136, 142))	('PDAC', 'Disease', (197, 201))	('PDAC', 'Disease', 'MESH:D021441', (51, 55))	('human', 'Species', '9606', (45, 50))	('PDAC', 'Disease', (51, 55))	('mutations', 'Var', (68, 77))
27296	31480737	Homozygous deletion of the P53 tumor suppressor locus alone does not induce pancreatic neoplasia; however, concurrent KrasG12D expression and p53 nullizygosity drives the development of highly aggressive PDAC within 8-12 weeks.	('PDAC', 'Disease', 'MESH:D021441', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('p53', 'Gene', (142, 145))	('PDAC', 'Disease', (204, 208))	('highly aggressive', 'CPA', (186, 203))	('pancreatic neoplasia', 'Disease', (76, 96))	('KrasG12D', 'Gene', '16653', (118, 126))	('tumor', 'Disease', (31, 36))	('nullizygosity', 'Var', (146, 159))	('PDAC', 'Phenotype', 'HP:0006725', (204, 208))	('neoplasia', 'Phenotype', 'HP:0002664', (87, 96))	('P53', 'Gene', (27, 30))	('pancreatic neoplasia', 'Phenotype', 'HP:0002894', (76, 96))	('pancreatic neoplasia', 'Disease', 'MESH:D009369', (76, 96))	('P53', 'Gene', '22059', (27, 30))	('KrasG12D', 'Gene', (118, 126))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('drives', 'PosReg', (160, 166))
27299	31480737	Recent studies of engineered mouse models of de novo pancreatic cancer, characterized in unprecedented detail, the aberrant lesional microenvironment and its malignant regulation by genetic mutations during multistage progression.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (53, 70))	('genetic mutations', 'Var', (182, 199))	('mouse', 'Species', '10090', (29, 34))	('pancreatic cancer', 'Disease', (53, 70))	('pancreatic cancer', 'Disease', 'MESH:D010190', (53, 70))	('regulation', 'biological_process', 'GO:0065007', ('168', '178'))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
27307	31500518	Irreversible electroporation has many advantages over thermal therapies due to its nonthermal mechanism: (1) reduced risk of injury to surrounding organs and (2) no "heat-sink" effect due to nearby blood vessels.	('injury', 'Disease', (125, 131))	('electroporation', 'Var', (13, 28))	('injury', 'Disease', 'MESH:D058186', (125, 131))
27315	31500518	The combination of electroporation with chemotherapeutic drugs rapidly attracted great attention in the field of cancer treatment and was used as an independent treatment, known as electrochemotherapy (ECT).	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('electroporation', 'Var', (19, 34))
27318	31500518	As a result of these defects or pores, many events occur in the membrane, such as electroconformational protein denaturation, osmotic imbalance, flush in/out of ions, depletion of adenosine triphosphate (ATP), and uptake of toxic/foreign molecules, which eventually lead to cell death.	('cell death', 'biological_process', 'GO:0008219', ('274', '284'))	('cell death', 'CPA', (274, 284))	('membrane', 'cellular_component', 'GO:0016020', ('64', '72'))	('occur', 'Reg', (51, 56))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('osmotic imbalance', 'MPA', (126, 143))	('uptake', 'CPA', (214, 220))	('lead to', 'Reg', (266, 273))	('flush', 'Disease', (145, 150))	('ATP', 'Chemical', 'MESH:D000255', (204, 207))	('uptake', 'biological_process', 'GO:0098657', ('214', '220'))	('imbalance', 'Phenotype', 'HP:0002172', (134, 143))	('depletion of adenosine triphosphate', 'MPA', (167, 202))	('uptake', 'biological_process', 'GO:0098739', ('214', '220'))	('electroconformational protein denaturation', 'MPA', (82, 124))	('flush', 'Disease', 'MESH:D005483', (145, 150))	('defects', 'Var', (21, 28))	('flush', 'Phenotype', 'HP:0031284', (145, 150))	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (180, 202))	('protein denaturation', 'biological_process', 'GO:0030164', ('104', '124'))
27326	31500518	In another word, by introducing chemical drugs or ions, the ablation zone of IRE could be enlarged by ECT or calcium electroporation (IRE region + RE region).	('ablation', 'MPA', (60, 68))	('calcium electroporation', 'Var', (109, 132))	('IRE', 'Disease', (77, 80))	('calcium', 'Chemical', 'MESH:D002118', (109, 116))
27335	31500518	Similarly, Souza et al  found that the use of electroporation increased the cytotoxic effect of carboplatin on the equine sarcoid cell line 3-fold.	('increased', 'PosReg', (62, 71))	('electroporation', 'Var', (46, 61))	('carboplatin', 'Chemical', 'MESH:D016190', (96, 107))	('cytotoxic effect', 'CPA', (76, 92))	('equine', 'Species', '9796', (115, 121))
27340	31500518	If, on the other hand, cells contain several million bleomycin molecules, they are destroyed much more rapidly, within a few minutes, due to pseudoapoptosis because bleomycin short-circuits the apoptosis pathway by creating the characteristic DNA fragmentation.	('bleomycin', 'Var', (165, 174))	('bleomycin', 'Chemical', 'MESH:D001761', (165, 174))	('apoptosis', 'biological_process', 'GO:0006915', ('194', '203'))	('apoptosis pathway', 'Pathway', (194, 211))	('DNA fragmentation', 'biological_process', 'GO:0006309', ('243', '260'))	('short-circuits', 'NegReg', (175, 189))	('DNA fragmentation', 'CPA', (243, 260))	('DNA', 'cellular_component', 'GO:0005574', ('243', '246'))	('bleomycin', 'Chemical', 'MESH:D001761', (53, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('194', '203'))
27341	31500518	Cell toxicity caused by bleomycin can be enhanced by electroporation, administered 1 to 15 minutes after infusion of bleomycin.	('bleomycin', 'Chemical', 'MESH:D001761', (24, 33))	('electroporation', 'Var', (53, 68))	('enhanced', 'PosReg', (41, 49))	('bleomycin', 'Chemical', 'MESH:D001761', (117, 126))	('toxicity', 'Disease', 'MESH:D064420', (5, 13))	('toxicity', 'Disease', (5, 13))
27343	31500518	Sersa et al  demonstrated that in addition to the well-established direct cytotoxic effect on tumor cells, a combination of bleomycin and electroporation also has an indirect effect on tumor necrosis via an effect on the tumor blood supply, something which is not seen with either bleomycin alone or IRE alone.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('necrosis', 'biological_process', 'GO:0070265', ('191', '199'))	('necrosis', 'biological_process', 'GO:0019835', ('191', '199'))	('necrosis', 'biological_process', 'GO:0001906', ('191', '199'))	('tumor', 'Disease', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor necrosis', 'Disease', 'MESH:D009336', (185, 199))	('electroporation', 'Var', (138, 153))	('tumor necrosis', 'Disease', (185, 199))	('tumor', 'Disease', (221, 226))	('bleomycin', 'Var', (124, 133))	('necrosis', 'biological_process', 'GO:0008219', ('191', '199'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Disease', (94, 99))	('effect', 'Reg', (207, 213))	('bleomycin', 'Chemical', 'MESH:D001761', (124, 133))	('necrosis', 'biological_process', 'GO:0008220', ('191', '199'))	('combination', 'Var', (109, 120))	('bleomycin', 'Chemical', 'MESH:D001761', (281, 290))
27355	31500518	Since bleomycin has been shown to cause alveolar cell damage and subsequent pulmonary inflammation, one of the potential advantages of ECT is to limit the dosage of the drug and reduce the side effects.	('pulmonary inflammation', 'Disease', 'MESH:D011014', (76, 98))	('alveolar cell damage', 'Disease', (40, 60))	('bleomycin', 'Var', (6, 15))	('alveolar cell damage', 'Disease', 'MESH:D002282', (40, 60))	('bleomycin', 'Chemical', 'MESH:D001761', (6, 15))	('cause', 'Reg', (34, 39))	('inflammation', 'biological_process', 'GO:0006954', ('86', '98'))	('dosage', 'MPA', (155, 161))	('limit', 'NegReg', (145, 150))	('pulmonary inflammation', 'Disease', (76, 98))
27356	31500518	Electrochemotherapy has been trialed clinically in patients with cutaneous and subcutaneous tumors; even for these superficial tumors, there are significant side effects noted and the incidence of toxicity in patients receiving doses of more than 450 mg/m2 rises sharply, and it has been reported that under doses of less than 100 mg, general anesthesia following bleomycin may be associated with postoperative respiratory failure and may be secondary to bleomycin-induced oxygen sensitivity.	('postoperative respiratory failure', 'Disease', (397, 430))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (79, 98))	('postoperative respiratory failure', 'Disease', 'MESH:D012131', (397, 430))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (79, 98))	('toxicity', 'Disease', 'MESH:D064420', (197, 205))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('general anesthesia', 'Disease', (335, 353))	('tumors', 'Disease', (127, 133))	('subcutaneous tumors', 'Disease', (79, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('patients', 'Species', '9606', (51, 59))	('tumors', 'Disease', (92, 98))	('toxicity', 'Disease', (197, 205))	('bleomycin', 'Chemical', 'MESH:D001761', (364, 373))	('oxygen', 'Chemical', 'MESH:D010100', (473, 479))	('associated with', 'Reg', (381, 396))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('respiratory failure', 'Phenotype', 'HP:0002878', (411, 430))	('patients', 'Species', '9606', (209, 217))	('cutaneous and subcutaneous tumors', 'Phenotype', 'HP:0008069', (65, 98))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('less', 'Var', (317, 321))	('bleomycin', 'Chemical', 'MESH:D001761', (455, 464))
27369	31500518	Similarly, a greater proportion of compete responses and survival rate was found in ECT with cisplatin compared to ECT with bleomycin (85% vs 33%) in the treatment of HPV-positive tumors.	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (167, 186))	('bleomycin', 'Chemical', 'MESH:D001761', (124, 133))	('HPV-positive tumors', 'Disease', (167, 186))	('compete responses', 'CPA', (35, 52))	('cisplatin', 'Var', (93, 102))	('survival', 'CPA', (57, 65))
27376	31500518	A 3-fold increase in the toxicity of carboplatin to the equine sarcoid cells can be achieved by using electroporation.	('carboplatin', 'Chemical', 'MESH:D016190', (37, 48))	('toxicity', 'Disease', 'MESH:D064420', (25, 33))	('toxicity', 'Disease', (25, 33))	('increase', 'PosReg', (9, 17))	('electroporation', 'Var', (102, 117))	('equine', 'Species', '9796', (56, 62))
27388	31500518	As shown in Figure 2, when cells undergo electroporation by external electric fields, the permeability of cell membrane increases, and Ca2+ and Na+ move into cells, resulting in an increase in both the intracellular calcium concentration and the activity of Ca2+-ATPase, thereby consuming a large amount of ATP.	('ATP', 'Chemical', 'MESH:D000255', (263, 266))	('permeability of cell membrane', 'MPA', (90, 119))	('Ca2+-ATPase', 'Protein', (258, 269))	('Ca2+', 'Chemical', 'MESH:D000069285', (258, 262))	('Ca2+', 'Var', (135, 139))	('cell membrane', 'cellular_component', 'GO:0005886', ('106', '119'))	('ATP', 'Chemical', 'MESH:D000255', (307, 310))	('activity', 'MPA', (246, 254))	('calcium', 'Chemical', 'MESH:D002118', (216, 223))	('Ca2+', 'Chemical', 'MESH:D000069285', (135, 139))	('increases', 'PosReg', (120, 129))	('intracellular calcium concentration', 'MPA', (202, 237))	('electroporation', 'Var', (41, 56))	('intracellular', 'cellular_component', 'GO:0005622', ('202', '215'))	('increase', 'PosReg', (181, 189))
27399	31500518	Biopsies collected 7 days after treatment showed a significant decrease in the number of cancer cells and a higher level of cell death in metastatic tumors treated with calcium electroporation compared to ECT with bleomycin.	('bleomycin', 'Chemical', 'MESH:D001761', (214, 223))	('calcium', 'Chemical', 'MESH:D002118', (169, 176))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('decrease', 'NegReg', (63, 71))	('tumors', 'Disease', (149, 155))	('cancer', 'Disease', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('cell death', 'CPA', (124, 134))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('cell death', 'biological_process', 'GO:0008219', ('124', '134'))	('calcium electroporation', 'Var', (169, 192))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
27402	31500518	The incidence of ulcers, itching, and exudation was slightly higher in metastatic tumors treated with ECT with bleomycin compared to calcium electroporation, and pigmentation only appeared in metastatic tumors treated by ECT with bleomycin.	('tumors', 'Disease', (82, 88))	('bleomycin', 'Var', (111, 120))	('itching', 'Disease', (25, 32))	('bleomycin', 'Chemical', 'MESH:D001761', (230, 239))	('exudation', 'CPA', (38, 47))	('ulcers', 'Disease', 'MESH:D014456', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('higher', 'PosReg', (61, 67))	('bleomycin', 'Chemical', 'MESH:D001761', (111, 120))	('pig', 'Species', '9823', (162, 165))	('itching', 'Disease', 'MESH:D011537', (25, 32))	('pigmentation', 'biological_process', 'GO:0043473', ('162', '174'))	('itching', 'Phenotype', 'HP:0000989', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('ECT', 'Var', (102, 105))	('tumors', 'Disease', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('calcium', 'Chemical', 'MESH:D002118', (133, 140))	('ulcers', 'Disease', (17, 23))
27413	31500518	Molecular dynamics simulation in Moldovan et al has demonstrated that 11.3 mol.% DMSO leads to over 90% decrease in line tension on modeled lipid bilayer membrane, which may cause a significant reduction in IRE threshold (Figure 3B).	('lipid', 'Chemical', 'MESH:D008055', (140, 145))	('DMSO', 'Var', (81, 85))	('DMSO', 'Chemical', 'MESH:D004121', (81, 85))	('reduction', 'NegReg', (194, 203))	('line tension on modeled lipid bilayer membrane', 'MPA', (116, 162))	('membrane', 'cellular_component', 'GO:0016020', ('154', '162'))	('decrease', 'NegReg', (104, 112))	('IRE threshold', 'MPA', (207, 220))
27426	31500518	Experiment results showed that the tumor ablation volume can be increased from 10 mm3 by IRE alone to 24.3 mm3 by combining DMSO (5% vol/vol) and IRE, indicating an increase in ablation volume by 136%.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('DMSO', 'Var', (124, 128))	('increased', 'PosReg', (64, 73))	('DMSO', 'Chemical', 'MESH:D004121', (124, 128))
27449	31500518	Previous studies have shown that SDS enhances the transdermal transport of molecules through electroporation, which is able to promote the destruction of the barrier during the pulse process and also extend the life of electric holes generated by the pulse.	('electroporation', 'Var', (93, 108))	('SDS', 'Chemical', 'MESH:D012967', (33, 36))	('transdermal transport of molecules', 'MPA', (50, 84))	('promote', 'PosReg', (127, 134))	('enhances', 'PosReg', (37, 45))	('extend', 'PosReg', (200, 206))	('electric holes', 'MPA', (219, 233))	('SDS', 'Var', (33, 36))	('transport', 'biological_process', 'GO:0006810', ('62', '71'))
27455	31500518	An increase in propranolol hydrochloride flux in human stratum corneum was also observed by combining SDS and electroporation.	('electroporation', 'Var', (110, 125))	('human', 'Species', '9606', (49, 54))	('SDS', 'Chemical', 'MESH:D012967', (102, 105))	('propranolol hydrochloride', 'Chemical', 'MESH:D011433', (15, 40))	('propranolol hydrochloride flux', 'MPA', (15, 45))	('SDS', 'Var', (102, 105))	('increase', 'PosReg', (3, 11))
27456	31500518	They believed that the combination of SDS and electroporation could reduce the adhesion between molecules in the skin's lipid bilayer, thus increasing skin permeability.	('lipid', 'Chemical', 'MESH:D008055', (120, 125))	('adhesion between molecules', 'MPA', (79, 105))	('increasing', 'PosReg', (140, 150))	('electroporation', 'Var', (46, 61))	('reduce', 'NegReg', (68, 74))	('skin permeability', 'MPA', (151, 168))	('SDS', 'Chemical', 'MESH:D012967', (38, 41))
27458	31500518	For instance, the impedance can be decreased by 60% using pulses of >100 V, while the reduction in impedance is negligible using pulses of >250 V. Murthy et al  found that in the absence of SDS, the translocation of glucose through the pulse at 500 V/cm was about 30 mug/cm2.	('impedance', 'MPA', (18, 27))	('SDS', 'Chemical', 'MESH:D012967', (190, 193))	('pulses', 'Var', (58, 64))	('decreased', 'NegReg', (35, 44))	('translocation of glucose', 'MPA', (199, 223))	('mug', 'molecular_function', 'GO:0043739', ('267', '270'))	('glucose', 'Chemical', 'MESH:D005947', (216, 223))
27459	31500518	With the administration of SDS, the same transmission can be achieved at 300 V/cm, which means that the presence of SDS was able to reduce the required electric dose for electroporation by about 40%.	('presence', 'Var', (104, 112))	('SDS', 'Chemical', 'MESH:D012967', (27, 30))	('SDS', 'Chemical', 'MESH:D012967', (116, 119))	('reduce', 'NegReg', (132, 138))	('SDS', 'Var', (116, 119))
27460	31500518	Therefore, the combination of electroporation and SDS can achieve a higher membrane permeability at a lower voltage.	('membrane permeability', 'MPA', (75, 96))	('SDS', 'Chemical', 'MESH:D012967', (50, 53))	('higher', 'PosReg', (68, 74))	('electroporation', 'Var', (30, 45))	('membrane', 'cellular_component', 'GO:0016020', ('75', '83'))
27461	31500518	The presence of SDS during electroporation increased glucose transport efficiency by about 5 times at 100 V. The increase in passive transport of the epidermis treated by SDS was approximately twice that treated by PBS.	('SDS', 'Chemical', 'MESH:D012967', (16, 19))	('glucose transport', 'biological_process', 'GO:1904659', ('53', '70'))	('PBS', 'Chemical', '-', (215, 218))	('glucose', 'Chemical', 'MESH:D005947', (53, 60))	('glucose transport', 'MPA', (53, 70))	('passive transport', 'MPA', (125, 142))	('SDS', 'Chemical', 'MESH:D012967', (171, 174))	('increased glucose', 'Phenotype', 'HP:0003074', (43, 60))	('increase', 'PosReg', (113, 121))	('increased', 'PosReg', (43, 52))	('transport', 'biological_process', 'GO:0006810', ('133', '142'))	('SDS', 'Var', (171, 174))
27475	31500518	The advantages of ECT include: (1) ECT with bleomycin had a significant antitumor effect on tumor growth and increased the extent in tumor necrosis than either electroporation alone or bleomycin injection alone and (2) ECT with cisplatin can achieve the lowest viability of cells from the pulmonary metastases of pancreatic cancer compared to either cisplatin or electroporation alone.	('bleomycin', 'Chemical', 'MESH:D001761', (185, 194))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (350, 359))	('increased', 'PosReg', (109, 118))	('tumor necrosis', 'Disease', 'MESH:D009336', (133, 147))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('pulmonary metastases of pancreatic cancer', 'Disease', (289, 330))	('tumor necrosis', 'Disease', (133, 147))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('necrosis', 'biological_process', 'GO:0008219', ('139', '147'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('cisplatin', 'Chemical', 'MESH:D002945', (228, 237))	('tumor', 'Disease', (133, 138))	('pulmonary metastases of pancreatic cancer', 'Disease', 'MESH:D009362', (289, 330))	('necrosis', 'biological_process', 'GO:0008220', ('139', '147'))	('bleomycin', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('lowest', 'NegReg', (254, 260))	('necrosis', 'biological_process', 'GO:0070265', ('139', '147'))	('necrosis', 'biological_process', 'GO:0019835', ('139', '147'))	('tumor', 'Disease', (92, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (313, 330))	('necrosis', 'biological_process', 'GO:0001906', ('139', '147'))	('bleomycin', 'Chemical', 'MESH:D001761', (44, 53))
27498	30820788	The authors studied 35 patients, 27 with PDAC and 8 with chronic pancreatitis and found that the presence of either exosomal miR 21 or 155 resulted in an accurate diagnosis of pancreatic cancer 83% and 89% of the time, respectively.	('patients', 'Species', '9606', (23, 31))	('presence', 'Var', (97, 105))	('pancreatitis', 'Disease', (65, 77))	('pancreatic cancer', 'Disease', (176, 193))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (57, 77))	('miR 21', 'Gene', '406991', (125, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (176, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('pancreatitis', 'Phenotype', 'HP:0001733', (65, 77))	('pancreatitis', 'Disease', 'MESH:D010195', (65, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (176, 193))	('miR 21', 'Gene', (125, 131))
27505	30820788	Ultimately, molecular diagnostics such as these must be studied prospectively in the context of screening programs for high risk groups such as those harboring germline pathogenic variants that confer cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('variants', 'Var', (180, 188))	('cancer', 'Disease', (201, 207))
27634	30732657	These changes are known to potentially cause heterogeneous dose distributions in the tumor and over- or undershooting of the target.	('cause', 'Reg', (39, 44))	('tumor', 'Disease', (85, 90))	('heterogeneous dose distributions', 'MPA', (45, 77))	('changes', 'Var', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
27646	30732657	In this study, we first aimed to quantify the patient-specificity of both day-to-day motion variations and the fractionation-induced interplay mitigation on the planned target dose and OARs.	('OAR', 'Gene', (185, 188))	('OAR', 'Gene', '4936', (185, 188))	('variations', 'Var', (92, 102))	('patient', 'Species', '9606', (46, 53))
27676	30732657	Moreover, the dose-volume-histograms (DVHs) for OARs, namely left/right kidney, spinal cord, liver and bowel were analyzed with respect to dmean, d2 and v30, where v30 denotes the volume that receives at least 30% of the dose.	('OAR', 'Gene', '4936', (48, 51))	('v30', 'Var', (164, 167))	('OAR', 'Gene', (48, 51))	('DVH', 'Chemical', '-', (38, 41))	('dmean', 'Chemical', '-', (139, 144))
27691	30732657	The 3D SFUD plans revealed an average mean dose of dmean = 99.6% (range 99.5-99.9%) with full CTV coverage (v95 = 100%, v107 = 0%), high dose homogeneity with d5/d95<=1.03 (range 1.01-1.03) and near maximum dose values of d2 < 103% (range 100.3-103.0%) for 8 out of the 9 patients.	('d5/d95<=1.03', 'Var', (159, 171))	('dmean', 'Chemical', '-', (51, 56))	('CTV', 'Chemical', '-', (94, 97))	('patients', 'Species', '9606', (272, 280))	('dmean =', 'Var', (51, 58))
27748	29186684	In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers.	('Ezetimibe', 'Chemical', 'MESH:D000069438', (51, 60))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (135, 152))	('inhibiting', 'Var', (28, 38))	('treating pancreatic cancers', 'Disease', (126, 153))	('NPC1L1', 'Gene', '29881', (39, 45))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (135, 153))	('NPC1L1', 'Gene', (39, 45))	('NPC', 'cellular_component', 'GO:0005643', ('39', '42'))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('treating pancreatic cancers', 'Disease', 'MESH:D010190', (126, 153))
27787	29186684	In order to uncover the tumor diversity of PDAC using PDX, unsupervised analyses were carried out independently on each of the tumor-specific genome-wide molecular profiles: protein coding mRNA, long non-coding RNA, microRNA, and non-island and island CpG methylation.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('long', 'MPA', (195, 199))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', (127, 132))	('PDAC', 'Phenotype', 'HP:0006725', (43, 47))	('methylation', 'biological_process', 'GO:0032259', ('256', '267'))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('mRNA', 'Var', (189, 193))	('PDAC', 'Chemical', '-', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('RNA', 'cellular_component', 'GO:0005562', ('211', '214'))
27790	29186684	Moreover, the genes that were associated with the CIMP hypermethylated CpG were more often found to be underexpressed in all classical samples (64 of the 184 hypermethylated genes found significantly underexpressed in classical samples as compared to basal samples) than specifically underexpressed in CIMP samples (neither of the 2 genes were found to be underexpressed in CIMP samples).	('underexpressed', 'NegReg', (200, 214))	('CIMP', 'Chemical', '-', (50, 54))	('CpG', 'Gene', (71, 74))	('CIMP', 'Chemical', '-', (374, 378))	('CIMP', 'Var', (50, 54))	('CIMP', 'Chemical', '-', (302, 306))
27793	29186684	Unsurprisingly, genomic alterations that are commonly found in PDAC (KRAS mutations, SMAD4 losses, CDKN2A inactivation, myc amplification, etc.	('KRAS', 'Gene', (69, 73))	('inactivation', 'Var', (106, 118))	('SMAD4', 'Gene', '4089', (85, 90))	('KRAS', 'Gene', '3845', (69, 73))	('CDKN2A', 'Gene', (99, 105))	('PDAC', 'Chemical', '-', (63, 67))	('losses', 'NegReg', (91, 97))	('mutations', 'Var', (74, 83))	('CDKN2A', 'Gene', '1029', (99, 105))	('SMAD4', 'Gene', (85, 90))	('PDAC', 'Phenotype', 'HP:0006725', (63, 67))	('myc', 'Gene', (120, 123))
27794	29186684	As previously observed, TP53 showed a slightly higher mutation rate in the basal subtype, although with virtually no discriminative power.	('TP53', 'Gene', (24, 28))	('mutation', 'Var', (54, 62))	('higher', 'PosReg', (47, 53))	('TP53', 'Gene', '7157', (24, 28))
27833	29186684	Interestingly, the upregulation and epigenetic deregulation of the glutamine transporter in classical tumors is associated to a strong increase in two nucleotides, inosine monophosphate (IMP) and uridine monophosphate (UMP) (Figure S4E).	('uridine monophosphate', 'Chemical', 'MESH:D014542', (196, 217))	('uridine monophosphate', 'MPA', (196, 217))	('IMP', 'molecular_function', 'GO:0004244', ('187', '190'))	('epigenetic deregulation', 'Var', (36, 59))	('increase', 'PosReg', (135, 143))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('IMP', 'Chemical', 'MESH:D007291', (187, 190))	('UMP', 'Chemical', 'MESH:D014542', (219, 222))	('IMP', 'cellular_component', 'GO:0042720', ('187', '190'))	('classical tumors', 'Disease', 'MESH:D005693', (92, 108))	('upregulation', 'PosReg', (19, 31))	('inosine monophosphate', 'MPA', (164, 185))	('two nucleotides', 'MPA', (147, 162))	('glutamine', 'Enzyme', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('inosine monophosphate', 'Chemical', 'MESH:D007291', (164, 185))	('classical tumors', 'Disease', (92, 108))
27835	29186684	Aberrant cholesterol uptake has been recently implicated in the proliferation and survival of pancreatic cancer cells.	('cholesterol', 'Chemical', 'MESH:D002784', (9, 20))	('survival', 'CPA', (82, 90))	('Aberrant', 'Var', (0, 8))	('implicated', 'Reg', (46, 56))	('pancreatic cancer', 'Disease', (94, 111))	('proliferation', 'CPA', (64, 77))	('pancreatic cancer', 'Disease', 'MESH:D010190', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cholesterol uptake', 'biological_process', 'GO:0070508', ('9', '27'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (94, 111))
27842	29186684	In particular, our integrated analysis examined the stroma as well as the epigenetic deregulation of cholesterol metabolism and uptake.	('epigenetic deregulation', 'Var', (74, 97))	('uptake', 'biological_process', 'GO:0098657', ('128', '134'))	('uptake', 'biological_process', 'GO:0098739', ('128', '134'))	('cholesterol metabolism', 'biological_process', 'GO:0008203', ('101', '123'))	('cholesterol metabolism', 'MPA', (101, 123))	('cholesterol', 'Chemical', 'MESH:D002784', (101, 112))
27844	29186684	As a proof of concept for defining therapeutic targets from the integrated multiomics analysis of PDX, we selected the highly epigenetically deregulated NPC1L1, for which an efficient inhibitor is clinically available: Ezetimibe.	('NPC', 'cellular_component', 'GO:0005643', ('153', '156'))	('epigenetically deregulated', 'Var', (126, 152))	('NPC1L1', 'Gene', '29881', (153, 159))	('NPC1L1', 'Gene', (153, 159))	('Ezetimibe', 'Chemical', 'MESH:D000069438', (219, 228))
27853	29186684	The knockdown of NPC1L1 made cells resistant to high levels of Ezetimibe, providing evidence for the specificity of the treatment (Figures S6E and S6F).	('NPC', 'cellular_component', 'GO:0005643', ('17', '20'))	('resistant', 'MPA', (35, 44))	('knockdown', 'Var', (4, 13))	('NPC1L1', 'Gene', '29881', (17, 23))	('Ezetimibe', 'Chemical', 'MESH:D000069438', (63, 72))	('NPC1L1', 'Gene', (17, 23))
27864	29186684	The most likely explanation for this observation is that genetic mutations, amplifications, and deletions are involved in the transformation process of PDAC, whereas the clinical outcome, response to treatments, and the phenotype of the tumors are controlled at the epigenetic level.	('PDAC', 'Disease', (152, 156))	('PDAC', 'Phenotype', 'HP:0006725', (152, 156))	('tumors', 'Disease', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('genetic mutations', 'Var', (57, 74))	('amplifications', 'Var', (76, 90))	('involved', 'Reg', (110, 118))	('deletions', 'Var', (96, 105))	('PDAC', 'Chemical', '-', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
27884	29186684	Notably, treatment with PEGPH20, a PEGylated human recombinant hyaluronidase, induces a rapid perfusion increase, leading to the inhibition of growth when combined with chemotherapy in mouse PDAC models.	('rapid perfusion', 'MPA', (88, 103))	('increase', 'PosReg', (104, 112))	('mouse', 'Species', '10090', (185, 190))	('PDAC', 'Chemical', '-', (191, 195))	('inhibition of growth', 'biological_process', 'GO:0045926', ('129', '149'))	('human', 'Species', '9606', (45, 50))	('inhibition', 'NegReg', (129, 139))	('growth', 'MPA', (143, 149))	('PEGPH20', 'Var', (24, 31))	('PDAC', 'Phenotype', 'HP:0006725', (191, 195))
27914	29186684	We transplanted two PDX samples (PDAC019T and PDAC003T) subcutaneously into 6-week-old male Swiss nude mice (Crl: Nu(lco)-Foxn1nu; Charles River Laboratories, Wilmington, MA).	('PDAC', 'Phenotype', 'HP:0006725', (46, 50))	('PDAC', 'Phenotype', 'HP:0006725', (33, 37))	('nude mice', 'Species', '10090', (98, 107))	('PDAC', 'Chemical', '-', (46, 50))	('PDAC003T', 'Var', (46, 54))	('PDAC', 'Chemical', '-', (33, 37))	('PDAC019T', 'Var', (33, 41))
27924	29384525	Genetic deletion of the Mtor gene in the pancreas results in exocrine and endocrine insufficiency.	('endocrine insufficiency', 'Disease', (74, 97))	('endocrine insufficiency', 'Disease', 'MESH:D000309', (74, 97))	('Genetic deletion', 'Var', (0, 16))	('results in', 'Reg', (50, 60))	('Mtor', 'Gene', (24, 28))
27929	29384525	Over 90% of pancreatic ductal adenocarcinoma (PDAC) patients harbour oncogenic KRAS mutations.	('PDAC', 'Phenotype', 'HP:0006725', (46, 50))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (12, 44))	('pancreatic ductal adenocarcinoma', 'Disease', (12, 44))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (12, 44))	('mutations', 'Var', (84, 93))	('PDAC', 'Chemical', '-', (46, 50))	('KRAS', 'Gene', (79, 83))	('patients', 'Species', '9606', (52, 60))
27930	29384525	Mutated KRAS initiates a complex and context-specific signalling, including canonical mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) or phosphoinositide 3-kinase (PI3K)-3-phosphoinositide-dependent protein kinase (PDK1) pathways.	('ERK', 'molecular_function', 'GO:0004707', ('171', '174'))	('extracellular', 'cellular_component', 'GO:0005576', ('132', '145'))	('PDK1', 'Gene', '228026', (257, 261))	('signalling', 'biological_process', 'GO:0023052', ('54', '64'))	('phosphoinositide 3-kinase', 'Gene', (179, 204))	('KRAS', 'Gene', (8, 12))	('PDK1', 'Gene', (257, 261))	('mitogen-activated protein kinase kinase', 'Gene', (86, 125))	('PI3K', 'molecular_function', 'GO:0016303', ('206', '210'))	('protein', 'cellular_component', 'GO:0003675', ('241', '248'))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('PDK1', 'molecular_function', 'GO:0004740', ('257', '261'))	('initiates', 'Reg', (13, 22))	('Mutated', 'Var', (0, 7))	('phosphoinositide 3-kinase', 'Gene', '18708', (179, 204))	('mitogen-activated protein kinase kinase', 'Gene', '17242', (86, 125))
27933	29384525	Moreover, the H1047R hotspot mutant of p110alpha drives carcinogenesis in the pancreas.	('drives', 'Reg', (49, 55))	('H1047R', 'Var', (14, 20))	('carcinogenesis', 'Disease', (56, 70))	('H1047R', 'Mutation', 'rs121913279', (14, 20))	('p110alpha', 'Gene', (39, 48))	('carcinogenesis', 'Disease', 'MESH:D063646', (56, 70))	('p110alpha', 'Gene', '18706', (39, 48))
27934	29384525	At the therapeutic level, it has been demonstrated that inhibition of the PI3K pathway leads to growth inhibition and temporal tumour stasis in PDAC GEMMs as well as patient-derived orthotopic xenotransplant models.	('PDAC', 'Chemical', '-', (144, 148))	('tumour stasis', 'Disease', (127, 140))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('patient', 'Species', '9606', (166, 173))	('tumour stasis', 'Disease', 'MESH:D014647', (127, 140))	('PDAC', 'Disease', (144, 148))	('PDAC', 'Phenotype', 'HP:0006725', (144, 148))	('PI3K pathway', 'Pathway', (74, 86))	('inhibition', 'Var', (56, 66))	('PI3K', 'molecular_function', 'GO:0016303', ('74', '78'))	('growth inhibition', 'CPA', (96, 113))
27940	29384525	Pancreatic ductal adenocarcinomas carry phosphorylation of Ser2448 of MTOR, which marks the activation of this signalling node.	('MTOR', 'Gene', (70, 74))	('phosphorylation of Ser2448', 'Var', (40, 66))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('Ser', 'cellular_component', 'GO:0005790', ('59', '62'))	('Ser2448', 'Chemical', '-', (59, 66))	('Pancreatic ductal adenocarcinomas', 'Disease', (0, 33))	('signalling', 'biological_process', 'GO:0023052', ('111', '121'))	('Pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (0, 33))
27944	29384525	To fulfil this task, we developed a new model to genetically inactivate Mtor in established murine PDAC cells.	('PDAC', 'Chemical', '-', (99, 103))	('Mtor', 'Gene', (72, 76))	('murine', 'Species', '10090', (92, 98))	('PDAC', 'Phenotype', 'HP:0006725', (99, 103))	('genetically inactivate', 'Var', (49, 71))
27945	29384525	We show that MTOR is a regulator of metabolic programmes and growth in PDAC, we describe adaptive rewiring of oncogenic signalling in response to the MTOR blockade and point to opportunities for dual MTOR inhibitor-based combination therapies by addressing adaptive rewiring programmes.	('oncogenic signalling', 'MPA', (110, 130))	('signalling', 'biological_process', 'GO:0023052', ('120', '130'))	('PDAC', 'Phenotype', 'HP:0006725', (71, 75))	('MTOR', 'Gene', (150, 154))	('blockade', 'Var', (155, 163))	('PDAC', 'Chemical', '-', (71, 75))
27952	29384525	The FSF-KrasG12D, Pdx1-Flp, FSF-R26CAG-CreERT2, Ptf1aCre, LSL-KrasG12D (5) and R26mT/mG lines have been described.	('Flp', 'Gene', '15445', (23, 26))	('Ptf1', 'Species', '32651', (48, 52))	('R26mT/mG', 'Var', (79, 87))	('Flp', 'Gene', (23, 26))
27962	29384525	To genetically manipulate Mtor expression, a cell line with the following genotype was generated: Pdx1-Flp;FSF-KrasG12D;FSF-R26CAG-CreERT2;R26mT/mG;mTorDeltaE3/lox (cell line: PPT4-ZH363-MtorDeltaE3/lox).	('Flp', 'Gene', (103, 106))	('Flp', 'Gene', '15445', (103, 106))	('PPT', 'molecular_function', 'GO:0015121', ('176', '179'))	('R26mT/mG', 'Var', (139, 147))	('PPT', 'molecular_function', 'GO:0043751', ('176', '179'))
27994	29384525	Compared to controls, the body weight of KC;Mtorlox/lox mice was reduced (Supplementary Figure 1C) and the pancreas was macroscopically atrophic (Supplementary Figure 1D).	('body weight', 'CPA', (26, 37))	('reduced', 'NegReg', (65, 72))	('atrophic', 'Disease', 'MESH:D020966', (136, 144))	('atrophic', 'Disease', (136, 144))	('mice', 'Species', '10090', (56, 60))	('KC;Mtorlox/lox', 'Var', (41, 55))
27996	29384525	Acinar to ductal metaplasia and low-grade pancreatic intraepithelial neoplasias develop in KC;Mtorlox/lox mice and desmoplasia is observed (Supplementary Figures 2A and B).	('mice', 'Species', '10090', (106, 110))	('neoplasias', 'Phenotype', 'HP:0002664', (69, 79))	('intraepithelial neoplasias', 'Phenotype', 'HP:0032187', (53, 79))	('pancreatic intraepithelial neoplasias', 'Disease', 'MESH:D018290', (42, 79))	('desmoplasia', 'Disease', (115, 126))	('metaplasia', 'biological_process', 'GO:0036074', ('17', '27'))	('KC', 'Var', (91, 93))	('metaplasia', 'Disease', 'MESH:D008679', (17, 27))	('pancreatic intraepithelial neoplasias', 'Disease', (42, 79))	('desmoplasia', 'Disease', 'None', (115, 126))	('metaplasia', 'Disease', (17, 27))
28000	29384525	Coincidently, increased blood glucose levels were detected and KC;Mtorlox/lox mice, which develop diabetes mellitus at 11 weeks of age (Supplementary Figure 3D).	('increased', 'PosReg', (14, 23))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (98, 115))	('glucose', 'Chemical', 'MESH:D005947', (30, 37))	('increased blood glucose', 'Phenotype', 'HP:0003074', (14, 37))	('blood glucose levels', 'MPA', (24, 44))	('diabetes mellitus', 'Disease', (98, 115))	('KC;Mtorlox/lox', 'Var', (63, 77))	('diabetes mellitus', 'Disease', 'MESH:D003920', (98, 115))	('mice', 'Species', '10090', (78, 82))
28007	29384525	To minimise the probability of escape from Mtor deletion and to allow efficient genetic inactivation of the pathway, we established a murine PDAC cell line with already one deleted Mtor allele (PPT4-ZH363-MtorDeltaE3/lox cells).	('PPT', 'molecular_function', 'GO:0043751', ('194', '197'))	('PPT4-ZH363-MtorDeltaE3/lox', 'Var', (194, 220))	('PDAC', 'Chemical', '-', (141, 145))	('murine', 'Species', '10090', (134, 140))	('PPT', 'molecular_function', 'GO:0015121', ('194', '197'))	('deletion', 'Var', (48, 56))	('PDAC', 'Phenotype', 'HP:0006725', (141, 145))
28019	29384525	Consistent with the genetic deletion of Mtor, INK-128 treatment increased the fraction of cells in the G1 phase of the cell cycle (Figure 2F).	('increased', 'PosReg', (64, 73))	('Mtor', 'Gene', (40, 44))	('cell cycle', 'biological_process', 'GO:0007049', ('119', '129'))	('G1 phase', 'biological_process', 'GO:0051318', ('103', '111'))	('deletion', 'Var', (28, 36))	('INK-128', 'Chemical', 'MESH:C572449', (46, 53))
28021	29384525	Consistently, while treatment with bortezomib and the chemotherapeutic camptothecin was followed by cleavage of caspase-3 and the caspase substrate PARP, neither INK-128 nor genetic deletion of Mtor induced such changes (Figure 2G).	('caspase-3', 'Gene', '12367', (112, 121))	('PARP', 'Gene', '11545', (148, 152))	('Mtor', 'Gene', (194, 198))	('cleavage', 'MPA', (100, 108))	('caspase-3', 'Gene', (112, 121))	('bortezomib', 'Chemical', 'MESH:D000069286', (35, 45))	('PARP', 'Gene', (148, 152))	('INK-128', 'Chemical', 'MESH:C572449', (162, 169))	('camptothecin', 'Chemical', 'MESH:D002166', (71, 83))	('genetic deletion', 'Var', (174, 190))
28026	29384525	In addition, expression of enzymes involved in glucose metabolism, including Ldha and PfkI, decreased upon the genetic inactivation of Mtor (Figures 3D and E).	('glucose metabolism', 'Disease', (47, 65))	('Mtor', 'Gene', (135, 139))	('expression', 'MPA', (13, 23))	('glucose metabolism', 'biological_process', 'GO:0006006', ('47', '65'))	('Ldha', 'Gene', (77, 81))	('PfkI', 'Gene', (86, 90))	('glucose metabolism', 'Disease', 'MESH:D044882', (47, 65))	('genetic inactivation', 'Var', (111, 131))	('decreased', 'NegReg', (92, 101))	('Ldha', 'Gene', '16828', (77, 81))
28031	29384525	In addition, high LDHA mRNA expression marks PDACs with a worse prognosis (Supplementary Figure 7C), in line with recent observations.	('PDAC', 'Chemical', '-', (45, 49))	('LDHA', 'Gene', (18, 22))	('high', 'Var', (13, 17))	('LDHA', 'Gene', '16828', (18, 22))	('PDAC', 'Phenotype', 'HP:0006725', (45, 49))
28033	29384525	To find adaptive signalling processes occurring after deletion of Mtor we focused on two main driver pathways in PDAC, the ERK and the PI3K signalling pathways.	('PDAC', 'Disease', (113, 117))	('PDAC', 'Phenotype', 'HP:0006725', (113, 117))	('deletion', 'Var', (54, 62))	('signalling', 'biological_process', 'GO:0023052', ('17', '27'))	('ERK', 'molecular_function', 'GO:0004707', ('123', '126'))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('PDAC', 'Chemical', '-', (113, 117))	('Mtor', 'Gene', (66, 70))	('signalling', 'biological_process', 'GO:0023052', ('140', '150'))
28034	29384525	Quantification of independent biological replicates yields a significantly increased phosphorylation of AKT at Thr308 and Ser473 as well as ERK upon the genetic deletion of Mtor (Figure 4B).	('ERK', 'molecular_function', 'GO:0004707', ('140', '143'))	('phosphorylation', 'MPA', (85, 100))	('Mtor', 'Gene', (173, 177))	('Ser473', 'Var', (122, 128))	('Thr308', 'Chemical', '-', (111, 117))	('Ser', 'cellular_component', 'GO:0005790', ('122', '125'))	('ERK', 'MPA', (140, 143))	('Ser473', 'Chemical', '-', (122, 128))	('increased', 'PosReg', (75, 84))	('AKT', 'Pathway', (104, 107))	('phosphorylation', 'biological_process', 'GO:0016310', ('85', '100'))
28035	29384525	Applying an antibody which detects Ser217/221 phosphorylated MEK1/2, we observed increased phosphorylation of MEK1/2 upon deletion of Mtor (Figure 4C).	('phosphorylation', 'MPA', (91, 106))	('Ser', 'cellular_component', 'GO:0005790', ('35', '38'))	('antibody', 'cellular_component', 'GO:0042571', ('12', '20'))	('MEK1/2', 'Gene', (110, 116))	('MEK1/2', 'Gene', '26395;26396', (110, 116))	('MEK1', 'molecular_function', 'GO:0004708', ('61', '65'))	('Ser217', 'Chemical', '-', (35, 41))	('Mtor', 'Gene', (134, 138))	('deletion', 'Var', (122, 130))	('MEK1', 'molecular_function', 'GO:0004708', ('110', '114'))	('MEK1/2', 'Gene', '26395;26396', (61, 67))	('antibody', 'molecular_function', 'GO:0003823', ('12', '20'))	('antibody', 'cellular_component', 'GO:0019814', ('12', '20'))	('phosphorylation', 'biological_process', 'GO:0016310', ('91', '106'))	('antibody', 'cellular_component', 'GO:0019815', ('12', '20'))	('increased', 'PosReg', (81, 90))	('MEK1/2', 'Gene', (61, 67))
28040	29384525	Compared to the reactivation of the PI3K-AKT pathway, phosphorylation of ERK was detected earlier in the time course of INK-128 treatment (Figure 4E).	('INK-128', 'Var', (120, 127))	('ERK', 'molecular_function', 'GO:0004707', ('73', '76'))	('INK-128', 'Chemical', 'MESH:C572449', (120, 127))	('ERK', 'Protein', (73, 76))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('PI3K', 'molecular_function', 'GO:0016303', ('36', '40'))	('phosphorylation', 'MPA', (54, 69))
28041	29384525	Recent investigations demonstrated that AKT Ser473 phosphorylation is significantly blocked in murine PDAC in vivo upon dual MTOR inhibition.	('PDAC', 'Chemical', '-', (102, 106))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('AKT', 'Pathway', (40, 43))	('blocked', 'NegReg', (84, 91))	('Ser473', 'Var', (44, 50))	('murine', 'Species', '10090', (95, 101))	('PDAC', 'Phenotype', 'HP:0006725', (102, 106))	('Ser', 'cellular_component', 'GO:0005790', ('44', '47'))	('phosphorylation', 'MPA', (51, 66))	('Ser473', 'Chemical', '-', (44, 50))
28043	29384525	Again, AKT Ser473 phosphorylation was significantly decreased 24 h after treatment of cells with AZD2014 (Figure 4F).	('Ser', 'cellular_component', 'GO:0005790', ('11', '14'))	('decreased', 'NegReg', (52, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('18', '33'))	('AZD2014', 'Chemical', 'MESH:C585537', (97, 104))	('AZD2014', 'Var', (97, 104))	('phosphorylation', 'MPA', (18, 33))	('Ser473', 'Chemical', '-', (11, 17))	('AKT Ser473', 'Pathway', (7, 17))
28044	29384525	However, an increase of AKT Ser473 phosphorylation was observed at days 3 and 4 upon continuous treatment with AZD2014 (Figure 4F).	('increase', 'PosReg', (12, 20))	('AZD2014', 'Chemical', 'MESH:C585537', (111, 118))	('AKT Ser473', 'Protein', (24, 34))	('AZD2014', 'Var', (111, 118))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('Ser473', 'Chemical', '-', (28, 34))	('Ser', 'cellular_component', 'GO:0005790', ('28', '31'))
28045	29384525	Important recent work has demonstrated that the noncanonical IkappaB-related kinase IKBKE phosphorylates Ser473 of AKT upon dual MTOR inhibition.	('AKT', 'Pathway', (115, 118))	('Ser', 'cellular_component', 'GO:0005790', ('105', '108'))	('Ser473', 'Var', (105, 111))	('IKBKE', 'Gene', '56489', (84, 89))	('IKBKE', 'Gene', (84, 89))	('Ser473', 'Chemical', '-', (105, 111))
28046	29384525	To test the contribution of IKBKE for AKT Ser473 phosphorylation upon genetic Mtor deletion, we used the IKBKE inhibitor MRT67307.	('IKBKE', 'Gene', '56489', (105, 110))	('phosphorylation', 'biological_process', 'GO:0016310', ('49', '64'))	('IKBKE', 'Gene', (105, 110))	('deletion', 'Var', (83, 91))	('IKBKE', 'Gene', '56489', (28, 33))	('Ser', 'cellular_component', 'GO:0005790', ('42', '45'))	('Ser473', 'Chemical', '-', (42, 48))	('IKBKE', 'Gene', (28, 33))
28047	29384525	Again, genetic deletion of Mtor increased phosphorylation of Ser473 of AKT (Supplementary Figure 8).	('Ser', 'cellular_component', 'GO:0005790', ('61', '64'))	('genetic deletion', 'Var', (7, 23))	('phosphorylation of Ser473', 'MPA', (42, 67))	('AKT', 'Pathway', (71, 74))	('Ser473', 'Chemical', '-', (61, 67))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('Mtor', 'Gene', (27, 31))	('increased', 'PosReg', (32, 41))
28049	29384525	Activation of the ERK and the PI3K pathway upon inhibition of MTOR prompted us to test the dual MTOR inhibitor INK-128 together with PI3K (GDC-0941), AKT (MK-2206) or MEK (PD-325901) inhibitors in human and murine PDAC models, respectively.	('murine', 'Species', '10090', (207, 213))	('PI3K', 'molecular_function', 'GO:0016303', ('30', '34'))	('PDAC', 'Phenotype', 'HP:0006725', (214, 218))	('MK-2206', 'Chemical', 'MESH:C548887', (155, 162))	('ERK', 'molecular_function', 'GO:0004707', ('18', '21'))	('GDC-0941', 'Chemical', 'MESH:C532162', (139, 147))	('inhibition', 'Var', (48, 58))	('PD-325901', 'Chemical', 'MESH:C506614', (172, 181))	('PI3K pathway', 'Pathway', (30, 42))	('INK-128', 'Gene', (111, 118))	('ERK', 'Pathway', (18, 21))	('PDAC', 'Chemical', '-', (214, 218))	('PI3K', 'molecular_function', 'GO:0016303', ('133', '137'))	('human', 'Species', '9606', (197, 202))	('MTOR', 'Gene', (62, 66))	('INK-128', 'Chemical', 'MESH:C572449', (111, 118))
28050	29384525	Efficacy of INK-128 was increased to different extents in the investigated models by combined PI3K, AKT or MEK inhibition.	('Efficacy', 'MPA', (0, 8))	('MEK', 'CPA', (107, 110))	('AKT', 'CPA', (100, 103))	('PI3K', 'molecular_function', 'GO:0016303', ('94', '98'))	('PI3K', 'Var', (94, 98))	('INK-128', 'Chemical', 'MESH:C572449', (12, 19))	('INK-128', 'Gene', (12, 19))	('increased', 'PosReg', (24, 33))	('inhibition', 'NegReg', (111, 121))
28051	29384525	Figure 5A demonstrates the dose response of INK-128 in a human and murine PDAC cell line in the presence and absence of MK-2206, GDC-0941 or PD-325901.	('MK-2206', 'Var', (120, 127))	('INK-128', 'Chemical', 'MESH:C572449', (44, 51))	('murine', 'Species', '10090', (67, 73))	('PDAC', 'Phenotype', 'HP:0006725', (74, 78))	('GDC-0941', 'Chemical', 'MESH:C532162', (129, 137))	('PD-325901', 'Chemical', 'MESH:C506614', (141, 150))	('PD-325901', 'Var', (141, 150))	('PDAC', 'Chemical', '-', (74, 78))	('INK-128', 'Gene', (44, 51))	('MK-2206', 'Chemical', 'MESH:C548887', (120, 127))	('human', 'Species', '9606', (57, 62))
28055	29384525	Again, human primary PDAC 3D cultures were more sensitive to INK-128 in case of AKT, PI3K or MEK coinhibition (Figure 5B and Supplementary Table 2).	('PDAC', 'Chemical', '-', (21, 25))	('AKT', 'Pathway', (80, 83))	('INK-128', 'Var', (61, 68))	('INK-128', 'Chemical', 'MESH:C572449', (61, 68))	('human', 'Species', '9606', (7, 12))	('PDAC', 'Phenotype', 'HP:0006725', (21, 25))	('sensitive', 'MPA', (48, 57))	('PI3K', 'molecular_function', 'GO:0016303', ('85', '89'))
28057	29384525	Taken together, blocking adaptive rewiring of oncogenic signalling upon MTOR inhibition is relevant in some of the investigated PDAC models.	('inhibition', 'Var', (77, 87))	('PDAC', 'Chemical', '-', (128, 132))	('oncogenic signalling', 'MPA', (46, 66))	('signalling', 'biological_process', 'GO:0023052', ('56', '66'))	('PDAC', 'Phenotype', 'HP:0006725', (128, 132))	('PDAC', 'Disease', (128, 132))
28060	29384525	Inhibitors of mTORC1 can drive activation of PI3K-, AKT- or ERK-directed pathways and the feedback phosphorylation of Ser473 of AKT by mTORC2 in response to rapalogues is a prominent example.	('mTORC1', 'Gene', (14, 20))	('AKT-', 'Gene', '11651', (52, 56))	('mTORC2', 'Gene', '74343', (135, 141))	('Ser473', 'Chemical', '-', (118, 124))	('ERK-directed pathways', 'Pathway', (60, 81))	('PI3K', 'molecular_function', 'GO:0016303', ('45', '49'))	('ERK', 'molecular_function', 'GO:0004707', ('60', '63'))	('Inhibitors', 'Var', (0, 10))	('mTORC1', 'Gene', '382056', (14, 20))	('mTORC2', 'cellular_component', 'GO:0031932', ('135', '141'))	('Ser', 'cellular_component', 'GO:0005790', ('118', '121'))	('mTORC1', 'cellular_component', 'GO:0031931', ('14', '20'))	('AKT-', 'Gene', (52, 56))	('activation', 'PosReg', (31, 41))	('PI3K-', 'Pathway', (45, 50))	('mTORC2', 'Gene', (135, 141))	('phosphorylation', 'biological_process', 'GO:0016310', ('99', '114'))
28062	29384525	The dual mTORC1/TORC2 inhibitor AZD2014 prolonged survival in an aggressive PDAC mouse model, which relies on the simultaneous expression of the KrasG12D oncogene and the mutated tumour suppressor p53R172H.	('mTORC1', 'Gene', (9, 15))	('prolonged', 'PosReg', (40, 49))	('PDAC', 'Phenotype', 'HP:0006725', (76, 80))	('mTORC1', 'cellular_component', 'GO:0031931', ('9', '15'))	('AZD2014', 'Var', (32, 39))	('AZD2014', 'Chemical', 'MESH:C585537', (32, 39))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('mTORC1', 'Gene', '382056', (9, 15))	('p53', 'Gene', (197, 200))	('PDAC', 'Chemical', '-', (76, 80))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('p53', 'Gene', '22059', (197, 200))	('TORC2', 'Gene', '74343', (16, 21))	('TORC2', 'cellular_component', 'GO:0031932', ('16', '21'))	('mouse', 'Species', '10090', (81, 86))	('survival', 'CPA', (50, 58))	('tumour', 'Disease', (179, 185))	('TORC2', 'Gene', (16, 21))
28064	29384525	To further support such a note and to mimic specific dual mTORC1/TORC2 inhibitors, we developed a novel model, allowing the genetic inactivation of MTOR in PDAC cells.	('MTOR', 'Gene', (148, 152))	('TORC2', 'Gene', '74343', (65, 70))	('mTORC1', 'Gene', '382056', (58, 64))	('TORC2', 'Gene', (65, 70))	('TORC2', 'cellular_component', 'GO:0031932', ('65', '70'))	('PDAC', 'Chemical', '-', (156, 160))	('genetic inactivation', 'Var', (124, 144))	('mTORC1', 'Gene', (58, 64))	('mTORC1', 'cellular_component', 'GO:0031931', ('58', '64'))	('PDAC', 'Phenotype', 'HP:0006725', (156, 160))
28065	29384525	We demonstrate impaired glucose uptake upon MTOR deletion and a reduced expression of glycolytic enzymes, which are relevant in a subgroup of the human disease.	('glycolytic enzymes', 'Enzyme', (86, 104))	('glucose', 'Chemical', 'MESH:D005947', (24, 31))	('impaired', 'NegReg', (15, 23))	('MTOR', 'Gene', (44, 48))	('expression', 'MPA', (72, 82))	('glucose uptake', 'MPA', (24, 38))	('human', 'Species', '9606', (146, 151))	('glucose uptake', 'biological_process', 'GO:0046323', ('24', '38'))	('reduced', 'NegReg', (64, 71))	('deletion', 'Var', (49, 57))
28067	29384525	Early after the deletion or inhibition of the MTOR kinase in murine PDAC cells, we detected adaptive activation of the canonical ERK and PI3K-AKT pathways.	('ERK', 'molecular_function', 'GO:0004707', ('129', '132'))	('PDAC', 'Phenotype', 'HP:0006725', (68, 72))	('activation', 'PosReg', (101, 111))	('deletion', 'Var', (16, 24))	('PI3K', 'molecular_function', 'GO:0016303', ('137', '141'))	('murine', 'Species', '10090', (61, 67))	('inhibition', 'NegReg', (28, 38))	('PDAC', 'Chemical', '-', (68, 72))
28068	29384525	Increased phosphorylation of Thr308 as well as Ser473 of AKT was detected.	('phosphorylation', 'biological_process', 'GO:0016310', ('10', '25'))	('Ser473', 'Var', (47, 53))	('AKT', 'Pathway', (57, 60))	('phosphorylation', 'MPA', (10, 25))	('Ser473', 'Chemical', '-', (47, 53))	('Thr308', 'Chemical', '-', (29, 35))	('Ser', 'cellular_component', 'GO:0005790', ('47', '50'))	('Thr308', 'Protein', (29, 35))
28069	29384525	Phosphorylation of Ser473 upon MTOR deletion is consistent with a recent publication, demonstrating phosphorylation of Ser473 of AKT upon treatment of PDAC cells with the dual mTORC1/TORC2 inhibitor Torin-1.	('Torin', 'Gene', '21672', (199, 204))	('phosphorylation', 'biological_process', 'GO:0016310', ('100', '115'))	('Torin', 'Gene', (199, 204))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('Ser', 'cellular_component', 'GO:0005790', ('19', '22'))	('mTORC1', 'Gene', (176, 182))	('AKT', 'Pathway', (129, 132))	('Ser473', 'Chemical', '-', (19, 25))	('TORC2', 'Gene', '74343', (183, 188))	('mTORC1', 'Gene', '382056', (176, 182))	('TORC2', 'Gene', (183, 188))	('TORC2', 'cellular_component', 'GO:0031932', ('183', '188'))	('Ser', 'cellular_component', 'GO:0005790', ('119', '122'))	('deletion', 'Var', (36, 44))	('mTORC1', 'cellular_component', 'GO:0031931', ('176', '182'))	('phosphorylation', 'MPA', (100, 115))	('Ser473', 'Var', (119, 125))	('Ser473', 'Chemical', '-', (119, 125))	('MTOR', 'Gene', (31, 35))	('PDAC', 'Chemical', '-', (151, 155))	('PDAC', 'Phenotype', 'HP:0006725', (151, 155))
28071	29384525	We observed that increased phosphorylation of Ser473 of AKT upon Mtor deletion was partially blocked by MRT67307, an inhibitor which targets IKBKE.	('deletion', 'Var', (70, 78))	('increased', 'PosReg', (17, 26))	('IKBKE', 'Gene', '56489', (141, 146))	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('IKBKE', 'Gene', (141, 146))	('Ser473', 'Var', (46, 52))	('Ser473', 'Chemical', '-', (46, 52))	('phosphorylation', 'MPA', (27, 42))	('Ser', 'cellular_component', 'GO:0005790', ('46', '49'))	('Mtor', 'Gene', (65, 69))	('AKT', 'Pathway', (56, 59))
28076	29384525	Here, SC was highest for the combination of INK-128 and PD-325901 and some PDAC models show an up to a 350-fold increased sensitivity towards the dual MTOR inhibitor if MEK is blocked.	('INK-128', 'Chemical', 'MESH:C572449', (44, 51))	('PDAC', 'Phenotype', 'HP:0006725', (75, 79))	('PD-325901', 'Chemical', 'MESH:C506614', (56, 65))	('sensitivity towards the dual MTOR inhibitor', 'MPA', (122, 165))	('increased', 'PosReg', (112, 121))	('PDAC', 'Chemical', '-', (75, 79))	('PD-325901', 'Var', (56, 65))
28085	29384525	Congruently, RTK-dependent adaptive responses occurring upon the blockade of relevant driver pathways were described in numerous cancer models involving different molecular mechanisms.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('numerous cancer', 'Disease', (120, 135))	('blockade', 'Var', (65, 73))	('numerous cancer', 'Disease', 'MESH:D009369', (120, 135))
28093	29384525	The combination of a MEKi and a PI3Ki induced a partial response (>30% reduction in tumour volume) in only ~13% of animals in a PDAC mouse model generated by the activation KrasG12D and simultaneous inactivation of Cdkn2a and in 50% of animals in a PDAC mouse model generated by the activation KrasG12D and simultaneous inactivation of p53.	('PDAC', 'Phenotype', 'HP:0006725', (249, 253))	('tumour volume', 'Disease', 'MESH:D009369', (84, 97))	('inactivation', 'NegReg', (199, 211))	('Cdkn2a', 'Gene', '12578', (215, 221))	('mouse', 'Species', '10090', (254, 259))	('PDAC', 'Chemical', '-', (128, 132))	('reduction', 'NegReg', (71, 80))	('PI3Ki', 'Var', (32, 37))	('Cdkn2a', 'Gene', (215, 221))	('tumour volume', 'Disease', (84, 97))	('activation KrasG12D', 'Var', (162, 181))	('KrasG12D', 'Var', (173, 181))	('p53', 'Gene', '22059', (336, 339))	('mouse', 'Species', '10090', (133, 138))	('PDAC', 'Chemical', '-', (249, 253))	('PDAC', 'Phenotype', 'HP:0006725', (128, 132))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('p53', 'Gene', (336, 339))
28097	29384525	Therefore, further work needs to include (I) predictive biomarkers for mTORC1/TORC2 inhibitor-based therapies, (II) a detailed molecular understanding of adaptive rewiring of oncogenic pathways upon mTORC1/TORC2 inhibition and (III) unbiased MTOR-centred synthetic lethality screens to increase the chance to successfully establish dual MTOR inhibitor-based therapies.	('TORC2', 'Gene', (78, 83))	('TORC2', 'Gene', '74343', (206, 211))	('TORC2', 'cellular_component', 'GO:0031932', ('78', '83'))	('mTORC1', 'Gene', '382056', (199, 205))	('mTORC1', 'cellular_component', 'GO:0031931', ('71', '77'))	('mTORC1', 'Gene', (71, 77))	('mTORC1', 'cellular_component', 'GO:0031931', ('199', '205'))	('oncogenic pathways', 'Pathway', (175, 193))	('TORC2', 'Gene', (206, 211))	('inhibition', 'Var', (212, 222))	('mTORC1', 'Gene', (199, 205))	('TORC2', 'Gene', '74343', (78, 83))	('mTORC1', 'Gene', '382056', (71, 77))	('TORC2', 'cellular_component', 'GO:0031932', ('206', '211'))
28105	28405146	Patients with AIP + PC were significantly older (60.5 vs 49 years of age, P = 0.045), more likely to have been recently diagnosed with diabetes (67% vs 11%, P = 0.09), and had experienced greater weight loss (15.5 kg vs 8.5 kg, P = 0.03) than AIP patients without PC.	('AIP + PC', 'Var', (14, 22))	('weight loss', 'Disease', (196, 207))	('PC', 'Phenotype', 'HP:0006725', (264, 266))	('weight loss', 'Phenotype', 'HP:0001824', (196, 207))	('diabetes', 'Disease', (135, 143))	('patients', 'Species', '9606', (247, 255))	('Patients', 'Species', '9606', (0, 8))	('PC', 'Phenotype', 'HP:0002894', (20, 22))	('diabetes', 'Disease', 'MESH:D003920', (135, 143))	('weight loss', 'Disease', 'MESH:D015431', (196, 207))	('PC', 'Phenotype', 'HP:0006725', (20, 22))	('PC', 'Phenotype', 'HP:0002894', (264, 266))
28140	28405146	Patients with AIP + PC were significantly older (median age 60.5 vs 49, P =0.045) and were more likely to have been diagnosed with recent-onset diabetes mellitus (within six months prior to resection) in the preoperative period (67% vs 11%, P = 0.09).	('AIP + PC', 'Var', (14, 22))	('diabetes mellitus', 'Disease', 'MESH:D003920', (144, 161))	('Patients', 'Species', '9606', (0, 8))	('PC', 'Phenotype', 'HP:0002894', (20, 22))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (144, 161))	('PC', 'Phenotype', 'HP:0006725', (20, 22))	('recent-onset diabetes', 'Phenotype', 'HP:0100651', (131, 152))	('diabetes mellitus', 'Disease', (144, 161))
28144	28405146	Six patients with AIP had a history of pancreatic disease - three had chronic pancreatitis (two with AIP and one with AIP + PC), and three patients with AIP alone had experienced an acute episode of pancreatitis of unspecified etiology.	('acute episode of pancreatitis', 'Phenotype', 'HP:0001735', (182, 211))	('pancreatitis', 'Phenotype', 'HP:0001733', (78, 90))	('pancreatitis', 'Disease', 'MESH:D010195', (199, 211))	('pancreatic disease', 'Phenotype', 'HP:0001732', (39, 57))	('pancreatic disease', 'Disease', (39, 57))	('pancreatitis', 'Disease', (199, 211))	('pancreatitis', 'Disease', 'MESH:D010195', (78, 90))	('patients', 'Species', '9606', (4, 12))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (70, 90))	('pancreatitis', 'Disease', (78, 90))	('PC', 'Phenotype', 'HP:0006725', (124, 126))	('patients', 'Species', '9606', (139, 147))	('episode of pancreatitis', 'Phenotype', 'HP:0100027', (188, 211))	('PC', 'Phenotype', 'HP:0002894', (124, 126))	('unspecified', 'Species', '32644', (215, 226))	('pancreatic disease', 'Disease', 'MESH:D010182', (39, 57))	('AIP', 'Var', (18, 21))	('chronic pancreatitis', 'Disease', (70, 90))	('pancreatitis', 'Phenotype', 'HP:0001733', (199, 211))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (70, 90))
28146	28405146	Two patients with AIP type 1 had an involvement of other organs (IgG4-sclerosing cholangitis and sialadenitis) manifesting during postsurgical follow-up.	('cholangitis', 'Disease', (81, 92))	('AIP type 1', 'Var', (18, 28))	('sialadenitis', 'Phenotype', 'HP:0031281', (97, 109))	('IgG4', 'cellular_component', 'GO:0071735', ('65', '69'))	('involvement', 'Reg', (36, 47))	('sialadenitis', 'Disease', 'MESH:D012793', (97, 109))	('cholangitis', 'Disease', 'MESH:D002761', (81, 92))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (70, 92))	('men', 'Species', '9606', (43, 46))	('patients', 'Species', '9606', (4, 12))	('sialadenitis', 'Disease', (97, 109))	('cholangitis', 'Phenotype', 'HP:0030151', (81, 92))
28147	28405146	One patient with AIP type 1 had autoimmune thyroiditis, and one patient with AIP type 2 had a history of Crohn's disease.	('patient', 'Species', '9606', (64, 71))	('thyroiditis', 'Phenotype', 'HP:0100646', (43, 54))	('patient', 'Species', '9606', (4, 11))	("Crohn's disease", 'Phenotype', 'HP:0100280', (105, 120))	('autoimmune thyroiditis', 'Disease', 'MESH:D013967', (32, 54))	("Crohn's disease", 'Disease', (105, 120))	("Crohn's disease", 'Disease', 'MESH:D003424', (105, 120))	('autoimmune thyroiditis', 'Disease', (32, 54))	('AIP type 1', 'Var', (17, 27))
28182	28405146	The first one considers AIP as a precursor for pancreatic cancer due to chronic inflammation which leads to harboring of mutations and, over time, to development of cancer.	('inflammation', 'Disease', 'MESH:D007249', (80, 92))	('mutations', 'Var', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('inflammation', 'Disease', (80, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (47, 64))	('inflammation', 'biological_process', 'GO:0006954', ('80', '92'))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('men', 'Species', '9606', (157, 160))	('cancer', 'Disease', (58, 64))	('pancreatic cancer', 'Disease', 'MESH:D010190', (47, 64))	('pancreatic cancer', 'Disease', (47, 64))
28189	28405146	The high frequency of K-ras mutations found in pancreatic tissue of patients with AIP further supports the association of the two diseases.	('pancreatic', 'Disease', 'MESH:D010195', (47, 57))	('pancreatic', 'Disease', (47, 57))	('K-ras', 'Gene', (22, 27))	('patients', 'Species', '9606', (68, 76))	('K-ras', 'Gene', '3845', (22, 27))	('association', 'Interaction', (107, 118))	('AIP', 'Disease', (82, 85))	('mutations', 'Var', (28, 37))
28202	28405146	The significantly higher age of patients with AIP + PC may be somewhat expected due to the mechanism of cancer development, presumed to be a long-term chronic inflammatory process.	('PC', 'Phenotype', 'HP:0006725', (52, 54))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('AIP + PC', 'Var', (46, 54))	('men', 'Species', '9606', (118, 121))	('PC', 'Phenotype', 'HP:0002894', (52, 54))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
28204	28405146	The higher proportion of recent onset diabetes in patients with AIP + PC compared with patients with AIP only is an interesting finding.	('PC', 'Phenotype', 'HP:0006725', (70, 72))	('diabetes', 'Disease', (38, 46))	('patients', 'Species', '9606', (50, 58))	('diabetes', 'Disease', 'MESH:D003920', (38, 46))	('AIP', 'Var', (64, 67))	('PC', 'Phenotype', 'HP:0002894', (70, 72))	('patients', 'Species', '9606', (87, 95))	('recent onset diabetes', 'Phenotype', 'HP:0100651', (25, 46))
28222	28405146	AIP may mimic pancreatic cancer (PC), as it often presents with obstructive jaundice and focal pancreatic enlargement.	('pancreatic cancer', 'Disease', (14, 31))	('PC', 'Phenotype', 'HP:0002894', (33, 35))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('pancreatic enlargement', 'Disease', 'MESH:D010195', (95, 117))	('pancreatic cancer', 'Disease', 'MESH:D010190', (14, 31))	('obstructive jaundice', 'Disease', 'MESH:D041781', (64, 84))	('PC', 'Phenotype', 'HP:0006725', (33, 35))	('pancreatic enlargement', 'Disease', (95, 117))	('obstructive jaundice', 'Disease', (64, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (14, 31))	('AIP', 'Var', (0, 3))	('jaundice', 'Phenotype', 'HP:0000952', (76, 84))	('pancreatic enlargement', 'Phenotype', 'HP:0006277', (95, 117))
28237	27483328	During the progression of cancer, however, the expression of aberrant and truncated glycans is commonly observed.	('aberrant', 'Var', (61, 69))	('glycans', 'Protein', (84, 91))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('glycans', 'Chemical', 'MESH:D011134', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('truncated', 'Var', (74, 83))
28240	27483328	Within this review, we highlight both the processes involved in the expression of aberrant glycan structures on mucins, as well as the potential downstream impacts on cellular signaling.	('mucin', 'Gene', (112, 117))	('impacts', 'Reg', (156, 163))	('signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('mucin', 'Gene', '100508689', (112, 117))	('glycan structures', 'Protein', (91, 108))	('aberrant', 'Var', (82, 90))	('glycan', 'Chemical', 'MESH:D011134', (91, 97))
28265	27483328	Elevation of MUC16 (CA125) is well studied in ovarian cancer, and recently expression of MUC16 has been implicated as a significant factor in pancreatic cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (46, 60))	('MUC16', 'Gene', '94025', (89, 94))	('ovarian cancer', 'Disease', 'MESH:D010051', (46, 60))	('MUC16', 'Gene', '94025', (13, 18))	('CA125', 'Gene', '94025', (20, 25))	('pancreatic cancer', 'Disease', (142, 159))	('ovarian cancer', 'Disease', (46, 60))	('expression', 'Var', (75, 85))	('pancreatic cancer', 'Disease', 'MESH:D010190', (142, 159))	('CA125', 'Gene', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('MUC16', 'Gene', (13, 18))	('MUC16', 'Gene', (89, 94))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('factor', 'Reg', (132, 138))
28266	27483328	Many tumors exhibit aberrant O-glycans.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('aberrant', 'Var', (20, 28))	('O-glycans', 'Protein', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('O-glycans', 'Chemical', '-', (29, 38))
28268	27483328	The expression of truncated Core 1 based structures, such as T, Tn, or sialyl-Tn (STn), are observed in a majority of human carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('carcinomas', 'Disease', 'MESH:D002277', (124, 134))	('sialyl-Tn', 'Var', (71, 80))	('carcinomas', 'Disease', (124, 134))	('human', 'Species', '9606', (118, 123))
28271	27483328	Furthermore, a significant percentage of cancers exhibit hypermethylation of the Cosmc gene, resulting in decreased expression and increased formation of Tn and STn epitopes.	('decreased', 'NegReg', (106, 115))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('expression', 'MPA', (116, 126))	('Cosmc', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('increased', 'PosReg', (131, 140))	('formation', 'biological_process', 'GO:0009058', ('141', '150'))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('Cosmc', 'Gene', '29071', (81, 86))	('hypermethylation', 'Var', (57, 73))	('cancers', 'Disease', (41, 48))
28277	27483328	Redistribution of GalNAc-Ts has been shown to result in increased density of GalNAc modification within a six tandem repeat model of MUC1, indicating a role for this process in the glycosylation of mucins.	('mucin', 'Gene', (198, 203))	('glycosylation', 'biological_process', 'GO:0070085', ('181', '194'))	('modification', 'Var', (84, 96))	('GalNAc', 'Chemical', '-', (77, 83))	('increased', 'PosReg', (56, 65))	('GalNAc-T', 'Gene', '2583', (18, 26))	('mucin', 'Gene', '100508689', (198, 203))	('GalNAc-T', 'Gene', (18, 26))	('density', 'MPA', (66, 73))	('GalNAc', 'Gene', (77, 83))	('GalNAc', 'Chemical', '-', (18, 24))
28284	27483328	Alterations in levels of acceptor substrates for O-glycans (mucin core proteins) in tumor cells may also explain in part the observed increased expression of some glycoepitopes, such as sialyl-LewisX/A, which are commonly observed in adenocarcinomas.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('sialyl-LewisX/A', 'Var', (186, 201))	('mucin', 'Gene', (60, 65))	('expression', 'MPA', (144, 154))	('adenocarcinomas', 'Disease', 'MESH:D000230', (234, 249))	('adenocarcinomas', 'Disease', (234, 249))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('levels', 'MPA', (15, 21))	('tumor', 'Disease', (84, 89))	('O-glycans', 'Chemical', '-', (49, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (239, 249))	('increased', 'PosReg', (134, 143))	('mucin', 'Gene', '100508689', (60, 65))	('Alterations', 'Reg', (0, 11))	('core', 'cellular_component', 'GO:0019013', ('66', '70'))
28285	27483328	Phenotypically, altered expression of mucin-type glycoproteins bearing aberrant O-glycans is associated with increased aggressiveness and metastatic behavior in a variety of cancers.	('metastatic behavior', 'CPA', (138, 157))	('mucin', 'Gene', '100508689', (38, 43))	('aggressiveness', 'Disease', (119, 133))	('O-glycans', 'Protein', (80, 89))	('aggressiveness', 'Disease', 'MESH:D001523', (119, 133))	('expression', 'MPA', (24, 34))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Disease', (174, 181))	('mucin', 'Gene', (38, 43))	('associated', 'Reg', (93, 103))	('altered', 'Reg', (16, 23))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('aggressiveness', 'Phenotype', 'HP:0000718', (119, 133))	('O-glycans', 'Chemical', '-', (80, 89))	('increased', 'PosReg', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('aberrant', 'Var', (71, 79))
28288	27483328	Within this review, we discuss potential molecular mechanisms whereby alterations in mucin type O-glycosylation mediate functional effects, particularly in regards to modulation of downstream signaling through the cell surface mucins MUC1, MUC4, and MUC16 (Figure 2).	('alterations', 'Var', (70, 81))	('mucin', 'Gene', '100508689', (227, 232))	('glycosylation', 'biological_process', 'GO:0070085', ('98', '111'))	('cell surface', 'cellular_component', 'GO:0009986', ('214', '226'))	('modulation', 'Reg', (167, 177))	('mucin', 'Gene', (85, 90))	('MUC4', 'Gene', (240, 244))	('mucin', 'Gene', (227, 232))	('MUC16', 'Gene', (250, 255))	('signaling', 'biological_process', 'GO:0023052', ('192', '201'))	('mucin', 'Gene', '100508689', (85, 90))	('MUC16', 'Gene', '94025', (250, 255))	('MUC4', 'Gene', '4585', (240, 244))
28297	27483328	Loss of Core 1 derived glycans through knockout of C1GalT1 in a mouse model of breast cancer was shown to decrease the incidence of tumor development.	('glycans', 'Protein', (23, 30))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('knockout', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('decrease', 'NegReg', (106, 114))	('breast cancer', 'Disease', (79, 92))	('Loss', 'NegReg', (0, 4))	('C1GalT1', 'Gene', (51, 58))	('glycans', 'Chemical', 'MESH:D011134', (23, 30))	('tumor', 'Disease', (132, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('mouse', 'Species', '10090', (64, 69))
28298	27483328	While, presumably, loss of C1GalT1 should favor formation of truncated glycans and tumor progression, loss of Core 1 glycans may favor formation of Core 3 or 4 structures that correlate with less aggressive tumors.	('formation', 'biological_process', 'GO:0009058', ('48', '57'))	('formation', 'biological_process', 'GO:0009058', ('135', '144'))	('tumor', 'Disease', (83, 88))	('aggressive tumors', 'Disease', 'MESH:D001523', (196, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('loss', 'Var', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('glycans', 'Chemical', 'MESH:D011134', (71, 78))	('C1GalT1', 'Gene', (27, 34))	('formation of truncated glycans', 'MPA', (48, 78))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('favor', 'PosReg', (129, 134))	('loss', 'Var', (19, 23))	('tumor', 'Disease', (207, 212))	('favor', 'PosReg', (42, 47))	('glycans', 'Chemical', 'MESH:D011134', (117, 124))	('formation of Core 3 or 4 structures', 'MPA', (135, 170))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('aggressive tumors', 'Disease', (196, 213))
28302	27483328	Interestingly, overexpression of MUC1 in human breast cancer lines as well as murine lines results in decreased expression of the extension enzymes core 2 beta1,6-N-acetylglucosaminyl transferase 1 (C2GnT1) and ST3 beta-galactosidase alpha-2,3-sialyl transferase 1(ST3Gal1) suggesting that MUC1 can potentiate expression of truncated glycans in a feed forward manner.	('glycans', 'Chemical', 'MESH:D011134', (334, 341))	('ST3Gal1', 'Gene', (265, 272))	('breast cancer', 'Disease', (47, 60))	('core', 'cellular_component', 'GO:0019013', ('148', '152'))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('C2GnT1', 'Gene', (199, 205))	('MUC1', 'Var', (33, 37))	('human', 'Species', '9606', (41, 46))	('murine', 'Species', '10090', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('ST3Gal1', 'Gene', '20442', (265, 272))	('decreased', 'NegReg', (102, 111))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('expression', 'MPA', (112, 122))
28303	27483328	Additional studies in breast cancer demonstrate that hypoglycosylation of MUC1 to form Tn and STn antigens results in increased association with the SH3 domain-containing kinase-binding protein 1, CIN85.	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('MUC1', 'Gene', (74, 78))	('kinase-binding', 'molecular_function', 'GO:0019900', ('171', '185'))	('SH3 domain-containing kinase-binding protein 1', 'Gene', '30011', (149, 195))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('increased', 'PosReg', (118, 127))	('protein', 'cellular_component', 'GO:0003675', ('186', '193'))	('association', 'Interaction', (128, 139))	('SH3 domain-containing kinase-binding protein 1', 'Gene', (149, 195))	('hypoglycosylation', 'Var', (53, 70))	('CIN85', 'Gene', '30011', (197, 202))	('CIN85', 'Gene', (197, 202))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
28307	27483328	MUC1 is also known to potentiate downstream signaling through both the ERK and AKT signaling cascades.	('ERK', 'Gene', '5594', (71, 74))	('AKT', 'Gene', (79, 82))	('ERK', 'Gene', (71, 74))	('signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('ERK', 'molecular_function', 'GO:0004707', ('71', '74'))	('AKT', 'Gene', '207', (79, 82))	('MUC1', 'Var', (0, 4))	('downstream signaling', 'MPA', (33, 53))	('AKT signaling', 'biological_process', 'GO:0043491', ('79', '92'))	('potentiate', 'PosReg', (22, 32))
28310	27483328	These results suggest that altered MUC1 glycosylation may readily promote the association of MUC1 and EGFR and also integrate morphogenetic signals from the Wnt pathway.	('altered', 'Var', (27, 34))	('EGFR', 'Gene', '1956', (102, 106))	('MUC1', 'Protein', (93, 97))	('MUC1 glycosylation', 'Protein', (35, 53))	('promote', 'PosReg', (66, 73))	('integrate', 'Reg', (116, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('glycosylation', 'biological_process', 'GO:0070085', ('40', '53'))	('glycosylation', 'Protein', (40, 53))	('EGFR', 'Gene', (102, 106))	('association', 'Interaction', (78, 89))
28319	27483328	While these studies have focused solely on the role of galectin-3, it is possible that truncated glycan structures may also disrupt the dense barrier surrounding tumor cells independent of galectin-3.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('dense', 'MPA', (136, 141))	('glycan structures', 'Protein', (97, 114))	('truncated', 'Var', (87, 96))	('disrupt', 'NegReg', (124, 131))	('tumor', 'Disease', (162, 167))	('galectin-3', 'Gene', '3958', (55, 65))	('galectin-3', 'Gene', '3958', (189, 199))	('glycan', 'Chemical', 'MESH:D011134', (97, 103))	('galectin-3', 'Gene', (55, 65))	('galectin-3', 'Gene', (189, 199))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
28320	27483328	As such, modulation of glycan length may play a critical role in balancing adhesive and anti-adhesive features in the absence of galectin-3.	('glycan', 'Chemical', 'MESH:D011134', (23, 29))	('absence of galectin-3', 'Phenotype', 'HP:0032205', (118, 139))	('modulation', 'Var', (9, 19))	('galectin-3', 'Gene', (129, 139))	('glycan length', 'Protein', (23, 36))	('adhesive', 'CPA', (75, 83))	('galectin', 'molecular_function', 'GO:0001577', ('129', '137'))	('galectin-3', 'Gene', '3958', (129, 139))	('anti-adhesive features', 'CPA', (88, 110))
28339	27483328	Recently, the AMOP domain of MUC4 has been demonstrated to play a role in the metastatic spread of pancreatic cancer cells.	('pancreatic cancer', 'Disease', (99, 116))	('role', 'Reg', (66, 70))	('MUC4', 'Gene', '4585', (29, 33))	('metastatic spread', 'CPA', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (99, 116))	('play', 'Reg', (59, 63))	('AMOP domain', 'Var', (14, 25))	('MUC4', 'Gene', (29, 33))	('pancreatic cancer', 'Disease', 'MESH:D010190', (99, 116))
28342	27483328	The AMOP domain was also shown to be critical for the expression of vascular endothelial growth factor (VEGF)-A and matrix metallopeptidase (MMP)-9, which are both downregulated in response to MUC4 knockdown.	('MMP)-9', 'molecular_function', 'GO:0004229', ('141', '147'))	('MUC4', 'Gene', '4585', (193, 197))	('vascular endothelial growth factor', 'Gene', (68, 102))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('68', '102'))	('knockdown', 'Var', (198, 207))	('downregulated', 'NegReg', (164, 177))	('VEGF', 'Gene', '7422', (104, 108))	('vascular endothelial growth factor', 'Gene', '7422', (68, 102))	('MUC4', 'Gene', (193, 197))	('matrix metallopeptidase (MMP)-9', 'Gene', '4318', (116, 147))	('VEGF', 'Gene', (104, 108))
28357	27483328	Disruptions in glycosylation may readily expose MUC16 for proteolytic cleavage of the extracellular domain, and thus potentiate signaling of the cytoplasmic tail to drive progression of cancer.	('MUC16', 'Gene', (48, 53))	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('Disruptions', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('potentiate', 'PosReg', (117, 127))	('MUC16', 'Gene', '94025', (48, 53))	('signaling of the cytoplasmic tail', 'MPA', (128, 161))	('proteolytic cleavage', 'MPA', (58, 78))	('extracellular', 'cellular_component', 'GO:0005576', ('86', '99'))	('glycosylation', 'biological_process', 'GO:0070085', ('15', '28'))	('expose', 'Reg', (41, 47))	('glycosylation', 'MPA', (15, 28))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
28360	27483328	This interaction is potentially mediated by the poly-basic sequence (RRRKK) of the MUC16 cytoplasmic tail that has been shown to interact with the ezrin/radixin/moesin family of proteins (ERM).	('mediated', 'Reg', (32, 40))	('MUC16', 'Gene', '94025', (83, 88))	('poly-basic sequence', 'Var', (48, 67))	('interact', 'Interaction', (129, 137))	('MUC16', 'Gene', (83, 88))
28364	27483328	This interaction results in phosphorylation of tyrosine 22142 in the cytoplasmic tail of MUC16, and promotes shedding of the extracellular domain.	('tyrosine', 'Chemical', 'MESH:D014443', (47, 55))	('MUC16', 'Gene', '94025', (89, 94))	('promotes', 'PosReg', (100, 108))	('phosphorylation', 'MPA', (28, 43))	('tyrosine 22142', 'Var', (47, 61))	('extracellular', 'cellular_component', 'GO:0005576', ('125', '138'))	('results in', 'Reg', (17, 27))	('shedding of the extracellular domain', 'MPA', (109, 145))	('MUC16', 'Gene', (89, 94))	('interaction', 'Interaction', (5, 16))	('phosphorylation', 'biological_process', 'GO:0016310', ('28', '43'))
28365	27483328	This phosphorylation of the MUC16 cytoplasmic tail may also lead to deregulation of beta-catenin and E-cadherin at junctional complexes, as MUC16 has been shown to interact with both of these proteins.	('interact', 'Interaction', (164, 172))	('cadherin', 'molecular_function', 'GO:0008014', ('103', '111'))	('E-cadherin', 'Gene', (101, 111))	('lead to', 'Reg', (60, 67))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('phosphorylation', 'Var', (5, 20))	('MUC16', 'Gene', '94025', (28, 33))	('E-cadherin', 'Gene', '999', (101, 111))	('beta-catenin', 'Gene', (84, 96))	('deregulation', 'MPA', (68, 80))	('MUC16', 'Gene', (140, 145))	('beta-catenin', 'Gene', '1499', (84, 96))	('MUC16', 'Gene', '94025', (140, 145))	('MUC16', 'Gene', (28, 33))
28368	27483328	Beyond the capacity of glycosylation to alter downstream signaling through the cytoplasmic tails of mucins, these alterations can significantly influence the interactions of tumor cells with the surrounding microenvironment.	('tumor', 'Disease', (174, 179))	('mucin', 'Gene', '100508689', (100, 105))	('alter', 'Reg', (40, 45))	('alterations', 'Var', (114, 125))	('interactions', 'Interaction', (158, 170))	('glycosylation', 'biological_process', 'GO:0070085', ('23', '36'))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('influence', 'Reg', (144, 153))	('mucin', 'Gene', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
28369	27483328	Altered glycosylation of mucins often provokes immune responses in humans, as evidenced by the fact that many patients exhibit autoantibodies against various mucin epitopes.	('glycosylation', 'MPA', (8, 21))	('immune responses', 'MPA', (47, 63))	('mucin', 'Gene', '100508689', (25, 30))	('humans', 'Species', '9606', (67, 73))	('mucin', 'Gene', (158, 163))	('Altered', 'Var', (0, 7))	('provokes', 'Reg', (38, 46))	('glycosylation', 'biological_process', 'GO:0070085', ('8', '21'))	('mucin', 'Gene', (25, 30))	('mucin', 'Gene', '100508689', (158, 163))	('patients', 'Species', '9606', (110, 118))
28370	27483328	These glycoepitopes are also commonly used as biomarkers for overall cancer progression, including CA19-9, CA15-3, DU-PAN-2, and CA-125.	('PAN', 'cellular_component', 'GO:0022623', ('118', '121'))	('PAN-2', 'Gene', '9924', (118, 123))	('CA19-9', 'Var', (99, 105))	('CA-125', 'Gene', '94025', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PAN-2', 'Gene', (118, 123))	('CA15-3', 'Gene', '4582', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('CA15-3', 'Gene', (107, 113))	('CA-125', 'Gene', (129, 135))	('cancer', 'Disease', (69, 75))
28371	27483328	Aberrantly expressed oligosaccharides may also play a role in immune evasion.	('Aberrantly expressed', 'Var', (0, 20))	('play', 'Reg', (47, 51))	('immune evasion', 'MPA', (62, 76))	('oligosaccharides', 'Protein', (21, 37))	('immune evasion', 'biological_process', 'GO:0042783', ('62', '76'))	('oligosaccharides', 'Chemical', 'MESH:D009844', (21, 37))	('immune evasion', 'biological_process', 'GO:0051842', ('62', '76'))
28376	27483328	These effects may be dependent on a balance between the formation of truncated O-glycan structures and elongation, as Cosmc knockout cells exhibit increased sensitivity to both NK cells and cytotoxic T lymphocyte-mediated cell death.	('O-glycan', 'Protein', (79, 87))	('sensitivity', 'MPA', (157, 168))	('Cosmc', 'Gene', (118, 123))	('increased', 'PosReg', (147, 156))	('cell death', 'biological_process', 'GO:0008219', ('222', '232'))	('Cosmc', 'Gene', '29071', (118, 123))	('O-glycan', 'Chemical', '-', (79, 87))	('knockout', 'Var', (124, 132))	('formation', 'biological_process', 'GO:0009058', ('56', '65'))
28378	27483328	Expression of the carbohydrate structures sialyl-LewisX and sialyl-LewisA on MUC1 enable the binding of MUC1 to both E-selectin and intercellular adhesion molecule (ICAM)-1.	('E-selectin', 'Gene', '6401', (117, 127))	('E-selectin', 'Gene', (117, 127))	('selectin', 'molecular_function', 'GO:0008337', ('119', '127'))	('binding', 'molecular_function', 'GO:0005488', ('93', '100'))	('carbohydrate', 'Chemical', 'MESH:D002241', (18, 30))	('binding', 'Interaction', (93, 100))	('MUC1', 'Gene', (77, 81))	('intercellular adhesion molecule (ICAM)-1', 'Gene', '3383', (132, 172))	('selectin', 'molecular_function', 'GO:0030246', ('119', '127'))	('MUC1', 'Gene', (104, 108))	('enable', 'PosReg', (82, 88))	('sialyl-LewisA', 'Var', (60, 73))
28381	27483328	Mucins and proteins with mucin-type domains are decorated with a wide variety of carbohydrate moieties, and it is imperative to better understand the functional outcome of alterations in glycosylation for the future study of cancer and other disease processes (Figure 5).	('mucin', 'Gene', '100508689', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('glycosylation', 'biological_process', 'GO:0070085', ('187', '200'))	('cancer', 'Disease', (225, 231))	('mucin', 'Gene', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('carbohydrate', 'Chemical', 'MESH:D002241', (81, 93))	('alterations', 'Var', (172, 183))
28382	27483328	Many studies have demonstrated that expression of truncated glycan structures modulates proliferative, migratory and invasive behaviors of tumor cells, in part by altering the interactions between the cell and the surrounding environment and by affecting important signaling pathways in cells.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('signaling', 'biological_process', 'GO:0023052', ('265', '274'))	('proliferative', 'CPA', (88, 101))	('expression', 'Var', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('altering', 'Reg', (163, 171))	('glycan structures', 'Protein', (60, 77))	('truncated', 'Var', (50, 59))	('signaling pathways', 'Pathway', (265, 283))	('interactions', 'Interaction', (176, 188))	('modulates', 'Reg', (78, 87))	('affecting', 'Reg', (245, 254))	('glycan', 'Chemical', 'MESH:D011134', (60, 66))
28422	25792009	for the convenience of prognostic analysis as follows: age (<65 or >=65 years), gender (male or female), Eastern Cooperative Oncology Group (ECOG) score (0-1 or 2), primary tumor location (head or body/tail), prior tumor resection (no or yes), distant metastasis (no or yes), levels of carbohydrate antigen 19-9 (CA19-9 <1000 or >=1000 U/mL), carcinoembryonic antigen (CEA <5 or >=5 ng/mL), C-reactive protein (CRP <5 or >=5 mg/L), hemoglobin (<100 or >=100 g/L), neutrophil-to-lymphocyte ratio (NLR <5 or >=5), platelet to lymphocyte ratio (PLR <150 or >=150), and albumin (<35 or >=35 g/L).	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('CRP', 'Gene', (411, 414))	('neutrophil-to-lymphocyte ratio', 'MPA', (464, 494))	('protein', 'cellular_component', 'GO:0003675', ('402', '409'))	('CEA', 'Gene', (369, 372))	('albumin', 'MPA', (566, 573))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('<100', 'Var', (444, 448))	('C-reactive protein', 'Gene', (391, 409))	('Oncology', 'Phenotype', 'HP:0002664', (125, 133))	('carcinoembryonic', 'Disease', (343, 359))	('hemoglobin', 'MPA', (432, 442))	('primary tumor', 'Disease', 'MESH:D009369', (165, 178))	('platelet to lymphocyte ratio', 'MPA', (512, 540))	('tumor', 'Disease', (215, 220))	('C-reactive protein', 'Gene', '1401', (391, 409))	('CRP', 'Gene', '1401', (411, 414))	('primary tumor', 'Disease', (165, 178))	('distant metastasis', 'CPA', (244, 262))	('carcinoembryonic', 'Disease', 'None', (343, 359))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('CEA', 'Gene', '1048', (369, 372))	('tumor', 'Disease', (173, 178))
28445	25792009	The median OS for patients with CRP levels >=5 mg/L was 5.9 months (95 % CI 4.4-7.4) compared with 10.6 months (95 % CI 6.6-14.6) in patients with CRP levels <5 mg/L (HR 0.49; 95 % CI 0.27-0.89; P = 0.019).	('OS', 'Chemical', '-', (11, 13))	('CRP', 'Gene', '1401', (147, 150))	('CRP', 'Gene', (32, 35))	('patients', 'Species', '9606', (133, 141))	('CRP', 'Gene', '1401', (32, 35))	('patients', 'Species', '9606', (18, 26))	('CRP', 'Gene', (147, 150))	('>=5 mg/L', 'Var', (43, 51))
28494	25780901	Common genetic changes associated with pancreatic cancer, such as mutations in KRAS and TP53, are not reliable clinical parameters for predicting invasive pancreatic cancer.	('mutations', 'Var', (66, 75))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (155, 172))	('invasive pancreatic cancer', 'Disease', (146, 172))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (39, 56))	('KRAS', 'Gene', '3845', (79, 83))	('pancreatic cancer', 'Disease', 'MESH:D010190', (155, 172))	('pancreatic cancer', 'Disease', 'MESH:D010190', (39, 56))	('TP53', 'Gene', '7157', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('pancreatic cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('TP53', 'Gene', (88, 92))	('KRAS', 'Gene', (79, 83))	('invasive pancreatic cancer', 'Disease', 'MESH:D010190', (146, 172))
28495	25780901	While mutations in KRAS present in >90% of PDAC, it alone is not sufficient for malignant transformation.	('PDAC', 'Disease', (43, 47))	('KRAS', 'Gene', (19, 23))	('KRAS', 'Gene', '3845', (19, 23))	('PDAC', 'Chemical', '-', (43, 47))	('mutations', 'Var', (6, 15))
28496	25780901	TP53 mutations also occur at high frequency in PDAC, but arise relatively late in the neoplastic progress towards the invasive pancreatic cancer.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('PDAC', 'Disease', (47, 51))	('invasive pancreatic cancer', 'Disease', 'MESH:D010190', (118, 144))	('mutations', 'Var', (5, 14))	('invasive pancreatic cancer', 'Disease', (118, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))	('PDAC', 'Chemical', '-', (47, 51))
28497	25780901	CA19-9 is the current clinical blood-based biomarkers for pancreatic cancer testing - mainly used for monitoring the progress of pancreatic cancer treatment, but does not provide sufficient accuracy for diagnosis of pancreatic cancer.	('pancreatic cancer', 'Disease', (216, 233))	('pancreatic cancer', 'Disease', (58, 75))	('pancreatic cancer', 'Disease', 'MESH:D010190', (216, 233))	('pancreatic cancer', 'Disease', 'MESH:D010190', (58, 75))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (216, 233))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('CA19-9', 'Var', (0, 6))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (58, 75))	('pancreatic cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
28518	25780901	The study identified 420 splice variant proteins in mouse plasma, including peptides from novel variants of muscle pyruvate kinase (Pkm), malate dehydrogenase 1 (Mdh1), glyceraldehyde-3-phosphate dehydrogenase (Gapdh), proteoglycan 4 (Prg4), minichromosome maintenance complex component 9 (Mcm9), high mobility group box 2 (Hmgb2), and hepatocyte growth factor activator (Hgfac).	('Mdh1', 'Gene', '17449', (162, 166))	('Hmgb2', 'Gene', (324, 329))	('minichromosome maintenance complex component 9', 'Gene', '71567', (242, 288))	('high mobility group box 2', 'Gene', (297, 322))	('Mcm9', 'Gene', (290, 294))	('Hgfac', 'Gene', '54426', (372, 377))	('malate dehydrogenase 1', 'Gene', (138, 160))	('Mdh', 'molecular_function', 'GO:0018468', ('162', '165'))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('336', '360'))	('variants', 'Var', (96, 104))	('Mdh', 'molecular_function', 'GO:0030060', ('162', '165'))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '14433', (169, 209))	('muscle pyruvate', 'Disease', 'MESH:D015325', (108, 123))	('hepatocyte growth factor activator', 'Gene', '54426', (336, 370))	('Prg4', 'Gene', '96875', (235, 239))	('Gapdh', 'Gene', (211, 216))	('Mdh', 'molecular_function', 'GO:0033720', ('162', '165'))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (169, 209))	('mouse', 'Species', '10090', (52, 57))	('hepatocyte growth factor activator', 'Gene', (336, 370))	('minichromosome maintenance complex component 9', 'Gene', (242, 288))	('proteoglycan', 'molecular_function', 'GO:0005203', ('219', '231'))	('Hgfac', 'Gene', (372, 377))	('malate dehydrogenase 1', 'Gene', '17449', (138, 160))	('Prg4', 'Gene', (235, 239))	('Pkm', 'Gene', (132, 135))	('proteoglycan 4', 'Gene', (219, 233))	('proteoglycan 4', 'Gene', '96875', (219, 233))	('muscle pyruvate', 'Disease', (108, 123))	('Gapdh', 'Gene', '14433', (211, 216))	('Mcm9', 'Gene', '71567', (290, 294))	('Hmgb2', 'Gene', '97165', (324, 329))	('high mobility group box 2', 'Gene', '97165', (297, 322))	('Mdh1', 'Gene', (162, 166))
28528	25780901	In addition to the global profiling studies, a combination of immuno-precipitation and mass spectrometry has been used to investigate the blood protein carriers of the CA19-9 antigen and identified several proteins associated with CA19-9, including apolipoprotein B-100 (APOB), kininogen (KNG1), armadillo repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF), and apolipoprotein E (APOE).	('CA19-9', 'Var', (231, 237))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('apolipoprotein B-100', 'Gene', '338', (249, 269))	('APOB', 'Gene', '338', (271, 275))	('apolipoprotein', 'molecular_function', 'GO:0005320', ('370', '384'))	('associated', 'Reg', (215, 225))	('KNG1', 'Gene', '3827', (289, 293))	('apolipoprotein E', 'Gene', (370, 386))	('APOE', 'Gene', '348', (388, 392))	('apolipoprotein', 'molecular_function', 'GO:0005319', ('249', '263'))	('KNG1', 'Gene', (289, 293))	('apolipoprotein B-100', 'Gene', (249, 269))	('APOB', 'Gene', (271, 275))	('APOE', 'Gene', (388, 392))	('apolipoprotein E', 'Gene', '348', (370, 386))	('apolipoprotein', 'molecular_function', 'GO:0005319', ('370', '384'))	('Velo-Cardio-Facial syndrome', 'Disease', 'MESH:D004062', (329, 356))	('Velo-Cardio-Facial syndrome', 'Disease', (329, 356))	('apolipoprotein', 'molecular_function', 'GO:0005320', ('249', '263'))
28537	25780901	An iTRAQ-based quantitative proteomics study investigated the proteome of pancreatic juice samples collected from patients with primary precancerous PanIN 3 (high-grade dysplasia) lesions compared to non-diseased controls, and found anterior gradient-2 (AGR2) overexpressed in the juice of the PanIN 3 cases.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('overexpressed', 'PosReg', (260, 273))	('AGR2', 'Gene', '10551', (254, 258))	('investigated', 'Reg', (45, 57))	('patients', 'Species', '9606', (114, 122))	('anterior gradient-2', 'Gene', (233, 252))	('dysplasia', 'Disease', (169, 178))	('pancreatic', 'Disease', 'MESH:D010195', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('dysplasia', 'Disease', 'MESH:D004476', (169, 178))	('non-disease', 'Disease', (200, 211))	('AGR2', 'Gene', (254, 258))	('pancreatic', 'Disease', (74, 84))	('non-disease', 'Disease', 'MESH:D000073296', (200, 211))	('lesions', 'Var', (180, 187))	('anterior gradient-2', 'Gene', '10551', (233, 252))	('cancer', 'Disease', (139, 145))
28556	25780901	In a different study, immunoaffinity chromatography and mass spectrometry were applied to detect different variants of SPINK1 - a protein that has long been associated with chronic pancreatitis, in the urine samples collected from pancreatitis patients and non-diseased controls.	('SPINK1', 'Gene', (119, 125))	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('SPINK1', 'Gene', '6690', (119, 125))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (173, 193))	('non-disease', 'Disease', (257, 268))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (173, 193))	('pancreatitis', 'Phenotype', 'HP:0001733', (231, 243))	('pancreatitis', 'Disease', (181, 193))	('associated with', 'Reg', (157, 172))	('pancreatitis', 'Disease', 'MESH:D010195', (231, 243))	('variants', 'Var', (107, 115))	('chronic pancreatitis', 'Disease', (173, 193))	('pancreatitis', 'Phenotype', 'HP:0001733', (181, 193))	('pancreatitis', 'Disease', (231, 243))	('non-disease', 'Disease', 'MESH:D000073296', (257, 268))	('patients', 'Species', '9606', (244, 252))	('pancreatitis', 'Disease', 'MESH:D010195', (181, 193))
28557	25780901	Although the pathophysiologic implications of SPINK1 variants in pancreatic cancer remains to be determined, the study demonstrated the precise detection of distinct SPINK1 genetic variants at the protein level in urine using a proteomics approach.	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('pancreatic cancer', 'Disease', (65, 82))	('variants', 'Var', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('SPINK1', 'Gene', (46, 52))	('SPINK1', 'Gene', (166, 172))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('protein level in urine', 'Phenotype', 'HP:0000093', (197, 219))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))	('SPINK1', 'Gene', '6690', (46, 52))	('SPINK1', 'Gene', '6690', (166, 172))	('variants', 'Var', (53, 61))
28564	25780901	Aberrant protein glycosylation has long been recognized as a molecular feature in epithelial cancer, including PDAC.	('protein glycosylation', 'biological_process', 'GO:0006486', ('9', '30'))	('Aberrant', 'Var', (0, 8))	('epithelial cancer', 'Phenotype', 'HP:0031492', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PDAC', 'Chemical', '-', (111, 115))	('protein', 'Protein', (9, 16))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('epithelial cancer', 'Disease', (82, 99))	('epithelial cancer', 'Disease', 'MESH:D000077216', (82, 99))	('PDAC', 'Disease', (111, 115))
28572	25780901	Notably, in addition to the alterations of glycan composition and structure, cancer-associated aberrant glycosylation can also involve changes in glycosylation site occupancy, which has been observed in pancreatic tumor tissues using quantitative glycoproteomics.	('changes', 'Reg', (135, 142))	('pancreatic tumor', 'Disease', 'MESH:D010190', (203, 219))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('glycosylation site occupancy', 'MPA', (146, 174))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('pancreatic tumor', 'Disease', (203, 219))	('glycosylation', 'MPA', (104, 117))	('glycan', 'Chemical', 'MESH:D011134', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (203, 219))	('aberrant', 'Var', (95, 103))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (95, 117))
28592	25193509	Moreover NBPs inhibited PSCs proliferation, activation, release of macrophage chemoattractant protein-1 (MCP-1) and type I collagen expression.	('NBPs', 'Var', (9, 13))	('collagen', 'molecular_function', 'GO:0005202', ('123', '131'))	('rat', 'Species', '10116', (36, 39))	('type I collagen expression', 'CPA', (116, 142))	('MCP', 'molecular_function', 'GO:0004298', ('105', '108'))	('activation', 'CPA', (44, 54))	('inhibited', 'NegReg', (14, 23))	('release of', 'MPA', (56, 66))	('PSCs proliferation', 'CPA', (24, 42))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
28593	25193509	In vivo, NBPs inactivated PSCs; reduced fibrosis; inhibited tumor volume, tumor weight, peritoneal dissemination, angiogenesis, and cell proliferation; and increased apoptosis in an orthotopic murine model of PDAC.	('apoptosis', 'biological_process', 'GO:0097194', ('166', '175'))	('increased', 'PosReg', (156, 165))	('apoptosis', 'biological_process', 'GO:0006915', ('166', '175'))	('tumor', 'Disease', (74, 79))	('angiogenesis', 'biological_process', 'GO:0001525', ('114', '126'))	('tumor', 'Disease', (60, 65))	('rat', 'Species', '10116', (144, 147))	('peritoneal dissemination', 'CPA', (88, 112))	('inhibited', 'NegReg', (50, 59))	('PSCs', 'Protein', (26, 30))	('NBPs', 'Var', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('reduced', 'NegReg', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('fibrosis', 'Disease', 'MESH:D005355', (40, 48))	('fibrosis', 'Disease', (40, 48))	('PDAC', 'Chemical', '-', (209, 213))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('PDAC', 'Phenotype', 'HP:0006725', (209, 213))	('murine', 'Species', '10090', (193, 199))	('inactivated', 'NegReg', (14, 25))	('cell proliferation', 'CPA', (132, 150))	('cell proliferation', 'biological_process', 'GO:0008283', ('132', '150'))	('apoptosis', 'CPA', (166, 175))	('angiogenesis', 'CPA', (114, 126))
28594	25193509	These in vivo antitumor effects were enhanced when NBPs were combined with nab-paclitaxel but not gemcitabine (Gem).	('paclitaxel', 'Chemical', 'MESH:D017239', (79, 89))	('combined', 'Interaction', (61, 69))	('gemcitabine', 'Chemical', 'MESH:C056507', (98, 109))	('tumor', 'Disease', (18, 23))	('nab', 'Chemical', '-', (75, 78))	('nab-paclitaxel', 'Var', (75, 89))	('Gem', 'Chemical', 'MESH:C056507', (111, 114))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('enhanced', 'PosReg', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
28610	25193509	Capan-2 human PDAC cells [American Type Culture Collection (ATCC), Manassas, VA] were transfected with luciferase and maintained in McCoy's 5A medium (Invitrogen Corporation) with 10% FBS in 5% CO2/95% air at 37 C. PBMs isolated from buffy coats of healthy adult donors (MDACC) and THP-1 human monocytic leukemia cells (ATCC) were both maintained in RPMI-1640 medium (Invitrogen) with 10% FBS.	('PDAC', 'Chemical', '-', (14, 18))	('PDAC', 'Phenotype', 'HP:0006725', (14, 18))	('rat', 'Species', '10116', (167, 170))	('FBS', 'Disease', (389, 392))	('human', 'Species', '9606', (288, 293))	('PBMs', 'Chemical', '-', (215, 219))	('CO2', 'Chemical', '-', (194, 197))	('RPMI-1640 medium', 'Chemical', '-', (350, 366))	('FBS', 'Disease', (184, 187))	('FBS', 'Disease', 'MESH:D005198', (389, 392))	('Capan-2', 'CellLine', 'CVCL:0026', (0, 7))	('human', 'Species', '9606', (8, 13))	('FBS', 'Disease', 'MESH:D005198', (184, 187))	('THP-1', 'Gene', '2736', (282, 287))	('THP-1', 'Gene', (282, 287))	('transfected', 'Var', (86, 97))	('leukemia', 'Phenotype', 'HP:0001909', (304, 312))	("McCoy's 5A medium", 'Chemical', 'MESH:C113109', (132, 149))	('leukemia', 'Disease', (304, 312))	('leukemia', 'Disease', 'MESH:D007938', (304, 312))
28676	25193509	Taken together, our observations suggest that inhibition of PSC proliferation by Pam was due to both apoptosis and cell cycle arrest in the G1 phase.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (115, 132))	('rat', 'Species', '10116', (71, 74))	('inhibition', 'NegReg', (46, 56))	('PSC', 'Disease', (60, 63))	('Pam', 'Var', (81, 84))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('cell cycle arrest in the G1 phase', 'CPA', (115, 148))	('G1 phase', 'biological_process', 'GO:0051318', ('140', '148'))	('Pam', 'Chemical', 'MESH:D000077268', (81, 84))	('apoptosis', 'CPA', (101, 110))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('115', '132'))
28695	25193509	On the basis of our observations of reduced PSCs function after treatment with the NBP Pam, we next evaluated the effectiveness of combining this treatment with cytotoxic chemotherapeutic agents in vivo.	('PSCs function', 'MPA', (44, 57))	('reduced', 'NegReg', (36, 43))	('Pam', 'Chemical', 'MESH:D000077268', (87, 90))	('NBP', 'Var', (83, 86))
28716	25193509	Preclinical studies in breast cancer demonstrated that nab-paclitaxel has higher penetration into tumor cells and antitumor activity, compared with an equal dose of paclitaxel  One week after mice were injected orthotopically with Capan-2 luciferase tumor cells, we assessed the first IVIS images to verify tumor implantation.	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('luciferase tumor', 'Disease', 'MESH:D009369', (239, 255))	('tumor', 'Disease', (307, 312))	('tumor', 'Disease', (98, 103))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('rat', 'Species', '10116', (86, 89))	('tumor', 'Disease', (250, 255))	('breast cancer', 'Disease', (23, 36))	('nab-paclitaxel', 'Var', (55, 69))	('paclitaxel', 'Chemical', 'MESH:D017239', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('Capan-2', 'CellLine', 'CVCL:0026', (231, 238))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('mice', 'Species', '10090', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('rat', 'Species', '10116', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('luciferase tumor', 'Disease', (239, 255))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('higher', 'PosReg', (74, 80))	('tumor', 'Disease', (118, 123))	('nab', 'Chemical', '-', (55, 58))	('paclitaxel', 'Chemical', 'MESH:D017239', (165, 175))
28726	25193509	Using conventional hematoxylin and eosin (H&E) staining, we also determined that mice treated with the combination of ZA and nab-paclitaxel exhibited significant reduction of fibrotic tissue compared with the saline controls (P<.05) (Fig.	('nab', 'Chemical', '-', (125, 128))	('mice', 'Species', '10090', (81, 85))	('eosin', 'Chemical', 'MESH:D004801', (35, 40))	('significant', 'NegReg', (150, 161))	('of fibrotic', 'CPA', (172, 183))	('H&E', 'Chemical', '-', (42, 45))	('paclitaxel', 'Chemical', 'MESH:D017239', (129, 139))	('ZA', 'Chemical', 'MESH:D000077211', (118, 120))	('and', 'Var', (121, 124))	('hematoxylin', 'Chemical', 'MESH:D006416', (19, 30))
28738	25193509	We also found that the silencing of caveolin-1 (Supplementary Fig.	('caveolin-1', 'Gene', '857', (36, 46))	('caveolin-1', 'Gene', (36, 46))	('silencing', 'Var', (23, 32))
28744	25193509	Furthermore, NBPs (such as Pam) have been observed to induce PSC death by apoptosis at a concentration (100 muM) previously shown to have this effect on macrophages, suggesting that PSCs can be treated in the same manner that macrophages are.	('apoptosis', 'CPA', (74, 83))	('Pam', 'Chemical', 'MESH:D000077268', (27, 30))	('muM', 'Gene', '56925', (108, 111))	('NBPs', 'Var', (13, 17))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('muM', 'Gene', (108, 111))	('PSC death', 'Disease', 'MESH:D015209', (61, 70))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('rat', 'Species', '10116', (96, 99))	('PSC death', 'Disease', (61, 70))
28751	25193509	We demonstrated in vitro and in vivo that the NBPs Pam and ZA can inactivate PSCs while inducing cell cycle arrest and inducing apoptosis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (97, 114))	('Pam', 'Chemical', 'MESH:D000077268', (51, 54))	('NBPs', 'Var', (46, 50))	('rat', 'Species', '10116', (10, 13))	('inducing', 'PosReg', (88, 96))	('cell cycle arrest', 'CPA', (97, 114))	('ZA', 'Chemical', 'MESH:D000077211', (59, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('128', '137'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('97', '114'))	('apoptosis', 'biological_process', 'GO:0006915', ('128', '137'))	('inactivate', 'NegReg', (66, 76))	('PSCs', 'Gene', (77, 81))	('inducing', 'Reg', (119, 127))	('apoptosis', 'CPA', (128, 137))
28766	25193509	Nab-paclitaxel is a mitotic inhibitor, whereas Gem is a modified nucleotide that blocks DNA synthesis.	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('DNA synthesis', 'biological_process', 'GO:0071897', ('88', '101'))	('Nab-paclitaxel', 'Var', (0, 14))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('blocks DNA synthesis', 'MPA', (81, 101))	('Gem', 'Chemical', 'MESH:C056507', (47, 50))
28773	24928781	We found that GPR81 was present in colon, breast, lung, hepatocellular, salivary gland, cervical and pancreatic carcinoma cell lines.	('pancreatic carcinoma', 'Disease', (101, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (101, 121))	('GPR81', 'Var', (14, 19))
28775	24928781	Functionally, we observed that the reduction of GPR81 levels using shRNA mediated silencing had little effect on pancreatic cancer cells cultured in high glucose, but led to the rapid death of cancer cells cultured in conditions of low glucose supplemented with lactate.	('GPR81', 'MPA', (48, 53))	('death of cancer', 'Disease', 'MESH:D003643', (184, 199))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('glucose', 'Chemical', 'MESH:D005947', (236, 243))	('silencing', 'Var', (82, 91))	('high glucose', 'Phenotype', 'HP:0003074', (149, 161))	('shRNA mediated', 'Gene', (67, 81))	('glucose', 'Chemical', 'MESH:D005947', (154, 161))	('pancreatic cancer', 'Disease', (113, 130))	('death of cancer', 'Disease', (184, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('pancreatic cancer', 'Disease', 'MESH:D010190', (113, 130))	('lactate', 'Chemical', 'MESH:D019344', (262, 269))	('reduction', 'NegReg', (35, 44))
28803	24928781	Silencing of GPR81 rendered cells insensitive to lactate levels that increased MCTs and PGC-1alpha in control cells.	('GPR81', 'Gene', (13, 18))	('MCT', 'Gene', (79, 82))	('increased', 'PosReg', (69, 78))	('lactate', 'Chemical', 'MESH:D019344', (49, 56))	('MCT', 'Gene', '6566', (79, 82))	('PGC-1alpha', 'MPA', (88, 98))	('Silencing', 'Var', (0, 9))
28805	24928781	Silencing of GPR81 also decreased tumor cell mitochondrial activity and decreased tumor cell proliferation when lactate was the only available energy source.	('GPR81', 'Gene', (13, 18))	('cell proliferation', 'biological_process', 'GO:0008283', ('88', '106'))	('decreased', 'NegReg', (24, 33))	('tumor', 'Disease', (34, 39))	('lactate', 'Chemical', 'MESH:D019344', (112, 119))	('decreased', 'NegReg', (72, 81))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
28822	24928781	Endogenous peroxidase was blocked with 4% H2O2 and protein-blocked with 4% fish gelatin.	('H2O2', 'Chemical', 'MESH:D006861', (42, 46))	('H2O2', 'Var', (42, 46))	('Endogenous peroxidase', 'Enzyme', (0, 21))	('protein-blocked', 'Protein', (51, 66))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
28824	24928781	Primary antibodies were incubated overnight at 4 C and included: rabbit anti-GPR81 (Abnova, Walnut, CA), 1:50 dilution; rabbit anti-MCT1 (Santa Cruz Biotechnology, Santa Cruz, CA), 1:50 dilution; rabbit anti-PGC1alpha (Novus Biologicals, Littleton, CO), 1:50 dilution; anti-Ki67 (Thermo Fischer Scientific, Waltham, MA).	('rabbit', 'Species', '9986', (65, 71))	('PGC1alpha', 'Gene', (208, 217))	('MCT', 'biological_process', 'GO:0120197', ('132', '135'))	('MCT1', 'Gene', (132, 136))	('anti-Ki67', 'Var', (269, 278))	('rabbit', 'Species', '9986', (120, 126))	('PGC1alpha', 'Gene', '10891', (208, 217))	('MCT1', 'Gene', '6566', (132, 136))	('rabbit', 'Species', '9986', (196, 202))
28856	24928781	Under standard culture conditions, GPR81-silenced Capan-II and BxPC3 cells had reduced levels of MCTs and PGC-1alpha compared to the control cells (Fig.	('BxPC3', 'CellLine', 'CVCL:0186', (63, 68))	('reduced', 'NegReg', (79, 86))	('levels', 'MPA', (87, 93))	('PGC-1alpha', 'MPA', (106, 116))	('GPR81-silenced', 'Var', (35, 49))	('MCT', 'Gene', (97, 100))	('MCT', 'Gene', '6566', (97, 100))
28858	24928781	In conditions simulating the tumor microenvironment (low glucose, glutamine and pyruvate), lactate treatment of parental Capan-II cells expressing GPR81 led to increased levels of MCT1, MCT4, CD147 and PGC1alpha mRNA after 6 hours (Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('MCT1', 'Gene', '6566', (180, 184))	('glutamine', 'Chemical', 'MESH:D005973', (66, 75))	('CD147', 'Gene', '682', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('lactate', 'Chemical', 'MESH:D019344', (91, 98))	('PGC1alpha', 'Gene', '10891', (202, 211))	('increased', 'PosReg', (160, 169))	('CD147', 'Gene', (192, 197))	('pyruvate', 'Chemical', 'MESH:D019289', (80, 88))	('MCT4', 'Gene', (186, 190))	('GPR81', 'Var', (147, 152))	('levels', 'MPA', (170, 176))	('MCT4', 'Gene', '9123', (186, 190))	('MCT', 'biological_process', 'GO:0120197', ('180', '183'))	('tumor', 'Disease', (29, 34))	('glucose', 'Chemical', 'MESH:D005947', (57, 64))	('MCT1', 'Gene', (180, 184))	('MCT', 'biological_process', 'GO:0120197', ('186', '189'))	('PGC1alpha', 'Gene', (202, 211))
28859	24928781	In contrast, after GPR81 silencing, lactate treatment had no effect on the mRNA levels of these molecules (Fig.	('mRNA levels of these molecules', 'MPA', (75, 105))	('silencing', 'Var', (25, 34))	('lactate', 'Chemical', 'MESH:D019344', (36, 43))	('GPR81', 'Gene', (19, 24))
28866	24928781	However, when the cells were grown in media lacking glucose, glutamine and pyruvate and with 20mM lactate as the main available energy source, silencing of GPR81 led to an ~50% reduction in mitochondrial activity within 24 hours (Fig.	('pyruvate', 'Chemical', 'MESH:D019289', (75, 83))	('glucose', 'Chemical', 'MESH:D005947', (52, 59))	('lactate', 'Chemical', 'MESH:D019344', (98, 105))	('reduction', 'NegReg', (177, 186))	('glutamine', 'Chemical', 'MESH:D005973', (61, 70))	('GPR81', 'Gene', (156, 161))	('silencing', 'Var', (143, 152))	('mitochondrial activity', 'MPA', (190, 212))
28867	24928781	In concert, there was no difference in mitochondrial activity of ASPC1 cells with high or low levels of GPR81 when cultured in the presence of glucose (Fig.	('glucose', 'Chemical', 'MESH:D005947', (143, 150))	('mitochondrial activity', 'MPA', (39, 61))	('GPR81', 'Var', (104, 109))
28876	24928781	MCT1 levels were found to be greatly reduced in tumors formed from cells lacking GPR81 (Fig.	('MCT1', 'Gene', (0, 4))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('MCT1', 'Gene', '6566', (0, 4))	('reduced', 'NegReg', (37, 44))	('GPR81', 'Var', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('MCT', 'biological_process', 'GO:0120197', ('0', '3'))
28901	24928781	These data support the idea that inhibition of lactate metabolism represents a potential therapeutic approach to cancer.	('lactate metabolism', 'MPA', (47, 65))	('inhibition', 'Var', (33, 43))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('lactate', 'Chemical', 'MESH:D019344', (47, 54))	('cancer', 'Disease', (113, 119))	('lactate metabolism', 'biological_process', 'GO:0006089', ('47', '65'))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
28903	24928781	The addition of lactate resulted in increased levels of PGC1alpha, MCT1 & MCT4 and CD147 in PDAC cells expressing GPR81, but not in those in which it was silenced.	('MCT1', 'Gene', (67, 71))	('lactate', 'Chemical', 'MESH:D019344', (16, 23))	('MCT1', 'Gene', '6566', (67, 71))	('MCT4', 'Gene', (74, 78))	('and', 'MPA', (79, 82))	('PGC1alpha', 'Gene', '10891', (56, 65))	('lactate', 'MPA', (16, 23))	('expressing', 'Var', (103, 113))	('levels', 'MPA', (46, 52))	('MCT', 'biological_process', 'GO:0120197', ('67', '70'))	('CD147', 'Gene', '682', (83, 88))	('increased', 'PosReg', (36, 45))	('MCT4', 'Gene', '9123', (74, 78))	('MCT', 'biological_process', 'GO:0120197', ('74', '77'))	('CD147', 'Gene', (83, 88))	('PGC1alpha', 'Gene', (56, 65))
28904	24928781	GPR81-silenced cells had reduced levels of lactate uptake, while there was increased lactate uptake in cells expressing higher levels of GPR81.	('uptake', 'biological_process', 'GO:0098657', ('93', '99'))	('uptake', 'biological_process', 'GO:0098739', ('93', '99'))	('reduced', 'NegReg', (25, 32))	('GPR81', 'Var', (137, 142))	('levels', 'MPA', (33, 39))	('lactate', 'Chemical', 'MESH:D019344', (43, 50))	('lactate', 'Chemical', 'MESH:D019344', (85, 92))	('uptake', 'biological_process', 'GO:0098739', ('51', '57'))	('uptake', 'biological_process', 'GO:0098657', ('51', '57'))	('lactate uptake', 'MPA', (85, 99))	('increased', 'PosReg', (75, 84))	('GPR81-silenced', 'Gene', (0, 14))
28909	24928781	We observed that the loss of GPR81 reduced MCT levels and diminished the ability of the cancer cells to grow as tumors and to undergo metastasis in vivo.	('loss', 'Var', (21, 25))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('reduced MCT', 'Phenotype', 'HP:0031851', (35, 46))	('reduced', 'NegReg', (35, 42))	('MCT', 'Gene', '6566', (43, 46))	('MCT', 'Gene', (43, 46))	('diminished', 'NegReg', (58, 68))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('MCT', 'biological_process', 'GO:0120197', ('43', '46'))	('GPR81', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
28933	24502441	Within the last two decades, research has shown that pancreatic cancer is fundamentally a genetic disease caused by inherited germline and acquired somatic mutations in cancer-associated genes, and more and more investigation of molecular pathogenesis has been used in the diagnosis and treatment of pancreatic cancer.	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', (311, 317))	('pancreatic cancer', 'Disease', 'MESH:D010190', (300, 317))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('pancreatic cancer', 'Disease', 'MESH:D010190', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('caused', 'Reg', (106, 112))	('pancreatic cancer', 'Disease', (300, 317))	('cancer', 'Disease', (64, 70))	('pancreatic cancer', 'Disease', (53, 70))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('mutations', 'Var', (156, 165))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (300, 317))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (53, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('genetic disease', 'Disease', 'MESH:D030342', (90, 105))	('pathogenesis', 'biological_process', 'GO:0009405', ('239', '251'))	('genetic disease', 'Disease', (90, 105))
28938	24502441	In vivo or in vitro experiments have confirmed that TSA could restrain the genesis of some tumors and control tumor progression by restraining tumor angiogenesis and changing the tumor microenvironment.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('restraining', 'NegReg', (131, 142))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('genesis', 'CPA', (75, 82))	('TSA', 'molecular_function', 'GO:0033984', ('52', '55'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('angiogenesis', 'biological_process', 'GO:0001525', ('149', '161'))	('TSA', 'Chemical', 'MESH:C012589', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('control', 'PosReg', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('changing', 'Reg', (166, 174))	('tumors', 'Disease', (91, 97))	('TSA', 'Var', (52, 55))	('tumor', 'Disease', (143, 148))	('restrain', 'NegReg', (62, 70))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
28941	24502441	The main MMR genes are hMSH1-6, hMLH1-5 and others, and the methylation of MMR genes and/or the loss of expression of their proteins plays an important role in malignant tumorigenesis.	('MMR', 'biological_process', 'GO:0006298', ('9', '12'))	('loss of', 'NegReg', (96, 103))	('hMLH1', 'Gene', '4292', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('MMR', 'Gene', (9, 12))	('MMR genes', 'Gene', (75, 84))	('methylation', 'Var', (60, 71))	('proteins', 'Protein', (124, 132))	('hMSH1-6', 'Gene', '4436;4437;4438;4439;2956', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('hMSH', 'molecular_function', 'GO:0018775', ('23', '27'))	('tumor', 'Disease', (170, 175))	('expression', 'MPA', (104, 114))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('hMSH1-6', 'Gene', (23, 30))	('hMLH1', 'Gene', (32, 37))	('MMR', 'biological_process', 'GO:0006298', ('75', '78'))
28975	24502441	Establishing of a pancreatic cancer model can be achieved through three kinds of methods: 1) exposing canine animal to carcinogen, 2) activating the oncogenes of transgenic mice, and 3) transplanting the xenogenic pancreatic cancer tissues to athymic mouse.	('activating', 'Var', (134, 144))	('oncogenes', 'Gene', (149, 158))	('pancreatic cancer', 'Disease', 'MESH:D010190', (214, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('mouse', 'Species', '10090', (251, 256))	('transgenic mice', 'Species', '10090', (162, 177))	('pancreatic cancer', 'Disease', (18, 35))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (214, 231))	('xenogenic pancreatic cancer', 'Disease', (204, 231))	('pancreatic cancer', 'Disease', 'MESH:D010190', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (18, 35))	('canine', 'Species', '9615', (102, 108))	('xenogenic pancreatic cancer', 'Disease', 'MESH:D010190', (204, 231))
28978	24502441	TSA can increase intracellular histone levels and up-regulate the expression of several genes.	('TSA', 'molecular_function', 'GO:0033984', ('0', '3'))	('increase', 'PosReg', (8, 16))	('TSA', 'Chemical', 'MESH:C012589', (0, 3))	('intracellular histone levels', 'MPA', (17, 45))	('expression', 'MPA', (66, 76))	('TSA', 'Var', (0, 3))	('up-regulate', 'PosReg', (50, 61))	('intracellular', 'cellular_component', 'GO:0005622', ('17', '30'))
28990	24502441	Mutation of the hMLH 1  gene will induce the genesis of many malignant tumors.	('induce', 'PosReg', (34, 40))	('hMLH 1', 'Gene', '4292', (16, 22))	('malignant tumors', 'Disease', (61, 77))	('Mutation', 'Var', (0, 8))	('hMLH 1', 'Gene', (16, 22))	('malignant tumors', 'Disease', 'MESH:D018198', (61, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('genesis', 'CPA', (45, 52))
28995	24088503	HOXB7 mRNA is overexpressed in pancreatic ductal adenocarcinomas and its knockdown induces cell cycle arrest and apoptosis Human homeobox genes encode nuclear proteins that act as transcription factors involved in the control of differentiation and proliferation.	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))	('transcription', 'biological_process', 'GO:0006351', ('180', '193'))	('arrest', 'Disease', (102, 108))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('91', '108'))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('Human', 'Species', '9606', (123, 128))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (31, 64))	('arrest', 'Disease', 'MESH:D006323', (102, 108))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (91, 108))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('homeobox genes', 'Gene', (129, 143))	('HOXB7', 'Gene', '3217', (0, 5))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (31, 63))	('pancreatic ductal adenocarcinomas', 'Disease', (31, 64))	('cell cycle', 'CPA', (91, 101))	('HOXB7', 'Gene', (0, 5))	('knockdown', 'Var', (73, 82))
28998	24088503	In the present study, the effects arising from the knockdown of HOXB7 in PDAC cell lines was investigated.	('HOXB7', 'Gene', '3217', (64, 69))	('PDAC', 'Chemical', '-', (73, 77))	('HOXB7', 'Gene', (64, 69))	('knockdown', 'Var', (51, 60))
29002	24088503	HOXB7 knockdown elicited (1) an increase in the expression of the pro-apoptotic proteins BAX and BAD in both cell lines; (2) a decrease in the expression of the anti-apoptotic protein BCL-2 and in cyclin D1 and an increase in the number of apoptotic cells in the MIA PaCa-2 cell line; (3) accumulation of cell in sub-G1 phase in both cell lines; (4) the modulation of several biological processes, especially in MIA PaCa-2, such as proteasomal ubiquitin-dependent catabolic process and cell cycle.	('BAX', 'Gene', (89, 92))	('BAX', 'Gene', '581', (89, 92))	('increase', 'PosReg', (214, 222))	('BCL-2', 'Gene', '596', (184, 189))	('HOXB7', 'Gene', '3217', (0, 5))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (263, 273))	('catabolic process', 'biological_process', 'GO:0009056', ('464', '481'))	('BCL-2', 'Gene', (184, 189))	('cell cycle', 'CPA', (486, 496))	('HOXB7', 'Gene', (0, 5))	('G1 phase', 'biological_process', 'GO:0051318', ('317', '325'))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))	('expression', 'MPA', (48, 58))	('proteasomal ubiquitin-dependent catabolic process', 'MPA', (432, 481))	('modulation', 'Reg', (354, 364))	('expression', 'MPA', (143, 153))	('cyclin', 'molecular_function', 'GO:0016538', ('197', '203'))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (412, 422))	('cell cycle', 'biological_process', 'GO:0007049', ('486', '496'))	('cyclin D1', 'Gene', (197, 206))	('BCL-2', 'molecular_function', 'GO:0015283', ('184', '189'))	('increase', 'PosReg', (32, 40))	('decrease', 'NegReg', (127, 135))	('cyclin D1', 'Gene', '595', (197, 206))	('ubiquitin', 'molecular_function', 'GO:0031386', ('444', '453'))	('knockdown', 'Var', (6, 15))
29009	24088503	Aberrant expression of homeobox genes have been shown in different tumour types, including leukemias, ovarian carcinoma, and breast cancer.	('shown', 'Reg', (48, 53))	('Aberrant', 'Var', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('tumour', 'Disease', (67, 73))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('homeobox genes', 'Gene', (23, 37))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('leukemias', 'Phenotype', 'HP:0001909', (91, 100))	('ovarian carcinoma', 'Disease', (102, 119))	('leukemias', 'Disease', (91, 100))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (102, 119))	('breast cancer', 'Disease', (125, 138))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('tumour', 'Disease', 'MESH:D009369', (67, 73))	('leukemias', 'Disease', 'MESH:D007938', (91, 100))
29013	24088503	In a breast cancer cell line (SkBr3), transduction of HOXB7 gene induces bFGF expression, increases growth rate and ability of cells to form colonies in semisolid medium.	('breast cancer', 'Phenotype', 'HP:0003002', (5, 18))	('transduction', 'biological_process', 'GO:0009293', ('38', '50'))	('expression', 'MPA', (78, 88))	('SkBr3', 'CellLine', 'CVCL:0033', (30, 35))	('transduction', 'Var', (38, 50))	('induces', 'PosReg', (65, 72))	('growth rate', 'CPA', (100, 111))	('increases', 'PosReg', (90, 99))	('bFGF', 'Gene', '2247', (73, 77))	('bFGF', 'Gene', (73, 77))	('HOXB7', 'Gene', '3217', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('breast cancer', 'Disease', 'MESH:D001943', (5, 18))	('HOXB7', 'Gene', (54, 59))	('breast cancer', 'Disease', (5, 18))
29034	24088503	Beta-2-microglobulin (beta2M) was used as reference gene for the evaluation of HOXB7 copy number.	('HOXB7', 'Gene', (79, 84))	('copy number', 'Var', (85, 96))	('Beta-2-microglobulin', 'Gene', '567', (0, 20))	('HOXB7', 'Gene', '3217', (79, 84))	('Beta-2-microglobulin', 'Gene', (0, 20))	('beta2M', 'Gene', (22, 28))	('beta2M', 'Gene', '567', (22, 28))
29048	24088503	Membranes were incubated for 18 hours in 5% skim milk phosphate buffer saline (PBS) with mouse monoclonal antibody HOXB7 (1:50, ab51237, Abcam Inc, Cambridge, MA, USA) followed by incubation with secondary antibody (1:400, RPN1001, GE Healthcare, Little Chalfont, Buckinghamshire, UK) and labeled with horseradish peroxidase (1:3000, GE Healthcare).	('antibody', 'cellular_component', 'GO:0019814', ('206', '214'))	('antibody', 'cellular_component', 'GO:0019815', ('206', '214'))	('antibody', 'cellular_component', 'GO:0042571', ('106', '114'))	('HOXB7', 'Gene', '3217', (115, 120))	('phosphate', 'Chemical', 'MESH:D010710', (54, 63))	('antibody', 'cellular_component', 'GO:0019815', ('106', '114'))	('antibody', 'molecular_function', 'GO:0003823', ('206', '214'))	('HOXB7', 'Gene', (115, 120))	('antibody', 'cellular_component', 'GO:0019814', ('106', '114'))	('1:400', 'Var', (216, 221))	('antibody', 'cellular_component', 'GO:0042571', ('206', '214'))	('antibody', 'molecular_function', 'GO:0003823', ('106', '114'))	('PBS', 'Chemical', '-', (79, 82))	('1:50', 'Var', (122, 126))	('saline', 'Chemical', 'MESH:D012965', (71, 77))	('mouse', 'Species', '10090', (89, 94))	('horseradish', 'Species', '3704', (302, 313))
29068	24088503	Validation of microarray was performed from the analysis of E2F and RB1 mRNA expression in Mia PaCa-2 cell line by RT-qPCR.	('Mia PaCa-2', 'CellLine', 'CVCL:0428', (91, 101))	('RB1', 'Gene', '5925', (68, 71))	('E2F', 'Var', (60, 63))	('RB1', 'Gene', (68, 71))
29089	24088503	In MIA PaCa-2, 679 genes were identified as downregulated after HOXB7 silencing in comparison to parental cells.	('downregulated', 'NegReg', (44, 57))	('silencing', 'Var', (70, 79))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (3, 13))	('HOXB7', 'Gene', '3217', (64, 69))	('HOXB7', 'Gene', (64, 69))
29092	24088503	The main findings of the present study was confirmation of HOXB7 mRNA overexpression in PDAC as well as the demonstration that its knockdown in two human PDAC cell lines increases expression of the pro-apoptotic proteins BAX and BAD, elicits an accumulation of cells in the sub-G1 phase and modulates cellular gene expression profile.	('cells in the sub-G1 phase', 'CPA', (261, 286))	('increases', 'PosReg', (170, 179))	('BAD', 'Protein', (229, 232))	('knockdown', 'Var', (131, 140))	('gene expression', 'biological_process', 'GO:0010467', ('310', '325'))	('BAX', 'Gene', (221, 224))	('cellular gene expression profile', 'MPA', (301, 333))	('modulates', 'Reg', (291, 300))	('BAX', 'Gene', '581', (221, 224))	('PDAC', 'Chemical', '-', (154, 158))	('expression', 'MPA', (180, 190))	('human', 'Species', '9606', (148, 153))	('accumulation', 'PosReg', (245, 257))	('HOXB7', 'Gene', '3217', (59, 64))	('PDAC', 'Chemical', '-', (88, 92))	('HOXB7', 'Gene', (59, 64))	('elicits', 'Reg', (234, 241))	('G1 phase', 'biological_process', 'GO:0051318', ('278', '286'))	('overexpression', 'PosReg', (70, 84))
29094	24088503	In that study, knockdown of HOXB7 by siRNA in the pancreatic cell lines BxPC3, MIA PaCa-2 and PANC1 resulted in decreased invasion but it did not influence cell proliferation or viability as evaluated by the MTT assay.	('HOXB7', 'Gene', (28, 33))	('knockdown', 'Var', (15, 24))	('pancreatic', 'Disease', 'MESH:D010195', (50, 60))	('BxPC3', 'CellLine', 'CVCL:0186', (72, 77))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (79, 89))	('invasion', 'CPA', (122, 130))	('pancreatic', 'Disease', (50, 60))	('cell proliferation', 'biological_process', 'GO:0008283', ('156', '174'))	('PANC1', 'CellLine', 'CVCL:0480', (94, 99))	('decreased', 'NegReg', (112, 121))	('MTT', 'Chemical', 'MESH:C070243', (208, 211))	('HOXB7', 'Gene', '3217', (28, 33))
29102	24088503	gene amplification may be an important mechanism underlying the increased expression of HOXB7 in breast cancer.	('expression', 'MPA', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('HOXB7', 'Gene', '3217', (88, 93))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('HOXB7', 'Gene', (88, 93))	('breast cancer', 'Disease', (97, 110))	('increased', 'PosReg', (64, 73))	('gene amplification', 'Var', (0, 18))
29105	24088503	Regardless of the mechanism by which HOXB7 mRNA expression is upregulated in PDAC, we have demonstrated that its knockdown increases apoptosis and also modulates several biological processes only in MIA PaCa-2.	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (199, 209))	('PDAC', 'Disease', (77, 81))	('apoptosis', 'CPA', (133, 142))	('HOXB7', 'Gene', '3217', (37, 42))	('modulates', 'Reg', (152, 161))	('upregulated', 'PosReg', (62, 73))	('HOXB7', 'Gene', (37, 42))	('knockdown', 'Var', (113, 122))	('PDAC', 'Chemical', '-', (77, 81))	('increases', 'PosReg', (123, 132))
29108	24088503	This event was also reported by Liao et al., who detected downregulation of cyclin D1 and up-regulation of p27 after HOXB7 gene silencing with consequent blocking G1-S.	('cyclin D1', 'Gene', '595', (76, 85))	('regulation', 'biological_process', 'GO:0065007', ('93', '103'))	('up-regulation', 'PosReg', (90, 103))	('cyclin D1', 'Gene', (76, 85))	('gene silencing', 'biological_process', 'GO:0016458', ('123', '137'))	('HOXB7', 'Gene', (117, 122))	('p27', 'Gene', '3429', (107, 110))	('downregulation', 'NegReg', (58, 72))	('gene silencing', 'Var', (123, 137))	('p27', 'Gene', (107, 110))	('cyclin', 'molecular_function', 'GO:0016538', ('76', '82'))	('HOXB7', 'Gene', '3217', (117, 122))
29134	20664585	Aberrant expression of CD70 in solid tumours and haematologic malignancies has also been described by various studies.	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('Aberrant', 'Var', (0, 8))	('solid tumours and haematologic malignancies', 'Disease', 'MESH:D019337', (31, 74))	('CD70', 'Gene', (23, 27))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))
29138	20664585	Both chimeric and humanised anti-CD70 monoclonal antibody (mAb) 1F6 conjugated to a microtubule-disrupting auristatin have been shown to be active in these tumours.	('tumours', 'Disease', 'MESH:D009369', (156, 163))	('anti-CD70', 'Var', (28, 37))	('tumours', 'Disease', (156, 163))	('human', 'Species', '9606', (18, 23))	('antibody', 'cellular_component', 'GO:0042571', ('49', '57'))	('microtubule', 'cellular_component', 'GO:0005874', ('84', '95'))	('antibody', 'cellular_component', 'GO:0019815', ('49', '57'))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('active', 'MPA', (140, 146))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))	('antibody', 'cellular_component', 'GO:0019814', ('49', '57'))	('auristatin', 'Chemical', 'MESH:C543533', (107, 117))	('antibody', 'molecular_function', 'GO:0003823', ('49', '57'))
29158	20664585	Positive hybridomas were then screened on formalin-fixed paraffin-embedded (FFPE) cell pellets to identify hybridomas that react with denatured CD70 for immunohistochemistry (IHC) analysis.	('paraffin', 'Chemical', 'MESH:D010232', (57, 65))	('denatured', 'Var', (134, 143))	('CD70', 'Protein', (144, 148))	('formalin', 'Chemical', 'MESH:D005557', (42, 50))
29220	20664585	CD70+ renal cell carcinomas tumours typically also have homogeneous high-intensity staining (3-4+, data not shown).	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('CD70+ renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 26))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (6, 26))	('CD70+', 'Var', (0, 5))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (6, 27))	('homogeneous high-intensity staining', 'MPA', (56, 91))	('renal cell carcinomas tumours', 'Disease', (6, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('renal cell carcinomas tumours', 'Disease', 'MESH:C538614', (6, 35))
29221	20664585	Other tumour types that expressed CD70 (Table 2) also showed heterogeneous staining pattern with lower intensity.	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('heterogeneous staining pattern', 'MPA', (61, 91))	('tumour', 'Disease', 'MESH:D009369', (6, 12))	('CD70', 'Var', (34, 38))	('tumour', 'Disease', (6, 12))
29222	20664585	In a number of cases, we also observed infiltrating leukocytes within the tumours that were CD70+ (data not shown).	('leukocytes within the tumours', 'Disease', 'MESH:D001929', (52, 81))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('leukocytes within the tumours', 'Disease', (52, 81))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('CD70+', 'Var', (92, 97))
29253	20664585	In addition, our expanded IHC analysis of CD70 identified other indications, in which an anti-CD70 ADC could potentially be tested, most notably a significant fraction of pancreatic and ovarian carcinoma cases.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (186, 203))	('pancreatic and ovarian carcinoma', 'Disease', 'MESH:D010051', (171, 203))	('anti-CD70', 'Gene', (89, 98))	('anti-CD70', 'Var', (89, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))
29259	20664585	However, EBV transformation causes up-regulation of CD70 in B cells and may contribute to the higher percentage of CD70+ nasopharyngeal cancers observed by.	('CD70', 'Protein', (52, 56))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('nasopharyngeal cancers', 'Disease', 'MESH:D009303', (121, 143))	('up-regulation', 'PosReg', (35, 48))	('EBV', 'Species', '10376', (9, 12))	('regulation', 'biological_process', 'GO:0065007', ('38', '48'))	('nasopharyngeal cancers', 'Disease', (121, 143))	('CD70+', 'Var', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
29260	20664585	We also found that only 6 out of 59 (10%) of brain cancer cases were CD70+, whereas found that 5 out of 12 of glioblastomas and 3 out of 4 anaplastic astrocytomas were positive for CD70 protein.	('astrocytoma', 'Phenotype', 'HP:0009592', (150, 161))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (139, 162))	('brain cancer', 'Disease', 'MESH:D001932', (45, 57))	('CD70 protein', 'Protein', (181, 193))	('glioblastomas', 'Disease', (110, 123))	('anaplastic astrocytomas', 'Disease', (139, 162))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('CD70+', 'Var', (69, 74))	('protein', 'cellular_component', 'GO:0003675', ('186', '193'))	('brain cancer', 'Phenotype', 'HP:0030692', (45, 57))	('glioblastomas', 'Phenotype', 'HP:0012174', (110, 123))	('glioblastoma', 'Phenotype', 'HP:0012174', (110, 122))	('brain cancer', 'Disease', (45, 57))	('glioblastomas', 'Disease', 'MESH:D005909', (110, 123))
29270	20664585	This is the first reported study of anti-CD70 ADC anti-tumour activity in pancreatic cancer.	('tumour', 'Disease', (55, 61))	('anti-CD70', 'Var', (36, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('pancreatic cancer', 'Disease', (74, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
29272	20664585	However, h1F6, the antibody backbone for SGN-75, also mediates complement-dependent cytotoxicity and engages effector cells by Fcgamma receptor to induce tumour cell lysis.	('h1F6', 'Var', (9, 13))	('cytotoxicity', 'Disease', (84, 96))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('men', 'Species', '9606', (69, 72))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('antibody', 'cellular_component', 'GO:0019815', ('19', '27'))	('complement-dependent cytotoxicity', 'biological_process', 'GO:0097278', ('63', '96'))	('induce', 'PosReg', (147, 153))	('SGN-75', 'Chemical', '-', (41, 47))	('antibody', 'cellular_component', 'GO:0019814', ('19', '27'))	('cytotoxicity', 'Disease', 'MESH:D064420', (84, 96))	('antibody', 'molecular_function', 'GO:0003823', ('19', '27'))	('tumour', 'Disease', (154, 160))	('lysis', 'biological_process', 'GO:0019835', ('166', '171'))	('mediates', 'Reg', (54, 62))	('antibody', 'cellular_component', 'GO:0042571', ('19', '27'))
29273	20664585	The effector-function-based activities of h1F6 are retained in the ADC (J McEarchern and C Law, unpublished observations), suggesting that SGN-75 has the potential to mediate anti-tumour activity in CD70+ tumours through multiple mechanisms.	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('tumours', 'Disease', 'MESH:D009369', (205, 212))	('tumour', 'Disease', (205, 211))	('tumours', 'Disease', (205, 212))	('CD70+', 'Var', (199, 204))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('SGN-75', 'Chemical', '-', (139, 145))	('SGN-75', 'Gene', (139, 145))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('tumours', 'Phenotype', 'HP:0002664', (205, 212))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('tumour', 'Disease', (180, 186))
29305	32181599	In the enrollment, the following criteria were used: (a) underwent cancer-directed surgical resection of primary PDAC; (b) complete information was provided about the T/N/M stage and LNC/LNR; (c) histology codes with 8140, 8141, 8142, 8143, 8144, 8145, 8146, and 8147, according to the International Classification of Disease 3rd edition (ICD-O3); and (d) data were provided for OS and CSS.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('8143', 'Var', (235, 239))	('8146', 'Var', (253, 257))	('cancer', 'Disease', (67, 73))	('8144', 'Var', (241, 245))	('8141', 'Var', (223, 227))	('PDAC', 'Phenotype', 'HP:0006725', (113, 117))	('8140', 'Var', (217, 221))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('8142', 'Var', (229, 233))	('8147', 'Var', (263, 267))	('Classification of Disease', 'Disease', (300, 325))	('8145', 'Var', (247, 251))	('PDAC', 'Chemical', '-', (113, 117))	('Classification of Disease', 'Disease', 'MESH:D008310', (300, 325))	('men', 'Species', '9606', (13, 16))
29555	31250356	Some patients reported that these symptoms may have been increased as a result of the broccoli sprouts, although the decrease in the Karnofsky performance status (in the range of 11% and 10% within 3 months after inclusion) was comparable between the two groups (Table 1).	('broccoli', 'Var', (86, 94))	('decrease', 'NegReg', (117, 125))	('patients', 'Species', '9606', (5, 13))	('Karnofsky performance status', 'MPA', (133, 161))
29631	31694706	PDAC show high frequencies of Kras mutations with high secretion of growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), which are responsible for emergency myelopoiesis recruiting myeloid cells into the TME.	('granulocyte colony-stimulating factor', 'Gene', (153, 190))	('myelopoiesis recruiting myeloid', 'Disease', (236, 267))	('myelopoiesis recruiting myeloid', 'Disease', 'MESH:C563551', (236, 267))	('Kras', 'Gene', (30, 34))	('G-CSF', 'Gene', (192, 197))	('granulocyte-macrophage colony-stimulating factor', 'molecular_function', 'GO:0005129', ('91', '139'))	('secretion', 'biological_process', 'GO:0046903', ('55', '64'))	('GM-CSF', 'Gene', (141, 147))	('Kras', 'Gene', '16653', (30, 34))	('granulocyte-macrophage colony-stimulating factor', 'Gene', '12981', (91, 139))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('G-CSF', 'Gene', '12985', (192, 197))	('granulocyte-macrophage colony-stimulating factor', 'Gene', (91, 139))	('granulocyte colony-stimulating factor', 'molecular_function', 'GO:0005130', ('153', '190'))	('granulocyte colony-stimulating factor', 'Gene', '12985', (153, 190))	('GM-CSF', 'Gene', '12981', (141, 147))	('mutations', 'Var', (35, 44))
29642	31694706	RLH ligands have emerged as promising candidates for tumor immunotherapy and have entered phase I/Ib clinical trials for the treatment of advanced solid tumors (NCT03739138, NCT02828098).	('NCT03739138', 'Var', (161, 172))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('solid tumors', 'Disease', (147, 159))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('solid tumors', 'Disease', 'MESH:D009369', (147, 159))	('RLH', 'Protein', (0, 3))	('tumor', 'Disease', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))
29643	31694706	Moreover, modifications of the RIG-I ligands, combining siRNA-targeted gene silencing with RIG-I activation, have already been evaluated in preclinical models and show enhanced tumor control.	('RIG-I', 'Gene', (31, 36))	('RIG-I', 'Gene', '230073', (31, 36))	('activation', 'PosReg', (97, 107))	('gene silencing', 'Var', (71, 85))	('siRNA-targeted', 'MPA', (56, 70))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('enhanced', 'PosReg', (168, 176))	('RIG-I', 'Gene', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('RIG-I', 'Gene', '230073', (91, 96))	('tumor', 'Disease', (177, 182))	('gene silencing', 'biological_process', 'GO:0016458', ('71', '85'))
29649	31694706	The KrasG12D p53fl/R172H Ptf1a-Cre (KPC)-derived T110299 pancreatic tumor cell line was provided by Prof. Jens Siveke, (University Hospital Essen, Germany), Ifnar1-/- mice (Ifnar1tm1Agt) were provided by Prof. Simon Rothenfusser (LMU Munich, Germany).	('Ptf1', 'Species', '32651', (25, 29))	('Ifnar1', 'Gene', (157, 163))	('R172H', 'Mutation', 'p.R172H', (19, 24))	('Ifnar1', 'Gene', '15975', (173, 179))	('pancreatic tumor', 'Disease', (57, 73))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (57, 73))	('Kras', 'Gene', (4, 8))	('Kras', 'Gene', '16653', (4, 8))	('Ifnar1', 'Gene', (173, 179))	('Ifnar1', 'Gene', '15975', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('pancreatic tumor', 'Disease', 'MESH:D010190', (57, 73))	('mice', 'Species', '10090', (167, 171))	('p53fl/R172H', 'Var', (13, 24))
29654	31694706	OVA+ T110299 cells were selected with G418 (geneticin).	('OVA', 'Gene', (0, 3))	('G418', 'Var', (38, 42))	('OVA', 'Gene', '282665', (0, 3))
29693	31694706	As such, we investigated the impact of T110299 tumors on myelopoiesis, the TME and its immune cell composition.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('myelopoiesis', 'Disease', (57, 69))	('myelopoiesis', 'Disease', 'MESH:C563551', (57, 69))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('T110299', 'Var', (39, 46))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
29714	31694706	In line with these in vitro findings, poly(I:C)c led to a profound upregulation of MHC-I molecules on tumor cells in vivo (Fig.	('poly(I:C)c', 'Var', (38, 48))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('upregulation', 'PosReg', (67, 79))	('MHC-I', 'Gene', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
29719	31694706	Both splenic and tumor-infiltrating T cells upregulated expression of the early activation marker CD69 in response to poly(I:C)c, whereas PD-1 expression was unaffected (Fig.	('tumor', 'Disease', (17, 22))	('CD69', 'Gene', (98, 102))	('upregulated', 'PosReg', (44, 55))	('expression', 'MPA', (56, 66))	('poly', 'Var', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('CD69', 'Gene', '12515', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
29722	31694706	As expected, at an effector (MDSC) to target (T cell) ratio of 1:1, IFN-gamma secretion was strongly suppressed by MDSC (Fig.	('IFN-gamma secretion', 'biological_process', 'GO:0072643', ('68', '87'))	('IFN-gamma', 'Gene', '15978', (68, 77))	('MDSC', 'Var', (115, 119))	('suppressed', 'NegReg', (101, 111))	('IFN-gamma', 'Gene', (68, 77))
29726	31694706	Poly(I:C)c treatment increased both the intratumoral frequency of migratory cross-presenting conventional DC 1 (cDC1) as well as their activation measured by CD40 expression.	('CD40', 'Gene', (158, 162))	('increased', 'PosReg', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Poly', 'Var', (0, 4))	('tumor', 'Disease', (45, 50))	('activation', 'MPA', (135, 145))	('Poly(I:C)c', 'Chemical', 'MESH:D011070', (0, 10))	('CD40', 'Gene', '21939', (158, 162))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
29737	31694706	In both PMN- and M-MDSC, essential components of the MHC-I-dependent antigen processing and presentation machinery, including the immunoproteasome, the peptide transporter TAP and the MHC-I complex, were up-regulated following poly(I:C)c therapy (Fig.	('poly(I:C)c therapy', 'Var', (227, 245))	('TAP', 'Gene', (172, 175))	('TAP', 'Gene', '110454', (172, 175))	('up-regulated', 'PosReg', (204, 216))	('PMN', 'biological_process', 'GO:0034727', ('8', '11'))	('antigen processing', 'MPA', (69, 87))	('immunoproteasome', 'MPA', (130, 146))	('antigen processing and presentation', 'biological_process', 'GO:0019882', ('69', '104'))	('MHC-I-dependent', 'Gene', (53, 68))
29749	31694706	Tumor weight was significantly decreased in wild-type mice after poly(I:C)c treatment, whereas no difference was observed in Ifnar1-/- mice, supporting a role of IFN signaling as a prerequisite for anti-tumor efficacy (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('Ifnar1', 'Gene', (125, 131))	('decreased', 'NegReg', (31, 40))	('Tumor weight', 'CPA', (0, 12))	('mice', 'Species', '10090', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('signaling', 'biological_process', 'GO:0023052', ('166', '175'))	('mice', 'Species', '10090', (54, 58))	('Ifnar1', 'Gene', '15975', (125, 131))	('poly(I:C)c treatment', 'Var', (65, 85))
29751	31694706	Untreated mice had comparable frequencies of MDSC and poly(I:C)c treatment led to a decrease of PMN-MDSC and an increase of M-MDSC numbers in wild-type mice, but not Ifnar1-/- mice (Fig.	('decrease', 'NegReg', (84, 92))	('Ifnar1', 'Gene', '15975', (166, 172))	('PMN-MDSC', 'MPA', (96, 104))	('mice', 'Species', '10090', (10, 14))	('mice', 'Species', '10090', (176, 180))	('M-MDSC numbers', 'CPA', (124, 138))	('increase', 'PosReg', (112, 120))	('mice', 'Species', '10090', (152, 156))	('Ifnar1', 'Gene', (166, 172))	('PMN', 'biological_process', 'GO:0034727', ('96', '99'))	('poly', 'Var', (54, 58))
29753	31694706	Neither the genotype nor the treatment had an influence on CD4+ and CD8+ T cell frequencies in spleen and tumor; however, poly(I:C)c failed to induce CD69 expression in T cells of Ifnar1-/- mice (Fig.	('poly', 'Var', (122, 126))	('CD4', 'Gene', (59, 62))	('CD69', 'Gene', (150, 154))	('CD4', 'Gene', '12504', (59, 62))	('Ifnar1', 'Gene', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mice', 'Species', '10090', (190, 194))	('CD69', 'Gene', '12515', (150, 154))	('tumor', 'Disease', (106, 111))	('Ifnar1', 'Gene', '15975', (180, 186))
29763	31694706	Using the KPC-derived pancreatic cancer model, we observed a more potent suppressive capacity of PMN-MDSC as compared to M-MDSC.	('PMN', 'biological_process', 'GO:0034727', ('97', '100'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (22, 39))	('PMN-MDSC', 'Var', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('pancreatic cancer', 'Disease', (22, 39))	('pancreatic cancer', 'Disease', 'MESH:D010190', (22, 39))	('suppressive', 'NegReg', (73, 84))
29781	31694706	The expression of MHC-I and PD-L1 were markedly elevated upon poly(I:C)c treatment, but greatly reduced in IFNAR-deficient mice.	('expression', 'MPA', (4, 14))	('poly(I:C)c', 'Var', (62, 72))	('IFNAR', 'Gene', (107, 112))	('IFNAR', 'Gene', '15975', (107, 112))	('MHC-I', 'Gene', (18, 23))	('PD-L1', 'Gene', (28, 33))	('elevated', 'PosReg', (48, 56))	('mice', 'Species', '10090', (123, 127))	('reduced', 'NegReg', (96, 103))
29795	31694706	RLH-signaling also induces proinflammatory cytokines via the NF-kappaB pathway consequentially upregulating CXCL10 and IL-6 levels.	('upregulating', 'PosReg', (95, 107))	('CXCL10', 'Gene', (108, 114))	('IL-6', 'Gene', (119, 123))	('IL-6', 'Gene', '16193', (119, 123))	('signaling', 'biological_process', 'GO:0023052', ('4', '13'))	('IL-6', 'molecular_function', 'GO:0005138', ('119', '123'))	('NF-kappaB pathway', 'Pathway', (61, 78))	('RLH-signaling', 'Var', (0, 13))	('CXCL10', 'Gene', '15945', (108, 114))	('proinflammatory cytokines', 'MPA', (27, 52))	('induces', 'Reg', (19, 26))
29798	31694706	We found that poly(I:C)c treatment reduced the suppressive capacity of MDSC populations in wild-type mice, but not in IFNAR1-deficient mice.	('IFNAR1', 'Gene', '15975', (118, 124))	('IFNAR1', 'Gene', (118, 124))	('poly', 'Var', (14, 18))	('reduced', 'NegReg', (35, 42))	('suppressive capacity of MDSC populations', 'CPA', (47, 87))	('mice', 'Species', '10090', (101, 105))	('mice', 'Species', '10090', (135, 139))
29817	31370893	In the multivariable cohort, a clear prognostic advantage of PTR was observed in overall survival (OS) (P < 0.001) and disease-specific survival (DSS) (P < 0.001) compared to patients after non-surgery therapy.	('PTR', 'molecular_function', 'GO:0008975', ('61', '64'))	('DSS', 'Gene', '5376', (146, 149))	('advantage', 'PosReg', (48, 57))	('patients', 'Species', '9606', (175, 183))	('PTR', 'Var', (61, 64))	('overall survival', 'CPA', (81, 97))	('OS', 'Chemical', '-', (99, 101))	('DSS', 'Gene', (146, 149))	('disease-specific survival', 'CPA', (119, 144))
29821	31370893	In IV analyses stratified by chemotherapy and tumor location, patients undergoing PTR had similar OS and DSS compared to patients in non-surgery group across all subgroups.	('DSS', 'Gene', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('DSS', 'Gene', '5376', (105, 108))	('PTR', 'molecular_function', 'GO:0008975', ('82', '85'))	('tumor', 'Disease', (46, 51))	('PTR', 'Var', (82, 85))	('OS', 'Chemical', '-', (98, 100))	('patients', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
29857	31370893	In the cohort for multivariable analyses (OS: n = 4322; DSS: n = 4055), after adjusting for potential confounding factors, a clear prognostic advantage of PTR was observed in OS (HR, 0.59; 95% CI, 0.53 to 0.66; P < 0.001) and DSS (HR, 0.57; 95% CI, 0.51 to 0.65; P < 0.001) compared to patients after non-surgery therapy (Table 2).	('DSS', 'Gene', (56, 59))	('OS', 'Chemical', '-', (175, 177))	('OS', 'Chemical', '-', (42, 44))	('DSS', 'Gene', '5376', (56, 59))	('DSS', 'Gene', (226, 229))	('DSS', 'Gene', '5376', (226, 229))	('PTR', 'molecular_function', 'GO:0008975', ('155', '158'))	('patients', 'Species', '9606', (286, 294))	('PTR', 'Var', (155, 158))
29867	31370893	In the PSM cohort, results from the univariate analysis indicated that cases with PTR had better OS (HR 0.59, 95% CI 0.50-0.69 P < 0.001) and DSS (HR 0.57, 95% CI 0.47-0.67, P < 0.001) compared to patients with non-surgery treatment (Table 2).	('patients', 'Species', '9606', (197, 205))	('PTR', 'molecular_function', 'GO:0008975', ('82', '85'))	('OS', 'Chemical', '-', (97, 99))	('PTR', 'Var', (82, 85))	('better', 'PosReg', (90, 96))	('DSS', 'Gene', (142, 145))	('DSS', 'Gene', '5376', (142, 145))
29868	31370893	In the PSM-adjusted population, patients in PTR group still showed a better OS and DSS (both P values < 0.001) compared to patients in non-surgery group by Kaplan-Meier method (Fig.	('DSS', 'Gene', '5376', (83, 86))	('patients', 'Species', '9606', (32, 40))	('OS', 'Chemical', '-', (76, 78))	('PTR', 'Var', (44, 47))	('patients', 'Species', '9606', (123, 131))	('better', 'PosReg', (69, 75))	('PTR', 'molecular_function', 'GO:0008975', ('44', '47'))	('DSS', 'Gene', (83, 86))
29878	31370893	In this study, utilizing IV analyses, we concluded that patients with S-III PDA receiving PTR had a similar long-term prognosis compared to those without PTR (only receive non-surgery treatments).	('patients', 'Species', '9606', (56, 64))	('PDA', 'Chemical', '-', (76, 79))	('PTR', 'molecular_function', 'GO:0008975', ('154', '157'))	('PTR', 'molecular_function', 'GO:0008975', ('90', '93'))	('PTR', 'Var', (90, 93))	('PDA', 'Disease', (76, 79))	('S-III PDA', 'Disease', (70, 79))
29892	31112530	Genetic silencing of Pik3ca in KrasG12D/Trp53R172H-driven pancreatic tumors resulted in infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice.	('mice', 'Species', '10090', (182, 186))	('Pik3ca', 'Gene', (21, 27))	('tumor', 'Disease', (122, 127))	('R172H', 'Mutation', 'p.R172H', (45, 50))	('pancreatic tumors', 'Disease', 'MESH:D010190', (58, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('pancreatic tumors', 'Disease', (58, 75))	('Genetic silencing', 'Var', (0, 17))	('infiltration', 'CPA', (88, 100))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('survival', 'CPA', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('Pik3ca', 'Gene', '18706', (21, 27))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (58, 74))	('tumor', 'Disease', (69, 74))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (58, 75))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('T cells', 'CPA', (104, 111))
29903	31112530	Pancreatic cancer cell lines isolated from KrasG12D or KrasG12D Trp53R172H mice and many human pancreatic cancers and pancreatic cancer cell lines have low MHC I levels that might contribute to immune evasion.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('pancreatic cancers', 'Disease', (95, 113))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('pancreatic cancer', 'Disease', 'MESH:D010190', (118, 135))	('KrasG12D', 'Var', (43, 51))	('immune evasion', 'biological_process', 'GO:0042783', ('194', '208'))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('immune evasion', 'biological_process', 'GO:0051842', ('194', '208'))	('low', 'NegReg', (152, 155))	('human', 'Species', '9606', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('KrasG12D', 'Var', (55, 63))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('pancreatic cancers', 'Disease', 'MESH:D010190', (95, 113))	('pancreatic cancer', 'Disease', (118, 135))	('mice', 'Species', '10090', (75, 79))	('Pancreatic cancer', 'Disease', (0, 17))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (95, 112))	('MHC I levels', 'MPA', (156, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (95, 112))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (118, 135))	('immune evasion', 'MPA', (194, 208))	('R172H', 'Mutation', 'p.R172H', (69, 74))	('contribute', 'Reg', (180, 190))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (95, 113))
29904	31112530	In addition to TCR activation, the coreceptor CD28 expressed on T cells is stimulated by CD80.	('CD28', 'Gene', '12487', (46, 50))	('TCR', 'biological_process', 'GO:0006283', ('15', '18'))	('stimulated', 'PosReg', (75, 85))	('TCR', 'cellular_component', 'GO:0042101', ('15', '18'))	('CD28', 'Gene', (46, 50))	('CD80', 'Var', (89, 93))
29907	31112530	More than 90% of PDACs have oncogenic mutations in the KRAS gene.	('KRAS', 'Gene', (55, 59))	('oncogenic', 'CPA', (28, 37))	('KRAS', 'Gene', '16653', (55, 59))	('PDACs', 'Disease', (17, 22))	('PDAC', 'Phenotype', 'HP:0006725', (17, 21))	('mutations', 'Var', (38, 47))	('PDAC', 'Chemical', '-', (17, 21))
29911	31112530	PIP3 then recruits downstream effectors such as the protein kinase AKT to the cell membrane, aiding in its phosphorylation and activation.	('activation', 'MPA', (127, 137))	('aiding', 'PosReg', (93, 99))	('PIP3', 'Chemical', '-', (0, 4))	('phosphorylation', 'biological_process', 'GO:0016310', ('107', '122'))	('phosphorylation', 'MPA', (107, 122))	('cell membrane', 'cellular_component', 'GO:0005886', ('78', '91'))	('PIP3', 'Var', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
29913	31112530	PI3Ks in pancreatic cells and in immune cells have been shown to affect pancreatic tumorigenesis and cancer growth.	('affect', 'Reg', (65, 71))	('pancreatic', 'Disease', (72, 82))	('pancreatic tumor', 'Disease', (72, 88))	('pancreatic', 'Disease', (9, 19))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Disease', (101, 107))	('PI3Ks', 'Var', (0, 5))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (72, 88))	('pancreatic tumor', 'Disease', 'MESH:D010190', (72, 88))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('pancreatic', 'Disease', 'MESH:D010195', (72, 82))	('pancreatic', 'Disease', 'MESH:D010195', (9, 19))
29920	31112530	In this study, we examined the function of PIK3CA in a pancreatic cancer cell line derived from mice expressing KRASG12D and TRP53R172H.	('KRASG12D', 'Var', (112, 120))	('mice', 'Species', '10090', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('pancreatic cancer', 'Disease', 'MESH:D010190', (55, 72))	('R172H', 'Mutation', 'p.R172H', (130, 135))	('pancreatic cancer', 'Disease', (55, 72))	('PIK3CA', 'Gene', '18706', (43, 49))	('TRP53R172H', 'Var', (125, 135))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))	('PIK3CA', 'Gene', (43, 49))
29923	31112530	Both Pik3ca and Egfr have been shown to be required for KRASG12D-induced pancreatic tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('pancreatic tumor', 'Disease', 'MESH:D010190', (73, 89))	('pancreatic tumor', 'Disease', (73, 89))	('KRASG12D-induced', 'Var', (56, 72))	('Pik3ca and Egfr', 'Gene', '18706;13649', (5, 20))	('Egfr', 'molecular_function', 'GO:0005006', ('16', '20'))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (73, 89))
29927	31112530	Immunoblotting and reverse phase protein array (RPPA) analysis also revealed changes in signaling due to ablation of Pik3ca or Egfr.	('signaling', 'MPA', (88, 97))	('changes', 'Reg', (77, 84))	('Egfr', 'molecular_function', 'GO:0005006', ('127', '131'))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('signaling', 'biological_process', 'GO:0023052', ('88', '97'))	('ablation', 'Var', (105, 113))	('Pik3ca', 'Gene', '18706', (117, 123))	('Egfr', 'Gene', (127, 131))	('Pik3ca', 'Gene', (117, 123))
29944	31112530	All B6 mice implanted with WT DT10022 cells died from tumor progression by day 35, whereas all mice implanted with alphaKD cells were still alive at that time (Supplemental Figure 3B).	('mice', 'Species', '10090', (95, 99))	('DT10022', 'Var', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mice', 'Species', '10090', (7, 11))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
29952	31112530	We also harvested pancreata from B6 mice 10 days after implantation with alphaKD DT10022 cells, and immunohistochemistry showed that these tumors were also infiltrated with CD3+ and CD8+ T cells (Supplemental Figure 3D).	('CD8', 'Gene', (182, 185))	('DT10022', 'Var', (81, 88))	('CD8', 'Gene', '925', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('CD3', 'Gene', (173, 176))	('tumors', 'Disease', (139, 145))	('mice', 'Species', '10090', (36, 40))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('CD3', 'Gene', '12501', (173, 176))	('alphaKD DT10022', 'Var', (73, 88))
29956	31112530	All mice that received neutralizing antibodies died due to tumor growth, with a median survival of 29 days (Figure 2, D and E, and Table 1).	('neutralizing', 'Var', (23, 35))	('tumor', 'Disease', (59, 64))	('mice', 'Species', '10090', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
29979	31112530	Indeed, flow cytometry showed that cell surface expression of the MHC I heavy chain (H-2Kb in B6 mice) was 6.4 times higher in alphaKO KPC cells than in WT cells (Figure 4A; average geometric means of 14.7 vs 2.3, respectively).	('cell surface', 'cellular_component', 'GO:0009986', ('35', '47'))	('H-2Kb', 'Gene', '14972', (85, 90))	('alphaKO KPC', 'Var', (127, 138))	('mice', 'Species', '10090', (97, 101))	('H-2Kb', 'Gene', (85, 90))	('higher', 'PosReg', (117, 123))	('MHC I', 'Gene', (66, 71))	('cell surface expression', 'MPA', (35, 58))
29986	31112530	Therefore, we used shRNA to knock down the level of B2m in alphaKO or alphaKO/CD80KO cells to produce alphaKO/shB2m or alphaKO/CD80KO+shB2m cell lines, respectively.	('B2m', 'Gene', '12010', (112, 115))	('shB', 'Gene', '230126', (110, 113))	('B2m', 'Gene', '12010', (136, 139))	('B2m', 'Gene', (52, 55))	('shB', 'Gene', (134, 137))	('B2m', 'Gene', '12010', (52, 55))	('B2m', 'Gene', (112, 115))	('knock', 'Var', (28, 33))	('B2m', 'Gene', (136, 139))	('shB', 'Gene', '230126', (134, 137))	('shB', 'Gene', (110, 113))
29993	31112530	No tumors were detected in pancreatic tissue from 1 alphaKO/shB2m mouse or alphaKO/CD80KO mice that were sacrificed at 101 days or 160 days, respectively (Figure 4F).	('alphaKO/CD80KO', 'Var', (75, 89))	('B2m', 'Gene', '12010', (62, 65))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', (3, 9))	('shB', 'Gene', (60, 63))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('mouse', 'Species', '10090', (66, 71))	('shB', 'Gene', '230126', (60, 63))	('mice', 'Species', '10090', (90, 94))	('pancreatic', 'Disease', 'MESH:D010195', (27, 37))	('pancreatic', 'Disease', (27, 37))	('B2m', 'Gene', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
30023	31112530	Conversely, high MHC I expression in triple negative breast tumors is correlated with increased tumor-infiltrating lymphocytes and better prognosis in patients.	('increased', 'PosReg', (86, 95))	('high', 'Var', (12, 16))	('breast tumors', 'Disease', 'MESH:D001943', (53, 66))	('high MHC', 'Phenotype', 'HP:0025548', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (96, 101))	('breast tumors', 'Disease', (53, 66))	('patients', 'Species', '9606', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MHC I', 'Gene', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (60, 65))	('breast tumors', 'Phenotype', 'HP:0100013', (53, 66))	('expression', 'MPA', (23, 33))
30028	31112530	MAP2K1 (also called MEK1) and EGFR were validated as negative regulators by showing that treatment of several cancer cell lines with inhibitors of either enzyme increased mRNA levels and cell surface expression of HLA-A and B2m.	('MEK1', 'Gene', '26395', (20, 24))	('MAP2K1', 'Gene', (0, 6))	('B2m', 'Gene', (224, 227))	('cancer', 'Disease', (110, 116))	('cell surface expression', 'MPA', (187, 210))	('MAP2K1', 'Gene', '26395', (0, 6))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('B2m', 'Gene', '12010', (224, 227))	('inhibitors', 'Var', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cell surface', 'cellular_component', 'GO:0009986', ('187', '199'))	('MAP2K', 'molecular_function', 'GO:0004708', ('0', '5'))	('MEK1', 'Gene', (20, 24))	('increased', 'PosReg', (161, 170))	('mRNA levels', 'MPA', (171, 182))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('MEK1', 'molecular_function', 'GO:0004708', ('20', '24'))
30030	31112530	Interestingly, a key factor mediating HIV immune escape is the HIV-1 protein Nef, which acts through PI3K to downregulate trafficking of MHC I to the cell surface.	('MHC I', 'Protein', (137, 142))	('Nef', 'Gene', (77, 80))	('downregulate', 'NegReg', (109, 121))	('Nef', 'Gene', '156110', (77, 80))	('PI3K', 'Var', (101, 105))	('HIV-1', 'Species', '11676', (63, 68))	('PI3K', 'molecular_function', 'GO:0016303', ('101', '105'))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('trafficking', 'MPA', (122, 133))	('cell surface', 'cellular_component', 'GO:0009986', ('150', '162'))
30038	31112530	CD80 ligation with CTLA-4, unlike CD28, initiates a suppressive signaling cascade that leads to T cell exhaustion.	('signaling cascade', 'biological_process', 'GO:0007165', ('64', '81'))	('suppressive signaling cascade', 'MPA', (52, 81))	('CTLA-4', 'Gene', '12477', (19, 25))	('T cell exhaustion', 'CPA', (96, 113))	('ligation', 'Var', (5, 13))	('CD28', 'Gene', (34, 38))	('leads to', 'Reg', (87, 95))	('CD28', 'Gene', '12487', (34, 38))	('CTLA-4', 'Gene', (19, 25))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (96, 113))
30044	31112530	Deleting CD80 was not sufficient to convert "hot" alphaKO KPC tumors with infiltrating T cells into "cold" tumors that exclude T cells.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('KPC tumors', 'Disease', 'MESH:C565455', (58, 68))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('Deleting', 'Var', (0, 8))	('CD80', 'Gene', (9, 13))	('KPC tumors', 'Disease', (58, 68))
30045	31112530	Knock down of MHC I was more successful in this regard, but alphaKO/shB2m tumors progressed in only 3 of 8 implanted animals.	('B2m', 'Gene', (70, 73))	('shB', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('MHC I', 'Gene', (14, 19))	('B2m', 'Gene', '12010', (70, 73))	('shB', 'Gene', '230126', (68, 71))	('Knock down', 'Var', (0, 10))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
30063	31112530	A subsequent study showed that genetic ablation or systemic pharmacological inhibition of PIK3CG led to activation of T cells and slower PDAC growth in vivo.	('slower', 'NegReg', (130, 136))	('activation', 'PosReg', (104, 114))	('T cells', 'CPA', (118, 125))	('PIK3CG', 'Gene', (90, 96))	('PDAC', 'Phenotype', 'HP:0006725', (137, 141))	('genetic ablation', 'Var', (31, 47))	('PDAC', 'Chemical', '-', (137, 141))
30072	31112530	Based on our current understanding, systemic pharmacological inhibition of all PI3K isoforms should enhance the immunogenicity of the pancreatic tumors by upregulating MHC I and CD80, but inhibitory effects on cytotoxic T cells will negate these beneficial changes.	('immunogenicity', 'MPA', (112, 126))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (134, 151))	('inhibition', 'Var', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('enhance', 'PosReg', (100, 107))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('upregulating', 'PosReg', (155, 167))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (134, 150))	('pancreatic tumors', 'Disease', 'MESH:D010190', (134, 151))	('CD80', 'MPA', (178, 182))	('PI3K', 'molecular_function', 'GO:0016303', ('79', '83'))	('MHC I', 'Protein', (168, 173))	('pancreatic tumors', 'Disease', (134, 151))
30077	31112530	Based on our results, we believe that abrogating PIK3CA-AKT signaling in tumor cells attracts both CD4+ and CD8+ T cells to infiltrate the tumors.	('CD4', 'Gene', '12504', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PIK3CA', 'Gene', '18706', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('AKT signaling', 'biological_process', 'GO:0043491', ('56', '69'))	('tumor', 'Disease', (73, 78))	('PIK3CA', 'Gene', (49, 55))	('CD8', 'Gene', (108, 111))	('tumors', 'Disease', (139, 145))	('CD4', 'Gene', (99, 102))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('CD8', 'Gene', '925', (108, 111))	('abrogating', 'Var', (38, 48))
30082	31112530	DNA sequencing of exon 1 of the Kras gene confirmed that the cells have a G-to-D mutation at codon 12.	('Kras', 'Gene', (32, 36))	('Kras', 'Gene', '16653', (32, 36))	('G-to-D mutation at', 'Var', (74, 92))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))
30085	31112530	Loss of WT KRAS is frequently associated with amplification of the mutant allele and an increase in aggressiveness and migration of PDAC and other cancers.	('associated', 'Reg', (30, 40))	('KRAS', 'Gene', (11, 15))	('aggressiveness', 'Phenotype', 'HP:0000718', (100, 114))	('KRAS', 'Gene', '16653', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('amplification', 'Var', (46, 59))	('PDAC', 'Chemical', '-', (132, 136))	('aggressiveness', 'Disease', 'MESH:D001523', (100, 114))	('increase', 'PosReg', (88, 96))	('Loss', 'NegReg', (0, 4))	('aggressiveness', 'Disease', (100, 114))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('mutant', 'Var', (67, 73))	('cancers', 'Disease', (147, 154))	('PDAC', 'Disease', (132, 136))	('PDAC', 'Phenotype', 'HP:0006725', (132, 136))
30095	31112530	alphaKO-caAkt and alphaKO-Cont cells were generated by infecting alphaKO cells with lentiviral particles expressing a constitutively active human Akt1 mutant and EGFP or EGFP alone, respectively (pHRIG-Akt1; Addgene plasmid 53583; gift from Heng Zhao).	('Akt1', 'Gene', (146, 150))	('human', 'Species', '9606', (140, 145))	('mutant', 'Var', (151, 157))
30109	31112530	C57BL/6J (B6; stock 000664), B6.CB17-Prkdcscid/SzJ (SCID; stock 001913), B6.129S2-Cd4tm1Mak/J (CD4KO; stock 002663), and B6.129S2-Cd8atm1Mak/J (CD8KO; stock 002665) mice were purchased from Jackson Laboratories.	('mice', 'Species', '10090', (165, 169))	('B6.129S2', 'CellLine', 'CVCL:C319', (73, 81))	('B6.129S2', 'CellLine', 'CVCL:C319', (121, 129))	('B6.129S2-Cd4tm1Mak/J', 'Var', (73, 93))	('CD8', 'Gene', (144, 147))	('B6.129S2-Cd8atm1Mak/J', 'Var', (121, 142))	('CD4', 'Gene', (95, 98))	('SCID', 'Disease', (52, 56))	('CD8', 'Gene', '925', (144, 147))	('SCID', 'Disease', 'MESH:D053632', (52, 56))	('CD4', 'Gene', '12504', (95, 98))
30116	31112530	To monitor tumor growth, the animals were injected intraperitoneally with 100 mg/kg RediJect D-Luciferin (PerkinElmer) and imaged on the IVIS Lumina III imaging system (Xenogen).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('RediJect D-Luciferin', 'Var', (84, 104))	('tumor', 'Disease', (11, 16))	('D-Luciferin', 'Chemical', 'MESH:C532924', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
30150	31112530	Cells were detached from the plate using StemPro Accutase, washed 2 times in PBS, incubated with FcR block, stained with anti-CD80 and anti-H-2Kb (mouse) or anti-HLA-ABC and anti-CD80 (human) antibodies, and analyzed by flow cytometry (FACScalibur or DxP 8).	('H-2Kb', 'Gene', '14972', (140, 145))	('mouse', 'Species', '10090', (147, 152))	('human', 'Species', '9606', (185, 190))	('FcR', 'Gene', '109615', (97, 100))	('PBS', 'Gene', (77, 80))	('FcR', 'Gene', (97, 100))	('H-2Kb', 'Gene', (140, 145))	('DxP 8', 'Chemical', '-', (251, 256))	('PBS', 'Gene', '1131', (77, 80))	('anti-CD80', 'Var', (121, 130))
30152	31112530	Hprt (Mm00446068_m1), B2m (Mm00437762_m1), CD80 (Mm00711660_m1), and H-2Kb (Mm01612247_mH2-K1) were purchased from Thermo Fisher Scientific.	('B2m', 'Gene', '12010', (22, 25))	('Mm00711660_m1', 'Var', (49, 62))	('Hprt', 'molecular_function', 'GO:0004422', ('0', '4'))	('H-2Kb', 'Gene', '14972', (69, 74))	('B2m', 'Gene', (22, 25))	('Mm01612247_mH2-K1', 'Var', (76, 93))	('Mm00437762_m1', 'Var', (27, 40))	('Hprt', 'Gene', '15452', (0, 4))	('Mm00446068_m1', 'Var', (6, 19))	('Hprt', 'Gene', (0, 4))	('H-2Kb', 'Gene', (69, 74))
30207	31338486	One of the patient's affected lymph nodes was sent for next-generation sequencing (FoundationOne  CDx) testing, which revealed alterations in KRAS G12R (activating mutation), CDKN2A p16INK4a E120* (loss of function), and TP53 R273H (loss of function).	('KRAS', 'Gene', (142, 146))	('E120*', 'Var', (191, 196))	('CDKN2A', 'Gene', (175, 181))	('TP53', 'Gene', '7157', (221, 225))	('E120*', 'SUBSTITUTION', 'None', (191, 196))	('KRAS', 'Gene', '3845', (142, 146))	('G12R', 'Mutation', 'rs121913530', (147, 151))	('CDKN2A', 'Gene', '1029', (175, 181))	('patient', 'Species', '9606', (11, 18))	('TP53', 'Gene', (221, 225))	('p16INK4a', 'Gene', (182, 190))	('R273H', 'Mutation', 'rs28934576', (226, 231))	('CDx', 'Chemical', '-', (98, 101))	('p16INK4a', 'Gene', '1029', (182, 190))
30209	31338486	Given the patient's CKDN2A loss-of-function mutation, the patient was enrolled in a phase I clinical trial utilizing ribociclib (inhibitor of cyclin D1/CDK4 and CDK6), in addition to gemcitabine.	('mutation', 'Var', (44, 52))	('cyclin D1', 'Gene', (142, 151))	('CDK4', 'Gene', (152, 156))	('CDK4', 'Gene', '1019', (152, 156))	('cyclin', 'molecular_function', 'GO:0016538', ('142', '148'))	('patient', 'Species', '9606', (58, 65))	('loss-of-function', 'NegReg', (27, 43))	('CDK', 'molecular_function', 'GO:0004693', ('161', '164'))	('CDK6', 'Gene', (161, 165))	('patient', 'Species', '9606', (10, 17))	('CKDN2A', 'Gene', (20, 26))	('CDK6', 'Gene', '1021', (161, 165))	('CDK', 'molecular_function', 'GO:0004693', ('152', '155'))	('gemcitabine', 'Chemical', 'MESH:C056507', (183, 194))	('cyclin D1', 'Gene', '595', (142, 151))
30219	31338486	Genetically, UCOGC of the pancreas resembles PDAC, with both entities harboring frequent KRAS, TP53, CDKN2A, and SMAD4 mutations.	('SMAD4', 'Gene', '4089', (113, 118))	('PDAC', 'Chemical', '-', (45, 49))	('CDKN2A', 'Gene', (101, 107))	('CDKN2A', 'Gene', '1029', (101, 107))	('SMAD4', 'Gene', (113, 118))	('PDAC', 'Disease', (45, 49))	('UCOGC of', 'Disease', (13, 21))	('PDAC', 'Phenotype', 'HP:0006725', (45, 49))	('mutations', 'Var', (119, 128))	('KRAS', 'Gene', (89, 93))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))	('KRAS', 'Gene', '3845', (89, 93))
30242	31338486	Our case had a genetic alteration in the K-ras gene at codon 12 similar to two other cases in the literature.	('K-ras', 'Gene', (41, 46))	('K-ras', 'Gene', '3845', (41, 46))	('genetic alteration', 'Var', (15, 33))
30267	30717416	Researchers conducted a study in 1999 and concluded that tocotrienols (alpha, gamma and delta) and RRR-delta-tocopherol induced substantial apoptosis in breast cancer cell lines except the tocopherols (alpha, beta, and gamma) and the acetate derivative of RRR-alpha-tocopherol (RRR-alpha-tocopheryl acetate).	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('tocotrienols', 'Chemical', 'MESH:D024508', (57, 69))	('RRR-delta-tocopherol', 'Var', (99, 119))	('delta-tocopherol', 'Chemical', 'MESH:C479072', (103, 119))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (260, 276))	('apoptosis', 'CPA', (140, 149))	('tocopheryl acetate', 'Chemical', 'MESH:D024502', (288, 306))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('tocopherols', 'Chemical', 'MESH:D024505', (189, 200))	('acetate', 'Chemical', 'MESH:D000085', (234, 241))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('acetate', 'Chemical', 'MESH:D000085', (299, 306))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('breast cancer', 'Disease', (153, 166))
30270	30717416	Another study suggested that Bcl-2 family members and caspase-3 were the key regulators in gamma-T3-induced apoptosis in gastric cancer SGC-7901 cells and apoptosis was mediated through the down-regulation of the Raf-ERK signaling pathway.	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('regulation', 'biological_process', 'GO:0065007', ('195', '205'))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('Bcl-2', 'Gene', (29, 34))	('caspase-3', 'Gene', '836', (54, 63))	('ERK', 'Gene', '5594', (217, 220))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('caspase-3', 'Gene', (54, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('signaling pathway', 'biological_process', 'GO:0007165', ('221', '238'))	('Raf', 'Gene', (213, 216))	('down-regulation', 'NegReg', (190, 205))	('Bcl-2', 'Gene', '596', (29, 34))	('ERK', 'molecular_function', 'GO:0004707', ('217', '220'))	('SGC-7901', 'CellLine', 'CVCL:0520', (136, 144))	('apoptosis', 'CPA', (108, 117))	('ERK', 'Gene', (217, 220))	('gamma-T3-induced', 'Var', (91, 107))	('Raf', 'Gene', '22882', (213, 216))	('gastric cancer', 'Disease', (121, 135))	('apoptosis', 'biological_process', 'GO:0097194', ('155', '164'))	('gamma-T3', 'Chemical', '-', (91, 99))	('apoptosis', 'biological_process', 'GO:0006915', ('155', '164'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('29', '34'))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
30271	30717416	Narimah et al., demonstrated that gamma-T3 and alpha-tocopherol showed anti-proliferative activities and induced apoptosis in Caski (cervical carcinoma cell line) and Alexander cells (hepatoma cell line).	('gamma-T3', 'Var', (34, 42))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (47, 63))	('cervical carcinoma', 'Disease', (133, 151))	('apoptosis', 'CPA', (113, 122))	('cervical carcinoma', 'Disease', 'MESH:D002575', (133, 151))	('hepatoma', 'Disease', (184, 192))	('hepatoma', 'Disease', 'MESH:D006528', (184, 192))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('gamma-T3', 'Chemical', '-', (34, 42))	('induced', 'PosReg', (105, 112))	('anti-proliferative activities', 'CPA', (71, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))
30273	30717416	Similarly, another report suggested that tocotrienols can induce apoptosis in breast cancer cell lines via upregulation of DR5 that was dependent on JNK and p38 MAPK activation and mediated through endoplasmic reticulum stress.	('upregulation', 'PosReg', (107, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('MAPK activation', 'biological_process', 'GO:0000187', ('161', '176'))	('activation', 'PosReg', (166, 176))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('JNK', 'Gene', '5599', (149, 152))	('JNK', 'molecular_function', 'GO:0004705', ('149', '152'))	('p38', 'Var', (157, 160))	('tocotrienols', 'Chemical', 'MESH:D024508', (41, 53))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('198', '219'))	('apoptosis', 'CPA', (65, 74))	('MAPK', 'molecular_function', 'GO:0004707', ('161', '165'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('DR5', 'Gene', (123, 126))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('JNK', 'Gene', (149, 152))	('breast cancer', 'Disease', (78, 91))
30277	30717416	In another study, the authors showed that delta-T3 has higher efficacy and effectiveness in carrying out apoptosis in both human lung adenocarcinoma A549 and glioblastoma U87MG cells as compared to alpha- and gamma-T3.	('apoptosis', 'biological_process', 'GO:0097194', ('105', '114'))	('carrying out apoptosis', 'CPA', (92, 114))	('human', 'Species', '9606', (123, 128))	('U87MG', 'CellLine', 'CVCL:0022', (171, 176))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (129, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('lung adenocarcinoma A549', 'Disease', (129, 153))	('glioblastoma', 'Disease', (158, 170))	('lung adenocarcinoma A549', 'Disease', 'MESH:D000077192', (129, 153))	('delta-T3', 'Var', (42, 50))	('glioblastoma', 'Disease', 'MESH:D005909', (158, 170))	('apoptosis', 'biological_process', 'GO:0006915', ('105', '114'))	('gamma-T3', 'Chemical', '-', (209, 217))	('glioblastoma', 'Phenotype', 'HP:0012174', (158, 170))	('delta-T3', 'Chemical', '-', (42, 50))
30279	30717416	Moreover, it was noted that delta-T3 arrested the growth of human bladder cancer cells, induced apoptosis, and chemosensitization by inhibiting STAT3 pathway.	('arrested', 'NegReg', (37, 45))	('induced', 'Reg', (88, 95))	('inhibiting', 'NegReg', (133, 143))	('delta-T3', 'Chemical', '-', (28, 36))	('bladder cancer', 'Phenotype', 'HP:0009725', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('delta-T3', 'Var', (28, 36))	('growth', 'CPA', (50, 56))	('apoptosis', 'CPA', (96, 105))	('STAT3', 'Gene', '6774', (144, 149))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('chemosensitization', 'CPA', (111, 129))	('human', 'Species', '9606', (60, 65))	('bladder cancer', 'Disease', 'MESH:D001749', (66, 80))	('bladder cancer', 'Disease', (66, 80))	('STAT3', 'Gene', (144, 149))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
30281	30717416	Another report also found that gamma-T3-induced ER stress-mediated apoptosis and autophagy in breast cancer MCF-7 and MDA-MB-231 cells.	('autophagy', 'biological_process', 'GO:0016236', ('81', '90'))	('gamma-T3-induced', 'Var', (31, 47))	('MCF-7', 'CellLine', 'CVCL:0031', (108, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('ER stress-mediated apoptosis', 'CPA', (48, 76))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (118, 128))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('autophagy', 'biological_process', 'GO:0006914', ('81', '90'))	('gamma-T3', 'Chemical', '-', (31, 39))	('autophagy', 'CPA', (81, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('67', '76'))	('apoptosis', 'biological_process', 'GO:0006915', ('67', '76'))	('breast cancer', 'Disease', (94, 107))
30282	30717416	gamma-T3 acted as an effective inducer of apoptosis in K562 chronic myeloid leukemia cells, which was mediated by both extrinsic and intrinsic apoptotic pathways.	('myeloid leukemia', 'Disease', 'MESH:D007951', (68, 84))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (68, 84))	('gamma-T3', 'Var', (0, 8))	('apoptosis', 'CPA', (42, 51))	('K562', 'CellLine', 'CVCL:0004', (55, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('gamma-T3', 'Chemical', '-', (0, 8))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('myeloid leukemia', 'Disease', (68, 84))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (60, 84))
30284	30717416	In 2017, Xu et al., concluded that gamma-T3 acted as anti-proliferative agent and induced apoptosis in HeLa cells via the mitochondrial pathway.	('mitochondrial', 'CPA', (122, 135))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('gamma-T3', 'Var', (35, 43))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('induced', 'Reg', (82, 89))	('apoptosis', 'CPA', (90, 99))	('gamma-T3', 'Chemical', '-', (35, 43))	('HeLa', 'CellLine', 'CVCL:0030', (103, 107))
30293	30717416	gamma-T3 was also reported to arrest cell cycle at G0/G1 phase and reduce the S phase in HeLa cells.	('reduce', 'NegReg', (67, 73))	('S phase', 'CPA', (78, 85))	('G1 phase', 'biological_process', 'GO:0051318', ('54', '62'))	('gamma-T3', 'Var', (0, 8))	('cell cycle', 'biological_process', 'GO:0007049', ('37', '47'))	('arrest', 'PosReg', (30, 36))	('gamma-T3', 'Chemical', '-', (0, 8))	('HeLa', 'CellLine', 'CVCL:0030', (89, 93))	('S phase', 'biological_process', 'GO:0051320', ('78', '85'))	('cell cycle at G0/G1 phase', 'CPA', (37, 62))
30303	30717416	In another study carried out by Husain and colleagues, it was demonstrated that delta-T3 inhibited biomarkers of tumor angiogenesis (VEGF and MMP-9) in pancreatic cancer cells (L3.6pl and MiaPaCa-2) in vitro and decreased the expression of CSCs cell surface markers (CD31 and CD44).	('delta-T3', 'Chemical', '-', (80, 88))	('expression', 'MPA', (226, 236))	('angiogenesis', 'biological_process', 'GO:0001525', ('119', '131'))	('cell surface', 'cellular_component', 'GO:0009986', ('245', '257'))	('delta-T3', 'Var', (80, 88))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (152, 169))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (188, 197))	('biomarkers', 'MPA', (99, 109))	('CD31', 'Gene', '5175', (267, 271))	('CD44', 'Gene', '960', (276, 280))	('MMP-9', 'molecular_function', 'GO:0004229', ('142', '147'))	('decreased', 'NegReg', (212, 221))	('tumor', 'Disease', (113, 118))	('CD44', 'Gene', (276, 280))	('inhibited', 'NegReg', (89, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (152, 169))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('VEGF', 'Gene', '7422', (133, 137))	('MMP-9', 'Gene', '4318', (142, 147))	('CD31', 'Gene', (267, 271))	('MMP-9', 'Gene', (142, 147))	('pancreatic cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('VEGF', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
30304	30717416	Also, delta-T3 has exhibited significant efficacy against both melanoma and its associated stem cells.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('delta-T3', 'Var', (6, 14))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('delta-T3', 'Chemical', '-', (6, 14))
30305	30717416	(2018) have also clearly demonstrated the suppressive actions of delta-T3 on hypoxia adaptation of prostate cancer stem-like cells.	('delta-T3', 'Chemical', '-', (65, 73))	('hypoxia adaptation of prostate cancer', 'Disease', 'MESH:D011471', (77, 114))	('hypoxia adaptation of prostate cancer', 'Disease', (77, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('delta-T3', 'Var', (65, 73))	('suppressive', 'NegReg', (42, 53))	('prostate cancer', 'Phenotype', 'HP:0012125', (99, 114))
30307	30717416	In addition, pre-clinical data from numerous other studies have also reported that gamma-T3 alleviates angiogenic protein expression (VEGF) in colorectal cancer, malignant mesothelioma, breast cancer, ovarian carcinoma, head and neck squamous cell carcinomas, and other cancers.	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (229, 258))	('alleviates', 'NegReg', (92, 102))	('ovarian carcinoma', 'Disease', (201, 218))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('colorectal cancer', 'Disease', 'MESH:D015179', (143, 160))	('pre', 'molecular_function', 'GO:0003904', ('13', '16'))	('carcinomas', 'Phenotype', 'HP:0030731', (248, 258))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (201, 218))	('colorectal cancer', 'Disease', (143, 160))	('cancers', 'Phenotype', 'HP:0002664', (270, 277))	('gamma-T3', 'Var', (83, 91))	('cancers', 'Disease', (270, 277))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (234, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (162, 184))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('angiogenic protein expression', 'MPA', (103, 132))	('breast cancer', 'Disease', (186, 199))	('neck', 'cellular_component', 'GO:0044326', ('229', '233'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (143, 160))	('malignant mesothelioma', 'Disease', (162, 184))	('VEGF', 'Gene', '7422', (134, 138))	('cancers', 'Disease', 'MESH:D009369', (270, 277))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('neck squamous cell carcinomas', 'Disease', (229, 258))	('VEGF', 'Gene', (134, 138))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (162, 184))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('gamma-T3', 'Chemical', '-', (83, 91))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (201, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
30321	30717416	Ahmed and coworkers in 2016 concluded that reversal of epithelial-mesenchymal transition by gamma-T3 in MDA-MB-231 and T47D cells was associated with the attenuation of canonical Wnt signaling.	('signaling', 'biological_process', 'GO:0023052', ('183', '192'))	('canonical Wnt signaling', 'Pathway', (169, 192))	('gamma-T3', 'Chemical', '-', (92, 100))	('epithelial-mesenchymal transition', 'CPA', (55, 88))	('attenuation', 'NegReg', (154, 165))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (104, 114))	('gamma-T3', 'Var', (92, 100))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('55', '88'))	('T47D', 'CellLine', 'CVCL:0553', (119, 123))
30329	30717416	The above-mentioned ncRNAs are found to play important roles in regulating the various biological processes, and alterations in their expression may have drastic effects on cellular functions and can contribute to disease etiology, including cancer.	('cancer', 'Disease', (242, 248))	('expression', 'MPA', (134, 144))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('effects', 'Reg', (162, 169))	('cellular functions', 'CPA', (173, 191))	('alterations', 'Var', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('contribute', 'Reg', (200, 210))
30333	30717416	The authors found that the treatment with delta-T3 inhibited the proliferation of these cells in a dose-dependent manner.	('delta-T3', 'Var', (42, 50))	('proliferation of these cells', 'CPA', (65, 93))	('inhibited', 'NegReg', (51, 60))	('delta-T3', 'Chemical', '-', (42, 50))
30335	30717416	Interestingly, they found that delta-T3-treated cells significantly expressed a low level of miR-429 compared to the untreated cells.	('low', 'NegReg', (80, 83))	('delta-T3-treated', 'Var', (31, 47))	('miR-429', 'Gene', '554210', (93, 100))	('miR-429', 'Gene', (93, 100))	('delta-T3', 'Chemical', '-', (31, 39))
30336	30717416	In addition, the delta-T3 treatment resulted in a marked induction of caspase-3 activity and apoptosis in the cells transfected with control miRNAs compared to those transfected with the miR-429 inhibitor.	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))	('induction', 'PosReg', (57, 66))	('caspase-3', 'Gene', (70, 79))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('70', '88'))	('delta-T3', 'Var', (17, 25))	('caspase-3', 'Gene', '836', (70, 79))	('activity', 'MPA', (80, 88))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('70', '88'))	('miR-429', 'Gene', '554210', (187, 194))	('delta-T3', 'Chemical', '-', (17, 25))	('apoptosis', 'CPA', (93, 102))	('miR-429', 'Gene', (187, 194))
30337	30717416	Furthermore, they observed that inhibition of miR-429 partially rescued the apoptosis induced by delta-T3 in MDA-MB-231 cells.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (109, 119))	('miR-429', 'Gene', (46, 53))	('inhibition', 'Var', (32, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('delta-T3', 'Chemical', '-', (97, 105))	('delta-T3', 'Var', (97, 105))	('miR-429', 'Gene', '554210', (46, 53))	('apoptosis', 'CPA', (76, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))
30342	30717416	By miRNA array analysis, the authors found that delta-T3 significantly up-regulated the expression of miR-34a in treated H1650 and A549 cell lines compared to the untreated cells.	('delta-T3', 'Var', (48, 56))	('A549', 'CellLine', 'CVCL:0023', (131, 135))	('miR-34a', 'Gene', '407040', (102, 109))	('up-regulated', 'PosReg', (71, 83))	('H1650', 'CellLine', 'CVCL:1483', (121, 126))	('miR-34a', 'Gene', (102, 109))	('expression', 'MPA', (88, 98))	('delta-T3', 'Chemical', '-', (48, 56))
30343	30717416	They also observed a significant increase in miR-34a expression in the delta-T3-treated cells compared to control in a dose and time-dependent manner.	('miR-34a', 'Gene', (45, 52))	('increase', 'PosReg', (33, 41))	('delta-T3', 'Chemical', '-', (71, 79))	('expression', 'MPA', (53, 63))	('miR-34a', 'Gene', '407040', (45, 52))	('delta-T3-treated', 'Var', (71, 87))
30345	30717416	Furthermore, it was observed that cell proliferation was inhibited by 74% upon delta-T3 exposure alone in A549 cells, whereas the combination treatment of AS-miR-34a (miRNA-34 inhibitor) and delta-T3 reduced it by 57%.	('delta-T3', 'Chemical', '-', (79, 87))	('cell proliferation', 'CPA', (34, 52))	('inhibited', 'NegReg', (57, 66))	('delta-T3', 'Chemical', '-', (191, 199))	('miR-34a', 'Gene', '407040', (158, 165))	('delta-T3', 'Var', (79, 87))	('cell proliferation', 'biological_process', 'GO:0008283', ('34', '52'))	('miR-34a', 'Gene', (158, 165))	('A549', 'CellLine', 'CVCL:0023', (106, 110))
30346	30717416	Mechanistically, it was demonstrated that delta-T3 inhibited the cell proliferation and invasion by up-regulating the expression of miR-34a and suppressing Notch-1 signaling pathway.	('inhibited', 'NegReg', (51, 60))	('up-regulating', 'PosReg', (100, 113))	('miR-34a', 'Gene', '407040', (132, 139))	('invasion', 'CPA', (88, 96))	('suppressing', 'NegReg', (144, 155))	('miR-34a', 'Gene', (132, 139))	('delta-T3', 'Var', (42, 50))	('signaling pathway', 'biological_process', 'GO:0007165', ('164', '181'))	('cell proliferation', 'biological_process', 'GO:0008283', ('65', '83'))	('cell proliferation', 'CPA', (65, 83))	('expression', 'MPA', (118, 128))	('Notch-1', 'Gene', (156, 163))	('Notch-1', 'Gene', '4851', (156, 163))	('delta-T3', 'Chemical', '-', (42, 50))
30354	30717416	Moreover, delta-T3, inhibited Src kinase, Janus kinase (JAK) 1, and JAK2, thus eventually downregulating STAT3 activation in bladder cancer cells.	('JAK2', 'Gene', '3717', (68, 72))	('STAT3', 'Gene', '6774', (105, 110))	('JAK2', 'Gene', (68, 72))	('downregulating', 'NegReg', (90, 104))	('Src kinase', 'Enzyme', (30, 40))	('Janus kinase (JAK) 1', 'Gene', '3716', (42, 62))	('delta-T3', 'Var', (10, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('JAK', 'molecular_function', 'GO:0004713', ('68', '71'))	('inhibited', 'NegReg', (20, 29))	('bladder cancer', 'Disease', (125, 139))	('JAK', 'molecular_function', 'GO:0004713', ('56', '59'))	('STAT3', 'Gene', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('delta-T3', 'Chemical', '-', (10, 18))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('Janus kinase (JAK) 1', 'Gene', (42, 62))
30390	30147846	Apparently, PSCs can activate the mitogen-activated protein kinase and Akt pathways in tumor cells, causing enhanced tumor growth and metastasis.	('Akt', 'Gene', '207', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('activate', 'PosReg', (21, 29))	('tumor', 'Disease', (117, 122))	('Akt', 'Gene', (71, 74))	('tumor', 'Disease', (87, 92))	('PSCs', 'Var', (12, 16))	('enhanced', 'PosReg', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
30405	30147846	These findings suggested that the tumor stromal modulation (reprogramming) by inactivating PSCs could be a reasonable treatment strategy for PC.	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('nab', 'Chemical', '-', (112, 115))	('tumor stroma', 'Disease', 'MESH:D009369', (34, 46))	('PC', 'Phenotype', 'HP:0002894', (141, 143))	('tumor stroma', 'Disease', (34, 46))	('inactivating', 'Var', (78, 90))	('rat', 'Species', '10116', (130, 133))	('PSCs', 'Gene', (91, 95))
30415	30147846	In mice bearing orthotopically implanted PC and PSCs, pirfenidone was shown to suppress the tumor growth and metastasis formation and displayed a synergistic antitumor effect with gemcitabine.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('pirfenidone', 'Var', (54, 65))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('mice', 'Species', '10090', (3, 7))	('tumor', 'Disease', (162, 167))	('pirfenidone', 'Chemical', 'MESH:C093844', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('gemcitabine', 'Chemical', 'MESH:C056507', (180, 191))	('PC', 'Phenotype', 'HP:0002894', (41, 43))	('formation', 'biological_process', 'GO:0009058', ('120', '129'))	('tumor', 'Disease', (92, 97))	('suppress', 'NegReg', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
30425	30147846	Donahue et al reported that a high stromal miR-21 level correlated with worse overall survival in patients with PC who received adjuvant 5-fluorouracil but not gemcitabine.	('D', 'Chemical', 'MESH:D003903', (0, 1))	('PC', 'Phenotype', 'HP:0002894', (112, 114))	('miR-21', 'Gene', '406991', (43, 49))	('worse', 'NegReg', (72, 77))	('patients', 'Species', '9606', (98, 106))	('overall survival', 'MPA', (78, 94))	('high', 'Var', (30, 34))	('miR-21', 'Gene', (43, 49))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (137, 151))	('gemcitabine', 'Chemical', 'MESH:C056507', (160, 171))
30429	30147846	The dysregulation of miR-320a, miR-365, miR-200, and miR-210 has been found to be involved in tumor invasion, epithelial to mesenchymal transition development, and chemotherapeutic drug resistance in PC.	('miR-320a', 'Gene', '407037', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('involved', 'Reg', (82, 90))	('drug resistance', 'biological_process', 'GO:0009315', ('181', '196'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('miR-210', 'Gene', (53, 60))	('dysregulation', 'Var', (4, 17))	('miR-210', 'Gene', '406992', (53, 60))	('drug resistance', 'Phenotype', 'HP:0020174', (181, 196))	('drug resistance', 'biological_process', 'GO:0042493', ('181', '196'))	('tumor', 'Disease', (94, 99))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('110', '146'))	('miR-365', 'Var', (31, 38))	('epithelial to mesenchymal transition development', 'CPA', (110, 158))	('miR-320a', 'Gene', (21, 29))	('miR-200', 'Gene', (40, 47))	('PC', 'Phenotype', 'HP:0002894', (200, 202))
30430	30147846	Thus, silencing of specific miRNAs by chemically modified antisense oligonucleotides could be a novel therapeutic intervention for PC.	('antisense oligonucleotides', 'Var', (58, 84))	('oligonucleotides', 'Chemical', 'MESH:D009841', (68, 84))	('miRNAs', 'Protein', (28, 34))	('silencing', 'NegReg', (6, 15))	('PC', 'Phenotype', 'HP:0002894', (131, 133))
30432	30147846	In addition, sonic Hh has been shown to promote desmoplasia in orthotopic mouse models of PC, and inhibiting sonic Hh with monoclonal antibody 5E1 markedly decreased the degree of desmoplasia.	('antibody', 'cellular_component', 'GO:0019814', ('134', '142'))	('promote', 'PosReg', (40, 47))	('antibody', 'cellular_component', 'GO:0019815', ('134', '142'))	('desmoplasia', 'Disease', (48, 59))	('antibody', 'molecular_function', 'GO:0003823', ('134', '142'))	('desmoplasia', 'Disease', (180, 191))	('decreased', 'NegReg', (156, 165))	('desmoplasia', 'Disease', 'None', (48, 59))	('mouse', 'Species', '10090', (74, 79))	('antibody', 'cellular_component', 'GO:0042571', ('134', '142'))	('inhibiting', 'Var', (98, 108))	('PC', 'Phenotype', 'HP:0002894', (90, 92))	('desmoplasia', 'Disease', 'None', (180, 191))
30446	30147846	In fact, signaling through these pathways accelerates the proliferation, epithelial-to-mesenchymal transition, stemness, and metastatic capacity of PC cells and increases their resistance against chemotherapeutic drugs.	('PC', 'Phenotype', 'HP:0002894', (148, 150))	('epithelial-to-mesenchymal transition', 'CPA', (73, 109))	('proliferation', 'CPA', (58, 71))	('signaling', 'Var', (9, 18))	('signaling', 'biological_process', 'GO:0023052', ('9', '18'))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('73', '109'))	('metastatic capacity', 'CPA', (125, 144))	('accelerates', 'PosReg', (42, 53))	('resistance against chemotherapeutic', 'CPA', (177, 212))	('stemness', 'Disease', 'MESH:D020295', (111, 119))	('stemness', 'Disease', (111, 119))	('increases', 'PosReg', (161, 170))	('rat', 'Species', '10116', (48, 51))	('rat', 'Species', '10116', (65, 68))
30449	30147846	Furthermore, the combined use of gemcitabine and PEGPH20 exhibited a synergistic effect and substantially inhibited the tumor growth, resulting in the upgraded survival of animals.	('PEGPH20', 'Chemical', '-', (49, 56))	('inhibited', 'NegReg', (106, 115))	('upgraded', 'PosReg', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('PEGPH20', 'Var', (49, 56))	('survival of animals', 'CPA', (160, 179))	('gemcitabine', 'Chemical', 'MESH:C056507', (33, 44))	('tumor', 'Disease', (120, 125))
30451	30147846	Provenzano et al reported similar findings and observed that PEGPH20 effectively ablated HA from metastatic deposits as with primary tumors and reinstated the vascular pattern.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('vascular pattern', 'MPA', (159, 175))	('primary tumors', 'Disease', (125, 139))	('PEGPH20', 'Var', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('primary tumors', 'Disease', 'MESH:D009369', (125, 139))	('PEGPH20', 'Chemical', '-', (61, 68))	('HA from metastatic', 'MPA', (89, 107))	('reinstated', 'PosReg', (144, 154))	('ablated', 'NegReg', (81, 88))
30459	30147846	In HA-high patients (34% of enrolled patients), a significant increase was again noted in the progression-free survival with PEGPH20 plus chemotherapy compared with chemotherapy alone (median: 9.2 mo vs 5.2 mo; P = 0.48).	('PEGPH20', 'Var', (125, 132))	('patients', 'Species', '9606', (37, 45))	('PEGPH20', 'Chemical', '-', (125, 132))	('progression-free survival', 'CPA', (94, 119))	('patients', 'Species', '9606', (11, 19))	('increase', 'PosReg', (62, 70))
30461	30147846	In the first stage of this phase 2 study, none of the patients randomized to PEGFP20 arm was provided thromboprophylaxis, and 43% of these developed thrombosis, causing a temporary cessation in the treatment.	('patients', 'Species', '9606', (54, 62))	('thrombosis', 'Disease', (149, 159))	('PEGFP20', 'Var', (77, 84))	('thrombosis', 'Disease', 'MESH:D013927', (149, 159))
30463	30147846	PEGPH20 treatment was also associated with increased incidence and severity of other manageable side effects, such as painful muscle spasms, arthralgia, peripheral edema, and neutropenia.	('peripheral edema', 'Disease', (153, 169))	('painful muscle spasms', 'Disease', 'MESH:D063806', (118, 139))	('neutropenia', 'Phenotype', 'HP:0001875', (175, 186))	('neutropenia', 'Disease', 'MESH:D009503', (175, 186))	('arthralgia', 'Disease', (141, 151))	('PEGPH20 treatment', 'Var', (0, 17))	('arthralgia', 'Phenotype', 'HP:0002829', (141, 151))	('painful muscle', 'Phenotype', 'HP:0003326', (118, 132))	('peripheral edema', 'Phenotype', 'HP:0012398', (153, 169))	('muscle spasms', 'Phenotype', 'HP:0003394', (126, 139))	('arthralgia', 'Disease', 'MESH:D018771', (141, 151))	('neutropenia', 'Disease', (175, 186))	('peripheral edema', 'Disease', 'MESH:D004487', (153, 169))	('edema', 'Phenotype', 'HP:0000969', (164, 169))	('PEGPH20', 'Chemical', '-', (0, 7))	('painful muscle spasms', 'Disease', (118, 139))
30466	30147846	In contrast, a recently presented randomized phase I/II study evaluating the efficacy of PEGPH20 and modified FOLFIRINOX in patients with metastatic PC who have a good performance status suggested that PEGPH20 can have a detrimental effect on OS (HR = 0.48).	('PEGPH20', 'Var', (202, 209))	('PEGPH20', 'Chemical', '-', (89, 96))	('metastatic PC', 'Disease', (138, 151))	('PEGPH20', 'Chemical', '-', (202, 209))	('PC', 'Phenotype', 'HP:0002894', (149, 151))	('patients', 'Species', '9606', (124, 132))	('FOLFIRINOX', 'Chemical', '-', (110, 120))
30470	30147846	In addition, PC cells fail to produce SPARC because of aberrant hypermethylation in their SPARC gene.	('SPARC', 'Gene', '6678', (38, 43))	('SPARC', 'Gene', (38, 43))	('PC', 'Phenotype', 'HP:0002894', (13, 15))	('SPARC', 'Gene', '6678', (90, 95))	('hypermethylation', 'Var', (64, 80))	('SPARC', 'Gene', (90, 95))	('aberrant hypermethylation', 'Var', (55, 80))
30478	30147846	In the study, the SPARC status was assessed in 36 patients, and patients whose tumors had high SPARC expression (n = 19) exhibited better overall survival than patients whose tumors displayed low SPARC expression (median: 17.8 mo vs 8.1 mo; P = 0.0431).	('tumors', 'Disease', (175, 181))	('SPARC', 'Gene', '6678', (196, 201))	('SPARC', 'Gene', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('better', 'PosReg', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('SPARC', 'Gene', '6678', (18, 23))	('tumors', 'Disease', (79, 85))	('patients', 'Species', '9606', (50, 58))	('overall survival', 'CPA', (138, 154))	('SPARC', 'Gene', (95, 100))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('SPARC', 'Gene', '6678', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('patients', 'Species', '9606', (160, 168))	('patients', 'Species', '9606', (64, 72))	('SPARC', 'Gene', (196, 201))	('high', 'Var', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
30483	30147846	Thus, the intratumoral concentration of gemcitabine was determined to be 2.8-fold higher in nab-paclitaxel plus gemcitabine-treated mice compared with mice receiving gemcitabine alone.	('paclitaxel', 'Chemical', 'MESH:D017239', (96, 106))	('gemcitabine', 'Chemical', 'MESH:C056507', (112, 123))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('mice', 'Species', '10090', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('nab-paclitaxel', 'Var', (92, 106))	('higher', 'PosReg', (82, 88))	('nab', 'Chemical', '-', (92, 95))	('rat', 'Species', '10116', (30, 33))	('mice', 'Species', '10090', (132, 136))	('rat', 'Species', '10116', (13, 16))	('tumor', 'Disease', (15, 20))	('gemcitabine', 'Chemical', 'MESH:C056507', (166, 177))	('gemcitabine', 'Chemical', 'MESH:C056507', (40, 51))
30486	30147846	In addition, patients receiving nab-paclitaxel plus gemcitabine exhibited longer median overall survival compared with those receiving gemcitabine alone (8.5 mo vs 6.7 mo; P < 0.001).	('nab', 'Chemical', '-', (32, 35))	('nab-paclitaxel', 'Var', (32, 46))	('longer', 'PosReg', (74, 80))	('patients', 'Species', '9606', (13, 21))	('overall survival', 'MPA', (88, 104))	('gemcitabine', 'Chemical', 'MESH:C056507', (52, 63))	('paclitaxel', 'Chemical', 'MESH:D017239', (36, 46))	('gemcitabine', 'Chemical', 'MESH:C056507', (135, 146))
30492	30147846	After the announcement of the final outcomes of the phase III HALO Pancreatic 301 study, PEGPH20 could be incorporated into standard-of-care treatment regimens in metastatic PC.	('Pancreatic', 'Disease', (67, 77))	('PEGPH20', 'Var', (89, 96))	('Pancreatic', 'Disease', 'MESH:D010195', (67, 77))	('HALO', 'cellular_component', 'GO:1990038', ('62', '66'))	('rat', 'Species', '10116', (113, 116))	('PC', 'Phenotype', 'HP:0002894', (174, 176))	('PEGPH20', 'Chemical', '-', (89, 96))	('metastatic PC', 'Disease', (163, 176))
30533	29535824	The HIF-1alpha knockdown slightly but significantly suppressed the induction of SHH expression under hypoxic conditions (Figure 1G).	('HIF-1alpha', 'Gene', (4, 14))	('SHH', 'Gene', '6469', (80, 83))	('induction', 'MPA', (67, 76))	('knockdown', 'Var', (15, 24))	('SHH', 'Gene', (80, 83))	('HIF-1alpha', 'Gene', '3091', (4, 14))	('suppressed', 'NegReg', (52, 62))	('hypoxic conditions', 'Disease', (101, 119))	('hypoxic conditions', 'Disease', 'MESH:D009135', (101, 119))
30540	29535824	SHH is known to activate a key transcription factor, Gli-1, through the inactivation of PTCH and resultant activation of SMO in the hedgehog signaling pathway; therefore, we considered that a reporter gene expressing luciferase bioluminescence in a Gli-1-dependent manner would meet our purpose (Supplementary Figure 1A).	('PTCH', 'Gene', '5727', (88, 92))	('transcription factor', 'molecular_function', 'GO:0000981', ('31', '51'))	('SHH', 'Gene', (0, 3))	('Gli-1', 'Gene', (53, 58))	('PTCH', 'Gene', (88, 92))	('SMO', 'Gene', '6608', (121, 124))	('SMO', 'Gene', (121, 124))	('hedgehog signaling pathway', 'biological_process', 'GO:0007224', ('132', '158'))	('transcription', 'biological_process', 'GO:0006351', ('31', '44'))	('bioluminescence', 'biological_process', 'GO:0008218', ('228', '243'))	('SHH', 'Gene', '6469', (0, 3))	('Gli-1', 'Gene', (249, 254))	('inactivation', 'Var', (72, 84))	('hedgehog signaling pathway', 'Pathway', (132, 158))	('Gli-1', 'Gene', '2735', (249, 254))	('activation', 'PosReg', (107, 117))	('Gli-1', 'Gene', '2735', (53, 58))
30557	29535824	As expected, treatment with TAK-441 suppressed the SHH-mediated increase in the hedgehog signaling activity in fibroblasts in a dose-dependent manner (Figure 3C), but the effect of TAK-441 was completely abolished by the overexpression of SMO (Figure 3D).	('suppressed', 'NegReg', (36, 46))	('SHH', 'Gene', (51, 54))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('hedgehog signaling', 'Pathway', (80, 98))	('TAK-441', 'Chemical', 'MESH:C577980', (181, 188))	('increase', 'PosReg', (64, 72))	('TAK-441', 'Var', (28, 35))	('TAK-441', 'Chemical', 'MESH:C577980', (28, 35))	('SMO', 'Gene', '6608', (239, 242))	('SMO', 'Gene', (239, 242))	('SHH', 'Gene', '6469', (51, 54))
30558	29535824	The cell proliferation assay also revealed that treatment with TAK-441 suppressed the SHH-stimulated growth of the fibroblasts as well (Figure 3E).	('SHH', 'Gene', (86, 89))	('TAK-441', 'Chemical', 'MESH:C577980', (63, 70))	('SHH', 'Gene', '6469', (86, 89))	('TAK-441', 'Var', (63, 70))	('cell proliferation', 'biological_process', 'GO:0008283', ('4', '22'))	('suppressed', 'NegReg', (71, 81))
30590	29535824	To construct pcDNA4/HIF-1alpha3A, which expresses a constitutively active mutant of HIF-1alpha under the control of the CMV promoter, three point mutations, P402A, P564A, and N803A, were introduced into pcDNA4/HIF-1alpha by site-directed mutagenesis.	('HIF-1alpha', 'Gene', (210, 220))	('N803A', 'Var', (175, 180))	('P402A', 'Mutation', 'p.P402A', (157, 162))	('HIF-1alpha', 'Gene', '3091', (20, 30))	('P402A', 'Var', (157, 162))	('HIF-1alpha', 'Gene', (84, 94))	('P564A', 'Mutation', 'p.P564A', (164, 169))	('HIF-1alpha', 'Gene', '3091', (210, 220))	('N803A', 'Mutation', 'p.N803A', (175, 180))	('P564A', 'Var', (164, 169))	('HIF-1alpha', 'Gene', (20, 30))	('mutagenesis', 'biological_process', 'GO:0006280', ('238', '249'))	('HIF-1alpha', 'Gene', '3091', (84, 94))
30604	29535824	Double-stranded RNAs for the transient silencing of HIF-1alpha (silencer Select Validated siRNA, HSS104774, HSS104775, HSS179231) and for the negative control (Cat# 12935-300) were purchased from Life Technologies.	('HIF-1alpha', 'Gene', (52, 62))	('HSS179231', 'Var', (119, 128))	('Cat', 'molecular_function', 'GO:0004096', ('160', '163'))	('silencing', 'NegReg', (39, 48))	('HSS104774', 'Var', (97, 106))	('HIF-1alpha', 'Gene', '3091', (52, 62))	('HSS104775', 'Var', (108, 117))
30612	29535824	Quantitative real-time PCR analyses were conducted using the Thermal Cycler Dice Real Time System Single (TP-850; Takara Bio) with the SYBR Premix Ex Taq Kit (Takara Bio) and commercial primers (TaKaRa Primer Set ID HA198516 for human SHH mRNA, HA067803 for human beta-actin mRNA, MA108100 for mouse bcl-2 mRNA, and MA169281 for mouse cyclin D1 mRNA) according to the manufacturer's instructions, as described previously.	('mouse', 'Species', '10090', (294, 299))	('human', 'Species', '9606', (258, 263))	('SHH', 'Gene', '6469', (235, 238))	('MA169281', 'Var', (316, 324))	('HA198516', 'Var', (216, 224))	('MA108100', 'Var', (281, 289))	('beta-actin', 'Gene', '728378', (264, 274))	('beta-actin', 'Gene', (264, 274))	('HA067803', 'Var', (245, 253))	('human', 'Species', '9606', (229, 234))	('SHH', 'Gene', (235, 238))	('mouse', 'Species', '10090', (329, 334))
30622	26226899	It reviews the established genetic hallmarks, examines more recently described mutations and altered pathways, and highlights key biological principles identified in PDA with a focus on those most likely to lead to future therapeutic targets.	('PDA', 'Disease', (166, 169))	('PDA', 'Chemical', '-', (166, 169))	('mutations', 'Var', (79, 88))
30623	26226899	Pancreatic adenocarcinoma shows genetic homogeneity on one level with mutations in KRAS, found in anywhere from 90% to 95% of advanced pancreatic cancers, and additional frequent and well-characterized mutations in the key tumor suppressor pathways TP53/p19ARF, RB/CDKN2A/INK4A, and TGFBeta/SMAD4.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('pancreatic cancers', 'Disease', (135, 153))	('KRAS', 'Gene', '3845', (83, 87))	('INK4A', 'Gene', '1029', (272, 277))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('CDKN2A', 'Gene', (265, 271))	('Pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (0, 25))	('KRAS', 'Gene', (83, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('223', '239'))	('pancreatic cancers', 'Disease', 'MESH:D010190', (135, 153))	('SMAD4', 'Gene', (291, 296))	('TP53', 'Gene', (249, 253))	('found', 'Reg', (89, 94))	('p19ARF', 'Gene', '1029', (254, 260))	('p19ARF', 'Gene', (254, 260))	('tumor suppressor', 'biological_process', 'GO:0051726', ('223', '239'))	('CDKN2A', 'Gene', '1029', (265, 271))	('INK4A', 'Gene', (272, 277))	('Pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (0, 25))	('mutations', 'Var', (70, 79))	('tumor', 'Disease', (223, 228))	('Pancreatic adenocarcinoma', 'Disease', (0, 25))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (135, 152))	('TGFBeta', 'Gene', '7040', (283, 290))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('SMAD4', 'Gene', '4089', (291, 296))	('TGFBeta', 'Gene', (283, 290))	('p19', 'cellular_component', 'GO:0070743', ('254', '257'))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (135, 153))	('TP53', 'Gene', '7157', (249, 253))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('mutations', 'Var', (202, 211))
30624	26226899	Beyond this element of genetic homogeneity, PDA is broadly characterized by general genetic instability with widespread mutations and chromosomal translocations, including the recent discovery of many additional mutated loci and classes of genes whose full cancer-specific functions have yet to be fully explored.	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('PDA', 'Disease', (44, 47))	('PDA', 'Chemical', '-', (44, 47))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('mutations', 'Var', (120, 129))	('cancer', 'Disease', (257, 263))
30631	26226899	Consequently, mutant RAS is a difficult therapeutic target because the loss of its GTPase enzymatic activity is not easily pharmacologically restored.	('mutant', 'Var', (14, 20))	('GTP', 'Chemical', 'MESH:D006160', (83, 86))	('RAS', 'Gene', (21, 24))
30633	26226899	KRAS mutation leads to constitutive activations of key mitogenic and survival signaling pathways, including RAF/MEK/ERK and phosphatidylinositol 3 kinase (PI3K).	('phosphatidylinositol 3 kinase', 'Gene', '5293', (124, 153))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('PI3K', 'molecular_function', 'GO:0016303', ('155', '159'))	('ERK', 'molecular_function', 'GO:0004707', ('116', '119'))	('ERK', 'Gene', '5594', (116, 119))	('activations', 'PosReg', (36, 47))	('ERK', 'Gene', (116, 119))	('KRAS', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('phosphatidylinositol 3 kinase', 'Gene', (124, 153))	('KRAS', 'Gene', '3845', (0, 4))
30636	26226899	Furthermore, a Braf and Tp53 mutated model showed clear evidence of PDA with extensive metastasis.	('Tp53', 'Gene', (24, 28))	('Braf', 'Gene', (15, 19))	('PDA', 'Disease', (68, 71))	('Braf', 'Gene', '673', (15, 19))	('Tp53', 'Gene', '7157', (24, 28))	('PDA', 'Chemical', '-', (68, 71))	('mutated', 'Var', (29, 36))
30641	26226899	The addiction of subsets of PDAs to KRAS has been well described, shown by tumor regression with mutant Kras extinction.	('PDA', 'Chemical', '-', (28, 31))	('mutant', 'Var', (97, 103))	('KRAS', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('KRAS', 'Gene', '3845', (36, 40))	('Kras', 'Gene', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
30642	26226899	Dependence on mutant KRAS can be overcome, however, similar to the mechanisms of resistance described in many targeted therapies, and was recently described via amplification and overexpression of YAP-1.	('KRAS', 'Gene', '3845', (21, 25))	('YAP-1', 'Gene', (197, 202))	('mutant', 'Var', (14, 20))	('KRAS', 'Gene', (21, 25))	('YAP-1', 'Gene', '10413', (197, 202))
30645	26226899	Loss of INK4a function brought about by mutation, deletion, or promoter hypermethylation occurs in about 80% to 95% of sporadic PDA.	('PDA', 'Chemical', '-', (128, 131))	('mutation', 'Var', (40, 48))	('deletion', 'Var', (50, 58))	('function', 'MPA', (14, 22))	('Loss', 'NegReg', (0, 4))	('INK4a', 'Gene', (8, 13))	('promoter hypermethylation', 'Var', (63, 88))	('PDA', 'Disease', (128, 131))	('INK4a', 'Gene', '1029', (8, 13))
30648	26226899	Pancreatic cancers with mutations at this locus may sustain loss of both INK4a and ARF tumor suppression pathways, although some mutations have been found to affect loss of p16 alone.	('Pancreatic cancers', 'Phenotype', 'HP:0002894', (0, 18))	('ARF tumor', 'Disease', 'MESH:D009369', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('p16', 'Gene', '1029', (173, 176))	('Pancreatic cancers', 'Disease', (0, 18))	('ARF tumor', 'Disease', (83, 92))	('loss', 'NegReg', (60, 64))	('Pancreatic cancers', 'Disease', 'MESH:D010190', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('INK4a', 'Gene', (73, 78))	('p16', 'Gene', (173, 176))	('mutations', 'Var', (24, 33))	('INK4a', 'Gene', '1029', (73, 78))
30649	26226899	The importance of Ink4a in restraining PDA has been shown in murine models with engineered mutations in this locus designed to affect both p16Ink4a and p19Arf genes or p16Ink4a alone.	('p16Ink4a', 'Gene', '12578', (139, 147))	('p19Arf', 'Gene', '12578', (152, 158))	('PDA', 'Disease', (39, 42))	('Ink4a', 'Gene', '12578', (18, 23))	('p16Ink4a', 'Gene', (139, 147))	('Ink4a', 'Gene', (171, 176))	('Ink4a', 'Gene', '12578', (142, 147))	('p19Arf', 'Gene', (152, 158))	('PDA', 'Chemical', '-', (39, 42))	('murine', 'Species', '10090', (61, 67))	('mutations', 'Var', (91, 100))	('Ink4a', 'Gene', (18, 23))	('p16Ink4a', 'Gene', '12578', (168, 176))	('Ink4a', 'Gene', (142, 147))	('p16Ink4a', 'Gene', (168, 176))	('Ink4a', 'Gene', '12578', (171, 176))	('affect', 'Reg', (127, 133))	('p19', 'cellular_component', 'GO:0070743', ('152', '155'))
30650	26226899	Mutations, predominantly missense, in the TP53 tumor suppressor gene occur in approximately 75% to 80% of human PDA cases.	('missense', 'Var', (25, 33))	('TP53', 'Gene', '7157', (42, 46))	('human', 'Species', '9606', (106, 111))	('TP53', 'Gene', (42, 46))	('tumor suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('PDA', 'Disease', (112, 115))	('PDA', 'Chemical', '-', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('tumor', 'Disease', (47, 52))
30653	26226899	The role of TP53 loss in cancer is well established in that its mutation has been described in most human cancers and germline mutation of TP53 leads to the early development of sarcomas and carcinomas, also known as the Li-Fraumeni syndrome (for in-depth review of p53, see "The p53 Family," subject collection in CSH Perspectives in Biology, 2010).	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('sarcomas and carcinomas', 'Disease', 'MESH:D012509', (178, 201))	('p53', 'Gene', (280, 283))	('cancer', 'Disease', (106, 112))	('Li-Fraumeni syndrome', 'Disease', (221, 241))	('cancers', 'Disease', (106, 113))	('cancer', 'Disease', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('leads to', 'Reg', (144, 152))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (221, 241))	('carcinomas', 'Phenotype', 'HP:0030731', (191, 201))	('TP53', 'Gene', (139, 143))	('TP53', 'Gene', (12, 16))	('loss', 'NegReg', (17, 21))	('sarcomas', 'Phenotype', 'HP:0100242', (178, 186))	('mutation', 'Var', (64, 72))	('germline mutation', 'Var', (118, 135))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('p53', 'Gene', '7157', (266, 269))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('human', 'Species', '9606', (100, 105))	('TP53', 'Gene', '7157', (139, 143))	('p53', 'Gene', (266, 269))	('TP53', 'Gene', '7157', (12, 16))	('p53', 'Gene', '7157', (280, 283))
30654	26226899	Evidence from PDA precursor lesions (PanINs) suggests that loss or mutation of TP53 is a late event possibly caused by selective pressure after the collective accumulation of genetic aberrations, reactive oxygen species (ROS), and telomere erosion.	('PDA', 'Chemical', '-', (14, 17))	('TP53', 'Gene', '7157', (79, 83))	('mutation', 'Var', (67, 75))	('TP53', 'Gene', (79, 83))	('telomere', 'cellular_component', 'GO:0000781', ('231', '239'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (196, 219))	('ROS', 'Chemical', 'MESH:D017382', (221, 224))	('telomere', 'cellular_component', 'GO:0005696', ('231', '239'))	('loss', 'NegReg', (59, 63))
30655	26226899	The loss of p19ARF coexists with TP53 mutations in only about 40% of tumors, whereas the loss of TP53 or inactivation of this pathway is a more common feature of PDA, leading many to believe that these tumor suppressors have some overlapping function as well as independent capabilities.	('TP53', 'Gene', '7157', (97, 101))	('TP53', 'Gene', '7157', (33, 37))	('p19ARF', 'Gene', '1029', (12, 18))	('inactivation', 'NegReg', (105, 117))	('p19ARF', 'Gene', (12, 18))	('loss', 'NegReg', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('PDA', 'Disease', (162, 165))	('tumor', 'Disease', (202, 207))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('mutations', 'Var', (38, 47))	('PDA', 'Chemical', '-', (162, 165))	('TP53', 'Gene', (97, 101))	('tumors', 'Disease', (69, 75))	('TP53', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('p19', 'cellular_component', 'GO:0070743', ('12', '15'))	('tumor', 'Disease', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
30660	26226899	Somatic mutation of Smad4, as well as the type 2 TGF-beta receptor in the murine pancreatic epithelium, neither disrupted pancreatic development nor induced malignancy, but hastened PDA development when coupled with Kras mutation.	('malignancy', 'Disease', 'MESH:D009369', (157, 167))	('Smad4', 'Gene', (20, 25))	('malignancy', 'Disease', (157, 167))	('Smad4', 'Gene', '17128', (20, 25))	('murine', 'Species', '10090', (74, 80))	('disrupted', 'NegReg', (112, 121))	('pancreatic development', 'CPA', (122, 144))	('hastened', 'NegReg', (173, 181))	('PDA', 'Chemical', '-', (182, 185))	('mutation', 'Var', (8, 16))	('PDA development', 'CPA', (182, 197))
30664	26226899	The application of whole-genome sequencing to PDA has revealed additional new mutations in genes and pathways not previously recognized as being important in its pathogenesis as well as insights into its genetic evolution.	('pathogenesis', 'biological_process', 'GO:0009405', ('162', '174'))	('genes', 'Gene', (91, 96))	('PDA', 'Chemical', '-', (46, 49))	('mutations', 'Var', (78, 87))	('pathways', 'Pathway', (101, 109))
30667	26226899	Separately, whole-exon sequencing of 99 patients confirmed these described mutations and identified novel mutations in PDA, including the axon guidance pathway genes SLIT and ROBO, previously known to be important in embryogenesis and central nervous system development (Table 2).	('central nervous system development', 'biological_process', 'GO:0007417', ('235', '269'))	('SLIT', 'Disease', (166, 170))	('axon guidance', 'biological_process', 'GO:0007411', ('138', '151'))	('embryogenesis', 'biological_process', 'GO:0009790', ('217', '230'))	('patients', 'Species', '9606', (40, 48))	('embryogenesis', 'biological_process', 'GO:0009793', ('217', '230'))	('PDA', 'Chemical', '-', (119, 122))	('PDA', 'Gene', (119, 122))	('axon', 'cellular_component', 'GO:0030424', ('138', '142'))	('mutations', 'Var', (75, 84))	('mutations', 'Var', (106, 115))	('ROBO', 'Gene', (175, 179))	('SLIT', 'Disease', 'None', (166, 170))	('embryogenesis', 'biological_process', 'GO:0009792', ('217', '230'))
30668	26226899	SLIT2/ROBO2 inactivating mutations were present in 5% of the cohort with copy number losses in ROBO1 and SLIT2 in another 15% of the population.	('SLIT2', 'Gene', '9353', (0, 5))	('ROBO1', 'Gene', '6091', (95, 100))	('ROBO1', 'Gene', (95, 100))	('ROBO2', 'Gene', '6092', (6, 11))	('SLIT2', 'Gene', '9353', (105, 110))	('ROBO2', 'Gene', (6, 11))	('SLIT2', 'Gene', (105, 110))	('copy number losses', 'Var', (73, 91))	('SLIT2', 'Gene', (0, 5))
30669	26226899	The biological impact of SLIT/ROBO mutations in PDA is unexplored but, in other contexts, affects both MET and WNT signaling.	('PDA', 'Chemical', '-', (48, 51))	('SLIT', 'Disease', 'None', (25, 29))	('SLIT', 'Disease', (25, 29))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('affects', 'Reg', (90, 97))	('mutations', 'Var', (35, 44))
30670	26226899	In addition, novel mutations were discovered in EPC1 (3%) and ARID2 (3%), which affect chromatin modification, and in ATM (5%), with likely more of the cohort affected because of copy number variation losses in a small percentage of each gene.	('ATM', 'Gene', (118, 121))	('ARID2', 'Gene', (62, 67))	('chromatin modification', 'biological_process', 'GO:0006325', ('87', '109'))	('affect', 'Reg', (80, 86))	('chromatin modification', 'biological_process', 'GO:0016569', ('87', '109'))	('mutations', 'Var', (19, 28))	('ATM', 'Gene', '472', (118, 121))	('EPC1', 'Gene', (48, 52))	('chromatin', 'cellular_component', 'GO:0000785', ('87', '96'))	('chromatin modification', 'MPA', (87, 109))	('EPC1', 'Gene', '80314', (48, 52))	('copy number variation losses', 'Var', (179, 207))	('ARID2', 'Gene', '196528', (62, 67))
30673	26226899	Although most of the 206 rearrangements were found in the primary tumor and all metastatic sites, supporting a conserved origin, clonal evolution was also identified.	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('rearrangements', 'Var', (25, 39))
30674	26226899	Furthermore, some genetic aberrations found in metastatic sites were organ specific, including mutations in MYC and CCNE1 that were found exclusively in lung metastases, suggesting that certain subclones may evolve in an organ-specific manner.	('CCNE1', 'Gene', '898', (116, 121))	('lung metastases', 'Disease', (153, 168))	('CCNE1', 'Gene', (116, 121))	('lung metastases', 'Disease', 'MESH:D009362', (153, 168))	('MYC', 'Gene', (108, 111))	('mutations', 'Var', (95, 104))	('MYC', 'Gene', '4609', (108, 111))
30680	26226899	Sixty-six percent of IPMNs harbor mutations in GNAS.	('GNAS', 'Gene', '2778', (47, 51))	('IPMNs', 'Disease', (21, 26))	('mutations', 'Var', (34, 43))	('GNAS', 'Gene', (47, 51))
30682	26226899	These findings were corroborated through sequencing of 48 IPMNs that identified GNAS mutations in 79% of patients; only 50% harbored KRAS mutations and fewer showed loss of p16 (36%) and SMAD4 (24%).	('SMAD4', 'Gene', (187, 192))	('patients', 'Species', '9606', (105, 113))	('p16', 'Gene', '1029', (173, 176))	('GNAS', 'Gene', '2778', (80, 84))	('mutations', 'Var', (85, 94))	('KRAS', 'Gene', (133, 137))	('SMAD4', 'Gene', '4089', (187, 192))	('p16', 'Gene', (173, 176))	('GNAS', 'Gene', (80, 84))	('KRAS', 'Gene', '3845', (133, 137))	('mutations', 'Var', (138, 147))
30689	26226899	Administration of IPI-926, an inhibitor of the Shh pathway, in murine models has been shown to reduce tumor-associated stromal tissue burden, promote angiogenesis, and enhance drug delivery, and combining IPI-926 with gemcitabine resulted in doubling of overall survival compared with those mice treated with gemcitabine alone.	('mice', 'Species', '10090', (291, 295))	('gemcitabine', 'Chemical', 'MESH:C056507', (218, 229))	('enhance', 'PosReg', (168, 175))	('IPI-926', 'Var', (18, 25))	('drug delivery', 'MPA', (176, 189))	('reduce', 'NegReg', (95, 101))	('IPI-926', 'Chemical', 'MESH:C541444', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('IPI-926', 'Var', (205, 212))	('angiogenesis', 'CPA', (150, 162))	('gemcitabine', 'Chemical', 'MESH:C056507', (309, 320))	('angiogenesis', 'biological_process', 'GO:0001525', ('150', '162'))	('IPI-926', 'Chemical', 'MESH:C541444', (205, 212))	('promote', 'PosReg', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('murine', 'Species', '10090', (63, 69))	('overall survival', 'CPA', (254, 270))
30692	26226899	By administering pegylated hyaluronidase (PEGPH20), tumors showed decreased IFP, increased chemotherapy delivery, and greater patency of the vasculature that previously collapsed amid increased interstitial pressures.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('patency', 'MPA', (126, 133))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('decreased', 'NegReg', (66, 75))	('IFP', 'MPA', (76, 79))	('tumors', 'Disease', (52, 58))	('chemotherapy delivery', 'MPA', (91, 112))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('greater', 'PosReg', (118, 125))	('PEGPH20', 'Var', (42, 49))	('increased', 'PosReg', (81, 90))
30693	26226899	Furthermore, improved response rates and overall survival were seen with mouse models when combining PEGPH20 with gemcitabine compared with gemcitabine alone.	('gemcitabine', 'Chemical', 'MESH:C056507', (140, 151))	('PEGPH20', 'Var', (101, 108))	('gemcitabine', 'Chemical', 'MESH:C056507', (114, 125))	('combining', 'Interaction', (91, 100))	('mouse', 'Species', '10090', (73, 78))	('response rates', 'CPA', (22, 36))	('improved', 'PosReg', (13, 21))
30695	26226899	Although previous work showed prolonged survival in mice with PDA with pharmacologic inhibition of Shh, the somatic deletion of Shh in a murine PDA model conversely led to more aggressive pancreatic tumors with an increased metastatic burden.	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (188, 205))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (188, 204))	('murine', 'Species', '10090', (137, 143))	('mice', 'Species', '10090', (52, 56))	('deletion', 'Var', (116, 124))	('aggressive pancreatic tumors', 'Disease', 'MESH:D010190', (177, 205))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('PDA', 'Chemical', '-', (62, 65))	('more', 'PosReg', (172, 176))	('metastatic burden', 'CPA', (224, 241))	('aggressive pancreatic tumors', 'Disease', (177, 205))	('Shh', 'Gene', (128, 131))	('led to', 'Reg', (165, 171))	('PDA', 'Chemical', '-', (144, 147))
30705	26226899	In a Kras-mutant mouse model, an intense desmoplastic reaction with a prominent leukocytic infiltration was observed that was predominantly made up of Treg cells, which can abrogate the immune response, MDSCs, and TAMs and lacked effector T cells.	('immune response', 'CPA', (186, 201))	('mouse', 'Species', '10090', (17, 22))	('leukocytic infiltration', 'Disease', 'MESH:D017254', (80, 103))	('abrogate', 'NegReg', (173, 181))	('immune response', 'biological_process', 'GO:0006955', ('186', '201'))	('desmoplastic reaction', 'Disease', 'MESH:D004342', (41, 62))	('desmoplastic reaction', 'Disease', (41, 62))	('Kras-mutant', 'Var', (5, 16))	('TAMs', 'Chemical', '-', (214, 218))	('leukocytic infiltration', 'Disease', (80, 103))
30709	26226899	When GM-CSF is knocked down in Kras-mutated grafts, GR-1+ CD11b+ cells are scarce, there is an increase in CD8+ T cells, and orthotopic engrafted pancreatic tumor cells are subsequently eliminated.	('knocked down', 'Var', (15, 27))	('CD11b', 'Gene', (58, 63))	('CD11b', 'Gene', '3684', (58, 63))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (146, 162))	('increase', 'PosReg', (95, 103))	('pancreatic tumor', 'Disease', 'MESH:D010190', (146, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('CD8', 'Gene', (107, 110))	('CD8', 'Gene', '925', (107, 110))	('pancreatic tumor', 'Disease', (146, 162))
30716	26226899	The recognition that PDA has unique metabolic requirements, compared with untransformed epithelial cells, has emerged from the basic study of mutations associated with the disease (eg, KRAS, TP53) as well as direct attention paid to metabolites that promote the tumor's growth.	('mutations', 'Var', (142, 151))	('KRAS', 'Gene', '3845', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', (262, 267))	('TP53', 'Gene', '7157', (191, 195))	('TP53', 'Gene', (191, 195))	('direct attention paid', 'Phenotype', 'HP:0000736', (208, 229))	('PDA', 'Chemical', '-', (21, 24))	('associated', 'Reg', (152, 162))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('KRAS', 'Gene', (185, 189))
30722	26226899	When autophagy genes Atg5 or Atg7 were knocked down, RAS-expressing cells died in nutrient-deplete conditions; cells were found lacking substrates for tricarboxylic acid (TCA) cycle metabolism normally produced in the mitochondria.	('Atg5', 'Gene', (21, 25))	('TCA', 'Chemical', 'MESH:D014233', (171, 174))	('metabolism', 'biological_process', 'GO:0008152', ('182', '192'))	('autophagy', 'biological_process', 'GO:0016236', ('5', '14'))	('Atg7', 'Gene', (29, 33))	('TCA) cycle', 'biological_process', 'GO:0006099', ('171', '181'))	('autophagy', 'biological_process', 'GO:0006914', ('5', '14'))	('Atg7', 'Gene', '10533', (29, 33))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (151, 169))	('lacking', 'NegReg', (128, 135))	('Atg5', 'Gene', '9474', (21, 25))	('mitochondria', 'cellular_component', 'GO:0005739', ('218', '230'))	('knocked down', 'Var', (39, 51))
30728	26226899	RAS mutation has also been found to be pivotal in other metabolic pathways responsible for sustaining growth, including broadly reprogramming glucose use and glutamine metabolism to maintain optimal reduction and oxidation (REDOX) balance as well as via direct transcriptional upregulation of NRF2 pathways.	('NRF2', 'Gene', '4780', (293, 297))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('158', '178'))	('glucose use', 'MPA', (142, 153))	('RAS', 'Gene', (0, 3))	('glucose', 'Chemical', 'MESH:D005947', (142, 149))	('NRF2', 'Gene', (293, 297))	('mutation', 'Var', (4, 12))	('upregulation', 'PosReg', (277, 289))	('glutamine metabolism', 'MPA', (158, 178))	('glutamine', 'Chemical', 'MESH:D005973', (158, 167))
30734	26226899	KRAS mutations lead to a coordinated acquisition of macromolecules, via both internal scavenging, through autophagy, and from the external environment, via macropinocytosis, and then use of pathways that optimize cellular REDOX balance can be appreciated.	('internal scavenging', 'MPA', (77, 96))	('autophagy', 'biological_process', 'GO:0006914', ('106', '115'))	('acquisition', 'PosReg', (37, 48))	('mutations', 'Var', (5, 14))	('macropinocytosis', 'biological_process', 'GO:0044351', ('156', '172'))	('autophagy', 'CPA', (106, 115))	('KRAS', 'Gene', (0, 4))	('autophagy', 'biological_process', 'GO:0016236', ('106', '115'))	('KRAS', 'Gene', '3845', (0, 4))
30741	26226899	Mouse models with K-RAS mutations typically require subsequent genetic events, such as loss of tumor suppressor genes INK4A, P53, or SMAD4, to develop tumors similar to human PDA.	('SMAD4', 'Gene', (133, 138))	('loss of tumor', 'Disease', (87, 100))	('K-RAS', 'Gene', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('INK4A', 'Gene', (118, 123))	('human', 'Species', '9606', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutations', 'Var', (24, 33))	('develop', 'PosReg', (143, 150))	('K-RAS', 'Gene', '3845', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('SMAD4', 'Gene', '4089', (133, 138))	('P53', 'Gene', (125, 128))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('loss of tumor', 'Disease', 'MESH:D009369', (87, 100))	('P53', 'Gene', '7157', (125, 128))	('INK4A', 'Gene', '1029', (118, 123))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('Mouse', 'Species', '10090', (0, 5))	('PDA', 'Chemical', '-', (175, 178))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))
30742	26226899	Finding that loss of SMAD4 has a greater propensity for metastatic spread is an example of how genetic sequencing may help tailor future therapy to the individual.	('metastatic spread', 'CPA', (56, 73))	('loss', 'Var', (13, 17))	('SMAD4', 'Gene', '4089', (21, 26))	('SMAD4', 'Gene', (21, 26))
30743	26226899	More than 1500 mutations have been identified to occur in PDA; focusing on the core signaling cascades these affect may show greater promise than focusing on individual mutations.	('mutations', 'Var', (15, 24))	('core', 'cellular_component', 'GO:0019013', ('79', '83'))	('PDA', 'Disease', (58, 61))	('PDA', 'Chemical', '-', (58, 61))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))
30745	26226899	PanIns are precursor lesions that have tight genetic linkage with PDA; IPMNs are less common PDA precursor lesions found to have frequent mutation of GNAS and slightly better outcomes, suggesting a potential divergent phenotype.	('PDA', 'Chemical', '-', (93, 96))	('GNAS', 'Gene', (150, 154))	('mutation', 'Var', (138, 146))	('IPMNs', 'Disease', (71, 76))	('GNAS', 'Gene', '2778', (150, 154))	('PDA', 'Chemical', '-', (66, 69))
30749	28634187	REPLY: Telomere length and pancreatic cancer risk:Letter Our report showed that genetic risk scores computed from polymorphic variants previously associated with inter-individual variation in leukocyte telomere length are not associated with risk of pancreatic cancer (pancreatic ductal adenocarcinoma).	('pancreatic cancer', 'Disease', 'MESH:D010190', (250, 267))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('variation', 'Var', (179, 188))	('pancreatic cancer', 'Disease', (27, 44))	('associated', 'Reg', (226, 236))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (250, 267))	('pancreatic cancer', 'Disease', 'MESH:D010190', (27, 44))	('Telomere', 'cellular_component', 'GO:0000781', ('7', '15'))	('telomere', 'cellular_component', 'GO:0000781', ('202', '210'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (27, 44))	('Telomere', 'cellular_component', 'GO:0005696', ('7', '15'))	('telomere', 'cellular_component', 'GO:0005696', ('202', '210'))	('pancreatic cancer', 'Disease', (250, 267))	('pancreatic ductal adenocarcinoma', 'Disease', (269, 301))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (269, 301))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (269, 301))
30750	28634187	Consistent with our finding, a recent meta-analysis that used methods similar to ours (published while our manuscript was under review) found no association between genetically predicted telomere length and pancreatic cancer risk.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (207, 224))	('telomere length', 'Var', (187, 202))	('telomere', 'cellular_component', 'GO:0005696', ('187', '195'))	('pancreatic cancer', 'Disease', (207, 224))	('pancreatic cancer', 'Disease', 'MESH:D010190', (207, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('telomere', 'cellular_component', 'GO:0000781', ('187', '195'))
30751	28634187	We are not aware of any other published reports on the association between genetically predicted telomere length and pancreatic cancer risk.	('telomere', 'cellular_component', 'GO:0005696', ('97', '105'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('pancreatic cancer', 'Disease', (117, 134))	('telomere', 'Var', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('telomere', 'cellular_component', 'GO:0000781', ('97', '105'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))
30752	28634187	The author referred to a study by Lynch and colleagues and others and concluded that longer telomere length is associated with an increase in risk of pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('telomere', 'cellular_component', 'GO:0000781', ('92', '100'))	('longer telomere length', 'Var', (85, 107))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('telomere', 'cellular_component', 'GO:0005696', ('92', '100'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('pancreatic cancer', 'Disease', (150, 167))
30754	28634187	recently performed a pooled analysis of five prospective studies in the United States and found that short, rather than long, leukocyte telomere length is associated with an increase in risk of pancreatic cancer in a dose-response fashion.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (194, 211))	('short', 'Var', (101, 106))	('telomere', 'cellular_component', 'GO:0000781', ('136', '144'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (194, 211))	('pancreatic cancer', 'Disease', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('telomere', 'cellular_component', 'GO:0005696', ('136', '144'))
30761	26919188	rpS6 phosphorylation deficiency failed to block Akttg-induced hypertrophy and aneuploidy in beta-cells, as well as the improved glucose homeostasis, indicating that Akt carries out these functions independently of rpS6 phosphorylation.	('glucose homeostasis', 'biological_process', 'GO:0042593', ('128', '147'))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('aneuploidy', 'Disease', 'MESH:D000782', (78, 88))	('glucose homeostasis', 'Disease', 'MESH:D018149', (128, 147))	('hypertrophy', 'Disease', (62, 73))	('glucose homeostasis', 'Disease', (128, 147))	('hypertrophy', 'Disease', 'MESH:D006984', (62, 73))	('deficiency', 'Var', (21, 31))	('phosphorylation', 'biological_process', 'GO:0016310', ('219', '234'))	('improved', 'PosReg', (119, 127))	('aneuploidy', 'Disease', (78, 88))
30762	26919188	In contrast, rpS6 phosphorylation deficiency efficiently restrained the reduction in nuclear localization of the cell cycle inhibitor p27, as well as the development of Akttg-driven hyperplasia and tumor formation in beta-cells.	('reduction', 'NegReg', (72, 81))	('cell cycle', 'biological_process', 'GO:0007049', ('113', '123'))	('hyperplasia', 'Disease', 'MESH:D006965', (182, 193))	('deficiency', 'Var', (34, 44))	('p27', 'Gene', (134, 137))	('p27', 'Gene', '12576', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('rpS6', 'Protein', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('formation', 'biological_process', 'GO:0009058', ('204', '213'))	('restrained', 'NegReg', (57, 67))	('localization', 'biological_process', 'GO:0051179', ('93', '105'))	('hyperplasia', 'Disease', (182, 193))	('phosphorylation deficiency', 'Var', (18, 44))	('tumor', 'Disease', (198, 203))	('nuclear localization', 'MPA', (85, 105))	('phosphorylation', 'biological_process', 'GO:0016310', ('18', '33'))
30763	26919188	In vitro experiments with Akttg and rpS6P-/-;Akttg fibroblasts demonstrated that rpS6 phosphorylation deficiency leads to reduced translation fidelity, which might underlie its anti-tumorigenic effect in the pancreas.	('translation', 'biological_process', 'GO:0006412', ('130', '141'))	('phosphorylation', 'biological_process', 'GO:0016310', ('86', '101'))	('rat', 'Species', '10116', (70, 73))	('tumor', 'Disease', (182, 187))	('translation fidelity', 'MPA', (130, 150))	('deficiency', 'Var', (102, 112))	('phosphorylation', 'MPA', (86, 101))	('rpS6', 'Gene', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('reduced', 'NegReg', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
30764	26919188	However, the role of translation infidelity in tumor suppression cannot simply be inferred from this heterologous experimental model, as rpS6 phosphorylation deficiency unexpectedly elevated the resistance of Akttg fibroblasts to proteotoxic, genotoxic as well as autophagic stresses.	('deficiency', 'Var', (158, 168))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('phosphorylation', 'biological_process', 'GO:0016310', ('142', '157'))	('phosphorylation', 'CPA', (142, 157))	('resistance', 'MPA', (195, 205))	('rpS6', 'Gene', (137, 141))	('elevated', 'PosReg', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('translation', 'biological_process', 'GO:0006412', ('21', '32'))
30765	26919188	In contrast, rpS6P-/- fibroblasts exhibited a higher sensitivity to these stresses upon constitutive expression of oncogenic Kras.	('higher', 'PosReg', (46, 52))	('rpS6P-/-', 'Var', (13, 21))	('expression', 'Species', '29278', (101, 111))	('sensitivity', 'MPA', (53, 64))	('Kras', 'Gene', (125, 129))	('Kras', 'Gene', '16653', (125, 129))
30766	26919188	The latter result provides a possible mechanistic explanation for the ability of rpS6 phosphorylation deficiency to enhance DNA damage and protect mice from Kras-induced neoplastic transformation in the exocrine pancreas.	('DNA damage', 'MPA', (124, 134))	('mice', 'Species', '10090', (147, 151))	('phosphorylation', 'biological_process', 'GO:0016310', ('86', '101'))	('enhance', 'PosReg', (116, 123))	('deficiency', 'Var', (102, 112))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('Kras', 'Gene', (157, 161))	('Kras', 'Gene', '16653', (157, 161))	('rpS6', 'Gene', (81, 85))	('phosphorylation deficiency', 'Var', (86, 112))
30784	26919188	Moreover, rpS6P-/- mice have diminished levels of pancreatic insulin, hypoinsulinemia, impaired glucose tolerance, reduced muscle energy content, compromised compensatory renal hypertrophy and impaired parathyroid hormone secretion after experimental uremia.	('renal hypertrophy', 'Disease', (171, 188))	('reduced', 'NegReg', (115, 122))	('hypoinsulinemia', 'Phenotype', 'HP:0040216', (70, 85))	('insulin', 'molecular_function', 'GO:0016088', ('61', '68'))	('impaired glucose tolerance', 'Disease', 'MESH:D018149', (87, 113))	('uremia', 'Disease', 'MESH:D014511', (251, 257))	('impaired parathyroid hormone secretion', 'Disease', (193, 231))	('rpS6P-/-', 'Var', (10, 18))	('renal hypertrophy', 'Phenotype', 'HP:0000105', (171, 188))	('muscle energy content', 'MPA', (123, 144))	('uremia', 'Disease', (251, 257))	('impaired glucose tolerance', 'Disease', (87, 113))	('parathyroid hormone secretion', 'biological_process', 'GO:0035898', ('202', '231'))	('mice', 'Species', '10090', (19, 23))	('impaired parathyroid hormone secretion', 'Disease', 'MESH:D010279', (193, 231))	('diminished levels of pancreatic insulin', 'Phenotype', 'HP:0006274', (29, 68))	('pancreatic insulin, hypoinsulinemia', 'Disease', 'MESH:D010195', (50, 85))	('diminished', 'NegReg', (29, 39))	('renal hypertrophy', 'Disease', 'MESH:D006984', (171, 188))	('impaired glucose tolerance', 'Phenotype', 'HP:0040270', (87, 113))	('impaired parathyroid hormone secretion', 'Phenotype', 'HP:0000829', (193, 231))	('compromised', 'NegReg', (146, 157))
30785	26919188	Interestingly, we have recently shown that rpS6 phosphorylation deficiency enhances Kras-induced DNA damage in the exocrine pancreas and consequently boosts p53-mediated tumor suppression.	('phosphorylation', 'Protein', (48, 63))	('boosts', 'PosReg', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('rpS6 phosphorylation', 'Protein', (43, 63))	('deficiency', 'Var', (64, 74))	('Kras', 'Gene', (84, 88))	('Kras', 'Gene', '16653', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('p53', 'Gene', '22060', (157, 160))	('enhances', 'PosReg', (75, 83))	('tumor', 'Disease', (170, 175))	('p53', 'Gene', (157, 160))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))
30791	26919188	Mechanistically, rpS6 phosphorylation deficiency failed to protect beta-cells from Akttg induced aneuploidy, and therefore, does not block insulinomas development by interfering with their ploidy.	('insulinoma', 'Phenotype', 'HP:0012197', (139, 149))	('deficiency', 'Var', (38, 48))	('aneuploidy', 'Disease', (97, 107))	('block insulinomas', 'Disease', 'MESH:D007340', (133, 150))	('block insulinomas', 'Disease', (133, 150))	('rpS6', 'Protein', (17, 21))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('interfering', 'NegReg', (166, 177))	('aneuploidy', 'Disease', 'MESH:D000782', (97, 107))	('ploidy', 'MPA', (189, 195))
30792	26919188	Contrarily, immortalized rpS6P-/- MEFs exhibit impaired translation fidelity, even in the presence of Akttg, potentially contributing to the antitumorigenic effect of rpS6 phosphorylation deficiency.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('translation', 'biological_process', 'GO:0006412', ('56', '67'))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('MEFs', 'CellLine', 'CVCL:9115', (34, 38))	('rpS6', 'Protein', (167, 171))	('phosphorylation', 'biological_process', 'GO:0016310', ('172', '187'))	('impaired', 'NegReg', (47, 55))	('tumor', 'Disease', (145, 150))	('rpS6P-/- MEFs', 'Var', (25, 38))	('translation fidelity', 'MPA', (56, 76))	('phosphorylation deficiency', 'Var', (172, 198))
30796	26919188	Mice were genotyped by PCR analysis using specific primers for myr-Akt: (5' CAGGCAAGTGTTTGGAAACTGC 3' and 5' AAAGGTCTTCATGGTGGCACCGTC 3') as well as for the rpS6P-/- and rpS6P+/+ alleles.	('rpS6P+/+', 'Var', (170, 178))	('rpS6P-/-', 'Var', (157, 165))	('Mice', 'Species', '10090', (0, 4))
30829	26919188	Cloning of mouse rpS6 coding sequence with different residues replacing the phosphorylatable serine residues into pHAGE was carried out in multiple steps: a) generation of PCR fragments encoding rpS6 with 5 Serine [5S], 5 Alanine [5A], or 5 Aspartic acid [5D; b) cloning of these fragment into pcDNA3.1; c) a 800 bp PCR fragments generated using each of the pcDNA3.1 cloned rpS6 variants was digested with BglII and AgeI and ligated in between BglII and AgeI sites in pEGFP-N1 (Clontech) to yield GFP open reading frame (ORF) followed in frame by the carboxy terminus of the rpS6 variant.	('rat', 'Species', '10116', (162, 165))	('mouse', 'Species', '10090', (11, 16))	('rpS6', 'Gene', (575, 579))	('variants', 'Var', (379, 387))	('variant', 'Var', (580, 587))	('serine', 'Chemical', 'MESH:D012694', (93, 99))	('rat', 'Species', '10116', (334, 337))	('rpS6', 'Gene', (374, 378))
30849	26919188	rpS6 phosphorylation deficient mice exhibit decreased beta-cell size and impaired glucose tolerance.	('impaired glucose tolerance', 'Disease', 'MESH:D018149', (73, 99))	('impaired glucose tolerance', 'Disease', (73, 99))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('mice', 'Species', '10090', (31, 35))	('beta-cell size', 'CPA', (54, 68))	('impaired glucose tolerance', 'Phenotype', 'HP:0040270', (73, 99))	('rpS6', 'Protein', (0, 4))	('phosphorylation deficient', 'Var', (5, 30))	('decreased beta-cell', 'Phenotype', 'HP:0006274', (44, 63))	('decreased', 'NegReg', (44, 53))
30852	26919188	Morphometric analysis confirmed the opposite effects of rpS6 phosphorylation deficiency and constitutive Akt1 activity on beta-cell size (smaller beta-cells in rpS6P-/- mice and larger beta-cells in Akttg mice, Fig 1A and 1B, as well as).	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))	('deficiency', 'Var', (77, 87))	('rpS6P-/-', 'Var', (160, 168))	('rpS6', 'Gene', (56, 60))	('activity', 'MPA', (110, 118))	('smaller', 'NegReg', (138, 145))	('mice', 'Species', '10090', (205, 209))	('mice', 'Species', '10090', (169, 173))	('Akt1', 'Gene', (105, 109))	('larger', 'PosReg', (178, 184))
30853	26919188	It has previously been reported that the small-cell-size phenotype of rpS6P-/- MEFs is accompanied by accelerated proliferation rate, relative to WT MEFs.	('rat', 'Species', '10116', (108, 111))	('rpS6P-/-', 'Var', (70, 78))	('proliferation rate', 'CPA', (114, 132))	('rat', 'Species', '10116', (128, 131))	('accelerated', 'PosReg', (102, 113))	('MEFs', 'CellLine', 'CVCL:9115', (79, 83))	('MEFs', 'CellLine', 'CVCL:9115', (149, 153))	('rat', 'Species', '10116', (121, 124))
30854	26919188	Likewise, the engagement of rpS6P-/- beta-cells in the cell cycle, as exemplified by the percentage of Ki67-positive cells, significantly exceeds that of their WT counterparts.	('rpS6P-/-', 'Var', (28, 36))	('cell cycle', 'biological_process', 'GO:0007049', ('55', '65'))	('Ki67', 'Gene', '17345', (103, 107))	('cell cycle', 'CPA', (55, 65))	('Ki67', 'Gene', (103, 107))
30855	26919188	Interestingly, beta-cell replication was further increased in rpS6P-/-;Akttg mice (Fig 1D).	('rpS6P-/-', 'Var', (62, 70))	('increased', 'PosReg', (49, 58))	('mice', 'Species', '10090', (77, 81))	('beta-cell replication', 'CPA', (15, 36))
30856	26919188	The reciprocal impact of rpS6 phosphorylation deficiency and constitutively active myr-Akt1 on beta-cell size is reflected in opposite effects on glucose tolerance (Fig 1E) and glucose-stimulated insulin secretion (Fig 1F), namely impaired in rpS6P-/- while improved in Akttg, relative to WT.	('glucose tolerance', 'MPA', (146, 163))	('phosphorylation', 'biological_process', 'GO:0016310', ('30', '45'))	('glucose', 'Chemical', 'MESH:D005947', (146, 153))	('glucose', 'Chemical', 'MESH:D005947', (177, 184))	('insulin secretion', 'biological_process', 'GO:0030073', ('196', '213'))	('improved', 'PosReg', (258, 266))	('impaired', 'NegReg', (231, 239))	('rpS6P-/-', 'Var', (243, 251))	('glucose-stimulated insulin secretion', 'MPA', (177, 213))	('insulin', 'molecular_function', 'GO:0016088', ('196', '203'))	('rpS6', 'Gene', (25, 29))	('deficiency', 'Var', (46, 56))
30857	26919188	In accordance with the dominance of constitutively active myr-Akt1 over rpS6 phosphorylation deficiency on beta-cell size, the deficiency of rpS6 phosphorylation failed to correct glucose tolerance or insulin secretion in Akttg mice.	('insulin secretion', 'biological_process', 'GO:0030073', ('201', '218'))	('deficiency', 'Var', (127, 137))	('glucose tolerance or insulin secretion', 'Disease', (180, 218))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('phosphorylation', 'biological_process', 'GO:0016310', ('146', '161'))	('correct', 'Reg', (172, 179))	('glucose tolerance or insulin secretion', 'Disease', 'MESH:D018149', (180, 218))	('insulin', 'molecular_function', 'GO:0016088', ('201', '208'))	('mice', 'Species', '10090', (228, 232))
30858	26919188	In fact, rpS6 deficiency further exaggerated, rather than inhibited, insulin secretion in Akttg mice (Fig 1F).	('rat', 'Species', '10116', (46, 49))	('mice', 'Species', '10090', (96, 100))	('rpS6', 'Gene', (9, 13))	('insulin', 'molecular_function', 'GO:0016088', ('69', '76'))	('exaggerated', 'PosReg', (33, 44))	('rat', 'Species', '10116', (39, 42))	('insulin secretion', 'biological_process', 'GO:0030073', ('69', '86'))	('deficiency', 'Var', (14, 24))	('insulin secretion', 'MPA', (69, 86))
30861	26919188	Conceivably, the apparent similar beta-cell area in WT and rpS6P-/- mice (Fig 1G and), despite the small-cell-size phenotype of rpS6P-/- beta-cells, reflects an elevation in the number of the latters, due to their enhanced proliferation rate (Fig 1D).	('proliferation rate', 'CPA', (223, 241))	('mice', 'Species', '10090', (68, 72))	('elevation', 'PosReg', (161, 170))	('beta-cell area', 'CPA', (34, 48))	('rat', 'Species', '10116', (237, 240))	('rpS6P-/-', 'Var', (59, 67))	('rat', 'Species', '10116', (230, 233))	('enhanced', 'PosReg', (214, 222))	('rpS6P-/-', 'Var', (128, 136))
30865	26919188	In order to examine whether augmented phosphorylation of rpS6 is a byproduct or, alternatively, a prerequisite for the tumorigenic process, we searched for insulinoma in rpS6P-/-;Akttg mice.	('tumor', 'Disease', (119, 124))	('rpS6P-/-', 'Var', (170, 178))	('insulinoma', 'Phenotype', 'HP:0012197', (156, 166))	('insulinoma', 'Disease', (156, 166))	('insulinoma', 'Disease', 'MESH:D007340', (156, 166))	('mice', 'Species', '10090', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
30868	26919188	This observation accords with our earlier report on enhanced proliferation of rpS6P-/- MEFs.	('enhanced', 'PosReg', (52, 60))	('rat', 'Species', '10116', (68, 71))	('rpS6P-/-', 'Var', (78, 86))	('MEFs', 'CellLine', 'CVCL:9115', (87, 91))	('proliferation', 'CPA', (61, 74))
30872	26919188	Consistently with this report, fewer Akttg beta-cells had nuclear p27.	('Akttg beta-cells', 'CPA', (37, 53))	('p27', 'Gene', (66, 69))	('p27', 'Gene', '12576', (66, 69))	('nuclear', 'Var', (58, 65))
30873	26919188	Strikingly, rpS6 phosphorylation deficiency rescued nuclear localization of p27 in rpS6P-/-;Akttg relative to Akttg beta-cells cells (Fig 2E and S4 Fig).	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('rescued', 'PosReg', (44, 51))	('p27', 'Gene', '12576', (76, 79))	('nuclear localization', 'MPA', (52, 72))	('rpS6', 'Protein', (12, 16))	('localization', 'biological_process', 'GO:0051179', ('60', '72'))	('p27', 'Gene', (76, 79))	('deficiency', 'Var', (33, 43))	('rpS6P-/-', 'Var', (83, 91))
30876	26919188	One explanation for the neutralizing effect of the mutations in rpS6 in aging mice might be phenotypic changes that lead to a general loss of the dominance of myr-Akt over rpS6 phosphorylation deficiency.	('phosphorylation', 'biological_process', 'GO:0016310', ('177', '192'))	('mutations', 'Var', (51, 60))	('rpS6', 'Gene', (64, 68))	('aging', 'biological_process', 'GO:0007568', ('72', '77'))	('loss', 'NegReg', (134, 138))	('dominance', 'MPA', (146, 155))	('mice', 'Species', '10090', (78, 82))
30877	26919188	However, comparing the beta-cell size at different ages disproved this hypothesis, since the dominance of Akttg over rpS6 phosphorylation deficiency on the cell size phenotype was preserved in aging mice (Figs 2F, 1B and 1C and S3 Fig [see staining for insulin]).	('rpS6', 'Gene', (117, 121))	('mice', 'Species', '10090', (199, 203))	('phosphorylation', 'biological_process', 'GO:0016310', ('122', '137'))	('insulin', 'molecular_function', 'GO:0016088', ('253', '260'))	('deficiency', 'Var', (138, 148))	('aging', 'biological_process', 'GO:0007568', ('193', '198'))
30880	26919188	Interestingly, this inherent hepatic behavior relies on Akt, as pharmacological inhibition of Akt reduced the frequency of cytokinesis failure events in rat liver.	('Akt', 'Gene', (94, 97))	('rat', 'Species', '10116', (153, 156))	('reduced', 'NegReg', (98, 105))	('inhibition', 'Var', (80, 90))	('frequency', 'MPA', (110, 119))	('cytokinesis', 'biological_process', 'GO:0000910', ('123', '134'))
30883	26919188	We, therefore, monitored DNA content in beta-cells of Akttg and rpS6P-/- mice and examined how ploidy is affected by rpS6 phosphorylation deficiency.	('rpS6', 'Gene', (117, 121))	('mice', 'Species', '10090', (73, 77))	('phosphorylation', 'biological_process', 'GO:0016310', ('122', '137'))	('DNA content', 'MPA', (25, 36))	('deficiency', 'Var', (138, 148))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))
30884	26919188	As shown in Fig 3A, dissociated islet cells from rpS6P-/- and wild type mice displayed similar amounts of DNA, as assessed by FACS after Heochst staining.	('FACS', 'Gene', (126, 130))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('mice', 'Species', '10090', (72, 76))	('rpS6P-/-', 'Var', (49, 57))	('FACS', 'Gene', '14081', (126, 130))
30885	26919188	In contrast, beta-cells from HA+-Akttg mice were tetraploid on average, but displayed a wide distribution in the intensity of Hoechst staining (Fig 3B), suggesting excess or lacking chromosomes in many cells.	('lacking', 'NegReg', (174, 181))	('chromosomes', 'CPA', (182, 193))	('Hoechst', 'Chemical', '-', (126, 133))	('mice', 'Species', '10090', (39, 43))	('HA+-Akttg', 'Var', (29, 38))
30890	26919188	Strikingly, islet cells of rpS6P-/-;Akttg mice were aneuploid to a similar extent as cells from Akttg mice (Fig 3C).	('mice', 'Species', '10090', (102, 106))	('aneuploid', 'Disease', 'MESH:D000782', (52, 61))	('mice', 'Species', '10090', (42, 46))	('rpS6P-/-', 'Var', (27, 35))	('aneuploid', 'Disease', (52, 61))
30892	26919188	Combined with the inhibitory effects of rpS6 mutants on insulinoma development, this finding indicates that aneuploidy is not sufficient for malignant transformation of beta-cells, and that deficient phosphorylation of rpS6 does not prevent insulinomas development by interfering with ploidy.	('insulinomas', 'Disease', (241, 252))	('insulinoma', 'Disease', (56, 66))	('ploidy', 'MPA', (285, 291))	('insulinoma', 'Disease', 'MESH:D007340', (56, 66))	('aneuploidy', 'Disease', (108, 118))	('insulinoma', 'Phenotype', 'HP:0012197', (56, 66))	('interfering', 'NegReg', (268, 279))	('aneuploidy', 'Disease', 'MESH:D000782', (108, 118))	('insulinomas', 'Disease', 'MESH:D007340', (241, 252))	('insulinoma', 'Phenotype', 'HP:0012197', (241, 251))	('deficient', 'Var', (190, 199))	('phosphorylation', 'biological_process', 'GO:0016310', ('200', '215'))	('insulinoma', 'Disease', (241, 251))	('insulinoma', 'Disease', 'MESH:D007340', (241, 251))	('rpS6', 'Gene', (219, 223))
30893	26919188	The protection against the development of Akt-induced insulinoma in rpS6P-/-;Akttg mice could not be explained by either restrained proliferation rate or altered ploidy of beta-cells.	('rat', 'Species', '10116', (146, 149))	('rat', 'Species', '10116', (139, 142))	('mice', 'Species', '10090', (83, 87))	('insulinoma', 'Phenotype', 'HP:0012197', (54, 64))	('rpS6P-/-', 'Var', (68, 76))	('insulinoma', 'Disease', 'MESH:D007340', (54, 64))	('insulinoma', 'Disease', (54, 64))
30895	26919188	We have previously shown that the development of precursor lesions for pancreatic ductal adenocarcinoma (PanIN lesions), in response to either chemical carcinogenesis or expression of transgenic mutant Kras, is greatly attenuated in rpS6P-/- mice.	('attenuated', 'NegReg', (219, 229))	('pancreatic ductal adenocarcinoma', 'Disease', (71, 103))	('carcinogenesis', 'Disease', (152, 166))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (71, 103))	('transgenic', 'Species', '10090', (184, 194))	('PanIN lesion', 'Disease', (105, 117))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (71, 103))	('Kras', 'Gene', (202, 206))	('Kras', 'Gene', '16653', (202, 206))	('PanIN lesion', 'Disease', 'MESH:D051437', (105, 117))	('expression', 'Species', '29278', (170, 180))	('mutant', 'Var', (195, 201))	('carcinogenesis', 'Disease', 'MESH:D063646', (152, 166))	('mice', 'Species', '10090', (242, 246))
30896	26919188	Furthermore, acinar to ductal metaplasia regions in rpS6P-/- mice displayed elevated DNA damage markers, specifically responding to double strand breaks.	('responding', 'Reg', (118, 128))	('rpS6P-/-', 'Var', (52, 60))	('elevated', 'PosReg', (76, 84))	('mice', 'Species', '10090', (61, 65))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('metaplasia', 'biological_process', 'GO:0036074', ('30', '40'))	('double strand breaks', 'MPA', (132, 152))	('acinar to ductal metaplasia regions', 'CPA', (13, 48))	('DNA damage markers', 'MPA', (85, 103))
30897	26919188	Hence, protection from cancer in rpS6P-/- mice was likely due to enhanced elimination of damaged cells.	('elimination', 'CPA', (74, 85))	('mice', 'Species', '10090', (42, 46))	('rpS6P-/-', 'Var', (33, 41))	('cancer', 'Disease', (23, 29))	('enhanced', 'PosReg', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
30901	26919188	Fig 4B demonstrates an enhanced rate of proliferation, as inferred from the population doubling time (td), in RasG12D expressing MEFs (13.4 h), relative to that of WT MEFs (td = 25.4 h, Fig 5B).	('enhanced', 'PosReg', (23, 31))	('MEFs', 'CellLine', 'CVCL:9115', (129, 133))	('MEFs', 'CellLine', 'CVCL:9115', (167, 171))	('RasG12D', 'Var', (110, 117))	('rat', 'Species', '10116', (32, 35))	('rat', 'Species', '10116', (47, 50))	('proliferation', 'CPA', (40, 53))	('rat', 'Species', '10116', (14, 17))	('MEFs', 'Var', (129, 133))
30903	26919188	Interestingly, when rpS6P-/-;RasG12D MEFs were subjected to such a treatment they exhibited enhanced sensitivity, relative to RasG12D MEFs, as exemplified by the reduced appearance of cleaved caspase 3 (Fig 4C).	('MEFs', 'CellLine', 'CVCL:9115', (37, 41))	('reduced', 'NegReg', (162, 169))	('MEFs', 'CellLine', 'CVCL:9115', (134, 138))	('RasG12D', 'Var', (29, 36))	('sensitivity', 'MPA', (101, 112))	('cleaved caspase', 'MPA', (184, 199))	('rpS6P-/-;RasG12D', 'Var', (20, 36))	('enhanced', 'PosReg', (92, 100))
30904	26919188	These results are in  good agreement with the increased DNA damage documented in PanIN lesions of rpS6P-/-;RasG12D vs. RasG12D mice, and support the hypothesis that absence of rpS6 phosphorylation may negate Kras-driven cancer development by enhancing tumor suppressive DNA damage.	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('DNA', 'cellular_component', 'GO:0005574', ('270', '273'))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('PanIN lesion', 'Disease', 'MESH:D051437', (81, 93))	('Kras', 'Gene', (208, 212))	('phosphorylation', 'biological_process', 'GO:0016310', ('181', '196'))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('DNA damage', 'MPA', (56, 66))	('Kras', 'Gene', '16653', (208, 212))	('absence', 'Var', (165, 172))	('cancer', 'Disease', (220, 226))	('enhancing', 'PosReg', (242, 251))	('mice', 'Species', '10090', (127, 131))	('rpS6', 'Protein', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('increased', 'PosReg', (46, 55))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('rpS6P-/-;RasG12D', 'Var', (98, 114))	('negate', 'NegReg', (201, 207))	('PanIN lesion', 'Disease', (81, 93))	('tumor', 'Disease', (252, 257))
30905	26919188	This hypersensitivity is not confined just to genotoxic stress, as rpS6 phosphorylation deficiency rendered Kras-expressing MEFs more sensitive to a proteasome inhibitor, GM132, that blocks both normal protein turnover and removal of aberrant proteins (Fig 4D).	('protein turnover', 'MPA', (202, 218))	('more', 'PosReg', (129, 133))	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('GM132', 'Chemical', '-', (171, 176))	('proteasome', 'molecular_function', 'GO:0004299', ('149', '159'))	('proteasome', 'cellular_component', 'GO:0000502', ('149', '159'))	('rpS6', 'Gene', (67, 71))	('sensitive', 'MPA', (134, 143))	('hypersensitivity', 'Disease', 'MESH:D004342', (5, 21))	('hypersensitivity', 'biological_process', 'GO:0002524', ('5', '21'))	('Kras', 'Gene', '16653', (108, 112))	('hypersensitivity', 'Disease', (5, 21))	('Kras', 'Gene', (108, 112))	('MEFs', 'CellLine', 'CVCL:9115', (124, 128))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('deficiency', 'Var', (88, 98))
30906	26919188	rpS6 phosphorylation deficiency exerts a wide range of effects that include reduced cell size, increased proliferation rate, reduced insulin secretion from beta cells, tumor suppression in pancreata expressing Akttg or RasG12D (Fig 2C and), and altered apoptotic response to proteotoxic and genotoxic stressors in fibroblasts (Fig 4).	('apoptotic', 'CPA', (253, 262))	('tumor', 'Disease', (168, 173))	('insulin', 'molecular_function', 'GO:0016088', ('133', '140'))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('insulin secretion from beta cells', 'MPA', (133, 166))	('rat', 'Species', '10116', (119, 122))	('reduced', 'NegReg', (125, 132))	('deficiency', 'Var', (21, 31))	('rat', 'Species', '10116', (112, 115))	('reduced', 'NegReg', (76, 83))	('altered', 'Reg', (245, 252))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('insulin secretion', 'biological_process', 'GO:0030073', ('133', '150'))	('proliferation rate', 'CPA', (105, 123))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('increased', 'PosReg', (95, 104))	('rpS6', 'Gene', (0, 4))	('cell size', 'CPA', (84, 93))
30907	26919188	First, we infected HEK293 cells with lentiviral vectors expressing three different rpS6-GFP chimeric proteins: pS65S-GFP (rpS6 with 5 phosphorylatable serine residues, equivalent to WT), pS65A-GFP (S to A replacement of all phosphorylatable serine residues, equivalent to rpS6P-/- mutant) and pS65D-GFP (S to D replacement of all phosphorylatable serine residues, phosphomimetic mutations).	('HEK293', 'CellLine', 'CVCL:0045', (19, 25))	('serine', 'Chemical', 'MESH:D012694', (151, 157))	('pS65A-GFP', 'Var', (187, 196))	('serine', 'Chemical', 'MESH:D012694', (347, 353))	('serine', 'Chemical', 'MESH:D012694', (241, 247))	('pS65S-GFP', 'Var', (111, 120))
30912	26919188	A higher rate of proliferation was observed in rpS6P-/-, relative to WT MEFs, in a close agreement with that observed in beta-cells of these genotypes (compare Fig 5B with Fig 2D).	('proliferation', 'CPA', (17, 30))	('higher', 'PosReg', (2, 8))	('rat', 'Species', '10116', (9, 12))	('rpS6P-/-', 'Var', (47, 55))	('MEFs', 'CellLine', 'CVCL:9115', (72, 76))	('rat', 'Species', '10116', (24, 27))
30913	26919188	Moreover, the proliferation of rpS6P-/-;Akttg MEFs was attenuated relative to Akttg immortalized MEFs (Fig 5B), although the effect was markedly less than that observed for beta-cells from 12-mo-old mice (compare Fig 5B with Fig 2D).	('mice', 'Species', '10090', (199, 203))	('proliferation', 'CPA', (14, 27))	('attenuated', 'NegReg', (55, 65))	('rpS6P-/-;Akttg', 'Var', (31, 45))	('rat', 'Species', '10116', (21, 24))	('Akttg', 'Var', (40, 45))	('MEFs', 'CellLine', 'CVCL:9115', (97, 101))	('MEFs', 'CellLine', 'CVCL:9115', (46, 50))
30916	26919188	Since primary rpS6P-/- MEFs have higher rates of both proliferation and protein synthesis, we hypothesized that the fidelity of the translation in this genotype might be impaired.	('protein synthesis', 'MPA', (72, 89))	('MEFs', 'CellLine', 'CVCL:9115', (23, 27))	('higher', 'PosReg', (33, 39))	('translation', 'biological_process', 'GO:0006412', ('132', '143'))	('rat', 'Species', '10116', (40, 43))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('rat', 'Species', '10116', (61, 64))	('rpS6P-/- MEFs', 'Var', (14, 27))	('proliferation', 'CPA', (54, 67))	('protein synthesis', 'biological_process', 'GO:0006412', ('72', '89'))	('rates', 'MPA', (40, 45))
30918	26919188	Although the difference between the two genotypes was statistically insignificant, rpS6P-/- MEFs displayed a tendency toward a higher rate of protein synthesis, which is consistent with the faster proliferation (Fig 5C and 5D).	('protein synthesis', 'MPA', (142, 159))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('rate', 'MPA', (134, 138))	('rat', 'Species', '10116', (204, 207))	('protein synthesis', 'biological_process', 'GO:0006412', ('142', '159'))	('rpS6P-/- MEFs', 'Var', (83, 96))	('higher', 'PosReg', (127, 133))	('rat', 'Species', '10116', (134, 137))	('MEFs', 'CellLine', 'CVCL:9115', (92, 96))
30919	26919188	To test if this tendency might correlate with decrease translation fidelity, we transfected cells with two luciferase reporters: a) Fluc(R218S), in which the arginine at the active-site (position 218) was mutated into serine that renders the resultant mutant protein devoid of enzymatic activity, and b) Fluc(Stop) that has leucine at position 210 replaced with a stop codon, which leads to the synthesis of a truncated and enzymatically inactive protein product.	('serine', 'Chemical', 'MESH:D012694', (218, 224))	('R218S', 'Mutation', 'p.R218S', (137, 142))	('synthesis', 'biological_process', 'GO:0009058', ('395', '404'))	('protein', 'cellular_component', 'GO:0003675', ('259', '266'))	('leucine at', 'Var', (324, 334))	('leucine', 'Chemical', 'MESH:D007930', (324, 331))	('mutated', 'Var', (205, 212))	('arginine', 'Chemical', 'MESH:D001120', (158, 166))	('mutant', 'Var', (252, 258))	('protein', 'cellular_component', 'GO:0003675', ('447', '454'))	('protein', 'Protein', (259, 266))	('leads to', 'Reg', (382, 390))	('synthesis of a truncated', 'MPA', (395, 419))	('translation', 'biological_process', 'GO:0006412', ('55', '66'))
30920	26919188	Fig 5E shows that rpS6 phosphorylation deficiency significantly reduced translation fidelity, as judged by the increased luciferase activity if transfected with Fluc(R218S), and to a much lesser extent if transfected with Fluc(Stop).	('deficiency', 'Var', (39, 49))	('translation', 'biological_process', 'GO:0006412', ('72', '83'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('121', '140'))	('phosphorylation', 'biological_process', 'GO:0016310', ('23', '38'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('121', '140'))	('increased', 'PosReg', (111, 120))	('luciferase activity', 'molecular_function', 'GO:0050397', ('121', '140'))	('activity', 'MPA', (132, 140))	('R218S', 'Mutation', 'p.R218S', (166, 171))	('R218S', 'Var', (166, 171))	('rpS6 phosphorylation', 'Protein', (18, 38))	('luciferase activity', 'molecular_function', 'GO:0047077', ('121', '140'))	('translation fidelity', 'MPA', (72, 92))	('reduced', 'NegReg', (64, 71))	('luciferase', 'Enzyme', (121, 131))	('luciferase activity', 'molecular_function', 'GO:0045289', ('121', '140'))
30921	26919188	Nevertheless, rpS6 phosphorylation deficiency induced a 2.6-fold reduction in the translation fidelity in rpS6P-/-;Akttg, relative to Akttg MEFs, regardless of the luciferase mutant used (Fig 5E).	('phosphorylation', 'biological_process', 'GO:0016310', ('19', '34'))	('translation fidelity', 'MPA', (82, 102))	('MEFs', 'CellLine', 'CVCL:9115', (140, 144))	('translation', 'biological_process', 'GO:0006412', ('82', '93'))	('deficiency', 'Var', (35, 45))	('rpS6', 'Protein', (14, 18))	('rpS6P-/-', 'Var', (106, 114))	('reduction', 'NegReg', (65, 74))
30923	26919188	Reduced fidelity of translation suggests a mechanism for how rpS6 phosphorylation deficiency may interfere with tumorigenesis.	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('Reduced', 'NegReg', (0, 7))	('rpS6', 'Protein', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('fidelity', 'MPA', (8, 16))	('translation', 'biological_process', 'GO:0006412', ('20', '31'))	('phosphorylation', 'biological_process', 'GO:0016310', ('66', '81'))	('phosphorylation deficiency', 'Var', (66, 92))	('interfere', 'NegReg', (97, 106))
30924	26919188	One consequence of the lower translation fidelity in rpS6P-/- and rpS6P-/-;Akttg MEFs might be a higher sensitivity to proteotoxic stress, as has previously been shown for cells with excessive protein synthesis.	('translation fidelity', 'MPA', (29, 49))	('proteotoxic stress', 'Disease', 'MESH:D004194', (119, 137))	('higher', 'PosReg', (97, 103))	('rpS6P-/-', 'Var', (66, 74))	('MEFs', 'CellLine', 'CVCL:9115', (81, 85))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('rpS6P-/-', 'Var', (53, 61))	('proteotoxic stress', 'Disease', (119, 137))	('sensitivity', 'MPA', (104, 115))	('lower', 'NegReg', (23, 28))	('translation', 'biological_process', 'GO:0006412', ('29', '40'))	('protein synthesis', 'biological_process', 'GO:0006412', ('193', '210'))	('Akttg', 'Gene', (75, 80))
30926	26919188	Unexpectedly and in a contrast to data obtained with rpS6P-/-;RasG12D, rpS6 phosphorylation deficiency diminished MG132-induced apoptosis in both rpS6P-/- and rpS6P-/-;Akttg MEFs (Fig 6A).	('deficiency', 'Var', (92, 102))	('rpS6P-/-', 'Var', (159, 167))	('phosphorylation', 'biological_process', 'GO:0016310', ('76', '91'))	('rpS6P-/-', 'Var', (146, 154))	('MEFs', 'CellLine', 'CVCL:9115', (174, 178))	('MG132', 'Chemical', 'MESH:C072553', (114, 119))	('rpS6', 'Gene', (71, 75))	('apoptosis', 'biological_process', 'GO:0097194', ('128', '137'))	('apoptosis', 'biological_process', 'GO:0006915', ('128', '137'))	('diminished', 'NegReg', (103, 113))	('MG132-induced', 'Gene', (114, 127))
30927	26919188	This seemingly protective role of rpS6 phosphorylation deficiency is also reflected in the survival of the different genotypes under this stress, as assessed by trypan blue exclusion (Fig 6B).	('trypan blue', 'Chemical', 'MESH:D014343', (161, 172))	('phosphorylation deficiency', 'Var', (39, 65))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('deficiency', 'Var', (55, 65))	('rpS6', 'Protein', (34, 38))
30929	26919188	Next, we examined the sensitivity of rpS6P-/- and rpS6P-/-;Akttg MEFs to genotoxic stress.	('rpS6P-/-', 'Var', (50, 58))	('MEFs', 'CellLine', 'CVCL:9115', (65, 69))	('rpS6P-/-', 'Var', (37, 45))
30930	26919188	As with MG132 treatment, rpS6 phosphorylation deficiency surprisingly rendered wild type as well as Akttg MEFs more resistant to the etoposide-induced apoptosis (Fig 6D).	('phosphorylation', 'biological_process', 'GO:0016310', ('30', '45'))	('MEFs', 'CellLine', 'CVCL:9115', (106, 110))	('apoptosis', 'biological_process', 'GO:0097194', ('151', '160'))	('apoptosis', 'biological_process', 'GO:0006915', ('151', '160'))	('phosphorylation deficiency', 'Var', (30, 56))	('etoposide', 'Chemical', 'MESH:D005047', (133, 142))	('rpS6', 'Protein', (25, 29))	('MG132', 'Chemical', 'MESH:C072553', (8, 13))	('resistant', 'MPA', (116, 125))	('deficiency', 'Var', (46, 56))
30939	26919188	The results of this experiment demonstrate that autophagy not only was not enhanced in rpS6P-/-;Akttg MEFs relative to Akttg MEFs, it might even have been suppressed (Fig 7).	('Akttg', 'Var', (96, 101))	('rpS6P-/-;Akttg', 'Var', (87, 101))	('autophagy', 'CPA', (48, 57))	('MEFs', 'CellLine', 'CVCL:9115', (102, 106))	('autophagy', 'biological_process', 'GO:0016236', ('48', '57'))	('autophagy', 'biological_process', 'GO:0006914', ('48', '57'))	('MEFs', 'CellLine', 'CVCL:9115', (125, 129))	('rat', 'Species', '10116', (38, 41))
30949	26919188	Conceivably, the expression of constitutively active Akt1 could induce insulinoma via activation of the mTORC1 pathway and thereby its downstream effectors, S6K1 and rpS6 phosphorylation in beta-cell ( and the present report).	('S6K1', 'Gene', (157, 161))	('induce', 'PosReg', (64, 70))	('mTORC1', 'cellular_component', 'GO:0031931', ('104', '110'))	('expression', 'Species', '29278', (17, 27))	('S6K1', 'Gene', '72508', (157, 161))	('phosphorylation', 'biological_process', 'GO:0016310', ('171', '186'))	('constitutively', 'Var', (31, 45))	('mTORC1', 'Gene', '382056', (104, 110))	('insulinoma', 'Phenotype', 'HP:0012197', (71, 81))	('insulinoma', 'Disease', (71, 81))	('insulinoma', 'Disease', 'MESH:D007340', (71, 81))	('expression', 'Var', (17, 27))	('activation', 'PosReg', (86, 96))	('mTORC1', 'Gene', (104, 110))	('Akt1', 'Gene', (53, 57))	('rpS6', 'Protein', (166, 170))
30952	26919188	However, deletion of S6K1 and S6K2 and thereby elimination of rpS6 phosphorylation had no impact on the development of pathological, physiological, or genetically induced cardiac hypertrophy.	('deletion', 'Var', (9, 17))	('cardiac hypertrophy', 'Disease', (171, 190))	('S6K1 and S6K2', 'Gene', '72508;58988', (21, 34))	('phosphorylation', 'biological_process', 'GO:0016310', ('67', '82'))	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (171, 190))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (171, 190))	('rpS6', 'Protein', (62, 66))
30958	26919188	We show here that rpS6 knockin mutant beta-cells are protected from the development of Akt-induced insulinoma, in a manner that resembles that observed in early human ribosomopathies (i.e.	('human', 'Species', '9606', (161, 166))	('mutant', 'Var', (31, 37))	('rpS6', 'Gene', (18, 22))	('insulinoma', 'Phenotype', 'HP:0012197', (99, 109))	('insulinoma', 'Disease', (99, 109))	('insulinoma', 'Disease', 'MESH:D007340', (99, 109))
30960	26919188	Moreover, we demonstrate here for the first time that the rpS6 phosphorylation deficiency is associated with about 2.6-fold decrease in translation fidelity in cells expressing a constitutively active Akt (Fig 5E).	('rpS6', 'Gene', (58, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('63', '78'))	('deficiency', 'Var', (79, 89))	('translation fidelity', 'MPA', (136, 156))	('translation', 'biological_process', 'GO:0006412', ('136', '147'))	('phosphorylation', 'MPA', (63, 78))	('decrease', 'NegReg', (124, 132))	('rat', 'Species', '10116', (20, 23))
30961	26919188	It should be noted, however, that we have not establish a causal relationship between the reduced translation fidelity and the anti-tumorigenic effect of the mutant rpS6.	('translation', 'biological_process', 'GO:0006412', ('98', '109'))	('reduced', 'NegReg', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('translation', 'MPA', (98, 109))	('tumor', 'Disease', (132, 137))	('rpS6', 'Gene', (165, 169))	('mutant', 'Var', (158, 164))
30963	26919188	Many of the phenotypic manifestations of mouse deficient of S6K1 are recapitulated in the rpS6 knockin mouse.	('deficient', 'Var', (47, 56))	('mouse', 'Species', '10090', (41, 46))	('mouse', 'Species', '10090', (103, 108))	('S6K1', 'Gene', '72508', (60, 64))	('S6K1', 'Gene', (60, 64))
30966	26919188	However, this explanation is inconsistent with the observation that rpS6 is still fully phosphorylated in S6K1 deficient mouse, due to the compensatory activity of S6K2.	('S6K1', 'Gene', (106, 110))	('S6K2', 'Gene', '58988', (164, 168))	('mouse', 'Species', '10090', (121, 126))	('S6K1', 'Gene', '72508', (106, 110))	('deficient', 'Var', (111, 120))	('S6K2', 'Gene', (164, 168))
30967	26919188	It appears, therefore, that rpS6 phosphorylation deficiency restrains the development of insulinoma by a mechanism that is distinct from that operated in S6K1 knockout mice.	('rpS6', 'Gene', (28, 32))	('phosphorylation deficiency', 'Var', (33, 59))	('S6K1', 'Gene', (154, 158))	('mice', 'Species', '10090', (168, 172))	('deficiency', 'Var', (49, 59))	('insulinoma', 'Phenotype', 'HP:0012197', (89, 99))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('restrains', 'NegReg', (60, 69))	('insulinoma', 'Disease', (89, 99))	('insulinoma', 'Disease', 'MESH:D007340', (89, 99))	('rat', 'Species', '10116', (145, 148))	('S6K1', 'Gene', '72508', (154, 158))
30968	26919188	rpS6 phosphorylation has been proposed to reduce Kras-induced DNA damage in acinar cells and in acinar-to-ductal metaplasia, and consequently attenuates p53-mediated tumor suppression.	('DNA damage', 'MPA', (62, 72))	('p53', 'Gene', '22060', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('metaplasia', 'biological_process', 'GO:0036074', ('113', '123'))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('phosphorylation', 'Var', (5, 20))	('tumor', 'Disease', (166, 171))	('attenuates', 'NegReg', (142, 152))	('p53', 'Gene', (153, 156))	('reduce', 'NegReg', (42, 48))	('rpS6', 'Protein', (0, 4))	('Kras', 'Gene', (49, 53))	('Kras', 'Gene', '16653', (49, 53))
30974	26919188	Notably, the expression of both oncogenic Ras and Akt induces DNA damage, consequently both Ras- and Akt-induced cancer cells mitigate DNA damage to a level that does not impair their proliferation (reviewed in).	('DNA damage', 'MPA', (62, 72))	('expression', 'Species', '29278', (13, 23))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('rat', 'Species', '10116', (191, 194))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('Akt', 'Gene', (50, 53))	('cancer', 'Disease', (113, 119))	('expression', 'Var', (13, 23))	('induces', 'Reg', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('mitigate', 'NegReg', (126, 134))
30980	26919188	Indeed, rpS6P-/- mice show altered transcription of the ribosome biogenesis program.	('mice', 'Species', '10090', (17, 21))	('altered', 'Reg', (27, 34))	('rpS6P-/-', 'Var', (8, 16))	('ribosome biogenesis', 'biological_process', 'GO:0042254', ('56', '75'))	('transcription', 'biological_process', 'GO:0006351', ('35', '48'))	('ribosome', 'cellular_component', 'GO:0005840', ('56', '64'))	('transcription', 'MPA', (35, 48))	('ribosome biogenesis program', 'Gene', (56, 83))
30981	26224874	Imaging Tumor Acidity: pH-Low Insertion Peptide Probe for Optoacoustic Tomography Optoacoustic tomography has been used for the detection of pancreatic ductal adenocarcinoma targeted by pH-Low Insertion Peptide (pHLIP) conjugated to near infrared fluorescent dye.	('pH-Low Insertion', 'Var', (186, 202))	('Tumor', 'Phenotype', 'HP:0002664', (8, 13))	('pancreatic ductal adenocarcinoma', 'Disease', (141, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (141, 173))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (141, 173))
31012	25096727	Most solid cancers are a heterogeneous collection of diseases as they develop from various combinations of genetic lesions and epigenetic modifications.	('solid cancers', 'Disease', (5, 18))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('epigenetic modifications', 'Var', (127, 151))	('solid cancers', 'Disease', 'MESH:D009369', (5, 18))	('genetic lesions', 'Disease', 'MESH:D020022', (107, 122))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('genetic lesions', 'Disease', (107, 122))
31072	25106741	CA19.9 has been widely used as a serologic diagnostic tumor marker for PDAC, and its usefulness and clinical significance have been reported in many studies.	('CA19', 'Chemical', '-', (0, 4))	('PDAC', 'Disease', (71, 75))	('PDAC', 'Phenotype', 'HP:0006725', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('PDAC', 'Chemical', '-', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('CA19.9', 'Var', (0, 6))	('tumor', 'Disease', (54, 59))
31098	25106741	We measured a panel of four markers, namely CEA, CA19.9, CA242 and MIC-1.	('CA19', 'Chemical', '-', (49, 53))	('CEA', 'Gene', (44, 47))	('CEA', 'Gene', '5670', (44, 47))	('CA242', 'Chemical', '-', (57, 62))	('CA242', 'Gene', (57, 62))	('MIC-1', 'Gene', (67, 72))	('CA19.9', 'Var', (49, 55))	('MIC-1', 'Gene', '9518', (67, 72))
31113	25106741	In comparison with healthy control subjects (416.8 +- 286.9 pg/mL), the levels of serum MIC-1 demonstrated a stepwise increase in patients with benign pancreas tumor (808.4 +- 483.9 pg/mL; P < 0.001), chronic Pancreatitis (1299.0 +- 709.6 pg/mL; P < 0.001) and PDAC (1731.0 +- 1181.0 pg/mL; P < 0.001) (Figure 1d).	('chronic Pancreatitis', 'Disease', 'MESH:D050500', (201, 221))	('benign pancreas tumor', 'Disease', (144, 165))	('levels', 'MPA', (72, 78))	('increase', 'PosReg', (118, 126))	('Pancreatitis', 'Phenotype', 'HP:0001733', (209, 221))	('1299.0 +- 709.6', 'Var', (223, 238))	('chronic Pancreatitis', 'Phenotype', 'HP:0006280', (201, 221))	('pancreas tumor', 'Phenotype', 'HP:0002894', (151, 165))	('PDAC', 'Chemical', '-', (261, 265))	('benign pancreas tumor', 'Disease', 'MESH:D010190', (144, 165))	('patients', 'Species', '9606', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('MIC-1', 'Gene', (88, 93))	('MIC-1', 'Gene', '9518', (88, 93))	('chronic Pancreatitis', 'Disease', (201, 221))	('PDAC', 'Phenotype', 'HP:0006725', (261, 265))
31125	25106741	We noticed that serum MIC-1 had an outstanding performance for distinguishing CA19.9-negative pancreatic carcinomas from non-pancreatic carcinoma controls including benign pancreas tumors (AUROC, 0.886; 95% CI, 0.865-0.906; Figure 2b).	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('pancreas tumor', 'Phenotype', 'HP:0002894', (172, 186))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('non-pancreatic carcinoma', 'Disease', (121, 145))	('benign pancreas tumors', 'Disease', (165, 187))	('non-pancreatic carcinoma', 'Disease', 'MESH:C562463', (121, 145))	('benign pancreas tumors', 'Disease', 'MESH:D010190', (165, 187))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (94, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('pancreatic carcinomas', 'Disease', (94, 115))	('CA19', 'Chemical', '-', (78, 82))	('MIC-1', 'Gene', (22, 27))	('CA19.9-negative', 'Var', (78, 93))	('MIC-1', 'Gene', '9518', (22, 27))
31131	25106741	At the cutoff value of 1000 pg/mL, only 10.42% (12 of 115) of patients with benign pancreas tumor exceeded the threshold; in contrast, 8.7% (10 of 115), 15.7% (18 of 115) and 15.7% (18 of 115), of these patients were above the cutoff value of CA242, CA19.9 and CEA, respectively.	('CEA', 'Gene', (261, 264))	('CA19.9', 'Var', (250, 256))	('pancreas tumor', 'Phenotype', 'HP:0002894', (83, 97))	('CEA', 'Gene', '5670', (261, 264))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('patients', 'Species', '9606', (203, 211))	('benign pancreas tumor', 'Disease', (76, 97))	('CA242', 'Var', (243, 248))	('benign pancreas tumor', 'Disease', 'MESH:D010190', (76, 97))	('patients', 'Species', '9606', (62, 70))	('CA242', 'Chemical', '-', (243, 248))	('CA19', 'Chemical', '-', (250, 254))
31136	25106741	In addition, the combination of CA19.9 and MIC-1 further significantly improved the detection rate of early PDAC (stage I and II) from 43.0% to 78.1%, which was much higher than the simultaneous use of CA19.9, CEA and CA242 (58.1%).	('MIC-1', 'Gene', '9518', (43, 48))	('combination', 'Var', (17, 28))	('CA19', 'Chemical', '-', (202, 206))	('CA19.9', 'Var', (32, 38))	('PDAC', 'Chemical', '-', (108, 112))	('CEA', 'Gene', '5670', (210, 213))	('CA242', 'Chemical', '-', (218, 223))	('early PDAC', 'Disease', (102, 112))	('CA19', 'Chemical', '-', (32, 36))	('MIC-1', 'Gene', (43, 48))	('PDAC', 'Phenotype', 'HP:0006725', (108, 112))	('improved', 'PosReg', (71, 79))	('CEA', 'Gene', (210, 213))
31143	25106741	In contrast, no statistically significant differences were observed in MIC-1 levels before (1984.0 +- 1479.0 pg/mL) or after surgery (1726.0 +- 907.5 pg/mL) in patients with noncurative resections (P = 0.636) (Figure 4c).	('1726.0 +- 907.5', 'Var', (134, 149))	('MIC-1', 'Gene', '9518', (71, 76))	('patients', 'Species', '9606', (160, 168))	('MIC-1', 'Gene', (71, 76))
31164	25106741	The combination of MIC-1 and CA19.9 could improve the diagnostic performance significantly.	('CA19.9', 'Var', (29, 35))	('improve', 'PosReg', (42, 49))	('MIC-1', 'Gene', (19, 24))	('diagnostic performance', 'CPA', (54, 76))	('CA19', 'Chemical', '-', (29, 33))	('MIC-1', 'Gene', '9518', (19, 24))
31172	25106741	In addition, the combination of CA19.9 and MIC-1 further significantly improved the detection rate of very early PDAC from 43.0% to 78.1%, which was much higher than the simultaneous use of CA19.9, CEA and CA242 (58.1%).	('CA242', 'Chemical', '-', (206, 211))	('MIC-1', 'Gene', '9518', (43, 48))	('combination', 'Var', (17, 28))	('CEA', 'Gene', '5670', (198, 201))	('CA19.9', 'Var', (32, 38))	('very early PDAC', 'Disease', (102, 117))	('PDAC', 'Phenotype', 'HP:0006725', (113, 117))	('CEA', 'Gene', (198, 201))	('CA19', 'Chemical', '-', (190, 194))	('CA19', 'Chemical', '-', (32, 36))	('MIC-1', 'Gene', (43, 48))	('PDAC', 'Chemical', '-', (113, 117))	('improved', 'PosReg', (71, 79))	('detection', 'MPA', (84, 93))
31173	25106741	Thus, the combination of MIC-1 and CA19.9 may be a promising strategy for early diagnosis of PDAC in the future.	('MIC-1', 'Gene', (25, 30))	('PDAC', 'Chemical', '-', (93, 97))	('MIC-1', 'Gene', '9518', (25, 30))	('CA19', 'Chemical', '-', (35, 39))	('PDAC', 'Disease', (93, 97))	('PDAC', 'Phenotype', 'HP:0006725', (93, 97))	('CA19.9', 'Var', (35, 41))
31188	20814421	KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma Pancreatic ductal adenocarcinoma (PDAC) is characterized by near-universal mutations in KRAS and frequent deregulation of crucial embryonic signalling pathways, including the Hedgehog (Hh) and Wnt-beta-catenin cascades.	('deregulation', 'Reg', (200, 212))	('mutations', 'Var', (169, 178))	('pancreatic ductal adenocarcinoma', 'Disease', (61, 93))	('KRAS', 'Gene', (182, 186))	('KRAS', 'Gene', '16653', (182, 186))	('Pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (94, 126))	('signalling', 'biological_process', 'GO:0023052', ('234', '244'))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (61, 93))	('embryonic signalling pathways', 'Pathway', (224, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('PDAC', 'Chemical', '-', (128, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('KRAS', 'Gene', '16653', (0, 4))	('PDAC', 'Phenotype', 'HP:0006725', (128, 132))	('KRAS', 'Gene', (0, 4))	('Pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (94, 126))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (61, 93))	('Wnt-beta-catenin cascades', 'Pathway', (287, 312))	('Pancreatic ductal adenocarcinoma', 'Disease', (94, 126))
31193	20814421	Unlike human tumours, such as medulloblastoma in which aberrant Hh signalling is sufficient for disease development, or colon cancer in which deregulated Wnt-beta-catenin can represent an initiating event, genetic experiments have revealed that the misregulation of Hh and Wnt-beta-catenin signalling alone is not sufficient to drive PDAC development.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('drive', 'PosReg', (328, 333))	('signalling', 'biological_process', 'GO:0023052', ('67', '77'))	('PDAC', 'Disease', (334, 338))	('medulloblastoma', 'Disease', 'MESH:D008527', (30, 45))	('medulloblastoma', 'Phenotype', 'HP:0002885', (30, 45))	('colon cancer', 'Phenotype', 'HP:0003003', (120, 132))	('medulloblastoma', 'Disease', (30, 45))	('misregulation', 'Var', (249, 262))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('PDAC', 'Chemical', '-', (334, 338))	('human', 'Species', '9606', (7, 12))	('signalling', 'biological_process', 'GO:0023052', ('290', '300'))	('colon cancer', 'Disease', 'MESH:D015179', (120, 132))	('tumours', 'Disease', (13, 20))	('PDAC', 'Phenotype', 'HP:0006725', (334, 338))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('colon cancer', 'Disease', (120, 132))
31197	20814421	Although some (~2-10%) PDACs seem to be associated with hereditary factors, most are associated with high-frequency somatic mutations in a subset of genes, including those that encode the small GTPase protein KRAS, and the tumour suppressors INK4A, p53 and SMAD4.	('SMAD4', 'Gene', '17128', (257, 262))	('mutations', 'Var', (124, 133))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('PDAC', 'Phenotype', 'HP:0006725', (23, 27))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('INK4A', 'Gene', '12578', (242, 247))	('INK4A', 'Gene', (242, 247))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('SMAD4', 'Gene', (257, 262))	('p53', 'Gene', (249, 252))	('tumour', 'Disease', (223, 229))	('PDACs', 'Disease', (23, 28))	('p53', 'Gene', '22059', (249, 252))	('GTP', 'Chemical', 'MESH:D006160', (194, 197))	('PDAC', 'Chemical', '-', (23, 27))	('associated', 'Reg', (40, 50))	('associated', 'Reg', (85, 95))
31199	20814421	The KRAS mutations found in PDAC result in a protein locked in a constitutively active state, unable to hydrolyse GTP, thus promoting persistent signalling to downstream effectors (reviewed in).	('promoting', 'PosReg', (124, 133))	('protein', 'Protein', (45, 52))	('mutations', 'Var', (9, 18))	('PDAC', 'Chemical', '-', (28, 32))	('PDAC', 'Gene', (28, 32))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('persistent signalling', 'MPA', (134, 155))	('GTP', 'Chemical', 'MESH:D006160', (114, 117))	('signalling', 'biological_process', 'GO:0023052', ('145', '155'))	('PDAC', 'Phenotype', 'HP:0006725', (28, 32))	('KRAS', 'Gene', (4, 8))	('result', 'Reg', (33, 39))
31200	20814421	Although large-scale genomic studies are expanding knowledge of the wider landscape of mutations found in PDAC, investigating the function of such 'classical' genes listed above in cell culture and animal models has considerably advanced insights into PDAC maintenance and progression.	('PDAC', 'Gene', (106, 110))	('PDAC', 'Phenotype', 'HP:0006725', (252, 256))	('PDAC', 'Phenotype', 'HP:0006725', (106, 110))	('PDAC', 'Disease', (252, 256))	('PDAC', 'Chemical', '-', (106, 110))	('PDAC', 'Chemical', '-', (252, 256))	('advanced', 'PosReg', (229, 237))	('mutations', 'Var', (87, 96))
31203	20814421	For example, PanIN1 lesions frequently possess mutated KRAS (estimates suggest 15-40%) but less often harbour mutations in p53 or SMAD4.	('KRAS', 'MPA', (55, 59))	('SMAD4', 'Gene', (130, 135))	('PanIN1', 'Gene', (13, 19))	('p53', 'Gene', (123, 126))	('mutated', 'Var', (47, 54))	('SMAD4', 'Gene', '17128', (130, 135))	('p53', 'Gene', '22059', (123, 126))
31204	20814421	PanIN3 lesions are more likely to express mutated KRAS, p53 and SMAD4.	('SMAD4', 'Gene', '17128', (64, 69))	('p53', 'Gene', (56, 59))	('p53', 'Gene', '22059', (56, 59))	('mutated KRAS', 'Var', (42, 54))	('express', 'Reg', (34, 41))	('KRAS', 'Var', (50, 54))	('SMAD4', 'Gene', (64, 69))	('PanIN3', 'Gene', (0, 6))
31205	20814421	Owing to its near universal frequency in PDAC, mutation of KRAS was proposed as an initiating genetic lesion in this disease.	('PDAC', 'Chemical', '-', (41, 45))	('mutation', 'Var', (47, 55))	('PDAC', 'Disease', (41, 45))	('PDAC', 'Phenotype', 'HP:0006725', (41, 45))	('genetic lesion', 'Disease', (94, 108))	('genetic lesion', 'Disease', 'MESH:D020022', (94, 108))	('KRAS', 'Gene', (59, 63))
31206	20814421	However, initial efforts to audit the sufficiency of mutant KRAS to initiate PDAC progression were stymied by the limitations of transgenic approaches.	('PDAC', 'Phenotype', 'HP:0006725', (77, 81))	('transgenic', 'Species', '10090', (129, 139))	('sufficiency', 'Disease', 'None', (38, 49))	('mutant', 'Var', (53, 59))	('PDAC', 'Chemical', '-', (77, 81))	('sufficiency', 'Disease', (38, 49))
31207	20814421	expression of mutant KRAS under acinar and ductal promoters resulted in ductal lesions reminiscent of PanINs and mixed acinar and ductal carcinomas, or periductal inflammation, respectively.	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('mixed acinar and', 'Disease', (113, 129))	('KRAS', 'Gene', (21, 25))	('inflammation', 'Disease', (163, 175))	('mutant', 'Var', (14, 20))	('resulted in', 'Reg', (60, 71))	('inflammation', 'biological_process', 'GO:0006954', ('163', '175'))	('ductal carcinomas', 'Disease', 'MESH:D044584', (130, 147))	('PanINs', 'Disease', (102, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('ductal carcinomas', 'Disease', (130, 147))	('periductal inflammation', 'Phenotype', 'HP:0012322', (152, 175))	('inflammation', 'Disease', 'MESH:D007249', (163, 175))	('ductal', 'MPA', (72, 78))
31210	20814421	The ability of mutant KRAS to drive PDAC was not successfully investigated until the development of a Cre-inducible conditional allele (lox-stop-lox KrasG12D (LSL-KrasG12D)) targeted to the endogenous Kras locus, thus allowing expression of constitutively active KRAS under temporal and spatial control.	('Kras', 'Gene', (149, 153))	('Kras', 'Gene', '16653', (149, 153))	('Kras', 'Gene', '16653', (163, 167))	('PDAC', 'Phenotype', 'HP:0006725', (36, 40))	('PDAC', 'Chemical', '-', (36, 40))	('mutant', 'Var', (15, 21))	('Kras', 'Gene', (201, 205))	('Kras', 'Gene', '16653', (201, 205))	('Kras', 'Gene', (163, 167))
31211	20814421	This tool eliminated possible issues of confounding cellular responses to overexpression, as transcription of the mutant Kras allele depends on the activity of the endogenous Kras promoter.	('transcription', 'biological_process', 'GO:0006351', ('93', '106'))	('Kras', 'Gene', (175, 179))	('depends', 'Reg', (133, 140))	('activity', 'MPA', (148, 156))	('transcription', 'MPA', (93, 106))	('mutant', 'Var', (114, 120))	('Kras', 'Gene', '16653', (175, 179))	('Kras', 'Gene', '16653', (121, 125))	('Kras', 'Gene', (121, 125))
31212	20814421	Initially, mice expressing the LSL-KrasG12D allele were crossed to mice that expressed Cre recombinase under the control of promoters of the key pancreatic progenitor genes: pancreatic and duodenal homeobox 1 (Pdx1) and p48 (also known as Ptf1a), thus targeting mutant KRAS to most cells in the developing pancreas.	('Pdx1', 'Gene', '18609', (210, 214))	('Kras', 'Gene', '16653', (35, 39))	('pancreatic', 'Disease', (145, 155))	('targeting', 'Reg', (252, 261))	('mutant', 'Var', (262, 268))	('KRAS', 'Gene', (269, 273))	('mice', 'Species', '10090', (11, 15))	('pancreatic', 'Disease', 'MESH:D010195', (174, 184))	('pancreatic', 'Disease', (174, 184))	('pancreatic', 'Disease', 'MESH:D010195', (145, 155))	('Pdx1', 'Gene', (210, 214))	('Kras', 'Gene', (35, 39))	('mice', 'Species', '10090', (67, 71))	('Ptf1', 'Species', '32651', (239, 243))
31215	20814421	Recently, these original models have been modified to begin to determine which pancreatic cell types can develop into PDAC when mutant KRAS is expressed.	('PDAC', 'Phenotype', 'HP:0006725', (118, 122))	('PDAC', 'Disease', (118, 122))	('KRAS', 'Gene', (135, 139))	('mutant', 'Var', (128, 134))	('pancreatic', 'Disease', 'MESH:D010195', (79, 89))	('PDAC', 'Chemical', '-', (118, 122))	('pancreatic', 'Disease', (79, 89))	('develop', 'Reg', (105, 112))
31217	20814421	Therefore, mutant KRAS is a crucial determinant of the PanIN-PDAC 'lineage' and is capable of driving pancreatic cells from terminal differentiation into a duct-like fate that can ultimately give rise to PDAC.	('mutant', 'Var', (11, 17))	('KRAS', 'Gene', (18, 22))	('PDAC', 'Disease', (204, 208))	('PDAC', 'Phenotype', 'HP:0006725', (204, 208))	('PDAC', 'Phenotype', 'HP:0006725', (61, 65))	('terminal differentiation', 'biological_process', 'GO:0048468', ('124', '148'))	('PDAC', 'Chemical', '-', (204, 208))	('pancreatic', 'Disease', 'MESH:D010195', (102, 112))	('give rise to', 'Reg', (191, 203))	('driving', 'PosReg', (94, 101))	('pancreatic', 'Disease', (102, 112))	('PDAC', 'Chemical', '-', (61, 65))
31221	20814421	This is likely to contrast to human tumour progression in which KRAS mutations seem to occur early in disease development, and cells subsequently undergo selection pressure and accumulate progressive tumour suppressor loss.	('tumour', 'Disease', (200, 206))	('mutations', 'Var', (69, 78))	('human', 'Species', '9606', (30, 35))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('KRAS', 'Gene', (64, 68))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('tumour', 'Disease', 'MESH:D009369', (200, 206))	('accumulate', 'PosReg', (177, 187))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))
31233	20814421	The first class is defined by cell-autonomous mutations in key regulatory proteins; for example, inactivating mutations in PTC or activating mutations in SMO, such as those observed in basal cell carcinoma and medulloblastoma.	('activating', 'PosReg', (130, 140))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (185, 205))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (185, 205))	('mutations', 'Var', (46, 55))	('basal cell carcinoma', 'Disease', (185, 205))	('inactivating mutations', 'Var', (97, 119))	('PTC', 'Gene', (123, 126))	('medulloblastoma', 'Disease', 'MESH:D008527', (210, 225))	('medulloblastoma', 'Phenotype', 'HP:0002885', (210, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('medulloblastoma', 'Disease', (210, 225))	('SMO', 'Gene', (154, 157))
31237	20814421	However, although chemical inhibitors targeting the pathway at the level of SMO (such as cyclopamine) or Hh ligand decrease the tumour burden and metastasis in xenotransplanted primary human tumours and cell lines, and SMO inhibition affects survival and tumour development in mutant KRAS-mutant mouse models, recent evidence indicates that epithelial PDAC cells do not respond to Hh ligand and are refractory to ligand inhibition.	('human', 'Species', '9606', (185, 190))	('KRAS-mutant', 'Gene', (284, 295))	('KRAS-mutant', 'Var', (284, 295))	('tumour burden', 'Disease', 'MESH:D009369', (128, 141))	('ligand', 'molecular_function', 'GO:0005488', ('384', '390'))	('tumours', 'Disease', (191, 198))	('cyclopamine', 'Chemical', 'MESH:C000541', (89, 100))	('affects', 'Reg', (234, 241))	('mutant', 'Var', (277, 283))	('tumours', 'Phenotype', 'HP:0002664', (191, 198))	('decrease', 'NegReg', (115, 123))	('survival', 'CPA', (242, 250))	('tumours', 'Disease', 'MESH:D009369', (191, 198))	('tumour', 'Phenotype', 'HP:0002664', (255, 261))	('tumour burden', 'Disease', (128, 141))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (255, 261))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('tumour', 'Disease', (255, 261))	('PDAC', 'Chemical', '-', (352, 356))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (191, 197))	('tumour', 'Disease', (128, 134))	('ligand', 'molecular_function', 'GO:0005488', ('108', '114'))	('tumour', 'Disease', (191, 197))	('mouse', 'Species', '10090', (296, 301))	('PDAC', 'Phenotype', 'HP:0006725', (352, 356))	('ligand', 'molecular_function', 'GO:0005488', ('413', '419'))
31242	20814421	Reconstitution experiments, in which tumour cells from various cancer types are admixed with CAFs and grown as xenografts, have shown that CAFs can promote transformation of immortalized epithelium (for example, SV40-immortalized prostate cells) and enhance tumour cell growth.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', (37, 43))	('tumour', 'Disease', (258, 264))	('tumour', 'Phenotype', 'HP:0002664', (258, 264))	('tumour', 'Disease', 'MESH:D009369', (258, 264))	('transformation', 'CPA', (156, 170))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('promote', 'PosReg', (148, 155))	('enhance', 'PosReg', (250, 257))	('CAFs', 'Var', (139, 143))	('cell growth', 'biological_process', 'GO:0016049', ('265', '276'))	('cancer', 'Disease', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
31253	20814421	bailey and colleagues showed that expression of SHH increased angiogenesis in xenografts of transformed human pancreatic ductal cells.	('increased', 'PosReg', (52, 61))	('SHH', 'Gene', (48, 51))	('expression', 'Var', (34, 44))	('human', 'Species', '9606', (104, 109))	('pancreatic ductal', 'Disease', (110, 127))	('pancreatic ductal', 'Disease', 'MESH:D021441', (110, 127))	('angiogenesis', 'biological_process', 'GO:0001525', ('62', '74'))	('angiogenesis', 'CPA', (62, 74))
31263	20814421	Targeting mutant KRAS directly by small interfering RNA (siRNA) or by targeting its downstream RAF-MAPK effector pathway with chemical inhibitors decreases the transcription of Gli-target genes and tumour cell growth.	('cell growth', 'biological_process', 'GO:0016049', ('205', '216'))	('tumour', 'Disease', (198, 204))	('mutant', 'Var', (10, 16))	('transcription', 'biological_process', 'GO:0006351', ('160', '173'))	('small interfering RNA', 'MPA', (34, 55))	('decreases', 'NegReg', (146, 155))	('Gli', 'Gene', (177, 180))	('RAF', 'Gene', (95, 98))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('KRAS', 'Gene', (17, 21))	('Gli', 'Gene', '2735', (177, 180))	('MAPK', 'molecular_function', 'GO:0004707', ('99', '103'))	('transcription', 'MPA', (160, 173))	('RAF', 'Gene', '387609', (95, 98))	('tumour', 'Disease', 'MESH:D009369', (198, 204))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))
31268	20814421	However, sequencing analysis has shown that GLI3 and the related gene GLI4 are mutated at a high frequency in PDAC.	('PDAC', 'Chemical', '-', (110, 114))	('mutated', 'Var', (79, 86))	('GLI4', 'Gene', (70, 74))	('PDAC', 'Disease', (110, 114))	('PDAC', 'Phenotype', 'HP:0006725', (110, 114))	('GLI3', 'Gene', (44, 48))	('GLI4', 'Gene', '100043133', (70, 74))	('GLI3', 'Gene', '14634', (44, 48))
31271	20814421	Several genetic approaches have been used to determine how modulating Hh signalling alone, as well as in the context of mutant KRAS, changes the course of PDAC inception (these models are summarized in TABLE 2).	('signalling', 'biological_process', 'GO:0023052', ('73', '83'))	('course', 'MPA', (145, 151))	('PDAC', 'Chemical', '-', (155, 159))	('changes', 'Reg', (133, 140))	('KRAS', 'Gene', (127, 131))	('PDAC', 'Phenotype', 'HP:0006725', (155, 159))	('mutant', 'Var', (120, 126))
31274	20814421	Interestingly, the ductal remnants morphologically resemble early human PanIN1-2 lesions, and several of these transgenic mice also developed spontaneous, pancreas-specific KRAS mutations, suggesting that inappropriate ligand expression may promote changes in tissue architecture and signalling involved in PDAC initiation.	('changes', 'Reg', (249, 256))	('signalling', 'biological_process', 'GO:0023052', ('284', '294'))	('ligand', 'molecular_function', 'GO:0005488', ('219', '225'))	('transgenic mice', 'Species', '10090', (111, 126))	('PDAC', 'Chemical', '-', (307, 311))	('tissue architecture', 'MPA', (260, 279))	('human', 'Species', '9606', (66, 71))	('PanIN1-2', 'Gene', (72, 80))	('KRAS', 'Gene', (173, 177))	('promote', 'PosReg', (241, 248))	('signalling', 'MPA', (284, 294))	('ligand', 'Protein', (219, 225))	('inappropriate', 'Var', (205, 218))	('PDAC', 'Phenotype', 'HP:0006725', (307, 311))	('mutations', 'Var', (178, 187))
31280	20814421	Given the high frequency of activating KRAS mutations in PDAC and that mutations in KRAS and persistent Gli activity are found in fully transformed PDAC lines, the ability of KRAS and Gli signalling to synergize to drive PDAC initiation and development was determined by intercrossing Pdx1-Cre;CLEG2 mice with LSL-KrasG12D animals.	('PDAC', 'Phenotype', 'HP:0006725', (221, 225))	('Kras', 'Gene', (314, 318))	('signalling', 'biological_process', 'GO:0023052', ('188', '198'))	('PDAC', 'Chemical', '-', (148, 152))	('Gli', 'Gene', '2735', (104, 107))	('KRAS', 'Gene', (84, 88))	('mice', 'Species', '10090', (300, 304))	('Gli', 'Gene', '2735', (184, 187))	('PDAC', 'Phenotype', 'HP:0006725', (148, 152))	('Kras', 'Gene', '16653', (314, 318))	('Pdx1', 'Gene', '18609', (285, 289))	('Gli', 'Gene', (104, 107))	('Gli', 'Gene', (184, 187))	('Pdx1', 'Gene', (285, 289))	('activating', 'PosReg', (28, 38))	('PDAC', 'Chemical', '-', (57, 61))	('PDAC', 'Phenotype', 'HP:0006725', (57, 61))	('PDAC', 'Chemical', '-', (221, 225))	('development', 'CPA', (241, 252))	('KRAS', 'Gene', (39, 43))	('mutations', 'Var', (44, 53))
31285	20814421	To determine if this role depended on ligand-dependent signalling in epithelial cells, Steveaux and colleagues generated p48-Cre; LSL-KrasG12D;Smoflox/flox mice, therefore rendering pancreatic progenitors insensitive to Hh ligand.	('signalling', 'biological_process', 'GO:0023052', ('55', '65'))	('Smo', 'Gene', '319757', (143, 146))	('Kras', 'Gene', (134, 138))	('Kras', 'Gene', '16653', (134, 138))	('p48-Cre', 'Var', (121, 128))	('pancreatic', 'Disease', 'MESH:D010195', (182, 192))	('Smo', 'Gene', (143, 146))	('ligand', 'molecular_function', 'GO:0005488', ('38', '44'))	('mice', 'Species', '10090', (156, 160))	('pancreatic', 'Disease', (182, 192))	('ligand', 'molecular_function', 'GO:0005488', ('223', '229'))
31288	20814421	Therefore, this model suggests that aberrant ligand expression and epithelial Gli signalling contribute to PDAC initiation and progression, but are uncoupled and evolve independently.	('contribute', 'Reg', (93, 103))	('signalling', 'biological_process', 'GO:0023052', ('82', '92'))	('PDAC', 'Chemical', '-', (107, 111))	('aberrant', 'Var', (36, 44))	('ligand', 'molecular_function', 'GO:0005488', ('45', '51'))	('Gli', 'Gene', (78, 81))	('PDAC', 'Disease', (107, 111))	('PDAC', 'Phenotype', 'HP:0006725', (107, 111))	('ligand', 'Protein', (45, 51))	('Gli', 'Gene', '2735', (78, 81))
31297	20814421	Mutations in genes encoding regulatory proteins of the canonical signalling cascade are associated with many tumour types and in some cases, such as colon cancer, can act as initiating genetic lesions.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('genetic lesion', 'Disease', (185, 199))	('colon cancer', 'Disease', 'MESH:D015179', (149, 161))	('genetic lesion', 'Disease', 'MESH:D020022', (185, 199))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('colon cancer', 'Disease', (149, 161))	('tumour', 'Disease', (109, 115))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (88, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (149, 161))	('signalling cascade', 'biological_process', 'GO:0007165', ('65', '83'))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
31298	20814421	loss-of-function mutations in negative regulators, such as APC, and gain-of-function mutations in beta-catenin itself activate constitutive, ligand-independent beta-catenin signalling in a similar fashion to PTC and SMO mutations.	('loss-of-function', 'NegReg', (0, 16))	('gain-of-function', 'PosReg', (68, 84))	('APC', 'Disease', 'MESH:D011125', (59, 62))	('signalling', 'biological_process', 'GO:0023052', ('173', '183'))	('PTC', 'Disease', (208, 211))	('SMO', 'Disease', (216, 219))	('beta-catenin', 'Protein', (98, 110))	('mutations', 'Var', (85, 94))	('activate', 'PosReg', (118, 126))	('mutations', 'Var', (17, 26))	('APC', 'Disease', (59, 62))	('ligand', 'molecular_function', 'GO:0005488', ('141', '147'))	('constitutive', 'MPA', (127, 139))	('APC', 'cellular_component', 'GO:0005680', ('59', '62'))
31299	20814421	like these Hh pathway mutations, genetic lesions in classical beta-catenin regulatory modules are rare in PDAC.	('PDAC', 'Disease', (106, 110))	('PDAC', 'Phenotype', 'HP:0006725', (106, 110))	('mutations', 'Var', (22, 31))	('genetic lesion', 'Disease', (33, 47))	('PDAC', 'Chemical', '-', (106, 110))	('genetic lesion', 'Disease', 'MESH:D020022', (33, 47))
31304	20814421	Inhibiting beta-catenin with siRNA substantially compromises PDAC proliferation and increases apoptosis.	('Inhibiting', 'Var', (0, 10))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))	('PDAC', 'Phenotype', 'HP:0006725', (61, 65))	('PDAC proliferation', 'CPA', (61, 79))	('increases', 'PosReg', (84, 93))	('PDAC', 'Chemical', '-', (61, 65))	('apoptosis', 'CPA', (94, 103))	('beta-catenin', 'Protein', (11, 23))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))	('compromises', 'NegReg', (49, 60))
31307	20814421	Inhibiting ATDC function in PDAC cell lines decreases beta-catenin activity, tumour growth and metastasis.	('Inhibiting', 'Var', (0, 10))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('PDAC', 'Chemical', '-', (28, 32))	('tumour', 'Disease', (77, 83))	('beta-catenin activity', 'MPA', (54, 75))	('metastasis', 'CPA', (95, 105))	('ATDC', 'Gene', (11, 15))	('PDAC', 'Phenotype', 'HP:0006725', (28, 32))	('decreases', 'NegReg', (44, 53))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
31330	20814421	These SPT-like tumours, which in humans have been shown to carry activating mutations in beta-catenin, are morphologically and molecularly distinct from PDAC.	('mutations', 'Var', (76, 85))	('PDAC', 'Disease', (153, 157))	('humans', 'Species', '9606', (33, 39))	('PDAC', 'Phenotype', 'HP:0006725', (153, 157))	('tumours', 'Disease', 'MESH:D009369', (15, 22))	('tumours', 'Disease', (15, 22))	('activating', 'PosReg', (65, 75))	('SPT', 'molecular_function', 'GO:0004760', ('6', '9'))	('SPT', 'molecular_function', 'GO:0004758', ('6', '9'))	('beta-catenin', 'Protein', (89, 101))	('PDAC', 'Chemical', '-', (153, 157))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('SPT-like', 'Disease', (6, 14))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))
31333	20814421	Surprisingly, p48-Cre;Ctnnb1exon3/+;LSL-KrasG12D mice did not develop SPT-like tumours, or PanINs or PDAC.	('Kras', 'Gene', (40, 44))	('Kras', 'Gene', '16653', (40, 44))	('PDAC', 'Phenotype', 'HP:0006725', (101, 105))	('p48-Cre', 'Var', (14, 21))	('SPT', 'molecular_function', 'GO:0004758', ('70', '73'))	('SPT', 'molecular_function', 'GO:0004760', ('70', '73'))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('mice', 'Species', '10090', (49, 53))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('PDAC', 'Chemical', '-', (101, 105))	('tumours', 'Disease', 'MESH:D009369', (79, 86))	('tumours', 'Disease', (79, 86))
31337	20814421	Recently, the discovery that pancreatitis, a potent risk factor for PDAC in humans, accelerates PanIN and PDAC development in mice expressing mutant KRAS in the exocrine compartment has led to insights into the role of beta-catenin in this process.	('mice', 'Species', '10090', (126, 130))	('accelerates', 'PosReg', (84, 95))	('PDAC', 'Phenotype', 'HP:0006725', (68, 72))	('pancreatitis', 'Phenotype', 'HP:0001733', (29, 41))	('KRAS', 'Gene', (149, 153))	('PDAC', 'Phenotype', 'HP:0006725', (106, 110))	('pancreatitis', 'Disease', 'MESH:D010195', (29, 41))	('mutant', 'Var', (142, 148))	('pancreatitis', 'Disease', (29, 41))	('PDAC', 'Chemical', '-', (68, 72))	('humans', 'Species', '9606', (76, 82))	('PDAC', 'Chemical', '-', (106, 110))
31343	20814421	Not only have these studies shown that pancreatitis accelerates PanIN and PDAC development, suggesting that tissue damage and inflammation cooperate with KRAS signalling to drive the disease, they have also indicated that KRAS substantially alters pancreatic regeneration and plasticity.	('regeneration', 'biological_process', 'GO:0031099', ('259', '271'))	('pancreatitis', 'Disease', (39, 51))	('pancreatic regeneration', 'Disease', (248, 271))	('PDAC', 'Phenotype', 'HP:0006725', (74, 78))	('pancreatitis', 'Disease', 'MESH:D010195', (39, 51))	('pancreatic regeneration', 'Disease', 'MESH:D010195', (248, 271))	('pancreatitis', 'Phenotype', 'HP:0001733', (39, 51))	('inflammation', 'biological_process', 'GO:0006954', ('126', '138'))	('alters', 'Reg', (241, 247))	('KRAS', 'Var', (222, 226))	('inflammation', 'Disease', 'MESH:D007249', (126, 138))	('signalling', 'biological_process', 'GO:0023052', ('159', '169'))	('accelerates', 'PosReg', (52, 63))	('PDAC', 'Chemical', '-', (74, 78))	('inflammation', 'Disease', (126, 138))
31344	20814421	The first study to directly investigate the effect of pancreatitis on PDAC development used a mouse model that allowed doxycycline-induced, temporal expression of constitutively active, mutant KRAS (KrasG12V) exclusively in the acinar and centroacinar compartment.	('PDAC', 'Phenotype', 'HP:0006725', (70, 74))	('pancreatitis', 'Phenotype', 'HP:0001733', (54, 66))	('pancreatitis', 'Disease', 'MESH:D010195', (54, 66))	('mutant', 'Var', (186, 192))	('mouse', 'Species', '10090', (94, 99))	('PDAC', 'Chemical', '-', (70, 74))	('doxycycline', 'Chemical', 'MESH:D004318', (119, 130))	('Kras', 'Gene', (199, 203))	('Kras', 'Gene', '16653', (199, 203))	('pancreatitis', 'Disease', (54, 66))
31347	20814421	Interestingly, these mice were refractory to PanIN-PDAC development when mutant KRAS was activated 60 days after birth.	('PDAC', 'Chemical', '-', (51, 55))	('KRAS', 'Gene', (80, 84))	('mice', 'Species', '10090', (21, 25))	('mutant', 'Var', (73, 79))	('PDAC', 'Phenotype', 'HP:0006725', (51, 55))
31353	20814421	Using other inducible Cre lines, adult acinar cells have been shown to be sensitive to spontaneous ductal reprogramming into PanINs by KRASG12D in the absence of pancreatitis.	('pancreatitis', 'Disease', (162, 174))	('pancreatitis', 'Phenotype', 'HP:0001733', (162, 174))	('pancreatitis', 'Disease', 'MESH:D010195', (162, 174))	('KRASG12D', 'Var', (135, 143))
31355	20814421	Ji and colleagues showed that levels of active, GTP-bound KRAS increase between cells derived from non-transformed pancreas expressing KRASG12D and cells derived from KRASG12D-driven PDAC.	('increase', 'PosReg', (63, 71))	('PDAC', 'Chemical', '-', (183, 187))	('GTP', 'Chemical', 'MESH:D006160', (48, 51))	('KRASG12D', 'Var', (135, 143))	('levels', 'MPA', (30, 36))	('PDAC', 'Phenotype', 'HP:0006725', (183, 187))
31358	20814421	In support of the need for a crucial KRAS activity threshold to initiate ductal reprogramming, Siveke and colleagues showed that combining overexpression of TGFalpha, which can activate KRAS downstream of the epidermal growth factor receptor, with mutant KRAS dramatically accelerates the elimination of normal acini and the development of PanINs and intraductal papillary mucinous neoplasm (IPMN).	('development', 'CPA', (325, 336))	('accelerates', 'PosReg', (273, 284))	('mutant', 'Var', (248, 254))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('209', '232'))	('TGFalpha', 'Gene', (157, 165))	('PanINs and', 'CPA', (340, 350))	('TGFalpha', 'Gene', '21802', (157, 165))	('epidermal growth factor receptor', 'Gene', '13649', (209, 241))	('elimination', 'CPA', (289, 300))	('neoplasm', 'Phenotype', 'HP:0002664', (382, 390))	('intraductal papillary mucinous neoplasm', 'Disease', (351, 390))	('intraductal papillary mucinous neoplasm', 'Disease', 'MESH:D000077779', (351, 390))	('KRAS', 'Gene', (255, 259))	('mucinous neoplasm', 'Phenotype', 'HP:0031495', (373, 390))	('epidermal growth factor receptor', 'Gene', (209, 241))
31360	20814421	Other studies have verified the ability of pancreatitis to provide a permissive environment for specifying PDAC precursors, demonstrating that acute pancreatitis potently accelerates PanIN development, and in some cases PDAC, in mice in which mutant KRAS is expressed in the exocrine compartment.	('PDAC', 'Chemical', '-', (220, 224))	('pancreatitis', 'Phenotype', 'HP:0001733', (149, 161))	('pancreatitis', 'Disease', 'MESH:D010195', (149, 161))	('PanIN development', 'CPA', (183, 200))	('PDAC', 'Chemical', '-', (107, 111))	('accelerates', 'PosReg', (171, 182))	('pancreatitis', 'Phenotype', 'HP:0001733', (43, 55))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (143, 161))	('KRAS', 'Gene', (250, 254))	('PDAC', 'Phenotype', 'HP:0006725', (220, 224))	('pancreatitis', 'Disease', 'MESH:D010195', (43, 55))	('PDAC', 'MPA', (220, 224))	('mice', 'Species', '10090', (229, 233))	('pancreatitis', 'Disease', (149, 161))	('PDAC', 'Phenotype', 'HP:0006725', (107, 111))	('mutant', 'Var', (243, 249))	('pancreatitis', 'Disease', (43, 55))
31365	20814421	Although most MMLs were derived from ductal or centroacinar cells, only a small percentage (~5%) were the result of ADM. Desai and colleagues also noted ADM in mice following pancreatic ductal ligation, a process characterized by severe acinar apoptosis and prolonged acinar loss.	('ADM', 'Var', (153, 156))	('pancreatic ductal', 'Disease', (175, 192))	('apoptosis', 'biological_process', 'GO:0006915', ('244', '253'))	('pancreatic ductal', 'Disease', 'MESH:D021441', (175, 192))	('mice', 'Species', '10090', (160, 164))	('acinar loss', 'Disease', (268, 279))	('acinar loss', 'Disease', 'MESH:D018267', (268, 279))	('apoptosis', 'biological_process', 'GO:0097194', ('244', '253'))
31366	20814421	However, ADM can readily be induced through activation of other signalling pathways, such as epidermal growth factor (EGF) and Notch signalling, by exposing acini to matrix metalloproteinase 7 (MMP7) and, as recently appreciated, activation of mutant KRAS.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('93', '116'))	('mutant', 'Var', (244, 250))	('matrix metalloproteinase 7', 'Gene', (166, 192))	('MMP7', 'molecular_function', 'GO:0004235', ('194', '198'))	('signalling', 'biological_process', 'GO:0023052', ('64', '74'))	('ADM', 'Disease', (9, 12))	('induced', 'Reg', (28, 35))	('activation', 'PosReg', (230, 240))	('MMP7', 'Gene', '17393', (194, 198))	('EGF', 'molecular_function', 'GO:0005154', ('118', '121'))	('MMP7', 'Gene', (194, 198))	('KRAS', 'Gene', (251, 255))	('matrix metalloproteinase 7', 'Gene', '17393', (166, 192))	('signalling', 'biological_process', 'GO:0023052', ('133', '143'))
31369	20814421	Our recent work has compared the regenerative response to acute pancreatitis of normal acini versus acini expressing mutant KRAS and found that this is the case with beta-catenin signalling.	('pancreatitis', 'Disease', (64, 76))	('KRAS', 'Gene', (124, 128))	('mutant', 'Var', (117, 123))	('pancreatitis', 'Phenotype', 'HP:0001733', (64, 76))	('signalling', 'biological_process', 'GO:0023052', ('179', '189'))	('pancreatitis', 'Disease', 'MESH:D010195', (64, 76))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (58, 76))
31370	20814421	Although acini expressing mutant KRAS assume a de-differentiated, ductal state similar to wild-type acini in response to acute pancreatitis, their ability to regenerate the acinar state is blocked.	('de-differentiated', 'MPA', (47, 64))	('pancreatitis', 'Disease', (127, 139))	('KRAS', 'Gene', (33, 37))	('pancreatitis', 'Phenotype', 'HP:0001733', (127, 139))	('pancreatitis', 'Disease', 'MESH:D010195', (127, 139))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (121, 139))	('mutant', 'Var', (26, 32))
31371	20814421	Instead, acini expressing mutant KRAS persistently express duct markers and reactivated elements of embryonic development, and rapidly give rise to PanIN lesions.	('duct', 'MPA', (59, 63))	('PanIN lesions', 'Disease', (148, 161))	('reactivated elements of embryonic development', 'CPA', (76, 121))	('KRAS', 'Gene', (33, 37))	('PanIN lesions', 'Disease', 'MESH:D051437', (148, 161))	('express', 'PosReg', (51, 58))	('give rise to', 'Reg', (135, 147))	('mutant', 'Var', (26, 32))
31373	20814421	Other mouse models that combine mutant KRAS with mutations in genes involved in maintaining acinar differentiation support this potentially obligate role for de-differentiation.	('mutant', 'Var', (32, 38))	('mutations', 'Var', (49, 58))	('mouse', 'Species', '10090', (6, 11))
31374	20814421	For example, inhibiting muscle, intestine and stomach 1 (MIST1) function, a transcription factor expressed in acinar cells, results in ADM that expresses markers characteristic of the de-differentiated acini found following acute pancreatitis and during KRAS-driven ductal reprogramming and PanIN formation.	('pancreatitis', 'Disease', (230, 242))	('inhibiting', 'NegReg', (13, 23))	('formation', 'biological_process', 'GO:0009058', ('297', '306'))	('MIST1', 'Gene', '17341', (57, 62))	('transcription', 'biological_process', 'GO:0006351', ('76', '89'))	('pancreatitis', 'Phenotype', 'HP:0001733', (230, 242))	('transcription factor', 'molecular_function', 'GO:0000981', ('76', '96'))	('pancreatitis', 'Disease', 'MESH:D010195', (230, 242))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (224, 242))	('muscle, intestine and stomach 1', 'Gene', '17341', (24, 55))	('MIST1', 'Gene', (57, 62))	('ADM', 'Var', (135, 138))	('results in', 'Reg', (124, 134))
31375	20814421	Indeed, combining Mist1-knockout mice with mutant KRAS significantly accelerates the development of acinar-derived PanINs, supporting a role for de-differentiation as a component of KRAS-driven PDAC initiation.	('Mist1', 'Gene', '17341', (18, 23))	('PDAC', 'Phenotype', 'HP:0006725', (194, 198))	('development', 'CPA', (85, 96))	('KRAS', 'Gene', (50, 54))	('Mist1', 'Gene', (18, 23))	('mutant', 'Var', (43, 49))	('PDAC', 'Chemical', '-', (194, 198))	('mice', 'Species', '10090', (33, 37))	('accelerates', 'PosReg', (69, 80))
31377	20814421	However, beta-catenin signalling is blocked at an equivalent time point in mice expressing mutant KRAS, representing an early stage of ductal reprogramming.	('mice', 'Species', '10090', (75, 79))	('signalling', 'biological_process', 'GO:0023052', ('22', '32'))	('blocked', 'NegReg', (36, 43))	('KRAS', 'Gene', (98, 102))	('mutant', 'Var', (91, 97))	('beta-catenin signalling', 'MPA', (9, 32))
31378	20814421	Challenging adult acinar cells expressing both mutant KRAS and stabilized beta-catenin with caerulein inhibits PanIN formation, and instead results in abnormal duct structures that frequently display nuclear accumulation of beta-catenin.	('duct structures', 'CPA', (160, 175))	('caerulein', 'Chemical', 'MESH:D002108', (92, 101))	('results in', 'Reg', (140, 150))	('KRAS', 'Var', (54, 58))	('PanIN formation', 'MPA', (111, 126))	('formation', 'biological_process', 'GO:0009058', ('117', '126'))	('mutant KRAS', 'Var', (47, 58))	('inhibits', 'NegReg', (102, 110))
31380	20814421	These studies suggest that mutations in classical beta-catenin pathway modulators are mainly absent in PDAC because they may block the ability of KRAS to initiate cells into a progenitor-like lineage capable of being driven into PDAC.	('mutations', 'Var', (27, 36))	('PDAC', 'Phenotype', 'HP:0006725', (229, 233))	('initiate cells into a progenitor-like lineage', 'CPA', (154, 199))	('ability', 'MPA', (135, 142))	('PDAC', 'Chemical', '-', (103, 107))	('block', 'NegReg', (125, 130))	('PDAC', 'Phenotype', 'HP:0006725', (103, 107))	('PDAC', 'Disease', (103, 107))	('PDAC', 'Chemical', '-', (229, 233))
31386	20814421	For example, Hanlon and colleagues have recently demonstrated that elimination of Notch1 in Pdx1-Cre;LSL-KrasG12D mice accelerates PanIN and PDAC development.	('Kras', 'Gene', (105, 109))	('Kras', 'Gene', '16653', (105, 109))	('Notch1', 'Gene', '18128', (82, 88))	('accelerates', 'PosReg', (119, 130))	('PDAC', 'Chemical', '-', (141, 145))	('Pdx1', 'Gene', (92, 96))	('elimination', 'Var', (67, 78))	('mice', 'Species', '10090', (114, 118))	('Pdx1', 'Gene', '18609', (92, 96))	('PDAC', 'Phenotype', 'HP:0006725', (141, 145))	('Notch1', 'Gene', (82, 88))
31400	20814421	Even though mutant KRAS is sufficient to initiate the PanIN-PDAC lineage in mice, there is some evidence that it may not be necessary.	('PanIN-PDAC lineage', 'CPA', (54, 72))	('PDAC', 'Phenotype', 'HP:0006725', (60, 64))	('KRAS', 'Gene', (19, 23))	('mutant', 'Var', (12, 18))	('mice', 'Species', '10090', (76, 80))	('PDAC', 'Chemical', '-', (60, 64))
31403	20814421	KRAS mutation becomes increasingly frequent in advanced PanINs and PDAC, leading to an important but unresolved question as to when deregulated KRAS activity becomes necessary for disease progression.	('PDAC', 'Phenotype', 'HP:0006725', (67, 71))	('PDAC', 'Disease', (67, 71))	('PanINs', 'Disease', (56, 62))	('PDAC', 'Chemical', '-', (67, 71))	('frequent', 'Reg', (35, 43))	('KRAS', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
31404	20814421	Mutations in KRAS are nearly universal in human pancreatic ductal adenocarcinoma (PDAC).	('PDAC', 'Chemical', '-', (82, 86))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (48, 80))	('human', 'Species', '9606', (42, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('PDAC', 'Phenotype', 'HP:0006725', (82, 86))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (13, 17))	('pancreatic ductal adenocarcinoma', 'Disease', (48, 80))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (48, 80))
31405	20814421	Mouse models in which mutant KRAS is targeted to the pancreas reveal that KRAS signalling is sufficient to reprogram pancreatic cells into duct-like lineages capable of progressing through preneoplastic lesions and, ultimately, PDAC in stages that are reminiscent of human disease.	('preneoplastic lesions', 'CPA', (189, 210))	('PDAC', 'Phenotype', 'HP:0006725', (228, 232))	('signalling', 'biological_process', 'GO:0023052', ('79', '89'))	('progressing', 'PosReg', (169, 180))	('KRAS', 'Gene', (74, 78))	('pancreatic', 'Disease', 'MESH:D010195', (117, 127))	('mutant', 'Var', (22, 28))	('PDAC', 'Chemical', '-', (228, 232))	('Mouse', 'Species', '10090', (0, 5))	('human', 'Species', '9606', (267, 272))	('pancreatic', 'Disease', (117, 127))
31447	22068166	We used 37 human paraffin samples (10 of normal pancreas, 12 with PanIN1, 22 with PanIN2, 9 with PanIN3 and 13 with invasive carcinoma).	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('human', 'Species', '9606', (11, 16))	('invasive carcinoma', 'Disease', 'MESH:D009361', (116, 134))	('PanIN2', 'Var', (82, 88))	('PanIN1', 'Var', (66, 72))	('invasive carcinoma', 'Disease', (116, 134))	('paraffin', 'Chemical', 'MESH:D010232', (17, 25))
31466	22068166	In addition, LSL-KRasG12D mice were crossed with floxed p53 mice and pancreatic-specific cre (Pdx-1-Cre) mice to yield mice that possessed conditional p53 deletion and endogenous levels of mutant KRasG12D.	('pancreatic', 'Disease', (69, 79))	('mice', 'Species', '10090', (105, 109))	('mice', 'Species', '10090', (119, 123))	('p53', 'Gene', (56, 59))	('KRasG12D', 'Var', (196, 204))	('mutant KRasG12D', 'Var', (189, 204))	('p53', 'Gene', '22060', (151, 154))	('Pdx-1', 'Gene', (94, 99))	('p53', 'Gene', '22060', (56, 59))	('deletion', 'Var', (155, 163))	('pancreatic', 'Disease', 'MESH:D010195', (69, 79))	('mice', 'Species', '10090', (60, 64))	('p53', 'Gene', (151, 154))	('Pdx-1', 'Gene', '18609', (94, 99))	('mice', 'Species', '10090', (26, 30))
31515	22068166	We observed that the Cath E probe generated a strong specific signal (approximately threefold, p=0.0058) in the pancreas of these mice bearing PanIN lesions when compared with normal pancreas (n=5; figure 4A,E) and this signal was significantly lower than that of PDAC tumours (figure 4A,E).	('mice', 'Species', '10090', (130, 134))	('PDAC tumours', 'Disease', (264, 276))	('PanIN', 'Disease', (143, 148))	('tumour', 'Phenotype', 'HP:0002664', (269, 275))	('PDAC tumours', 'Disease', 'MESH:C537768', (264, 276))	('specific signal', 'MPA', (53, 68))	('tumours', 'Phenotype', 'HP:0002664', (269, 276))	('lesions', 'Var', (149, 156))	('lower', 'NegReg', (245, 250))
31597	33827590	The proportion of tumors in the pancreatic head was larger in the TMB_low group (P = 0.007), while tumor purity was increased in the TMB_high group (P < 0.0001) (Table 1).	('TMB', 'Chemical', '-', (133, 136))	('tumor', 'Disease', (99, 104))	('TMB', 'Chemical', '-', (66, 69))	('tumor', 'Disease', (18, 23))	('TMB_low', 'Var', (66, 73))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('increased', 'PosReg', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('larger', 'PosReg', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
31602	33827590	Interestingly, the median OS was significantly increased in the TMB_low group, which had adjusted tumor purity, compared with the TMB_high group (Fig.	('TMB', 'Chemical', '-', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('increased', 'PosReg', (47, 56))	('tumor', 'Disease', (98, 103))	('TMB_low', 'Var', (64, 71))	('TMB', 'Chemical', '-', (130, 133))
31608	33827590	For example, TRGs may affect Th17 cell differentiation, leukocyte transendothelial migration, antigen presentation and processing and IgA production (Fig.	('Th17 cell differentiation', 'CPA', (29, 54))	('antigen presentation', 'biological_process', 'GO:0019882', ('94', '114'))	('leukocyte transendothelial migration', 'CPA', (56, 92))	('processing', 'MPA', (119, 129))	('antigen presentation', 'MPA', (94, 114))	('IgA production', 'MPA', (134, 148))	('affect', 'Reg', (22, 28))	('cell differentiation', 'biological_process', 'GO:0030154', ('34', '54'))	('TRGs', 'Chemical', '-', (13, 17))	('TRGs', 'Var', (13, 17))
31613	33827590	For example, the mutation frequency of DAMTS15 was ranked 10th in the TMB_high group (3%), but it dropped out of the top 20 most frequently mutated genes.	('DAMTS15', 'Gene', (39, 46))	('mutation', 'Var', (17, 25))	('TMB', 'Chemical', '-', (70, 73))
31637	33827590	However, several anticancer factors, such as NK cells and cytotoxic scores, were also enriched in the TMB_low group (Fig.	('TMB_low', 'Var', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cytotoxic scores', 'CPA', (58, 74))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('NK cells', 'CPA', (45, 53))	('TMB', 'Chemical', '-', (102, 105))
31673	33827590	On the other hand, pancreatic cancer has a low mutation load compared to other solid tumors, which partially restrains the production of neoantigens that induce an effective immune response.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (19, 36))	('immune response', 'biological_process', 'GO:0006955', ('174', '189'))	('mutation', 'Var', (47, 55))	('solid tumors', 'Disease', (79, 91))	('restrains', 'NegReg', (109, 118))	('pancreatic cancer', 'Disease', (19, 36))	('solid tumors', 'Disease', 'MESH:D009369', (79, 91))	('production of neoantigens', 'MPA', (123, 148))	('pancreatic cancer', 'Disease', 'MESH:D010190', (19, 36))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
31676	33827590	This suggests that high TMB could be a predictor for the prognosis of patients with PDAC beyond its conventional role in patients' selection for immunotherapy.	('patients', 'Species', '9606', (70, 78))	('TMB', 'MPA', (24, 27))	('high', 'Var', (19, 23))	('PDAC', 'Disease', (84, 88))	('PDAC', 'Phenotype', 'HP:0006725', (84, 88))	('TMB', 'Chemical', '-', (24, 27))	('PDAC', 'Chemical', '-', (84, 88))	('patients', 'Species', '9606', (121, 129))
31680	33827590	Interestingly, the TMBlowMSIhigh group featured significantly prolonged OS compared with their counterparts.	('TMBlowMSIhigh', 'Var', (19, 32))	('TMB', 'Chemical', '-', (19, 22))	('prolonged', 'PosReg', (62, 71))
31683	33827590	Notably, the expression of ANKRD55 was significantly associated with higher infiltration of CD8+ T cells and lower infiltration of MDSCs, which suggested that this gene may mediate the survival benefits observed in the TMBlowMSIhigh group through the remodeling of the immune microenvironment.	('infiltration', 'CPA', (76, 88))	('CD8', 'Gene', (92, 95))	('survival benefits', 'CPA', (185, 202))	('TMB', 'Chemical', '-', (219, 222))	('CD8', 'Gene', '925', (92, 95))	('ANKRD55', 'Gene', (27, 34))	('expression', 'Var', (13, 23))	('ANKRD55', 'Gene', '79722', (27, 34))	('higher', 'PosReg', (69, 75))
31684	33827590	Previous studies have reported that single nucleotide polymorphisms in ANKRD55, an autoimmune risk protein, are associated with type 2 diabetes susceptibility.	('associated with', 'Reg', (112, 127))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (128, 143))	('ANKRD55', 'Gene', '79722', (71, 78))	('type 2 diabetes', 'Disease', 'MESH:D003924', (128, 143))	('ANKRD55', 'Gene', (71, 78))	('type 2 diabetes', 'Disease', (128, 143))	('single nucleotide polymorphisms', 'Var', (36, 67))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))
31728	33648534	Single-cell RNA sequencing in cancer research Single-cell RNA sequencing (scRNA-seq), a technology that analyzes transcriptomes of complex tissues at single-cell levels, can identify differential gene expression and epigenetic factors caused by mutations in unicellular genomes, as well as new cell-specific markers and cell types.	('RNA', 'cellular_component', 'GO:0005562', ('58', '61'))	('mutations', 'Var', (245, 254))	('differential gene expression', 'MPA', (183, 211))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('RNA', 'cellular_component', 'GO:0005562', ('12', '15'))	('gene expression', 'biological_process', 'GO:0010467', ('196', '211'))	('epigenetic factors', 'Var', (216, 234))
31735	33648534	Malignant tumors are caused by genetic mutations that result from the influence of endogenous and environmental factors, and this challenging aspect of oncology has always been a hot topic in medical research.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('Malignant tumors', 'Disease', 'MESH:D009369', (0, 16))	('mutations', 'Var', (39, 48))	('Malignant tumors', 'Disease', (0, 16))	('caused by', 'Reg', (21, 30))	('oncology', 'Phenotype', 'HP:0002664', (152, 160))
31736	33648534	Tumor development is a complex and multi-stage process whereby normal cells develop into malignant tumors, through a series of multiple gene mutations and accumulation in somatic cells.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (141, 150))	('malignant tumors', 'Disease', (89, 105))	('malignant tumors', 'Disease', 'MESH:D009369', (89, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
31737	33648534	During the development of a variety of tumors, several important gene mutations are common which drive the malignant differentiation of cells, as seen by the limitless proliferation, metastasis, and angiogenesis.	('mutations', 'Var', (70, 79))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('metastasis', 'CPA', (183, 193))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('angiogenesis', 'CPA', (199, 211))	('limitless proliferation', 'CPA', (158, 181))	('tumors', 'Disease', (39, 45))	('angiogenesis', 'biological_process', 'GO:0001525', ('199', '211'))	('malignant differentiation', 'CPA', (107, 132))
31755	33648534	scRNA-seq of tumors at different time points can identify key gene mutations, as well as the dynamic change of the tumor heterogeneity over time.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', (115, 120))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
31777	33648534	These mutations occur randomly in different genomic regions, a few of which may lead to the malignant transformation of normal somatic cells.	('lead to', 'Reg', (80, 87))	('malignant transformation', 'Disease', 'MESH:D009369', (92, 116))	('mutations', 'Var', (6, 15))	('malignant transformation', 'Disease', (92, 116))
31778	33648534	Somatic mutations mainly include gene mutation heterogeneity (base pair replacement, insertion, and deletion) and genomic instability (chromosomal instability, chromosome rearrangement, copy number variations and microsatellite instability).Through next-generation sequencing (NGS), it was found that the occurrence of many tumors, such as breast cancer, hepatoma and lung cancer, were related to the mutation of oncogenes.	('related', 'Reg', (386, 393))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('breast cancer', 'Disease', 'MESH:D001943', (340, 353))	('lung cancer', 'Disease', 'MESH:D008175', (368, 379))	('breast cancer', 'Phenotype', 'HP:0003002', (340, 353))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('hepatoma', 'Disease', (355, 363))	('mutation', 'Var', (401, 409))	('breast cancer', 'Disease', (340, 353))	('hepatoma', 'Disease', 'MESH:D006528', (355, 363))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('chromosome', 'cellular_component', 'GO:0005694', ('160', '170'))	('tumors', 'Disease', (324, 330))	('chromosomal instability', 'Phenotype', 'HP:0040012', (135, 158))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('lung cancer', 'Disease', (368, 379))	('lung cancer', 'Phenotype', 'HP:0100526', (368, 379))	('tumors', 'Disease', 'MESH:D009369', (324, 330))
31782	33648534	scRNA-seq is performed on pancreatic epithelial cells with pancreatic intraepithelial neoplasia (PanIN) to analyze gene mutations related to proliferation, invasion, and metastasis, and to evaluate the risk of malignant transformation, so as to provide the possibility to curb further tumor development.	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('pancreatic intraepithelial neoplasia', 'Disease', (59, 95))	('pancreatic intraepithelial neoplasia', 'Disease', 'MESH:D018290', (59, 95))	('neoplasia', 'Phenotype', 'HP:0002664', (86, 95))	('tumor', 'Disease', (285, 290))	('malignant transformation', 'Disease', 'MESH:D009369', (210, 234))	('malignant transformation', 'Disease', (210, 234))	('mutations', 'Var', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (285, 290))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (70, 95))
31790	33648534	These data suggest that analysis of the relationship between metastasis and gene mutation of some tumor cells, may be a new way to control tumor metastasis.	('tumor metastasis', 'Disease', (139, 155))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor metastasis', 'Disease', 'MESH:D009362', (139, 155))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('gene mutation', 'Var', (76, 89))
31791	33648534	scRNA-seq can provide comprehensive information about gene expression and single nucleotide mutations in individual tumor cells and deepen our knowledge in the process of primary tumor metastasis.	('tumor metastasis', 'Disease', 'MESH:D009362', (179, 195))	('single nucleotide mutations', 'Var', (74, 101))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor metastasis', 'Disease', (179, 195))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('gene expression', 'biological_process', 'GO:0010467', ('54', '69'))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (179, 184))
31799	33648534	In addition to the above application in the study of tumorigenesis, scRNA-seq applies in the study of tumor heterogeneity includes cell typing of tumor tissue, and analysis of the characteristic cell state of malignant cells combined with the influence of tumor microenvironment, genetic factors and epigenetic.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Disease', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('epigenetic', 'Var', (300, 310))	('tumor', 'Disease', (256, 261))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
31804	33648534	In past studies, although the research on heterogeneity of cancer evolution and development mainly focused on genetic changes, the latest cancer research data emphasized the contribution of heritable epigenetic modifications to cancer development.	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', (228, 234))	('past', 'Gene', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('past', 'Gene', '10938', (3, 7))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('epigenetic modifications', 'Var', (200, 224))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
31805	33648534	In addition to genome-level mutations, epigenetic modification was found to be an important cause of tumor heterogeneity.	('cause', 'Reg', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('epigenetic modification', 'Var', (39, 62))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
31823	33648534	Finally, authors suggested that PARP, PIGF, HDAC2 and FGFR inhibitors that effectively targeted CSCs might be potential therapeutic strategies for CDRCC.	('PIGF', 'Gene', (38, 42))	('HDAC2', 'Gene', (44, 49))	('HDAC2', 'Gene', '3066', (44, 49))	('PIGF', 'Gene', '5281', (38, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('54', '58'))	('CDRCC', 'Disease', (147, 152))	('PARP', 'Gene', '142', (32, 36))	('inhibitors', 'Var', (59, 69))	('PARP', 'Gene', (32, 36))	('FGFR', 'Gene', (54, 58))
31826	33648534	https://github.com/broadinstitute/inferCNV) is used to explore tumor scRNA-seq data to identify evidence for somatic large-scale chromosomal copy number alterations.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (63, 68))	('chromosomal copy number alterations', 'Var', (129, 164))	('tumor', 'Disease', 'MESH:D009369', (63, 68))
31845	33648534	Immune surveillance is one of the most basic functions of the immune system whereby it prevents the occurrence of tumors by recognizing, killing, and eliminating mutant cells in the body.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mutant', 'Var', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))
31852	33648534	In the escape stage, the surviving tumor cells that are insensitive to immune attack by genetic variation begin to proliferate in an uncontrolled way, thereby leading to clinically observable malignant diseases.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('leading to', 'Reg', (159, 169))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('malignant diseases', 'Disease', 'MESH:D009369', (192, 210))	('tumor', 'Disease', (35, 40))	('proliferate', 'CPA', (115, 126))	('genetic variation', 'Var', (88, 105))	('malignant diseases', 'Disease', (192, 210))
31872	33648534	The genetic changes and epigenetic variations of malignant cells, which lead to the abnormal expression of protein and the formation of a variety of tumor antigens, are the principal causes of immunogenicity.	('genetic changes', 'Var', (4, 19))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('protein', 'Protein', (107, 114))	('expression', 'MPA', (93, 103))	('tumor', 'Disease', (149, 154))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('epigenetic variations', 'Var', (24, 45))	('causes', 'Reg', (183, 189))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))
31874	33648534	The NGS technology first detects the abnormal mutation sites in the tumor cells, and then combines the molecular characteristics of Major Histocompatibility Complex (MHC) to screen the mutant proteins with high binding potential to MHC, which can accurately predict the neoantigens that can be used for the reatment (Fig.	('tumor', 'Disease', (68, 73))	('mutant', 'Var', (185, 191))	('binding', 'molecular_function', 'GO:0005488', ('211', '218'))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mutation', 'Var', (46, 54))	('Major Histocompatibility Complex', 'biological_process', 'GO:0046776', ('132', '164'))
31877	33648534	used the T3 murine methylcholanthrene (MCA)-induced sarcoma line and established T3 tumors in four groups of naive mice, followed by treatment of each group with either control mAb, anti-PD-1, anti-CTLA-4 or anti-PD-1/anti-CTLA-4.	('sarcoma', 'Disease', 'MESH:D012509', (52, 59))	('sarcoma', 'Disease', (52, 59))	('methylcholanthrene', 'Chemical', 'MESH:D008748', (19, 37))	('anti-PD-1', 'Var', (182, 191))	('murine', 'Species', '10090', (12, 18))	('MCA', 'Chemical', 'MESH:D008748', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('anti-PD-1/anti-CTLA-4', 'Var', (208, 229))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('mice', 'Species', '10090', (115, 119))	('anti-CTLA-4', 'Var', (193, 204))
31880	33648534	At the same time, monocytes/macrophages also underwent significant remodeling after ICT: macrophages in the Mac_s3, Mac_s4 and Mac_s5 clusters increased dramatically upon ICT and achieved maximal levels in the combination ICT group.Mac_s4 clustersare active in inflammatory responses and hypoxia conditions and have strong glycolytic characteristics.	('active', 'PosReg', (251, 257))	('hypoxia', 'Disease', 'MESH:D000860', (288, 295))	('hypoxia', 'Disease', (288, 295))	('group.Mac_s4 clustersare', 'Var', (226, 250))
31882	33648534	In patients with resistance to ICI, this may also be due to mutations in human leukocyte antigen (HLA), an important recognition factor in the immune recognition.	('due', 'Reg', (53, 56))	('human', 'Species', '9606', (73, 78))	('HLA', 'Gene', (98, 101))	('patients', 'Species', '9606', (3, 11))	('resistance', 'Disease', (17, 27))	('mutations', 'Var', (60, 69))
31910	33648534	scRNA-seq shows that one or more important gene mutations occur in a few somatic cells, which indicate a series of processes such as precancerous lesions, in situ tumor formation, metastasis tumor formation, and cancer relapse.	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('formation', 'biological_process', 'GO:0009058', ('197', '206'))	('indicate', 'Reg', (94, 102))	('situ tumor', 'Disease', 'MESH:D002278', (158, 168))	('precancerous lesions', 'Disease', 'MESH:D011230', (133, 153))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('precancerous lesions', 'Disease', (133, 153))	('formation', 'biological_process', 'GO:0009058', ('169', '178'))	('metastasis tumor', 'Disease', (180, 196))	('situ tumor', 'Disease', (158, 168))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('metastasis tumor', 'Disease', 'MESH:D009362', (180, 196))
31912	33648534	When combined with genomic methylation and chromatin accessibility analysis, scRNA-seq reveals the impact of epigenetic modification on tumor heterogeneity in cancer patients and provides personalized treatment of patients.	('cancer', 'Disease', (159, 165))	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('epigenetic modification', 'Var', (109, 132))	('patients', 'Species', '9606', (214, 222))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('chromatin', 'cellular_component', 'GO:0000785', ('43', '52'))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Disease', (136, 141))	('patients', 'Species', '9606', (166, 174))
31983	33572222	For this, control cells and 3D spheroids not exposed to MNPs were used for subsequent normalization to get the iron levels originating from the MNP.	('MNP', 'Var', (144, 147))	('iron levels', 'MPA', (111, 122))	('iron', 'Chemical', 'MESH:D007501', (111, 115))
32051	33572222	However, less colonies were formed by cells treated with MNP and enzymes before hyperthermia than for those treated with MNP alone before magnetic hyperthermia.	('hyperthermia', 'Disease', 'MESH:D005334', (80, 92))	('less', 'NegReg', (9, 13))	('MNP', 'Var', (57, 60))	('hyperthermia', 'Phenotype', 'HP:0001945', (80, 92))	('hyperthermia', 'Disease', (80, 92))	('hyperthermia', 'Disease', 'MESH:D005334', (147, 159))	('hyperthermia', 'Phenotype', 'HP:0001945', (147, 159))	('hyperthermia', 'Disease', (147, 159))
32099	33572222	Hyaluronidases degrade HA in the extracellular matrix by proteolytic cleavage of the glycosidic bond between D-glucoronic acid and N-acetyl-D-glucosamine.	('degrade', 'NegReg', (15, 22))	('N-acetyl-D-glucosamine', 'MPA', (131, 153))	('HA in the extracellular matrix', 'MPA', (23, 53))	('N-acetyl-D-glucosamine', 'Chemical', 'MESH:D000117', (131, 153))	('HA', 'Chemical', 'MESH:D006820', (23, 25))	('cleavage', 'Var', (69, 77))	('Hyaluronidases', 'Protein', (0, 14))	('D-glucoronic acid', 'Chemical', '-', (109, 126))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('33', '53'))
32190	31770284	In the present study, we combined data from eleven eligible studies with a total of 2047 pancreatic cancer patients, and the results showed that high pretreatment CAR was significantly associated with poor OS of pancreatic cancer patients, although the heterogeneity was moderate.	('CAR', 'Gene', '653108', (163, 166))	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('pancreatic cancer', 'Disease', 'MESH:D010190', (212, 229))	('high', 'Var', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (212, 229))	('patients', 'Species', '9606', (230, 238))	('CAR', 'cellular_component', 'GO:0005826', ('163', '166'))	('CAR', 'Gene', (163, 166))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('patients', 'Species', '9606', (107, 115))	('pancreatic cancer', 'Disease', (89, 106))	('pancreatic cancer', 'Disease', (212, 229))
32208	31770284	Liu et al study showed that a high CAR value was associated with prognosis in patients at stage III and IV, but not stage I and II.	('CAR', 'Gene', '653108', (35, 38))	('associated', 'Reg', (49, 59))	('patients', 'Species', '9606', (78, 86))	('high', 'Var', (30, 34))	('CAR', 'Gene', (35, 38))	('CAR', 'cellular_component', 'GO:0005826', ('35', '38'))
32243	31500236	We also found that most patients who received 5-FU/oxaliplatin had relapsed after previous surgery and adjuvant chemotherapy and that the group treated with 5-FU/oxaliplatin/irinotecan had the highest proportion of patients who underwent exploration.	('patients', 'Species', '9606', (215, 223))	('oxaliplatin', 'Chemical', 'MESH:C030110', (162, 173))	('5-FU', 'Chemical', 'MESH:D005472', (157, 161))	('irinotecan', 'Chemical', 'MESH:C051890', (174, 184))	('patients', 'Species', '9606', (24, 32))	('5-FU', 'Chemical', 'MESH:D005472', (46, 50))	('oxaliplatin', 'Chemical', 'MESH:C030110', (51, 62))	('5-FU/oxaliplatin', 'Var', (46, 62))	('relapsed', 'CPA', (67, 75))
32258	31500236	Unexpectedly, among patients treated with 5-FU/oxaliplatin/irinotecan, the median OS was shorter for those with localized disease (9.9 months; 95% CI, 7.0-12.8) compared to those with metastatic disease (10.3 months; 95% CI, 8.6-12.0).	('irinotecan', 'Chemical', 'MESH:C051890', (59, 69))	('5-FU/oxaliplatin/irinotecan', 'Var', (42, 69))	('localized', 'Disease', (112, 121))	('5-FU', 'Chemical', 'MESH:D005472', (42, 46))	('oxaliplatin', 'Chemical', 'MESH:C030110', (47, 58))	('patients', 'Species', '9606', (20, 28))	('shorter', 'NegReg', (89, 96))
32267	31500236	For patients receiving BSC, the HR for death decreased until six months after the start of observation, but almost no difference compared to patients treated with gemcitabine was observed after that time point.	('death', 'Disease', 'MESH:D003643', (39, 44))	('death', 'Disease', (39, 44))	('BSC', 'Var', (23, 26))	('gemcitabine', 'Chemical', 'MESH:C056507', (163, 174))	('decreased', 'NegReg', (45, 54))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (141, 149))
32271	31500236	In contrast, patients who received 5-FU/oxaliplatin had a significantly shorter TTF than the gemcitabine-only group (Table 2).	('shorter', 'NegReg', (72, 79))	('patients', 'Species', '9606', (13, 21))	('oxaliplatin', 'Chemical', 'MESH:C030110', (40, 51))	('5-FU/oxaliplatin', 'Var', (35, 51))	('gemcitabine', 'Chemical', 'MESH:C056507', (93, 104))	('TTF', 'MPA', (80, 83))	('5-FU', 'Chemical', 'MESH:D005472', (35, 39))
32273	31500236	Proportions were lower for 5-FU/oxaliplatin/irinotecan (48.4%; 95% CI, 30.2-66.9%), 5-FU/oxaliplatin (45.7%; 95% CI, 28.8-63.4%), and gemcitabine (36.8%; 95% CI, 29.8-44.1%).	('5-FU/oxaliplatin', 'Var', (84, 100))	('5-FU/oxaliplatin/irinotecan', 'Var', (27, 54))	('oxaliplatin', 'Chemical', 'MESH:C030110', (32, 43))	('5-FU', 'Chemical', 'MESH:D005472', (27, 31))	('oxaliplatin', 'Chemical', 'MESH:C030110', (89, 100))	('irinotecan', 'Chemical', 'MESH:C051890', (44, 54))	('gemcitabine', 'Chemical', 'MESH:C056507', (134, 145))	('5-FU', 'Chemical', 'MESH:D005472', (84, 88))
32289	31500236	We observed significant differences across treatment groups, but the only identifiable pattern was the restriction of peripheral sensory neuropathy to patients treated with gemcitabine/nab-paclitaxel or 5-FU/oxaliplatin with or without irinotecan (Table 3).	('paclitaxel', 'Chemical', 'MESH:D017239', (189, 199))	('peripheral sensory neuropathy', 'Disease', 'MESH:D010523', (118, 147))	('oxaliplatin', 'Chemical', 'MESH:C030110', (208, 219))	('5-FU', 'Chemical', 'MESH:D005472', (203, 207))	('irinotecan', 'Chemical', 'MESH:C051890', (236, 246))	('neuropathy', 'Phenotype', 'HP:0009830', (137, 147))	('patients', 'Species', '9606', (151, 159))	('5-FU/oxaliplatin', 'Var', (203, 219))	('peripheral sensory neuropathy', 'Disease', (118, 147))	('gemcitabine', 'Chemical', 'MESH:C056507', (173, 184))	('peripheral sensory neuropathy', 'Phenotype', 'HP:0000763', (118, 147))
32303	31500236	In summary, we showed that gemcitabine/capecitabine was associated with greater survival benefits than what prospective RCTs have suggested, and it even outperformed gemcitabine/nab-paclitaxel in our cohort.	('paclitaxel', 'Chemical', 'MESH:D017239', (182, 192))	('capecitabine', 'Chemical', 'MESH:C110904', (39, 51))	('gemcitabine', 'Chemical', 'MESH:C056507', (27, 38))	('gemcitabine', 'Chemical', 'MESH:C056507', (166, 177))	('survival benefits', 'CPA', (80, 97))	('outperformed', 'NegReg', (153, 165))	('gemcitabine/capecitabine', 'Var', (27, 51))
32335	31412251	We recently demonstrated that ectopic HRasG12V promotes mitochondrial fragmentation and tumor growth through Erk phosphorylation of the mitochondrial fission GTPase Dynamin-related protein 1 (Drp1).	('Dynamin-related protein 1', 'Gene', '74006', (165, 190))	('ectopic', 'Var', (30, 37))	('HRasG12V', 'Gene', (38, 46))	('Drp1', 'Gene', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('promotes', 'PosReg', (47, 55))	('Erk', 'Gene', '26413', (109, 112))	('phosphorylation', 'biological_process', 'GO:0016310', ('113', '128'))	('Erk', 'molecular_function', 'GO:0004707', ('109', '112'))	('mitochondrial fragmentation', 'CPA', (56, 83))	('Dynamin-related protein 1', 'Gene', (165, 190))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Erk', 'Gene', (109, 112))	('tumor', 'Disease', (88, 93))	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))	('mitochondrial fission', 'biological_process', 'GO:0000266', ('136', '157'))
32337	31412251	Furthermore, Drp1 deletion imparts a significant survival advantage in a model of KRas-driven pancreatic cancer, and tumors exhibit a strong selective pressure against complete Drp1 deletion.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Drp1', 'Gene', (13, 17))	('Drp1', 'Gene', (177, 181))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('survival', 'CPA', (49, 57))	('pancreatic cancer', 'Disease', (94, 111))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('pancreatic cancer', 'Disease', 'MESH:D010190', (94, 111))	('deletion', 'Var', (182, 190))	('advantage', 'PosReg', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('deletion', 'Var', (18, 26))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (94, 111))
32341	31412251	The inhibition of Drp1 in cells expressing oncogenic KRas leads to impaired glycolytic flux and the eventual loss of mitochondrial metabolic function.	('impaired glycolytic flux', 'Disease', 'MESH:D009422', (67, 91))	('KRas', 'Var', (53, 57))	('loss', 'NegReg', (109, 113))	('Drp1', 'Gene', (18, 22))	('mitochondrial metabolic function', 'MPA', (117, 149))	('inhibition', 'NegReg', (4, 14))	('impaired glycolytic flux', 'Disease', (67, 91))
32343	31412251	Up to 90% of PDAC cases harbor a mutation in the gene encoding KRas, leading to its constitutive activation.	('constitutive activation', 'MPA', (84, 107))	('PDAC', 'Chemical', '-', (13, 17))	('mutation', 'Var', (33, 41))	('PDAC', 'Disease', (13, 17))	('KRas', 'Gene', (63, 67))
32346	31412251	For example, oncogenic KRas signaling induces glucose uptake and glycolysis in PDAC and promotes a non-canonical use of glutamine for redox homeostasis and increased macropinocytosis.	('promotes', 'PosReg', (88, 96))	('glucose uptake', 'biological_process', 'GO:0046323', ('46', '60'))	('induces', 'PosReg', (38, 45))	('PDAC', 'Chemical', '-', (79, 83))	('homeostasis', 'biological_process', 'GO:0042592', ('140', '151'))	('KRas', 'Gene', (23, 27))	('glucose uptake', 'MPA', (46, 60))	('increased', 'PosReg', (156, 165))	('glucose', 'Chemical', 'MESH:D005947', (46, 53))	('oncogenic', 'Var', (13, 22))	('glycolysis', 'biological_process', 'GO:0006096', ('65', '75'))	('signaling', 'biological_process', 'GO:0023052', ('28', '37'))	('glutamine', 'Chemical', 'MESH:D005973', (120, 129))	('macropinocytosis', 'MPA', (166, 182))	('macropinocytosis', 'biological_process', 'GO:0044351', ('166', '182'))	('glycolysis', 'MPA', (65, 75))
32355	31412251	Mechanistically, knockdown of Drp1 results in decreased glycolytic flux in both Ras-transformed MEFs and PDAC cells.	('glycolytic flux', 'MPA', (56, 71))	('Drp1', 'Gene', (30, 34))	('MEF', 'Gene', (96, 99))	('MEF', 'Gene', '56501', (96, 99))	('decreased', 'NegReg', (46, 55))	('knockdown', 'Var', (17, 26))	('PDAC', 'Chemical', '-', (105, 109))
32356	31412251	In a genetically engineered model of KRas-driven pancreatic cancer, deletion of Drp1 leads to a significant survival advantage over littermates with wild-type Drp1, and we observe a strong selective pressure against the loss of both alleles of Drp1.	('pancreatic cancer', 'Disease', (49, 66))	('pancreatic cancer', 'Disease', 'MESH:D010190', (49, 66))	('survival advantage', 'CPA', (108, 126))	('deletion', 'Var', (68, 76))	('Drp1', 'Gene', (244, 248))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (49, 66))	('Drp1', 'Gene', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
32361	31412251	To that end, we isolated MEFs from Trp53flox/flox (P), KrasLSL-G12D/+; Trp53flox/flox (KP), or KrasLSL-G12D/+; Trp53flox/flox; Drp1flox/flox (KPD) mice, treated them with adenoviral Cre to induce recombination, and isolated clonal cell lines (Figures 1A and S1A).	('KrasLSL-G12D/+', 'Var', (95, 109))	('mice', 'Species', '10090', (147, 151))	('Trp53', 'Gene', '22059', (71, 76))	('Trp53', 'Gene', (35, 40))	('Trp53', 'Gene', (111, 116))	('G12D', 'Mutation', 'rs121913529', (103, 107))	('MEF', 'Gene', (25, 28))	('MEF', 'Gene', '56501', (25, 28))	('Trp53', 'Gene', (71, 76))	('KPD', 'Disease', 'MESH:D003922', (142, 145))	('Trp53', 'Gene', '22059', (35, 40))	('Trp53', 'Gene', '22059', (111, 116))	('G12D', 'Mutation', 'rs121913529', (63, 67))	('KPD', 'Disease', (142, 145))
32362	31412251	Consistent with our observations in HRasG12V-expressing HEK cells, the expression of KRasG12D promotes a fragmented mitochondrial morphology (compare P to KP) that reverts to a more connected morphology upon deletion of Drp1 (KPD) (Figure 1B).	('HEK', 'CellLine', 'CVCL:M624', (56, 59))	('deletion', 'Var', (208, 216))	('KPD', 'Disease', 'MESH:D003922', (226, 229))	('KRasG12D', 'Gene', (85, 93))	('Drp1', 'Gene', (220, 224))	('G12D', 'Mutation', 'rs121913529', (89, 93))	('fragmented mitochondrial morphology', 'MPA', (105, 140))	('KPD', 'Disease', (226, 229))	('promotes', 'PosReg', (94, 102))
32363	31412251	While KP MEFs exhibit robust cellular expansion in vitro, the deletion of Drp1 reduces cell expansion to the levels of the KRasWT MEFs (Figures 1C and 1D).	('MEF', 'Gene', '56501', (9, 12))	('cell expansion', 'CPA', (87, 101))	('Drp1', 'Gene', (74, 78))	('reduces', 'NegReg', (79, 86))	('MEF', 'Gene', (130, 133))	('MEF', 'Gene', '56501', (130, 133))	('cell expansion', 'biological_process', 'GO:0016049', ('87', '101'))	('deletion', 'Var', (62, 70))	('MEF', 'Gene', (9, 12))
32364	31412251	Furthermore, the deletion of Drp1 does not affect cell expansion in KrasWT MEFs (Figure S1C).	('MEF', 'Gene', (75, 78))	('MEF', 'Gene', '56501', (75, 78))	('deletion', 'Var', (17, 25))	('cell expansion', 'biological_process', 'GO:0016049', ('50', '64'))	('cell expansion', 'CPA', (50, 64))	('Drp1', 'Gene', (29, 33))
32365	31412251	Consistent with these effects, the deletion of Drp1 leads to a loss of KRas-induced soft agar colony formation in both sets of MEFs (Figures 1E and S1D).	('KRas-induced soft agar colony formation', 'CPA', (71, 110))	('Drp1', 'Gene', (47, 51))	('agar', 'Chemical', 'MESH:D000362', (89, 93))	('MEF', 'Gene', (127, 130))	('MEF', 'Gene', '56501', (127, 130))	('deletion', 'Var', (35, 43))	('formation', 'biological_process', 'GO:0009058', ('101', '110'))	('loss', 'NegReg', (63, 67))
32368	31412251	Each line has a KRas mutation at codon 12, except PDX-188t, which encodes wild-type KRas at codons 12, 13, and 61, and each of the lines exhibits high MAPK activity and is sensitive to ERK inhibition.	('MAPK', 'Enzyme', (151, 155))	('ERK', 'Gene', '26413', (185, 188))	('KRas', 'Gene', (16, 20))	('mutation', 'Var', (21, 29))	('ERK', 'molecular_function', 'GO:0004707', ('185', '188'))	('MAPK', 'molecular_function', 'GO:0004707', ('151', '155'))	('ERK', 'Gene', (185, 188))
32369	31412251	Furthermore, each cell line exhibits decreased soft agar growth following Drp1 knockdown, and the two cell lines with the greatest degree of knockdown (188t, L3.6pL) demonstrate the most robust reduction in colony number (Figures 1J, 1K, S1I, and S1J).	('Drp1', 'Gene', (74, 78))	('S1I', 'Mutation', 'p.S1I', (238, 241))	('reduction', 'NegReg', (194, 203))	('colony number', 'CPA', (207, 220))	('agar', 'Chemical', 'MESH:D000362', (52, 56))	('knockdown', 'Var', (79, 88))	('decreased', 'NegReg', (37, 46))	('soft agar growth', 'CPA', (47, 63))
32374	31412251	The re-expression of murine Drp1 in the KPD MEFs is sufficient to increase ECAR to levels seen in KP MEFs (Figure S1M).	('MEF', 'Gene', (101, 104))	('MEF', 'Gene', '56501', (101, 104))	('increase', 'PosReg', (66, 74))	('MEF', 'Gene', (44, 47))	('murine', 'Var', (21, 27))	('MEF', 'Gene', '56501', (44, 47))	('KPD', 'Disease', (40, 43))	('ECAR', 'MPA', (75, 79))	('Drp1', 'Gene', (28, 32))	('murine', 'Species', '10090', (21, 27))	('KPD', 'Disease', 'MESH:D003922', (40, 43))
32376	31412251	Fourteen-day knockdown of Drp1 reduces both ECAR and 3H2O production compared to controls in both cell lines, which is consistent with the MEF data (Figures 2E and 2F).	('Drp1', 'Gene', (26, 30))	('MEF', 'Gene', (139, 142))	('MEF', 'Gene', '56501', (139, 142))	('reduces', 'NegReg', (31, 38))	('ECAR', 'MPA', (44, 48))	('3H2O', 'Chemical', '-', (53, 57))	('3H2O production', 'MPA', (53, 68))	('knockdown', 'Var', (13, 22))
32382	31412251	Stable re-expression of HK2 in KPD cells rescues ECAR to the levels observed in KP cells, suggesting that the loss of HK2 is sufficient to account for the loss of glycolytic flux (Figures 3E and 3F).	('HK2', 'Gene', (118, 121))	('loss', 'NegReg', (155, 159))	('loss', 'Var', (110, 114))	('HK2', 'molecular_function', 'GO:0008256', ('118', '121'))	('rescues', 'PosReg', (41, 48))	('KPD', 'Disease', 'MESH:D003922', (31, 34))	('HK2', 'molecular_function', 'GO:0008256', ('24', '27'))	('ECAR', 'MPA', (49, 53))	('KPD', 'Disease', (31, 34))	('HK2', 'Gene', (24, 27))	('glycolytic flux', 'MPA', (163, 178))
32384	31412251	To test whether the requirement for Drp1 for KRas-induced transformation extends to an in vivo setting, we crossed KrasLSL-G12D/+; Trp53flox/flox; Pdx-1-CreERTg/+ mice (29) to mice harboring two floxed alleles of Drp1 to generate KPDC mice.	('Trp53', 'Gene', (131, 136))	('KPD', 'Disease', 'MESH:D003922', (230, 233))	('KrasLSL-G12D/+', 'Var', (115, 129))	('mice', 'Species', '10090', (176, 180))	('mice', 'Species', '10090', (163, 167))	('G12D', 'Mutation', 'rs121913529', (123, 127))	('KPD', 'Disease', (230, 233))	('Pdx-1', 'Gene', '18609', (147, 152))	('mice', 'Species', '10090', (235, 239))	('Trp53', 'Gene', '22059', (131, 136))	('Pdx-1', 'Gene', (147, 152))
32385	31412251	We injected 30 mice of each genotype (KrasLSL-G12D/+; Trp53flox/flox; Pdx-1-CreERTg/+; Drp1+/+ OR Drp1flox/flox) with tamoxifen after weaning and monitored them for tumor development.	('Pdx-1', 'Gene', (70, 75))	('tamoxifen', 'Chemical', 'MESH:D013629', (118, 127))	('Trp53', 'Gene', '22059', (54, 59))	('G12D', 'Mutation', 'rs121913529', (46, 50))	('Drp1+/+', 'Var', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mice', 'Species', '10090', (15, 19))	('Pdx-1', 'Gene', '18609', (70, 75))	('Trp53', 'Gene', (54, 59))	('tumor', 'Disease', (165, 170))
32388	31412251	The masses of tumors, frequency of tumor sequelae, and overall weight gain were similar between Drp1WT and Drp1flox mice (Figures S2A-S2C).	('mice', 'Species', '10090', (116, 120))	('weight gain', 'Disease', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Drp1WT', 'Var', (96, 102))	('weight gain', 'Disease', 'MESH:D015430', (63, 74))	('tumor sequelae', 'Disease', (35, 49))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor sequelae', 'Disease', 'MESH:D009369', (35, 49))	('weight gain', 'Phenotype', 'HP:0004324', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
32389	31412251	We sought to determine whether Drp1flox mice progress to adenocarcinoma slower than Drp1WT mice, which could contribute to the survival advantage we observe.	('mice', 'Species', '10090', (91, 95))	('adenocarcinoma slower', 'Disease', 'MESH:D000230', (57, 78))	('adenocarcinoma slower', 'Disease', (57, 78))	('Drp1flox', 'Var', (31, 39))	('mice', 'Species', '10090', (40, 44))
32391	31412251	Pancreata from both Drp1flox and Drp1WT mice exhibit all subtypes of PanINs when analyzed either 40 or 60 days after tamoxifen injection (Figure S2D).	('mice', 'Species', '10090', (40, 44))	('tamoxifen', 'Chemical', 'MESH:D013629', (117, 126))	('exhibit', 'Reg', (45, 52))	('Drp1flox', 'Var', (20, 28))
32392	31412251	Although there are no differences in lesions after 40 days, Drp1flox mice exhibit decreased PanIN3, but not PanIN1/2 lesions compared to Drp1WT mice 60 days following injection, suggesting that the loss of Drp1 impairs the progression to PanIN3 and explaining, at least in part, the survival advantage observed for the Drp1flox mice (Figure 4D).	('mice', 'Species', '10090', (328, 332))	('mice', 'Species', '10090', (144, 148))	('Drp1', 'Gene', (206, 210))	('mice', 'Species', '10090', (69, 73))	('progression', 'MPA', (223, 234))	('survival advantage', 'CPA', (283, 301))	('PanIN3', 'MPA', (238, 244))	('loss', 'Var', (198, 202))	('decreased', 'NegReg', (82, 91))	('impairs', 'NegReg', (211, 218))
32404	31412251	Given that deletion or knockdown of Drp1 in both MEFs and PDAC cell lines impairs cell accumulation and growth in soft agar, these data suggest that the Drp1-/- tumor cells have acquired a set of physiological adaptations that allow them to overcome the loss of Drp1.	('impairs', 'NegReg', (74, 81))	('agar', 'Chemical', 'MESH:D000362', (119, 123))	('PDAC', 'Chemical', '-', (58, 62))	('Drp1-/-', 'Gene', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('MEF', 'Gene', (49, 52))	('MEF', 'Gene', '56501', (49, 52))	('deletion', 'Var', (11, 19))	('Drp1', 'Gene', (36, 40))	('tumor', 'Disease', (161, 166))
32405	31412251	Given the decrease in glycolytic flux upon deletion or knockdown of Drp1 in MEFs and patient-derived PDAC cell lines, we analyzed those parameters in the murine tumor-derived cell lines.	('patient', 'Species', '9606', (85, 92))	('knockdown', 'Var', (55, 64))	('MEF', 'Gene', '56501', (76, 79))	('Drp1', 'Gene', (68, 72))	('glycolytic flux', 'MPA', (22, 37))	('deletion', 'Var', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('murine', 'Species', '10090', (154, 160))	('decrease', 'NegReg', (10, 18))	('PDAC', 'Chemical', '-', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('MEF', 'Gene', (76, 79))	('tumor', 'Disease', (161, 166))
32412	31412251	We next performed pathway analyses using two independent metabolomics platforms:pathway enrichment analysis on the set of 350 metabolites significantly different between the pairwise comparison of all Drp1-/- and Drp1WT samples and topographical pathway analyses of our entire dataset identified the TCA cycle and fatty acid metabolism (i.e., glycerophospholipid) as potential top pathways that contribute to the global metabolic reprogramming occurring upon the loss of Drp1 in our KRas-driven cancer cells (Figures 5I and S4A).	('loss', 'Var', (463, 467))	('glycerophospholipid', 'Chemical', 'MESH:D020404', (343, 362))	('fatty acid', 'Chemical', 'MESH:D005227', (314, 324))	('cancer', 'Phenotype', 'HP:0002664', (495, 501))	('TCA', 'Chemical', 'MESH:D014233', (300, 303))	('Drp1', 'Gene', (471, 475))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('314', '335'))	('cancer', 'Disease', 'MESH:D009369', (495, 501))	('TCA cycle', 'biological_process', 'GO:0006099', ('300', '309'))	('cancer', 'Disease', (495, 501))
32413	31412251	The levels of succinate are increased in both Drp1-/- lines compared to Drp1WT, while the levels of fumarate are decreased (Figure 6A), suggesting a defect in succinate dehydrogenase (SDH) activity.	('increased', 'PosReg', (28, 37))	('succinate dehydrogenase', 'Gene', '30956', (159, 182))	('SDH', 'Gene', '30956', (184, 187))	('Drp1-/-', 'Var', (46, 53))	('levels of succinate', 'MPA', (4, 23))	('succinate', 'Chemical', 'MESH:D019802', (159, 168))	('SDH', 'Gene', (184, 187))	('defect', 'NegReg', (149, 155))	('fumarate', 'Chemical', 'MESH:D005650', (100, 108))	('succinate dehydrogenase', 'Gene', (159, 182))	('succinate', 'Chemical', 'MESH:D019802', (14, 23))	('levels of fumarate', 'MPA', (90, 108))	('activity', 'MPA', (189, 197))
32421	31412251	Furthermore, the metabolomics data reveal that the levels of short-chain acylcarnitines (C4, C6, and C8) are increased in the Drp1-/- cells compared to the Drp1WT cells (Figure 6E).	('acylcarnitines', 'Chemical', 'MESH:C116917', (73, 87))	('Drp1-/-', 'Var', (126, 133))	('increased', 'PosReg', (109, 118))	('levels', 'MPA', (51, 57))
32436	31412251	However, at 25 h, KP but not P MEFs exhibit a decrease in Red C12-LD colocalization, demonstrating that KRas promotes increased fatty acid egress from LDs (Figure S7).	('fatty acid egress', 'MPA', (128, 145))	('fatty acid', 'Chemical', 'MESH:D005227', (128, 138))	('Red C12-LD colocalization', 'MPA', (58, 83))	('increased', 'PosReg', (118, 127))	('MEF', 'Gene', (31, 34))	('KRas', 'Var', (104, 108))	('MEF', 'Gene', '56501', (31, 34))	('decrease', 'NegReg', (46, 54))
32437	31412251	KPD MEFs exhibit a similar degree of Red C12-LD colocalization as the KP MEFs, indicating that the loss of Drp1 in MEFs does not directly affect fatty acid trafficking (Figure S7) and suggesting the defect observed in the Drp1-/- tumor cell lines is instead a consequence of impaired mitochondrial function.	('MEF', 'Gene', (115, 118))	('tumor', 'Disease', (230, 235))	('MEF', 'Gene', '56501', (115, 118))	('MEF', 'Gene', '56501', (73, 76))	('fatty acid', 'Chemical', 'MESH:D005227', (145, 155))	('KPD', 'Disease', (0, 3))	('mitochondrial function', 'MPA', (284, 306))	('affect', 'Reg', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('MEF', 'Gene', (4, 7))	('KPD', 'Disease', 'MESH:D003922', (0, 3))	('impaired mitochondrial function', 'Phenotype', 'HP:0003287', (275, 306))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('MEF', 'Gene', '56501', (4, 7))	('Drp1', 'Gene', (107, 111))	('fatty acid trafficking', 'MPA', (145, 167))	('MEF', 'Gene', (73, 76))	('loss', 'Var', (99, 103))
32439	31412251	By seeding Drp1WT and Drp1-/- cells under a variety of nutrient conditions, we found that while removal of either glucose or glutamine had equivalent effects on cell viability, the removal of both, leaving serum as the sole source of carbon, led to a statistically significant difference in viability (Figure 7D).	('glutamine', 'Chemical', 'MESH:D005973', (125, 134))	('removal', 'Var', (181, 188))	('carbon', 'Chemical', 'MESH:D002244', (234, 240))	('glucose', 'Chemical', 'MESH:D005947', (114, 121))	('viability', 'MPA', (291, 300))
32444	31412251	The defects in transformation observed upon Drp1 knockout in vitro are also observed in vivo, as Drp1Fl/Fl mice exhibit fewer high-grade precursor lesions and a 45-day survival advantage over Drp1WT mice in an inducible model of PDAC.	('Drp1', 'Gene', (44, 48))	('high-grade precursor lesions', 'MPA', (126, 154))	('survival advantage', 'CPA', (168, 186))	('mice', 'Species', '10090', (199, 203))	('Drp1Fl/Fl', 'Var', (97, 106))	('mice', 'Species', '10090', (107, 111))	('PDAC', 'Chemical', '-', (229, 233))	('fewer', 'NegReg', (120, 125))
32448	31412251	Ultimately, these dual roles for Drp1 can account for the significant survival advantage we observe in the Drp1Fl/Fl mice, as tumors in these mice necessarily arise from cells that have lost only one allele of Drp1, which will be fewer than the number of potential initiating cells in the Drp1WT mice, or from cells that have overcome the loss of glycolytic metabolism through additional genetic events.	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('metabolism', 'biological_process', 'GO:0008152', ('358', '368'))	('mice', 'Species', '10090', (296, 300))	('mice', 'Species', '10090', (142, 146))	('Drp1', 'Gene', (210, 214))	('mice', 'Species', '10090', (117, 121))	('Drp1Fl/Fl', 'Var', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('lost', 'NegReg', (186, 190))
32452	31412251	ETC dysfunction would promote additional mitochondrial damage through the generation of reactive oxygen species.	('mitochondrial damage', 'MPA', (41, 61))	('dysfunction', 'Var', (4, 15))	('promote', 'PosReg', (22, 29))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (88, 111))
32453	31412251	In addition, the loss of Drp1 and mitochondrial fission may disrupt normal mitophagy, leading to the additional accumulation of dysfunctional mitochondria.	('accumulation', 'PosReg', (112, 124))	('mitochondrial fission', 'CPA', (34, 55))	('mitophagy', 'CPA', (75, 84))	('dysfunctional mitochondria', 'Disease', (128, 154))	('mitochondria', 'cellular_component', 'GO:0005739', ('142', '154'))	('Drp1', 'Gene', (25, 29))	('mitophagy', 'biological_process', 'GO:0000422', ('75', '84'))	('mitochondrial fission', 'biological_process', 'GO:0000266', ('34', '55'))	('disrupt', 'NegReg', (60, 67))	('mitophagy', 'biological_process', 'GO:0000423', ('75', '84'))	('loss', 'Var', (17, 21))	('dysfunctional mitochondria', 'Disease', 'MESH:C564925', (128, 154))
32454	31412251	The mitochondrial dysfunction we observe is most apparent in fatty acid utilization, in which loss of Drp1 reduces efficient fatty acid oxidation.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (4, 29))	('efficient fatty acid oxidation', 'MPA', (115, 145))	('fatty acid', 'Chemical', 'MESH:D005227', (125, 135))	('fatty acid utilization', 'MPA', (61, 83))	('mitochondrial dysfunction', 'Disease', (4, 29))	('Drp1', 'Gene', (102, 106))	('loss', 'Var', (94, 98))	('fatty acid', 'Chemical', 'MESH:D005227', (61, 71))	('reduces', 'NegReg', (107, 114))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('125', '145'))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (4, 29))
32460	31412251	Ultimately, our work suggests that the inhibition of Drp1 in cancer may have therapeutic value, either as a single agent or in combination with other approaches.	('inhibition', 'Var', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Drp1', 'Protein', (53, 57))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
32468	31412251	To generate clonal MEFs, we isolated E13.5-E14.5 aged embryos, removed fetal heart and liver structures, and digested remaining tissue both mechanically and enzymatically with 0.1% Trypsin (GIBCO) for 5 minutes at 37 C. Cell suspension from digested tissue was cultured overnight in DMEM supplemented with 10% FBS.	('MEF', 'Gene', (19, 22))	('MEF', 'Gene', '56501', (19, 22))	('FBS', 'Disease', (310, 313))	('E13.5-E14.5', 'Var', (37, 48))	('DMEM', 'Chemical', '-', (283, 287))	('FBS', 'Disease', 'MESH:D005198', (310, 313))
32534	31412251	Drp1 is required for oncogenic KRas-driven transformation Drp1 promotes KRas-driven glycolysis Loss of Drp1 inhibits pancreatic tumorigenesis Loss of Drp1 impairs mitochondrial metabolism in tumor cells	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mitochondrial metabolism', 'MPA', (163, 187))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('metabolism', 'biological_process', 'GO:0008152', ('177', '187'))	('pancreatic tumor', 'Disease', 'MESH:D010190', (117, 133))	('inhibits', 'NegReg', (108, 116))	('Drp1', 'Gene', (150, 154))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('impairs', 'NegReg', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('Drp1', 'Gene', (103, 107))	('Loss', 'Var', (95, 99))	('tumor', 'Disease', (191, 196))	('tumor', 'Disease', (128, 133))	('pancreatic tumor', 'Disease', (117, 133))	('glycolysis', 'biological_process', 'GO:0006096', ('84', '94'))
32542	31088502	Treatment with specific inhibitors of PDK1 impaired anchorage-dependent and anchorage-independent growth of pancreatic cancer cell lines, as well as pancreatic tumour growth in a xenograft model.	('pancreatic tumour', 'Disease', 'MESH:D010190', (149, 166))	('pancreatic tumour', 'Disease', (149, 166))	('PDK1', 'molecular_function', 'GO:0004740', ('38', '42'))	('impaired', 'NegReg', (43, 51))	('pancreatic cancer', 'Disease', (108, 125))	('inhibitors', 'Var', (24, 34))	('PDK1', 'Gene', (38, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('pancreatic tumour', 'Phenotype', 'HP:0002894', (149, 166))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))
32543	31088502	Mechanistically, inhibition or downregulation of PDK1 resulted in reduced activation of the serum/glucocorticoid regulated kinase family member 3 and subsequent reduced phosphorylation of its target N-Myc downstream regulated 1.	('reduced', 'NegReg', (66, 73))	('reduced', 'NegReg', (161, 168))	('N-Myc downstream regulated 1', 'Gene', '10397', (199, 227))	('inhibition', 'Var', (17, 27))	('PDK1', 'molecular_function', 'GO:0004740', ('49', '53'))	('phosphorylation', 'biological_process', 'GO:0016310', ('169', '184'))	('PDK1', 'Gene', (49, 53))	('activation', 'PosReg', (74, 84))	('N-Myc downstream regulated 1', 'Gene', (199, 227))	('serum/glucocorticoid regulated kinase family member 3', 'Gene', '23678', (92, 145))	('downregulation', 'NegReg', (31, 45))	('phosphorylation', 'MPA', (169, 184))
32544	31088502	Additionally, we found that combination of sub-optimal concentrations of inhibitors selective for PDK1 and the class IB PI3K isoform p110gamma inhibits pancreatic cancer cell growth and colonies formation more potently than each single treatment.	('inhibits', 'NegReg', (143, 151))	('p110gamma', 'Gene', (133, 142))	('PDK1', 'molecular_function', 'GO:0004740', ('98', '102'))	('PDK1', 'Gene', (98, 102))	('formation', 'biological_process', 'GO:0009058', ('195', '204'))	('PI3K', 'molecular_function', 'GO:0016303', ('120', '124'))	('PI3', 'Gene', '5266', (120, 123))	('pancreatic cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('pancreatic cancer', 'Disease', 'MESH:D010190', (152, 169))	('PI3', 'Gene', (120, 123))	('colonies formation', 'CPA', (186, 204))	('cell growth', 'biological_process', 'GO:0016049', ('170', '181'))	('p110gamma', 'Gene', '5294', (133, 142))	('inhibitors', 'Var', (73, 83))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (152, 169))
32547	31088502	PDAC is associated with high-frequency somatic mutations in a subset of genes, most frequently in the gene encoding the small GTPase KRAS, which is mutated in the majority of human PDAC (> 95%).	('human', 'Species', '9606', (175, 180))	('PDAC', 'Chemical', '-', (181, 185))	('PDAC', 'Chemical', '-', (0, 4))	('mutations', 'Var', (47, 56))	('PDAC', 'Disease', (0, 4))	('PDAC', 'Phenotype', 'HP:0006725', (181, 185))	('KRAS', 'Gene', (133, 137))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('KRAS', 'Gene', '3845', (133, 137))
32564	31088502	When these mice were crossed with tumourigenic heterozygous PTEN+/- mice, the prevalence of tumour development was reduced in mice with deficient PDK1 levels, confirming the importance of PDK1 in tumour development driven by loss of PTEN.	('mice', 'Species', '10090', (68, 72))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('mice', 'Species', '10090', (126, 130))	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('tumour', 'Disease', (92, 98))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('reduced', 'NegReg', (115, 122))	('deficient', 'Var', (136, 145))	('tumour', 'Disease', 'MESH:D009369', (196, 202))	('loss', 'Var', (225, 229))	('tumour', 'Disease', (34, 40))	('mice', 'Species', '10090', (11, 15))	('PDK1', 'Gene', (146, 150))	('tumour', 'Disease', (196, 202))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('PDK1', 'molecular_function', 'GO:0004740', ('146', '150'))	('PDK1', 'molecular_function', 'GO:0004740', ('188', '192'))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
32569	31088502	Furthermore, PDK1 mRNA is correlated with poor survival rates in untreated HCC patients and is the most prominent factor in the time to recurrence prediction, post-operatively.	('HCC', 'Gene', '619501', (75, 78))	('PDK1', 'Gene', (13, 17))	('HCC', 'Phenotype', 'HP:0001402', (75, 78))	('survival rates', 'MPA', (47, 61))	('patients', 'Species', '9606', (79, 87))	('PDK1', 'molecular_function', 'GO:0004740', ('13', '17'))	('poor', 'NegReg', (42, 46))	('mRNA', 'Var', (18, 22))	('HCC', 'Gene', (75, 78))
32577	31088502	A previous study reported that deletion of PDPK1 inhibits KRasG12D- driven PDAC development in a transgenic mouse model, revealing a key role for PDK1 in PDAC initiation.	('PDAC', 'Chemical', '-', (154, 158))	('KRas', 'Gene', '3845', (58, 62))	('inhibits', 'NegReg', (49, 57))	('PDAC', 'Phenotype', 'HP:0006725', (75, 79))	('mouse', 'Species', '10090', (108, 113))	('deletion', 'Var', (31, 39))	('PDAC', 'Phenotype', 'HP:0006725', (154, 158))	('PDPK1', 'Gene', (43, 48))	('KRas', 'Gene', (58, 62))	('PDAC', 'Chemical', '-', (75, 79))	('PDK1', 'molecular_function', 'GO:0004740', ('146', '150'))
32596	31088502	Primary antibodies used were: pFoxO1 (Thr24)/FoxO3a (Thr32) (#9464), pAkt (Thr308) (#4056), pSGK3 (Thr320) (#5642), pNDRG1 (Thr346) (#3217), Akt (#9272), SGK3 (#8156), PDK1 (#3062), NDRG1 (#5196), GAPDH (#5174).	('NDRG1', 'Gene', (117, 122))	('FoxO3a', 'Gene', (45, 51))	('PDK1', 'molecular_function', 'GO:0004740', ('168', '172'))	('Thr346', 'Chemical', '-', (124, 130))	('#4056', 'Var', (84, 89))	('Thr32', 'Chemical', '-', (53, 58))	('Akt', 'Gene', '207', (141, 144))	('FoxO3a', 'Gene', '2309', (45, 51))	('#3217', 'Var', (133, 138))	('Thr308', 'Chemical', '-', (75, 81))	('#3062', 'Var', (174, 179))	('#5196', 'Var', (189, 194))	('Akt', 'Gene', (70, 73))	('Thr320', 'Chemical', '-', (99, 105))	('Akt', 'Gene', '207', (70, 73))	('#5642', 'Var', (108, 113))	('Thr32', 'Chemical', '-', (99, 104))	('#9272', 'Var', (146, 151))	('SGK3', 'Gene', (154, 158))	('Thr24', 'Chemical', '-', (38, 43))	('NDRG1', 'Gene', '10397', (117, 122))	('NDRG1', 'Gene', '10397', (182, 187))	('#8156', 'Var', (160, 165))	('#5174', 'Var', (204, 209))	('GAPDH', 'Gene', '2597', (197, 202))	('FoxO1', 'Gene', (31, 36))	('#9464', 'Var', (61, 66))	('FoxO1', 'Gene', '2308', (31, 36))	('PDK1', 'Gene', (168, 172))	('GAPDH', 'Gene', (197, 202))	('NDRG1', 'Gene', (182, 187))	('Akt', 'Gene', (141, 144))
32607	31088502	Specifically, cells were treated with the small molecules GSK2334470 and MP7 as well as the Inositol (1,3,4,5,6) pentakisphosphate (InsP5) derivative 2-O-benzyl-InsP5 (2-O-Bn-InsP5) that we previously reported to target PDK1 selectively.	('GSK', 'molecular_function', 'GO:0050321', ('58', '61'))	('GSK2334470', 'Var', (58, 68))	('GSK2334470', 'Chemical', 'MESH:C555257', (58, 68))	('PDK1', 'Gene', (220, 224))	('PDK1', 'molecular_function', 'GO:0004740', ('220', '224'))	('Inositol (1,3,4,5,6) pentakisphosphate', 'Chemical', 'MESH:C451920', (92, 130))	('2-O-benzyl-InsP5', 'Chemical', '-', (150, 166))	('2-O-Bn-InsP5', 'Chemical', '-', (168, 180))	('MP7', 'Var', (73, 76))
32612	31088502	PDK1 inhibition also reduced anchorage-independent growth in CFPAC-1 (Additional file 2: Figure S1c,d), PANC-1 (Additional file 2: Figure S2c,d, Additional file 2: Figure S3b-d), and HPAF-II (Additional file 2: Figure S4a,b) cells.	('anchorage-independent growth', 'CPA', (29, 57))	('reduced', 'NegReg', (21, 28))	('CFPAC-1', 'CellLine', 'CVCL:1119', (61, 68))	('inhibition', 'Var', (5, 15))	('HPAF-II', 'Disease', 'MESH:C537730', (183, 190))	('PDK1', 'Gene', (0, 4))	('HPAF-II', 'Disease', (183, 190))	('PDK1', 'molecular_function', 'GO:0004740', ('0', '4'))	('PANC-1', 'CellLine', 'CVCL:0480', (104, 110))
32613	31088502	It has been reported previously that genetic ablation of PDPK1 reduces KRasG12D- driven PDAC development in a transgenic mouse model and that treatment with a pan class I PI3Ks inhibitor reduces PDAC progression in KPC mice, the animal model that most accurately recapitulates the human disease.	('PDAC progression', 'CPA', (195, 211))	('PDAC', 'Chemical', '-', (195, 199))	('genetic ablation', 'Var', (37, 53))	('mice', 'Species', '10090', (219, 223))	('PI3', 'Gene', '5266', (171, 174))	('KRas', 'Gene', (71, 75))	('human', 'Species', '9606', (281, 286))	('KRas', 'Gene', '3845', (71, 75))	('PDAC', 'Phenotype', 'HP:0006725', (88, 92))	('reduces', 'NegReg', (63, 70))	('mouse', 'Species', '10090', (121, 126))	('reduces', 'NegReg', (187, 194))	('PDAC', 'Phenotype', 'HP:0006725', (195, 199))	('PDPK1', 'Gene', (57, 62))	('PI3', 'Gene', (171, 174))	('PDAC', 'Chemical', '-', (88, 92))
32617	31088502	Treatment of mice with MP7 significantly inhibited tumour growth in vivo (Fig.	('mice', 'Species', '10090', (13, 17))	('MP7', 'Var', (23, 26))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('inhibited', 'NegReg', (41, 50))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', (51, 57))
32618	31088502	3d), indicating that targeting PDK1 pharmacologically is able to reduce PDAC progression in vivo.	('PDAC', 'Chemical', '-', (72, 76))	('targeting', 'Var', (21, 30))	('reduce', 'NegReg', (65, 71))	('PDK1', 'molecular_function', 'GO:0004740', ('31', '35'))	('PDK1', 'Gene', (31, 35))	('PDAC', 'Disease', (72, 76))	('PDAC', 'Phenotype', 'HP:0006725', (72, 76))
32619	31088502	Taken together these data indicate that PDK1 regulates PDAC cell proliferation and that inhibition of the enzyme can efficiently reduce PDAC growth in vitro.	('PDK1', 'Gene', (40, 44))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('reduce', 'NegReg', (129, 135))	('PDAC', 'Chemical', '-', (55, 59))	('PDAC', 'Phenotype', 'HP:0006725', (136, 140))	('PDAC cell proliferation', 'CPA', (55, 78))	('PDAC', 'Disease', (136, 140))	('regulates', 'Reg', (45, 54))	('PDAC', 'Phenotype', 'HP:0006725', (55, 59))	('PDK1', 'molecular_function', 'GO:0004740', ('40', '44'))	('PDAC', 'Chemical', '-', (136, 140))	('inhibition', 'Var', (88, 98))
32620	31088502	At the same time, our in vivo results, together with previous evidence using genetic approaches, indicate that PDK1 represents a novel important target to counteract PDAC progression, and that MP7 might represent a valuable drug to be used for PDAC treatment.	('PDAC', 'Disease', (166, 170))	('PDAC', 'Phenotype', 'HP:0006725', (166, 170))	('PDAC', 'Chemical', '-', (244, 248))	('PDK1', 'molecular_function', 'GO:0004740', ('111', '115'))	('PDAC', 'Chemical', '-', (166, 170))	('PDAC', 'Phenotype', 'HP:0006725', (244, 248))	('PDK1', 'Gene', (111, 115))	('MP7', 'Var', (193, 196))
32625	31088502	4 c) cells with either GSK2334470 or MP7 efficiently blocked the FBS-induced phosphorylation of Akt at its residue Thr308, a bona fide readout of PDK1 activity, without affecting the total levels of Akt.	('phosphorylation', 'MPA', (77, 92))	('Akt', 'Gene', (96, 99))	('MP7', 'Var', (37, 40))	('blocked', 'NegReg', (53, 60))	('GSK2334470', 'Chemical', 'MESH:C555257', (23, 33))	('Thr308', 'Chemical', '-', (115, 121))	('Akt', 'Gene', '207', (96, 99))	('Akt', 'Gene', '207', (199, 202))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('FBS-induced', 'Disease', (65, 76))	('GSK', 'molecular_function', 'GO:0050321', ('23', '26'))	('PDK1', 'molecular_function', 'GO:0004740', ('146', '150'))	('Akt', 'Gene', (199, 202))	('GSK2334470', 'Var', (23, 33))
32628	31088502	Consistent with data on Akt Thr308, inhibition of PDK1 also reduced SGK3 phosphorylation (Fig.	('PDK1', 'Gene', (50, 54))	('inhibition', 'Var', (36, 46))	('Thr308', 'Chemical', '-', (28, 34))	('PDK1', 'molecular_function', 'GO:0004740', ('50', '54'))	('SGK3', 'Protein', (68, 72))	('reduced', 'NegReg', (60, 67))	('Akt', 'Gene', '207', (24, 27))	('phosphorylation', 'MPA', (73, 88))	('phosphorylation', 'biological_process', 'GO:0016310', ('73', '88'))	('Akt', 'Gene', (24, 27))
32630	31088502	SGK3 has been reported to regulate NDRG1 phosphorylation at its residue Thr346, which leads to degradation of the protein.	('SGK3', 'Gene', (0, 4))	('NDRG1', 'Gene', (35, 40))	('Thr346', 'Chemical', '-', (72, 78))	('phosphorylation', 'biological_process', 'GO:0016310', ('41', '56'))	('regulate', 'Reg', (26, 34))	('phosphorylation', 'MPA', (41, 56))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('NDRG1', 'Gene', '10397', (35, 40))	('leads to', 'Reg', (86, 94))	('Thr346', 'Var', (72, 78))	('degradation of the protein', 'MPA', (95, 121))	('degradation', 'biological_process', 'GO:0009056', ('95', '106'))
32631	31088502	A clear inhibition of NDRG1 Thr346 phosphorylation (both in the absence and in the presence of FBS) was detected in AsPC-1 (Fig.	('Thr346', 'Chemical', '-', (28, 34))	('inhibition', 'NegReg', (8, 18))	('Thr346', 'Var', (28, 34))	('AsPC-1', 'CellLine', 'CVCL:0152', (116, 122))	('phosphorylation', 'MPA', (35, 50))	('NDRG1', 'Gene', (22, 27))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('NDRG1', 'Gene', '10397', (22, 27))
32643	31088502	6c) cells, suggesting that inhibition of PDK1 can partly affect PDAC cell proliferation through its effect on SGK3 activation.	('SGK3', 'Protein', (110, 114))	('PDK1', 'molecular_function', 'GO:0004740', ('41', '45'))	('activation', 'PosReg', (115, 125))	('PDAC', 'Phenotype', 'HP:0006725', (64, 68))	('PDAC', 'Disease', (64, 68))	('affect', 'Reg', (57, 63))	('inhibition', 'Var', (27, 37))	('PDK1', 'Gene', (41, 45))	('PDAC', 'Chemical', '-', (64, 68))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))
32648	31088502	Reduced cell growth was also detected in AsPC-1 cells upon treatment with IPI-742 (Additional file 2: Figure S5a).	('IPI-742', 'Chemical', '-', (74, 81))	('IPI-742', 'Var', (74, 81))	('cell growth', 'CPA', (8, 19))	('Reduced', 'NegReg', (0, 7))	('cell growth', 'biological_process', 'GO:0016049', ('8', '19'))	('AsPC-1', 'CellLine', 'CVCL:0152', (41, 47))
32656	31088502	Consistent with this, combination of GSK2334470 with IPI-742 (Additional file 2: Figure S6a) reduced numbers of AsPC-1 cells more potently than each inhibitor used at sub-optimal concentrations.	('GSK2334470', 'Chemical', 'MESH:C555257', (37, 47))	('combination', 'Interaction', (22, 33))	('reduced', 'NegReg', (93, 100))	('AsPC-1', 'CellLine', 'CVCL:0152', (112, 118))	('IPI-742', 'Chemical', '-', (53, 60))	('IPI-742', 'Gene', (53, 60))	('GSK2334470', 'Var', (37, 47))	('GSK', 'molecular_function', 'GO:0050321', ('37', '40'))	('numbers of AsPC-1 cells', 'CPA', (101, 124))
32657	31088502	A similar trend was observed in AsPC-1 cells upon combination of IPI-549 with GSK2334470 (Additional file 2: Figure S6b) and in CFPAC-1 cells upon combination of IPI-549 with either GSK2334470 or 2-O-Bn-InsP5 (Additional file 2: Figure S6c).	('combination', 'Interaction', (50, 61))	('GSK2334470', 'Var', (78, 88))	('AsPC-1', 'CellLine', 'CVCL:0152', (32, 38))	('GSK', 'molecular_function', 'GO:0050321', ('182', '185'))	('CFPAC-1', 'CellLine', 'CVCL:1119', (128, 135))	('GSK', 'molecular_function', 'GO:0050321', ('78', '81'))	('GSK2334470', 'Chemical', 'MESH:C555257', (78, 88))	('GSK2334470', 'Chemical', 'MESH:C555257', (182, 192))	('combination', 'Interaction', (147, 158))	('2-O-Bn-InsP5', 'Chemical', '-', (196, 208))	('IPI-549', 'Chemical', '-', (65, 72))	('IPI-549', 'Chemical', '-', (162, 169))
32658	31088502	Data indicated that treatment with IPI-742 in combination with either GSK2334470 or 2-O-Bn-InsP5 strongly reduced the number of HPAF-II colonies in soft agar assays, when sub-optimal concentrations of each inhibitor were used (Fig.	('HPAF-II colonies', 'Disease', (128, 144))	('2-O-Bn-InsP5', 'Chemical', '-', (84, 96))	('IPI-742', 'Chemical', '-', (35, 42))	('HPAF-II colonies', 'Disease', 'MESH:C537730', (128, 144))	('GSK2334470', 'Var', (70, 80))	('agar', 'Chemical', 'MESH:D000362', (153, 157))	('GSK2334470', 'Chemical', 'MESH:C555257', (70, 80))	('reduced', 'NegReg', (106, 113))	('GSK', 'molecular_function', 'GO:0050321', ('70', '73'))
32663	31088502	Our results are consistent with a previous study reporting that pancreas-specific deletion of PDPK1 reduced acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia formation and PDAC formation in a KRasG12D-driven transgenic model.	('PDAC formation', 'CPA', (188, 202))	('metaplasia', 'Disease', (125, 135))	('pancreatic intraepithelial neoplasia', 'Disease', 'MESH:D018290', (137, 173))	('KRas', 'Gene', (208, 212))	('KRas', 'Gene', '3845', (208, 212))	('metaplasia', 'biological_process', 'GO:0036074', ('125', '135'))	('PDAC', 'Phenotype', 'HP:0006725', (188, 192))	('reduced', 'NegReg', (100, 107))	('formation', 'biological_process', 'GO:0009058', ('174', '183'))	('PDPK1', 'Gene', (94, 99))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (148, 173))	('deletion', 'Var', (82, 90))	('PDAC', 'Chemical', '-', (188, 192))	('formation', 'biological_process', 'GO:0009058', ('193', '202'))	('metaplasia', 'Disease', 'MESH:D008679', (125, 135))	('neoplasia', 'Phenotype', 'HP:0002664', (164, 173))	('pancreatic intraepithelial neoplasia', 'Disease', (137, 173))
32664	31088502	Interestingly, ablation of PDPK11 did not affect lung tumour formation in KRasG12D-driven models of non small cell lung carcinoma, suggesting a specific role for the enzyme during PDAC development.	('PDAC', 'Phenotype', 'HP:0006725', (180, 184))	('formation', 'biological_process', 'GO:0009058', ('61', '70'))	('KRas', 'Gene', (74, 78))	('lung tumour', 'Disease', (49, 60))	('ablation', 'Var', (15, 23))	('lung tumour', 'Disease', 'MESH:D008175', (49, 60))	('KRas', 'Gene', '3845', (74, 78))	('PDAC', 'Chemical', '-', (180, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('non small cell lung carcinoma', 'Disease', (100, 129))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (104, 129))	('lung tumour', 'Phenotype', 'HP:0100526', (49, 60))	('non small cell lung carcinoma', 'Disease', 'MESH:D002289', (100, 129))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('PDPK11', 'Gene', (27, 33))
32665	31088502	Whether PDK1 might act specifically downstream of mutant KRas in the context of pancreatic cancer remains to be established.	('PDK1', 'molecular_function', 'GO:0004740', ('8', '12'))	('KRas', 'Gene', (57, 61))	('KRas', 'Gene', '3845', (57, 61))	('pancreatic cancer', 'Disease', (80, 97))	('pancreatic cancer', 'Disease', 'MESH:D010190', (80, 97))	('mutant', 'Var', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))	('PDK1', 'Gene', (8, 12))
32666	31088502	In this respect, it is worth mentioning that all PDAC cell lines used in our study bear a KRas mutation in G12, possibly providing further evidence of a specific KRas/PDK1 pathway in PDAC.	('bear', 'Reg', (83, 87))	('KRas', 'Gene', '3845', (90, 94))	('PDAC', 'Chemical', '-', (49, 53))	('G12', 'Gene', (107, 110))	('mutation in', 'Var', (95, 106))	('PDAC', 'Chemical', '-', (183, 187))	('PDK1', 'molecular_function', 'GO:0004740', ('167', '171'))	('KRas', 'Gene', '3845', (162, 166))	('PDAC', 'Phenotype', 'HP:0006725', (49, 53))	('KRas', 'Gene', (162, 166))	('KRas', 'Gene', (90, 94))	('PDAC', 'Phenotype', 'HP:0006725', (183, 187))
32672	31088502	Importantly, SGK3, that can be regulated through PDK1-dependent phosphorylation of residue Thr320 within its T-loop, has been identified as a key regulator of such PI3K/PDK1-dependent, Akt-independent signalling pathways in cancer.	('regulator', 'Reg', (146, 155))	('Thr320', 'Var', (91, 97))	('phosphorylation', 'biological_process', 'GO:0016310', ('64', '79'))	('PI3', 'Gene', '5266', (164, 167))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('PI3K', 'molecular_function', 'GO:0016303', ('164', '168'))	('PDK1', 'molecular_function', 'GO:0004740', ('49', '53'))	('Akt', 'Gene', '207', (185, 188))	('PI3', 'Gene', (164, 167))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('signalling', 'biological_process', 'GO:0023052', ('201', '211'))	('SGK3', 'Gene', (13, 17))	('PDK1', 'molecular_function', 'GO:0004740', ('169', '173'))	('Thr320', 'Chemical', '-', (91, 97))	('cancer', 'Disease', (224, 230))	('Akt', 'Gene', (185, 188))
32673	31088502	Evidence includes a study demonstrating that PDK1-mediated SGK3 activation was critical for anchorage-independent growth in a subset of PIK3CA (the gene encoding for p110alpha) mutant breast cancer cell lines with minimal Akt activation.	('PIK3CA', 'Gene', (136, 142))	('SGK3', 'Gene', (59, 63))	('p110alpha', 'Gene', (166, 175))	('p110alpha', 'Gene', '5290', (166, 175))	('Akt', 'Gene', '207', (222, 225))	('PDK1', 'molecular_function', 'GO:0004740', ('45', '49'))	('PIK3CA', 'Gene', '5290', (136, 142))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('mutant', 'Var', (177, 183))	('Akt', 'Gene', (222, 225))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Disease', (184, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))
32680	31088502	For instance, we reported that inhibition of PDK1 with 2-O-Bn-InsP5 was able to reduce cell numbers in different cancer cell lines as well as growth of prostate cancer PC3 cells in a xenograft model in nude mice.	('cancer', 'Disease', (161, 167))	('prostate cancer', 'Disease', (152, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('PDK1', 'molecular_function', 'GO:0004740', ('45', '49'))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('PC3', 'CellLine', 'CVCL:0035', (168, 171))	('PDK1', 'Gene', (45, 49))	('prostate cancer', 'Disease', 'MESH:D011471', (152, 167))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('prostate cancer', 'Phenotype', 'HP:0012125', (152, 167))	('inhibition', 'Var', (31, 41))	('reduce', 'NegReg', (80, 86))	('nude mice', 'Species', '10090', (202, 211))	('2-O-Bn-InsP5', 'Chemical', '-', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('growth', 'MPA', (142, 148))
32681	31088502	Similarly, MP7 reduced soft agar colony formation in a subset of cancer cell lines as well as primary tumour xenograft lines.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('soft agar colony formation', 'CPA', (23, 49))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('agar', 'Chemical', 'MESH:D000362', (28, 32))	('MP7', 'Var', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('formation', 'biological_process', 'GO:0009058', ('40', '49'))	('reduced', 'NegReg', (15, 22))	('tumour', 'Disease', (102, 108))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
32683	31088502	More importantly, our results indicate that inhibition of PDK1 can represent a useful strategy to counteract progression of PDAC.	('inhibition', 'Var', (44, 54))	('PDAC', 'Chemical', '-', (124, 128))	('PDK1', 'Gene', (58, 62))	('PDAC', 'Disease', (124, 128))	('PDAC', 'Phenotype', 'HP:0006725', (124, 128))	('PDK1', 'molecular_function', 'GO:0004740', ('58', '62'))
32685	31088502	Finally, we report that inhibition of PDK1 potentiates the effect of other drugs in PDAC cell lines.	('PDAC', 'Phenotype', 'HP:0006725', (84, 88))	('PDK1', 'molecular_function', 'GO:0004740', ('38', '42'))	('potentiates', 'PosReg', (43, 54))	('PDK1', 'Gene', (38, 42))	('inhibition', 'Var', (24, 34))	('PDAC', 'Chemical', '-', (84, 88))	('effect', 'MPA', (59, 65))
32693	31088502	In summary, in this study we demonstrated that inhibition of PDK1 reduces PDAC cell growth in vitro and in vivo.	('PDK1', 'molecular_function', 'GO:0004740', ('61', '65'))	('inhibition', 'Var', (47, 57))	('PDAC', 'Disease', (74, 78))	('reduces', 'NegReg', (66, 73))	('PDAC', 'Phenotype', 'HP:0006725', (74, 78))	('PDK1', 'Gene', (61, 65))	('cell growth', 'biological_process', 'GO:0016049', ('79', '90'))	('PDAC', 'Chemical', '-', (74, 78))
32694	31088502	These results, together with previous evidence using genetic ablation of PDPK1, provide a strong rationale to investigate further the use of PDK1 inhibitors in PDAC as novel therapeutic strategies for pancreatic cancer patients.	('PDK1', 'Gene', (141, 145))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (201, 218))	('PDAC', 'Phenotype', 'HP:0006725', (160, 164))	('inhibitors', 'Var', (146, 156))	('pancreatic cancer', 'Disease', (201, 218))	('pancreatic cancer', 'Disease', 'MESH:D010190', (201, 218))	('PDK1', 'molecular_function', 'GO:0004740', ('141', '145'))	('PDAC', 'Chemical', '-', (160, 164))	('patients', 'Species', '9606', (219, 227))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
32695	31088502	Our data further suggest that combination of PDK1 inhibitors with selective PI3K inhibitors might enhance their anti-cancer activity, possibly by targeting SGK3-dependent resistance mechanisms.	('enhance', 'PosReg', (98, 105))	('PI3', 'Gene', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('inhibitors', 'Var', (50, 60))	('PDK1', 'molecular_function', 'GO:0004740', ('45', '49'))	('combination', 'Interaction', (30, 41))	('PDK1', 'Gene', (45, 49))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('PI3', 'Gene', '5266', (76, 79))	('PI3K', 'molecular_function', 'GO:0016303', ('76', '80'))
32700	30976201	Overexpression and Tyr421-phosphorylation of cortactin is induced by three-dimensional spheroid culturing and contributes to migration and invasion of pancreatic ductal adenocarcinoma (PDAC) cells The nucleation-promoting factor cortactin is expressed and promotes tumor progression and metastasis in various cancers.	('cortactin', 'Gene', '2017', (45, 54))	('invasion', 'CPA', (139, 147))	('migration', 'CPA', (125, 134))	('cortactin', 'Gene', (229, 238))	('Tyr421-phosphorylation', 'Var', (19, 41))	('tumor', 'Disease', (265, 270))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (151, 183))	('cancers', 'Phenotype', 'HP:0002664', (309, 316))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('cancers', 'Disease', (309, 316))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('cortactin', 'Gene', '2017', (229, 238))	('contributes', 'Reg', (110, 121))	('pancreatic ductal adenocarcinoma', 'Disease', (151, 183))	('phosphorylation', 'biological_process', 'GO:0016310', ('26', '41'))	('cortactin', 'Gene', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('Tyr421', 'Chemical', '-', (19, 25))	('promotes', 'PosReg', (256, 264))	('metastasis', 'CPA', (287, 297))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (151, 183))	('cancers', 'Disease', 'MESH:D009369', (309, 316))
32706	30976201	In PDAC cell lines Panc-1 and BxPC-3, knockdown of cortactin impaired migration and invasion, while cell proliferation was not affected.	('PDAC', 'Chemical', '-', (3, 7))	('cell proliferation', 'biological_process', 'GO:0008283', ('100', '118'))	('cortactin', 'Gene', (51, 60))	('impaired', 'NegReg', (61, 69))	('BxPC-3', 'CellLine', 'CVCL:0186', (30, 36))	('knockdown', 'Var', (38, 47))	('Panc-1', 'CellLine', 'CVCL:0480', (19, 25))
32721	30976201	Phosphorylation of cortactin occurring primarily at tyrosine 421 (Tyr421), enhances the recruitment of SH2-domain proteins, the activation of Arp2/3 complex and focal adhesion stability and turnover.	('activation', 'PosReg', (128, 138))	('cortactin', 'Gene', (19, 28))	('SH2-domain proteins', 'Protein', (103, 122))	('tyrosine 421', 'Var', (52, 64))	('tyrosine', 'Chemical', 'MESH:D014443', (52, 60))	('Phosphorylation', 'MPA', (0, 15))	('Arp2/3 complex', 'Protein', (142, 156))	('recruitment', 'MPA', (88, 99))	('enhances', 'PosReg', (75, 83))	('focal adhesion stability', 'CPA', (161, 185))	('men', 'Species', '9606', (95, 98))	('Tyr421', 'Chemical', '-', (66, 72))	('focal adhesion', 'cellular_component', 'GO:0005925', ('161', '175'))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('turnover', 'CPA', (190, 198))
32724	30976201	Previously published data suggests an important role for cortactin in PDAC, indicating an association between high cortactin expression and decreased survival time.	('decreased', 'NegReg', (140, 149))	('survival time', 'CPA', (150, 163))	('expression', 'MPA', (125, 135))	('PDAC', 'Chemical', '-', (70, 74))	('high', 'Var', (110, 114))	('cortactin', 'Protein', (115, 124))	('PDAC', 'Disease', (70, 74))
32746	30976201	The following primary antibodies were used according to the manufacturer's instructions: cortactin (#3502), phospho-cortactin Tyr421 (#4569), ERK1/2 (#4695), phoshpho-ERK1/2 Thr202/Tyr204 (#4370), GAPDH clone D16H11 (#5174), Src (#2109) and phospho-Src Tyr416 (#2101), gelsolin D9W8Y (#12953) (all rabbit host species and obtained from Cell Signaling Technology) and E-cadherin NCH-38 (#MA5-12547, mouse, Thermo Fisher Scientific).	('Tyr', 'Chemical', 'MESH:D014443', (181, 184))	('mouse', 'Species', '10090', (398, 403))	('#5174', 'Var', (217, 222))	('Tyr421', 'Chemical', '-', (126, 132))	('rabbit', 'Species', '9986', (298, 304))	('gelsolin', 'Gene', '2934', (269, 277))	('#12953', 'Var', (285, 291))	('D9W8Y (#12953', 'Var', (278, 291))	('ERK', 'Gene', '5594', (167, 170))	('ERK1', 'molecular_function', 'GO:0004707', ('167', '171'))	('gelsolin', 'Gene', (269, 277))	('Signaling', 'biological_process', 'GO:0023052', ('341', '350'))	('ERK', 'Gene', '5594', (142, 145))	('GAPDH', 'Gene', '100009074', (197, 202))	('E-cadherin', 'Gene', (367, 377))	('#2109', 'Var', (230, 235))	('E-cadherin', 'Gene', '999', (367, 377))	('ERK', 'Gene', (167, 170))	('ERK', 'Gene', (142, 145))	('Thr', 'Chemical', 'MESH:D013912', (174, 177))	('#MA5-12547', 'Var', (386, 396))	('Tyr', 'Chemical', 'MESH:D014443', (253, 256))	('cadherin', 'molecular_function', 'GO:0008014', ('369', '377'))	('GAPDH', 'Gene', (197, 202))	('Tyr', 'Chemical', 'MESH:D014443', (126, 129))	('ERK1', 'molecular_function', 'GO:0004707', ('142', '146'))
32776	30976201	Tyr421 phosphorylated cortactin was detected in 92% of 64 tumor cores (two of the 66 tissue samples were excluded from further analysis due to low tumor percentage (< 5%); 8% of the cases showed negative tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (147, 152))	('Tyr421 phosphorylated', 'Var', (0, 21))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))	('Tyr421', 'Chemical', '-', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
32779	30976201	No significant correlations were observed for the overall survival rate, but patients with high cortactin expression had a trend towards shorter overall survival, as illustrated in Additional file 1: Figure S1.	('shorter', 'NegReg', (137, 144))	('high', 'Var', (91, 95))	('overall survival', 'MPA', (145, 161))	('expression', 'MPA', (106, 116))	('patients', 'Species', '9606', (77, 85))	('cortactin', 'Gene', (96, 105))
32827	30976201	Deregulated proteolysis might increase cortactin protein stability in cancer with high cortactin expression but without gene amplification.	('proteolysis', 'biological_process', 'GO:0006508', ('12', '23'))	('cortactin', 'MPA', (39, 48))	('high', 'Var', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('increase', 'PosReg', (30, 38))	('cortactin', 'Gene', (87, 96))	('cancer', 'Disease', (70, 76))	('Deregulated proteolysis', 'MPA', (0, 23))	('expression', 'MPA', (97, 107))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
32830	30976201	Elevated cortactin activation by phosphorylation has been revealed to promote cancer progression in breast cancer and malignant melanoma by, e.g.	('cortactin', 'Protein', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('phosphorylation', 'Var', (33, 48))	('cancer', 'Disease', (78, 84))	('activation', 'PosReg', (19, 29))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('malignant melanoma', 'Phenotype', 'HP:0002861', (118, 136))	('promote', 'PosReg', (70, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('breast cancer', 'Disease', (100, 113))	('malignant melanoma', 'Disease', (118, 136))	('malignant melanoma', 'Disease', 'MESH:D008545', (118, 136))	('cancer', 'Disease', (107, 113))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
32833	30976201	Interestingly, it has also been reported that hyperphosphorylated cortactin might suppress cell migration by a negative feedback mechanism, as knockdown of cortactin in gastric cancer cells with high cortactin phosphorylation levels and high migratory potential further enhanced cell migration.	('cortactin', 'Gene', (156, 165))	('gastric cancer', 'Disease', (169, 183))	('cortactin phosphorylation levels', 'MPA', (200, 232))	('negative feedback', 'MPA', (111, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('cell migration', 'biological_process', 'GO:0016477', ('279', '293'))	('cell migration', 'biological_process', 'GO:0016477', ('91', '105'))	('cell migration', 'CPA', (279, 293))	('high', 'PosReg', (195, 199))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('phosphorylation', 'biological_process', 'GO:0016310', ('210', '225'))	('suppress', 'NegReg', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('knockdown', 'Var', (143, 152))	('cell migration', 'CPA', (91, 105))	('enhanced', 'PosReg', (270, 278))
32835	30976201	In functional migration and invasion assays as well as proliferation assays with the two PDAC cell lines BxPC-3 and Panc-1, we were able to demonstrate that a CRISPR/Cas9-mediated cortactin knockout resulted in significant reduction in migration and invasion, while proliferation of the PDAC cells was unaltered.	('knockout', 'Var', (190, 198))	('cortactin', 'Gene', (180, 189))	('PDAC', 'Chemical', '-', (89, 93))	('invasion', 'CPA', (250, 258))	('BxPC-3', 'CellLine', 'CVCL:0186', (105, 111))	('migration', 'CPA', (236, 245))	('invasion', 'CPA', (28, 36))	('Cas', 'cellular_component', 'GO:0005650', ('166', '169'))	('reduction', 'NegReg', (223, 232))	('PDAC', 'Chemical', '-', (287, 291))	('Panc-1', 'CellLine', 'CVCL:0480', (116, 122))
32836	30976201	It has to be pointed out that, employing of a serum gradient, the xCELLigence assay is unable to clearly distinguish between chemotaxis and migration; however, the effects of CTTN knockout were also observed in scratch assays in the absence of a serum gradient.	('chemotaxis', 'biological_process', 'GO:0006935', ('125', '135'))	('CTTN', 'Gene', (175, 179))	('CTTN', 'Gene', '2017', (175, 179))	('knockout', 'Var', (180, 188))
32837	30976201	Comparable results using RNAi knockdown of cortactin were demonstrated by Miyazawa et al., showing that suppression of cortactin decreased CDCP1-PKCdelta-mediated cell migration and invasion of BxPC-3 cells.	('cell migration', 'biological_process', 'GO:0016477', ('163', '177'))	('CDCP1', 'Gene', (139, 144))	('invasion of BxPC-3 cells', 'CPA', (182, 206))	('PKCdelta', 'Gene', (145, 153))	('BxPC-3', 'CellLine', 'CVCL:0186', (194, 200))	('PKCdelta', 'Gene', '5580', (145, 153))	('PKCdelta', 'molecular_function', 'GO:0004697', ('145', '153'))	('cortactin', 'Gene', (119, 128))	('decreased', 'NegReg', (129, 138))	('RNAi', 'biological_process', 'GO:0016246', ('25', '29'))	('suppression', 'Var', (104, 115))	('CDCP1', 'Gene', '64866', (139, 144))
32839	30976201	Immunohistochemical staining confirmed the accumulation of phosphorylated cortactin at sites of cell-cell contacts together with the cell-cell contact molecule E-cadherin, which was re-expressed/upregulated in cells cultured in spheroids.	('accumulation', 'PosReg', (43, 55))	('cortactin', 'Gene', (74, 83))	('E-cadherin', 'Gene', (160, 170))	('E-cadherin', 'Gene', '999', (160, 170))	('cadherin', 'molecular_function', 'GO:0008014', ('162', '170'))	('phosphorylated', 'Var', (59, 73))
32855	30976201	described an EMT switch after gelsolin knockdown by siRNA with a conversion of E-cadherin to N-cadherin in mammary epithelial cells.	('EMT', 'Gene', '3702', (13, 16))	('cadherin', 'molecular_function', 'GO:0008014', ('95', '103'))	('gelsolin', 'Gene', (30, 38))	('EMT', 'biological_process', 'GO:0001837', ('13', '16'))	('knockdown', 'Var', (39, 48))	('E-cadherin', 'Gene', (79, 89))	('gelsolin', 'Gene', '2934', (30, 38))	('N-cadherin', 'Gene', (93, 103))	('E-cadherin', 'Gene', '999', (79, 89))	('N-cadherin', 'Gene', '1000', (93, 103))	('cadherin', 'molecular_function', 'GO:0008014', ('81', '89'))	('EMT', 'Gene', (13, 16))	('conversion', 'MPA', (65, 75))
32863	30976201	Cortactin expression and Tyr421-phosphorylation would then contribute to a pro-metastatic, migratory phenotype in PDAC.	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('PDAC', 'Disease', (114, 118))	('Tyr421-phosphorylation', 'Var', (25, 47))	('pro-metastatic', 'CPA', (75, 89))	('migratory', 'CPA', (91, 100))	('Cortactin', 'Gene', '2017', (0, 9))	('Tyr421', 'Chemical', '-', (25, 31))	('PDAC', 'Chemical', '-', (114, 118))	('contribute to', 'Reg', (59, 72))	('Cortactin', 'Gene', (0, 9))
32864	30976201	In conclusion, our results identify cortactin and its phosphorylation on Tyr421 as an important molecular player in PDAC progression.	('cortactin', 'Gene', (36, 45))	('phosphorylation', 'Var', (54, 69))	('PDAC', 'Disease', (116, 120))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('Tyr421', 'Chemical', '-', (73, 79))	('PDAC', 'Chemical', '-', (116, 120))
32873	29963165	Furthermore, it was demonstrated that the knockdown of FUT3 impaired the adhesion of Capan-1 with E-selectin and inhibited transforming growth factor (TGF)-beta-induced epithelial-mesenchymal transition.	('TGF', 'Gene', (151, 154))	('FUT3', 'Gene', (55, 59))	('Capan-1', 'Protein', (85, 92))	('inhibited', 'NegReg', (113, 122))	('TGF', 'Gene', '7040', (151, 154))	('selectin', 'molecular_function', 'GO:0030246', ('100', '108'))	('adhesion', 'MPA', (73, 81))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('169', '202'))	('impaired', 'NegReg', (60, 68))	('E-selectin', 'Gene', (98, 108))	('FUT3', 'Gene', '2525', (55, 59))	('Capan-1', 'CellLine', 'CVCL:0237', (85, 92))	('selectin', 'molecular_function', 'GO:0008337', ('100', '108'))	('E-selectin', 'Gene', '6401', (98, 108))	('knockdown', 'Var', (42, 51))
32874	29963165	These data suggest that the knockdown of FUT3 inhibits the tumorigenesis in vivo and FUT3 may be a promising target aiming at reducing the metastatic virulence of pancreatic cancer cells.	('FUT3', 'Gene', (41, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (163, 180))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('metastatic virulence', 'MPA', (139, 159))	('reducing', 'NegReg', (126, 134))	('FUT3', 'Gene', '2525', (85, 89))	('FUT3', 'Gene', '2525', (41, 45))	('virulence', 'biological_process', 'GO:0009405', ('150', '159'))	('inhibits', 'NegReg', (46, 54))	('virulence', 'biological_process', 'GO:0016032', ('150', '159'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (163, 180))	('pancreatic cancer', 'Disease', (163, 180))	('virulence', 'biological_process', 'GO:0009406', ('150', '159'))	('knockdown', 'Var', (28, 37))	('FUT3', 'Gene', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
32910	29963165	A total of 2 different sequences of shRNA for the FUT3 gene were examined (Clone ID: V2LHS_83410, 5'-TATAAGTGGTGGTCCTGGG-3' and V3LHS_392930, 5'-CCAAGTTGAACCAGATCCA-3' 10 microg lyophilized plasmid for each).	('FUT3', 'Gene', (50, 54))	('FUT3', 'Gene', '2525', (50, 54))	('V3LHS_392930', 'Var', (128, 140))	('V2LHS_83410', 'Var', (85, 96))
32939	29963165	The transwell assay indicated that the number of migrated FUT3 knockdown Capan-1 cells (shFUT3-2) was decreased almost 3-fold, compared with the shNT (Fig.	('FUT3', 'Gene', (58, 62))	('Capan-1', 'CellLine', 'CVCL:0237', (73, 80))	('FUT3', 'Gene', (90, 94))	('FUT3', 'Gene', '2525', (58, 62))	('FUT3', 'Gene', '2525', (90, 94))	('knockdown', 'Var', (63, 72))	('decreased', 'NegReg', (102, 111))
32958	29963165	The present study validated that the knockdown of FUT3 in Capan-1 cells decreased the adhesion of cancer cells to E-selectin, which is closely associated with the process of metastasis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('selectin', 'molecular_function', 'GO:0008337', ('116', '124'))	('adhesion', 'MPA', (86, 94))	('E-selectin', 'Gene', (114, 124))	('decreased', 'NegReg', (72, 81))	('knockdown', 'Var', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('E-selectin', 'Gene', '6401', (114, 124))	('FUT3', 'Gene', (50, 54))	('cancer', 'Disease', (98, 104))	('Capan-1', 'CellLine', 'CVCL:0237', (58, 65))	('selectin', 'molecular_function', 'GO:0030246', ('116', '124'))	('FUT3', 'Gene', '2525', (50, 54))
32961	29963165	The TGF-beta signaling pathway was activated by FUT3 through fucosylation of Type I TGF-beta receptors kinase in SLea and SLex-producing cancer cells, leading to EMT and augmentation of their malignant potential.	('EMT', 'biological_process', 'GO:0001837', ('162', '165'))	('fucosylation', 'Var', (61, 73))	('TGF-beta', 'Gene', (84, 92))	('cancer', 'Disease', (137, 143))	('FUT3', 'Gene', '2525', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('TGF-beta', 'Gene', (4, 12))	('FUT3', 'Gene', (48, 52))	('SLea', 'Disease', (113, 117))	('augmentation', 'PosReg', (170, 182))	('activated', 'PosReg', (35, 44))	('malignant potential', 'CPA', (192, 211))	('signaling pathway', 'biological_process', 'GO:0007165', ('13', '30'))	('EMT', 'CPA', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('fucosylation', 'biological_process', 'GO:0036065', ('61', '73'))	('SLea', 'Disease', 'None', (113, 117))	('TGF-beta', 'Gene', '7040', (84, 92))	('TGF-beta', 'Gene', '7040', (4, 12))
32962	29963165	The results of the present study demonstrated that the knockdown of FUT3 by shRNA in Capan-1 cells increased the expression of E-cadherin and decreased the rate of TGF-beta-induced EMT, which was in accordance with previous studies.	('expression', 'MPA', (113, 123))	('knockdown', 'Var', (55, 64))	('FUT3', 'Gene', '2525', (68, 72))	('EMT', 'biological_process', 'GO:0001837', ('181', '184'))	('TGF-beta', 'Gene', (164, 172))	('decreased', 'NegReg', (142, 151))	('cadherin', 'molecular_function', 'GO:0008014', ('129', '137'))	('E-cadherin', 'Gene', (127, 137))	('FUT3', 'Gene', (68, 72))	('Capan-1', 'CellLine', 'CVCL:0237', (85, 92))	('increased', 'PosReg', (99, 108))	('E-cadherin', 'Gene', '999', (127, 137))	('TGF-beta', 'Gene', '7040', (164, 172))
32966	29963165	In conclusion, the results of the present study suggest that knocking down of FUT3 was sufficient to impair tumorigenesis in vivo.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('FUT3', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('knocking down', 'Var', (61, 74))	('impair', 'NegReg', (101, 107))	('FUT3', 'Gene', '2525', (78, 82))
32976	29239017	We established a linear prognostic model of five lncRNA (C9orf139, MIR600HG, RP5-965G21.4, RP11-436K8.1, and CTC-327F10.4) and divided patients into high- and low-risk group according to the prognostic index.	('patients', 'Species', '9606', (135, 143))	('C9orf139', 'Gene', '401563', (57, 65))	('MIR600HG', 'Gene', (67, 75))	('RP11', 'Gene', (91, 95))	('MIR600HG', 'Gene', '81571', (67, 75))	('RP5-965G21.4', 'Var', (77, 89))	('C9orf139', 'Gene', (57, 65))	('RP11', 'Gene', '26121', (91, 95))
32997	29239017	We conducted univariate Cox regression between differentially expressed lncRNA profiles and PDAC patients, and the results were shown that a total of 13 lncRNAs (MIR600HG; CC9orf139; CTC-327F10.4; RP11-452H21.4; RP11-489O18.1; RP11-436K8.1; RP5-965G21.4; RP11-286H15.1; RP11-118B22.4; CTD-2527I21.15; CH507-513H4.5; FAM53B-AS1; and RP11-430C7.5) was significantly associated with OS when the P-value was less than 0.05.	('MIR600HG', 'Gene', (162, 170))	('RP11', 'Gene', '26121', (255, 259))	('FAM53B-AS1', 'Gene', (316, 326))	('RP11', 'Gene', (197, 201))	('FAM53B-AS1', 'Gene', '101927944;9679;5729', (316, 326))	('Cox', 'Gene', (24, 27))	('RP11', 'Gene', '26121', (270, 274))	('PDAC', 'Chemical', '-', (92, 96))	('C9orf139', 'Gene', (173, 181))	('CH507-513H4.5', 'Var', (301, 314))	('PDAC', 'Phenotype', 'HP:0006725', (92, 96))	('RP11', 'Gene', (227, 231))	('RP5-965G21.4', 'Var', (241, 253))	('MIR600HG', 'Gene', '81571', (162, 170))	('CH507-513H4.5', 'CellLine', 'CVCL:A570', (301, 314))	('RP11', 'Gene', (255, 259))	('RP11', 'Gene', '26121', (332, 336))	('RP11', 'Gene', '26121', (212, 216))	('RP11', 'Gene', (270, 274))	('C9orf139', 'Gene', '401563', (173, 181))	('RP11', 'Gene', '26121', (197, 201))	('patients', 'Species', '9606', (97, 105))	('CTD-2527I21.15; CH507-513H4.5', 'Var', (285, 314))	('associated with', 'Reg', (364, 379))	('RP11', 'Gene', '26121', (227, 231))	('Cox', 'Gene', '1351', (24, 27))	('RP11', 'Gene', (212, 216))	('RP11', 'Gene', (332, 336))
32998	29239017	The multivariate Cox proportional regression was applied to confirm the results above, and we found that the five lncRNA (C9orf139, MIR600HG, RP5-965G21.4, RP11-436K8.1, and CTC-327F10.4) were proved to be an independent prognostic indicator for PDAC (Table 1).	('C9orf139', 'Gene', (122, 130))	('Cox', 'Gene', '1351', (17, 20))	('PDAC', 'Disease', (246, 250))	('MIR600HG', 'Gene', (132, 140))	('PDAC', 'Phenotype', 'HP:0006725', (246, 250))	('RP11', 'Gene', (156, 160))	('Cox', 'Gene', (17, 20))	('MIR600HG', 'Gene', '81571', (132, 140))	('CTC-327F10.4', 'Var', (174, 186))	('RP5-965G21.4', 'Var', (142, 154))	('RP11', 'Gene', '26121', (156, 160))	('C9orf139', 'Gene', '401563', (122, 130))	('PDAC', 'Chemical', '-', (246, 250))
32999	29239017	The prognostic index was imputed as follows: (-0.235 * expression level of C9orf139) + (-0.403 * expression level of MIR600HG) + (0.163 * expression level of RP5-965G21.4) + (-0.187 * expression level of RP11-436K8.1) + (0.185 * expression level of CTC-327F10.4).	('MIR600HG', 'Gene', (117, 125))	('MIR600HG', 'Gene', '81571', (117, 125))	('RP11', 'Gene', (204, 208))	('-0.235 *', 'Var', (46, 54))	('C9orf139', 'Gene', '401563', (75, 83))	('RP11', 'Gene', '26121', (204, 208))	('C9orf139', 'Gene', (75, 83))
33001	29239017	CTC-327F10.4 and RP5-965G21.4 were high expressions in both groups, while C9orf139 and MIR600HG, RP11-436K8.1 were low expressions in PDAC group in both groups (Figure 4).	('PDAC', 'Chemical', '-', (134, 138))	('C9orf139', 'Gene', '401563', (74, 82))	('RP11', 'Gene', (97, 101))	('MIR600HG', 'Gene', '81571', (87, 95))	('RP11', 'Gene', '26121', (97, 101))	('CTC-327F10.4', 'Var', (0, 12))	('PDAC', 'Disease', (134, 138))	('PDAC', 'Phenotype', 'HP:0006725', (134, 138))	('C9orf139', 'Gene', (74, 82))	('RP5-965G21.4', 'Var', (17, 29))	('MIR600HG', 'Gene', (87, 95))
33015	29239017	However, only two key lncRNA expression (C9orf139 and MIR600HG) could find in two datasets (GSE28735 and GSE41368).	('C9orf139', 'Gene', (41, 49))	('GSE41368', 'Var', (105, 113))	('MIR600HG', 'Gene', (54, 62))	('C9orf139', 'Gene', '401563', (41, 49))	('MIR600HG', 'Gene', '81571', (54, 62))	('GSE28735', 'Var', (92, 100))
33025	29239017	Lastly, we have recognized five lncRNA consisting of C9orf139, MIR600HG, RP5-965G21.4, RP11-436K8.1, and CTC-327F10.4.	('CTC-327F10.4', 'Var', (105, 117))	('MIR600HG', 'Gene', '81571', (63, 71))	('C9orf139', 'Gene', '401563', (53, 61))	('RP5-965G21.4', 'Var', (73, 85))	('RP11', 'Gene', '26121', (87, 91))	('C9orf139', 'Gene', (53, 61))	('MIR600HG', 'Gene', (63, 71))	('RP11', 'Gene', (87, 91))
33028	29239017	Among these lncRNAs, low expression (CTD-2527I21.15 and CH507-513H4.5) and overexpression of lncRNA (MIR600HG and CC9orf139, RP11-489O18.1) were associated with poor prognosis in patients with PDAC.	('PDAC', 'Disease', (193, 197))	('PDAC', 'Phenotype', 'HP:0006725', (193, 197))	('MIR600HG', 'Gene', (101, 109))	('CH507-513H4.5', 'CellLine', 'CVCL:A570', (56, 69))	('overexpression', 'PosReg', (75, 89))	('RP11', 'Gene', (125, 129))	('expression', 'MPA', (25, 35))	('CTD-2527I21.15', 'Var', (37, 51))	('low', 'NegReg', (21, 24))	('MIR600HG', 'Gene', '81571', (101, 109))	('RP11', 'Gene', '26121', (125, 129))	('C9orf139', 'Gene', (115, 123))	('CH507-513H4.5', 'Var', (56, 69))	('PDAC', 'Chemical', '-', (193, 197))	('patients', 'Species', '9606', (179, 187))	('C9orf139', 'Gene', '401563', (115, 123))
33031	29239017	Aberrant activation of Primary immunodeficiency, natural killer cell mediated cytotoxicity, Rap1 signaling pathway, and regulation of actin cytoskeleton pathway may inhibit tumor cells growth and proliferation, progression.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('activation', 'PosReg', (9, 19))	('actin', 'Pathway', (134, 139))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('Primary immunodeficiency', 'Disease', 'MESH:D007153', (23, 47))	('inhibit', 'NegReg', (165, 172))	('regulation', 'biological_process', 'GO:0065007', ('120', '130'))	('cytotoxicity', 'Disease', (78, 90))	('cytotoxicity', 'Disease', 'MESH:D064420', (78, 90))	('Rap1', 'Gene', '5906', (92, 96))	('natural killer cell mediated cytotoxicity', 'biological_process', 'GO:0042267', ('49', '90'))	('progression', 'CPA', (211, 222))	('Rap1', 'Gene', (92, 96))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('134', '152'))	('signaling pathway', 'biological_process', 'GO:0007165', ('97', '114'))	('Primary immunodeficiency', 'Disease', (23, 47))	('tumor', 'Disease', (173, 178))	('immunodeficiency', 'Phenotype', 'HP:0002721', (31, 47))
33040	29560118	Short hairpin RNAs (shRNAs) were designed and constructed in lentivirus to knock down KLK7 in pancreatic cancer cell line PANC-1, and the real time cellular analysis (RTCA) was used to evaluate cell proliferation, migration and invasion abilities.	('KLK7', 'Gene', (86, 90))	('knock', 'Var', (75, 80))	('cell proliferation', 'biological_process', 'GO:0008283', ('194', '212'))	('KLK7', 'Gene', '5650', (86, 90))	('pancreatic cancer', 'Disease', (94, 111))	('PANC-1', 'CellLine', 'CVCL:0480', (122, 128))	('migration', 'CPA', (214, 223))	('invasion abilities', 'CPA', (228, 246))	('pancreatic cancer', 'Disease', 'MESH:D010190', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cell proliferation', 'CPA', (194, 212))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (94, 111))
33042	29560118	Our results confirmed that KLK7 is significantly up-regulated in pancreatic cancer tissue, and knocking down or inhibiting KLK7 efficiently inhibited the proliferation, migration and invasion of pancreatic cancer cells.	('pancreatic cancer', 'Disease', 'MESH:D010190', (195, 212))	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('KLK7', 'Gene', '5650', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('pancreatic cancer', 'Disease', (65, 82))	('inhibited', 'NegReg', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('KLK7', 'Gene', (27, 31))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (195, 212))	('KLK7', 'Gene', (123, 127))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('knocking down', 'Var', (95, 108))	('KLK7', 'Gene', '5650', (123, 127))	('invasion', 'CPA', (183, 191))	('proliferation', 'CPA', (154, 167))	('pancreatic cancer', 'Disease', (195, 212))	('inhibiting', 'NegReg', (112, 122))	('up-regulated', 'PosReg', (49, 61))
33068	29560118	The morphological observation showed that, unlike BC or NC cells, the KLK7 silenced PANC-1 cells are more likely to form clusters, especially for KD4 cells (Supplementary Figure 1).	('KLK7', 'Gene', (70, 74))	('PANC-1', 'CellLine', 'CVCL:0480', (84, 90))	('PANC-1', 'Gene', (84, 90))	('KLK7', 'Gene', '5650', (70, 74))	('silenced', 'Var', (75, 83))
33070	29560118	For KD4 group, the expression of KLK7 is decreased by around 90% compared to NC group.	('expression', 'MPA', (19, 29))	('decreased', 'NegReg', (41, 50))	('KLK7', 'Gene', '5650', (33, 37))	('KLK7', 'Gene', (33, 37))	('expression', 'Species', '29278', (19, 29))	('KD4', 'Var', (4, 7))
33072	29560118	As negative control, KLK7 silenced hepatocellular carcinoma HepG2 cells were established, but our data showed that unlike PANC-1 cells, the knocking down of KLK7 did not affect the proliferation, migration, and invasion of HepG2 cells (Supplementary Figure 2), demonstrating that our designed LV-hKLK7-shRNA-4 do not target other proteins.	('knocking down', 'Var', (140, 153))	('KLK7', 'Gene', '5650', (157, 161))	('HepG2', 'CellLine', 'CVCL:0027', (223, 228))	('KLK7', 'Gene', '5650', (21, 25))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (35, 59))	('hepatocellular carcinoma', 'Disease', (35, 59))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (35, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('PANC-1', 'CellLine', 'CVCL:0480', (122, 128))	('KLK7', 'Gene', (297, 301))	('hKLK7', 'Gene', (296, 301))	('hKLK7', 'Gene', '5650', (296, 301))	('HepG2', 'CellLine', 'CVCL:0027', (60, 65))	('KLK7', 'Gene', '5650', (297, 301))	('KLK7', 'Gene', (157, 161))	('KLK7', 'Gene', (21, 25))
33073	29560118	As KLK7 is a protease which can be secreted into intercellular space, we tested whether the proliferation, migration, and invasion capacities inhibited by KLK7 silencing could be recovered using exogenous KLK7.	('intercellular space', 'cellular_component', 'GO:0005615', ('49', '68'))	('KLK7', 'Gene', (3, 7))	('migration', 'CPA', (107, 116))	('tested', 'Reg', (73, 79))	('invasion capacities', 'CPA', (122, 141))	('KLK7', 'Gene', '5650', (3, 7))	('KLK7', 'Gene', '5650', (155, 159))	('silencing', 'Var', (160, 169))	('KLK7', 'Gene', (205, 209))	('KLK7', 'Gene', (155, 159))	('KLK7', 'Gene', '5650', (205, 209))	('inhibited', 'NegReg', (142, 151))	('proliferation', 'CPA', (92, 105))
33084	29560118	The 300 compounds purchased from the ChemDiv library were evaluated for the in vitro inhibition of KLK7 by measuring the hydrolysis of the FRET substrate MCA-Arg-Pro-Lys-Pro-Val-Glu-Nval-Trp-Arg-Lys(Dnp)-NH2.	('MCA-Arg-Pro-Lys-Pro-Val-Glu-Nval-Trp-Arg-Lys', 'Var', (154, 198))	('hydrolysis', 'MPA', (121, 131))	('Dnp', 'Chemical', 'MESH:D019297', (199, 202))	('KLK7', 'Gene', (99, 103))	('KLK7', 'Gene', '5650', (99, 103))
33106	29560118	Meanwhile, we discovered that knocking down of KLK7 in PANC-1 cells resulted in decrease in cell proliferation, migration and invasion abilities.	('PANC-1', 'CellLine', 'CVCL:0480', (55, 61))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('KLK7', 'Gene', (47, 51))	('migration', 'CPA', (112, 121))	('KLK7', 'Gene', '5650', (47, 51))	('cell proliferation', 'CPA', (92, 110))	('invasion abilities', 'CPA', (126, 144))	('knocking down', 'Var', (30, 43))	('decrease', 'NegReg', (80, 88))
33107	29560118	The molecular mechanisms associated with KLK7 silencing-induced anti-migration and anti-invasion abilities identified in our study can be interpreted as the cleavage of ECM proteins and junction/adhesion molecules by KLK7.	('KLK7', 'Gene', (217, 221))	('KLK7', 'Gene', '5650', (41, 45))	('KLK7', 'Gene', '5650', (217, 221))	('silencing-induced', 'Var', (46, 63))	('cleavage', 'MPA', (157, 165))	('anti-invasion abilities', 'CPA', (83, 106))	('anti-migration', 'CPA', (64, 78))	('ECM proteins', 'Protein', (169, 181))	('KLK7', 'Gene', (41, 45))
33108	29560118	We should also point out that compared to migration assay, in the matrigel invasion assay, no KD4 cells could pass the matrigel moving to the lower chamber of the plate, indicating that silencing KLK7 could more efficiently inhibit the invasion ability rather than the migration ability of PANC-1, and KLK7 might help the degradation of ECM In our study, anti-proliferative effect of silencing KLK7 on PANC-1 cells has also been observed, but the underlying mechanism has not been elucidated yet.	('KLK7', 'Gene', '5650', (394, 398))	('KLK7', 'Gene', (394, 398))	('invasion ability', 'CPA', (236, 252))	('degradation', 'biological_process', 'GO:0009056', ('322', '333'))	('PANC-1', 'CellLine', 'CVCL:0480', (402, 408))	('KLK7', 'Gene', (302, 306))	('silencing', 'Var', (186, 195))	('KLK7', 'Gene', '5650', (302, 306))	('PANC-1', 'CellLine', 'CVCL:0480', (290, 296))	('anti-proliferative', 'NegReg', (355, 373))	('KLK7', 'Gene', '5650', (196, 200))	('silencing', 'Var', (384, 393))	('inhibit', 'NegReg', (224, 231))	('KLK7', 'Gene', (196, 200))
33109	29560118	It's possible that the anti-proliferation induced by silencing KLK7 acts through protease-activated receptors-dependent proliferative pathways, or the regulation of androgen-mediated proliferation pathways and growth factor-mediated pathways, since these proliferation pathways are involved in several cancers where KLKs are deregulated.	('KLK7', 'Gene', '5650', (63, 67))	('KLK7', 'Gene', (63, 67))	('KLK', 'Gene', '3816;9622;5653;5653;5650', (316, 319))	('KLK', 'Gene', '3816;9622;5653;5653;5650', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('anti-proliferation', 'CPA', (23, 41))	('silencing', 'Var', (53, 62))	('cancers', 'Phenotype', 'HP:0002664', (302, 309))	('regulation', 'biological_process', 'GO:0065007', ('151', '161'))	('involved', 'Reg', (282, 290))	('KLK', 'Gene', (316, 319))	('KLK', 'Gene', (63, 66))	('cancers', 'Disease', (302, 309))	('cancers', 'Disease', 'MESH:D009369', (302, 309))
33112	29560118	In our study, the cell culture medium from wild type PANC-1 could significantly increase the migration and invasion capacities of KD4 cell, indicating that KLK7 can act as a paracrine factor on other cells located at the tumor microenvironment and regulate the malignant progress of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('increase', 'PosReg', (80, 88))	('cancer', 'Disease', (283, 289))	('PANC-1', 'CellLine', 'CVCL:0480', (53, 59))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('KLK7', 'Gene', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('PANC-1', 'Gene', (53, 59))	('KLK7', 'Gene', '5650', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('regulate', 'Reg', (248, 256))	('invasion capacities of KD4 cell', 'CPA', (107, 138))	('wild type', 'Var', (43, 52))
33116	29560118	Moreover, silencing KLK7 activity leads to PANC-1 cell regression and decreases the malignant progression of PDAC.	('malignant progression', 'CPA', (84, 105))	('KLK7', 'Gene', (20, 24))	('PDAC', 'Disease', (109, 113))	('decreases', 'NegReg', (70, 79))	('PANC-1', 'CellLine', 'CVCL:0480', (43, 49))	('PDAC', 'Chemical', '-', (109, 113))	('KLK7', 'Gene', '5650', (20, 24))	('PANC-1 cell regression', 'CPA', (43, 65))	('silencing', 'Var', (10, 19))	('activity', 'MPA', (25, 33))
33117	29560118	However, it was reported that Kallikrein-related peptidase 7 was down-regulated in prostate cancer, indicating that inhibition of KLK7 may influence the normal function of prostate, but this needs further investigations.	('influence', 'Reg', (139, 148))	('inhibition', 'Var', (116, 126))	('Kallikrein-related peptidase 7', 'Gene', (30, 60))	('prostate cancer', 'Disease', 'MESH:D011471', (83, 98))	('Kallikrein-related peptidase 7', 'Gene', '5650', (30, 60))	('Kallikrein', 'molecular_function', 'GO:0004293', ('30', '40'))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('normal', 'MPA', (153, 159))	('down-regulated', 'NegReg', (65, 79))	('Kallikrein', 'molecular_function', 'GO:0003807', ('30', '40'))	('prostate cancer', 'Disease', (83, 98))	('KLK7', 'Gene', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('KLK7', 'Gene', '5650', (130, 134))
33144	29560118	Real-time PCR was performed with the following specific primers of KLK7: sense, 5'-ACCTCATGCTCGTGAAGCTC-3'; anti-sense, 5'-CCGGAGACAGTACAGGTGGT-3'.	('KLK7', 'Gene', '5650', (67, 71))	('anti-sense', 'Var', (108, 118))	('KLK7', 'Gene', (67, 71))
33157	29560118	The druggable regions of KLK7 were firstly identified by DoGSiteScorer, and the docking step was then carried out using GOLD (GA runs = 30; Fitness & Search option was CHEMPLP; GA Setting was Automatic-searching efficiency: 30%; Active site: CMK, 10A) to generate a library containing molecules with appropriate shape complementarity with the search zone defined around Ser195 in the active site.	('KLK7', 'Gene', (25, 29))	('around', 'Var', (363, 369))	('Ser195', 'Chemical', '-', (370, 376))	('CMK', 'Gene', '51727', (242, 245))	('Ser', 'cellular_component', 'GO:0005790', ('370', '373'))	('CMK', 'Gene', (242, 245))	('KLK7', 'Gene', '5650', (25, 29))
33220	29340021	The present study showed that factors including histologic grade, AJCC7th N stage, AJCC7th T stage, primary therapy outcome success, AJCC8th N stage were associated with RFS.	('AJCC7th', 'Gene', (83, 90))	('AJCC8th', 'Var', (133, 140))	('RFS', 'Gene', '65211', (170, 173))	('RFS', 'Gene', (170, 173))	('associated', 'Reg', (154, 164))
33247	29340021	Recent study firstly stated that CA4 was a tumor suppressor in colorectal cancer (CRC) by inhibiting the Wnt signaling pathway.	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('105', '126'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('CA4', 'Var', (33, 36))	('colorectal cancer', 'Disease', (63, 80))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('inhibiting', 'NegReg', (90, 100))	('tumor', 'Disease', (43, 48))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))	('CR', 'Chemical', 'MESH:D002857', (82, 84))	('Wnt signaling pathway', 'Pathway', (105, 126))
33254	29340021	ASPM was connected with pancreatic epithelial tubulogenesis and over-expressed ASPM promoted aggressiveness of PDAC by regulating Wnt-beta-catenin signaling pathway.	('pancreatic epithelial', 'Disease', (24, 45))	('beta-catenin', 'Gene', '1499', (134, 146))	('aggressiveness', 'Phenotype', 'HP:0000718', (93, 107))	('promoted', 'PosReg', (84, 92))	('pancreatic epithelial', 'Disease', 'MESH:D010195', (24, 45))	('ASPM', 'Gene', '259266', (0, 4))	('regulating', 'Reg', (119, 129))	('signaling pathway', 'biological_process', 'GO:0007165', ('147', '164'))	('PDAC', 'Chemical', '-', (111, 115))	('over-expressed', 'Var', (64, 78))	('aggressiveness', 'Disease', 'MESH:D001523', (93, 107))	('ASPM', 'Gene', '259266', (79, 83))	('ASPM', 'Gene', (0, 4))	('tubulogenesis', 'biological_process', 'GO:0048754', ('46', '59'))	('ASPM', 'Gene', (79, 83))	('aggressiveness', 'Disease', (93, 107))	('beta-catenin', 'Gene', (134, 146))
33260	29340021	The hyper-methylation of COL17A1 promoter increased ductal breast cancer metastasis.	('increased', 'PosReg', (42, 51))	('breast cancer metastasis', 'Disease', 'MESH:D009362', (59, 83))	('breast cancer metastasis', 'Disease', (59, 83))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('COL17A1', 'Gene', '1308', (25, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('hyper-methylation', 'Var', (4, 21))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))	('COL17A1', 'Gene', (25, 32))
33261	29340021	But COL17A1 was over-expressed and its promoter was hypo-methylated in cervical cancer and other epithelial cancers.	('hypo-methylated', 'Var', (52, 67))	('COL17A1', 'Gene', (4, 11))	('cancer', 'Disease', (80, 86))	('epithelial cancers', 'Disease', (97, 115))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('COL17A1', 'Gene', '1308', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('over-expressed', 'PosReg', (16, 30))	('epithelial cancers', 'Disease', 'MESH:D000077216', (97, 115))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
33293	28460571	Studies demonstrating that abrogation of MUC4 expression reduces proliferation and metastasis of PC cells and enhances sensitivity to therapeutic agents affirm its utility as a therapeutic target.	('proliferation', 'CPA', (65, 78))	('sensitivity to therapeutic agents', 'MPA', (119, 152))	('metastasis', 'CPA', (83, 93))	('rat', 'Species', '10116', (72, 75))	('MUC4', 'Gene', (41, 45))	('rat', 'Species', '10116', (15, 18))	('PC', 'CellLine', 'CVCL:0152', (97, 99))	('enhances', 'PosReg', (110, 118))	('abrogation', 'Var', (27, 37))	('reduces', 'NegReg', (57, 64))
33303	28460571	Aberrant overexpression of various mucins is associated with, and contributes to, several inflammatory and malignant pathologies.	('overexpression', 'PosReg', (9, 23))	('Aberrant', 'Var', (0, 8))	('mucin', 'Gene', '100508689', (35, 40))	('contributes', 'Reg', (66, 77))	('associated', 'Reg', (45, 55))	('inflammatory', 'Disease', (90, 102))	('mucin', 'Gene', (35, 40))
33304	28460571	MUC4 is the most differentially overexpressed transmembrane mucin in PDAC and has been demonstrated to functionally contribute to the pathobiology and aggressiveness of the disease.	('rat', 'Species', '10116', (94, 97))	('transmembrane', 'cellular_component', 'GO:0044214', ('46', '59'))	('PDAC', 'Chemical', '-', (69, 73))	('mucin', 'Gene', (60, 65))	('contribute', 'Reg', (116, 126))	('MUC4', 'Var', (0, 4))	('transmembrane', 'cellular_component', 'GO:0016021', ('46', '59'))	('aggressiveness of the disease', 'Disease', 'MESH:D001523', (151, 180))	('mucin', 'Gene', '100508689', (60, 65))	('PDAC', 'Disease', (69, 73))	('aggressiveness of the disease', 'Disease', (151, 180))	('overexpressed', 'PosReg', (32, 45))	('aggressiveness', 'Phenotype', 'HP:0000718', (151, 165))
33306	28460571	Functionally, MUC4 expression induces neoplastic transformation, promotes tumorigenesis and metastasis, modulates the interaction of tumor cells with the components of tumor microenvironment, and contributes to the resistance of tumor cells to chemotherapeutic agents.	('MUC4', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('interaction', 'Interaction', (118, 129))	('modulates', 'Reg', (104, 113))	('tumor', 'Disease', (74, 79))	('induces', 'Reg', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('metastasis', 'CPA', (92, 102))	('resistance', 'CPA', (215, 225))	('tumor', 'Disease', (168, 173))	('expression', 'Var', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('promotes', 'PosReg', (65, 73))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('contributes', 'Reg', (196, 207))	('neoplastic transformation', 'CPA', (38, 63))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
33308	28460571	Furthermore, the expression of MUC4 on PDAC cells has been demonstrated to compromise the immune effector response by facilitating apoptosis of antigen-specific cytotoxic T cells.	('facilitating', 'PosReg', (118, 130))	('compromise', 'NegReg', (75, 85))	('immune effector response', 'CPA', (90, 114))	('apoptosis', 'biological_process', 'GO:0097194', ('131', '140'))	('MUC4', 'Gene', (31, 35))	('expression', 'Var', (17, 27))	('apoptosis', 'biological_process', 'GO:0006915', ('131', '140'))	('apoptosis', 'CPA', (131, 140))	('rat', 'Species', '10116', (66, 69))	('PDAC', 'Chemical', '-', (39, 43))
33310	28460571	In addition, high MUC4 expression in tumors was found to be an independent determinant of poor prognosis in PDAC patients.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('MUC4', 'Protein', (18, 22))	('high', 'Var', (13, 17))	('PDAC', 'Chemical', '-', (108, 112))	('patients', 'Species', '9606', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('PDAC', 'Disease', (108, 112))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('expression', 'MPA', (23, 33))
33312	28460571	Herein, we provide a brief overview of the MUC4 structure, summarize the functional relevance of its deregulated overexpression, and discuss the approaches that have been tested to abrogate or modulate MUC4 in PDAC.	('MUC4', 'Gene', (202, 206))	('PDAC', 'Chemical', '-', (210, 214))	('modulate', 'Var', (193, 201))	('overexpression', 'PosReg', (113, 127))	('abrogate', 'Var', (181, 189))	('PDAC', 'Disease', (210, 214))	('MUC4', 'Gene', (43, 47))
33317	28460571	MUC4beta contains a von Willebrand factor type D domain (vWD), three EGF-like domains, and a transmembrane domain followed by a short cytoplasmic tail (Figure 1).	('vWD', 'Gene', '7450', (57, 60))	('vWD', 'Gene', (57, 60))	('von Willebrand', 'Disease', (20, 34))	('MUC4beta', 'Var', (0, 8))	('transmembrane', 'cellular_component', 'GO:0044214', ('93', '106'))	('transmembrane', 'cellular_component', 'GO:0016021', ('93', '106'))	('EGF', 'Gene', (69, 72))	('EGF', 'molecular_function', 'GO:0005154', ('69', '72'))	('von Willebrand', 'Disease', 'MESH:D014842', (20, 34))	('EGF', 'Gene', '1950', (69, 72))
33329	28460571	In addition to its aberrant overexpression, deregulation in the glycosylation and splicing machineries during carcinogenesis may result in the expression of aberrant glycoforms and splice variants of MUC4 which may exhibit unique tumor-specific expression patterns and functions.	('glycosylation', 'MPA', (64, 77))	('tumor', 'Disease', (230, 235))	('aberrant', 'Var', (157, 165))	('splice', 'MPA', (181, 187))	('expression', 'MPA', (143, 153))	('glycoforms', 'MPA', (166, 176))	('splicing', 'biological_process', 'GO:0045292', ('82', '90'))	('result in', 'Reg', (129, 138))	('MUC4', 'Gene', (200, 204))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('overexpression', 'PosReg', (28, 42))	('carcinogenesis', 'Disease', 'MESH:D063646', (110, 124))	('deregulation', 'Var', (44, 56))	('glycosylation', 'biological_process', 'GO:0070085', ('64', '77'))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('carcinogenesis', 'Disease', (110, 124))
33339	28460571	Ectopic expression of MUC4 in MiaPaCa2, a PDAC cell line with no endogenous MUC4 expression, resulted in increased invasiveness of the cells in vitro and metastasis in vivo, by enhancing their ability to disrupt the basement membrane (BM) barrier.	('MUC4', 'Gene', (22, 26))	('invasiveness of the cells in vitro', 'CPA', (115, 149))	('PDAC', 'Chemical', '-', (42, 46))	('Ectopic expression', 'Var', (0, 18))	('basement membrane', 'cellular_component', 'GO:0005604', ('216', '233'))	('metastasis', 'CPA', (154, 164))	('MiaPaCa2', 'CellLine', 'CVCL:0428', (30, 38))	('increased', 'PosReg', (105, 114))	('enhancing', 'PosReg', (177, 186))
33341	28460571	Similarly, silencing MUC4 in CD18/HPAF cells increased integrin-mediated interaction of cells with various ECM proteins including, LI-cadherin, CEACAM6, RAC1, thrombomodulin, epiregulin, and neuregulin or basement membrane components like laminin, fibronectin, and collagens I and IV.	('silencing', 'Var', (11, 20))	('RAC1', 'Gene', '5879', (153, 157))	('CEACAM6', 'Gene', '4680', (144, 151))	('MUC4', 'Gene', (21, 25))	('fibronectin', 'Gene', (248, 259))	('increased', 'PosReg', (45, 54))	('cadherin', 'molecular_function', 'GO:0008014', ('134', '142'))	('thrombomodulin', 'Gene', '7056', (159, 173))	('thrombomodulin', 'Gene', (159, 173))	('RAC1', 'Gene', (153, 157))	('basement membrane', 'cellular_component', 'GO:0005604', ('205', '222'))	('LI-cadherin', 'Gene', (131, 142))	('CD18', 'Gene', '3689', (29, 33))	('CEACAM6', 'Gene', (144, 151))	('integrin-mediated', 'MPA', (55, 72))	('fibronectin', 'Gene', '2335', (248, 259))	('LI-cadherin', 'Gene', '1015', (131, 142))	('CD18', 'Gene', (29, 33))
33353	28460571	Another study found that the AMOP domain of MUC4/Y impacts the expression of VEGF A and ang-2, and its deletion significantly reduced the angiogenic and metastatic properties of PC cells in mice.	('VEGF A', 'Gene', '22339', (77, 83))	('MUC4/Y', 'Gene', (44, 50))	('ang-2', 'Gene', '11731', (88, 93))	('expression', 'MPA', (63, 73))	('VEGF A', 'Gene', (77, 83))	('ang-2', 'Gene', (88, 93))	('PC', 'CellLine', 'CVCL:0152', (178, 180))	('mice', 'Species', '10090', (190, 194))	('impacts', 'Reg', (51, 58))	('reduced', 'NegReg', (126, 133))	('deletion', 'Var', (103, 111))
33356	28460571	While the deletion of each of these domains reduced the oncogenic activity of MUC4/Y in Panc1 cells, simultaneous deletion suggested that the three domains promote proliferation and metastasis in a synergistic manner, possibly by modulating MUC4/EGF-ERB2-ERB3 signaling and downstream activation of MAPK and other singling networks.	('EGF', 'Gene', (246, 249))	('deletion', 'Var', (114, 122))	('MAPK', 'Gene', '5594', (299, 303))	('oncogenic activity', 'MPA', (56, 74))	('proliferation', 'CPA', (164, 177))	('EGF', 'Gene', '1950', (246, 249))	('signaling', 'biological_process', 'GO:0023052', ('260', '269'))	('modulating', 'Reg', (230, 240))	('EGF', 'molecular_function', 'GO:0005154', ('246', '249'))	('MUC4/Y', 'Gene', (78, 84))	('MAPK', 'Gene', (299, 303))	('Panc1', 'CellLine', 'CVCL:0480', (88, 93))	('MAPK', 'molecular_function', 'GO:0004707', ('299', '303'))	('rat', 'Species', '10116', (171, 174))	('reduced', 'NegReg', (44, 51))	('deletion', 'Var', (10, 18))	('metastasis', 'CPA', (182, 192))	('promote', 'PosReg', (156, 163))
33358	28460571	MUC4 reduced cytochrome c release in a HER2-dependent manner in response to gemcitabine treatment, leading to inhibition of apoptosis.	('inhibition', 'NegReg', (110, 120))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('110', '133'))	('response to gemcitabine', 'biological_process', 'GO:0036272', ('64', '87'))	('cytochrome c', 'molecular_function', 'GO:0045155', ('13', '25'))	('MUC4', 'Var', (0, 4))	('gemcitabine', 'Chemical', 'MESH:C056507', (76, 87))	('HER2', 'Gene', (39, 43))	('HER2', 'Gene', '2064', (39, 43))	('reduced', 'NegReg', (5, 12))	('cytochrome c', 'Gene', (13, 25))	('cytochrome c', 'molecular_function', 'GO:0009461', ('13', '25'))	('apoptosis', 'CPA', (124, 133))	('cytochrome c', 'Gene', '54205', (13, 25))
33359	28460571	revealed that knockdown of MUC4 in PDAC cells lines enhanced their sensitivity to gemcitabine with elevation in pro-apoptotic marker Bax and decreased levels of anti-apoptotic marker BclXL.	('MUC4', 'Gene', (27, 31))	('BclXL', 'Gene', '598', (183, 188))	('Bax', 'Gene', (133, 136))	('PDAC', 'Chemical', '-', (35, 39))	('elevation', 'PosReg', (99, 108))	('sensitivity to gemcitabine', 'MPA', (67, 93))	('enhanced', 'PosReg', (52, 60))	('BclXL', 'Gene', (183, 188))	('decreased', 'NegReg', (141, 150))	('knockdown', 'Var', (14, 23))	('Bax', 'Gene', '581', (133, 136))	('gemcitabine', 'Chemical', 'MESH:C056507', (82, 93))
33363	28460571	Knockdown of MUC4 expression resulted in a decrease in cancer stem cells, which have inherently high levels of MRP proteins and exhibit poor sensitivity to gemcitabine.	('decrease', 'NegReg', (43, 51))	('Knockdown', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('MRP proteins', 'Protein', (111, 123))	('gemcitabine', 'Chemical', 'MESH:C056507', (156, 167))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('MUC4', 'Gene', (13, 17))
33364	28460571	Similarly, apicidin treatment epigenetically abrogated the expression of MUC4 and sensitized PDAC cells to gemcitabine.	('abrogated', 'NegReg', (45, 54))	('epigenetically', 'Var', (30, 44))	('MUC4', 'Gene', (73, 77))	('PDAC', 'Chemical', '-', (93, 97))	('expression', 'MPA', (59, 69))	('gemcitabine', 'Chemical', 'MESH:C056507', (107, 118))	('apicidin', 'Chemical', 'MESH:C102351', (11, 19))	('sensitized', 'Reg', (82, 92))
33365	28460571	also demonstrated that silencing of MUC4 expression by siRNA enhanced the sensitivity of PDAC cells to gemcitabine; however, parental cells were found to be more sensitive to bortezomib, a proteasome inhibitor.	('bortezomib', 'Chemical', 'MESH:D000069286', (175, 185))	('PDAC', 'Chemical', '-', (89, 93))	('rat', 'Species', '10116', (12, 15))	('enhanced', 'PosReg', (61, 69))	('proteasome', 'cellular_component', 'GO:0000502', ('189', '199'))	('proteasome', 'molecular_function', 'GO:0004299', ('189', '199'))	('silencing', 'Var', (23, 32))	('gemcitabine', 'Chemical', 'MESH:C056507', (103, 114))	('MUC4', 'Gene', (36, 40))	('sensitivity', 'MPA', (74, 85))
33368	28460571	The distal region contains three transcriptional start sites (-2603, -2604, and -2605) and putative binding sites for Sp1, GATA, GR, cAMP-responsive element binding protein, AP-1/-2/-4, and STAT transcription factors.	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('transcription', 'biological_process', 'GO:0006351', ('195', '208'))	('cAMP', 'Chemical', '-', (133, 137))	('-2603', 'Var', (62, 67))	('GATA', 'Chemical', '-', (123, 127))	('AP-1', 'cellular_component', 'GO:0005907', ('174', '178'))	('Sp1', 'Gene', (118, 121))	('AP-1', 'Gene', (174, 178))	('AP-1', 'Gene', '3725', (174, 178))	('binding', 'molecular_function', 'GO:0005488', ('100', '107'))	('cAMP-responsive element binding', 'molecular_function', 'GO:0035497', ('133', '164'))
33377	28460571	Recent studies have provided new insights into the regulation of MUC4 expression in PDAC and suggest that MUC4 expression can be regulated by oncogenes (mutant Kras), epigenetic modifications, factors in the tumor microenvironment (bile acids and hypoxia), and signaling pathways (Wnt/beta-catenin), at both transcriptional and posttranscriptional levels.	('MUC4', 'Gene', (106, 110))	('epigenetic modifications', 'Var', (167, 191))	('Kras', 'Gene', '3845', (160, 164))	('PDAC', 'Disease', (84, 88))	('beta-catenin', 'Gene', (285, 297))	('regulated', 'Reg', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('regulation', 'biological_process', 'GO:0065007', ('51', '61'))	('signaling', 'biological_process', 'GO:0023052', ('261', '270'))	('hypoxia', 'Disease', 'MESH:D000860', (247, 254))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('expression', 'MPA', (111, 121))	('beta-catenin', 'Gene', '1499', (285, 297))	('hypoxia', 'Disease', (247, 254))	('tumor', 'Disease', (208, 213))	('PDAC', 'Chemical', '-', (84, 88))	('bile acids', 'Chemical', 'MESH:D001647', (232, 242))	('Kras', 'Gene', (160, 164))
33379	28460571	demonstrated that oncogenic K-rasG12D mutation regulates MUC4 at both transcriptional and posttranscriptional levels.	('K-ras', 'Gene', '3845', (28, 33))	('K-ras', 'Gene', (28, 33))	('regulates', 'Reg', (47, 56))	('rat', 'Species', '10116', (7, 10))	('mutation', 'Var', (38, 46))	('MUC4', 'Gene', (57, 61))
33381	28460571	Mucin genes are also subjected to epigenetic regulation by DNA methylation and histone acetylation.	('DNA methylation', 'Var', (59, 74))	('DNA methylation', 'biological_process', 'GO:0006306', ('59', '74'))	('regulation', 'biological_process', 'GO:0065007', ('45', '55'))	('Mucin', 'Gene', '100508689', (0, 5))	('histone acetylation', 'biological_process', 'GO:0016573', ('79', '98'))	('histone acetylation', 'MPA', (79, 98))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('Mucin', 'Gene', (0, 5))
33396	28460571	Both cell-intrinsic factors like oncogenes and epigenetic modifications, and cell-extrinsic factors like hypoxia and bile acids, orchestrate MUC4 expression at transcript and protein levels.	('epigenetic modifications', 'Var', (47, 71))	('hypoxia', 'Disease', (105, 112))	('hypoxia', 'Disease', 'MESH:D000860', (105, 112))	('bile acids', 'Chemical', 'MESH:D001647', (117, 127))	('MUC4', 'Gene', (141, 145))	('rat', 'Species', '10116', (136, 139))	('protein', 'cellular_component', 'GO:0003675', ('175', '182'))
33402	28460571	A combination of in vitro and in vivo assays demonstrated that silencing of MUC4 impacted cell growth and motility and significantly reduced tumorigenicity and metastasis.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('rat', 'Species', '10116', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cell growth', 'biological_process', 'GO:0016049', ('90', '101'))	('tumor', 'Disease', (141, 146))	('MUC4', 'Gene', (76, 80))	('reduced', 'NegReg', (133, 140))	('cell growth', 'CPA', (90, 101))	('impacted', 'Reg', (81, 89))	('silencing', 'Var', (63, 72))
33403	28460571	These antitumor effects were, in part, attributed to reduced HER2 levels upon MUC4 silencing.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('reduced', 'NegReg', (53, 60))	('HER2', 'Gene', (61, 65))	('MUC4', 'Protein', (78, 82))	('HER2', 'Gene', '2064', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('silencing', 'Var', (83, 92))
33409	28460571	We recently demonstrated that MUC4 expression can be indirectly downregulated by silencing NCOA3, one of the master regulators of MUC4 and other mucins using retroviral shRNA vector.	('MUC4', 'Gene', (30, 34))	('mucin', 'Gene', '100508689', (145, 150))	('NCOA3', 'Gene', (91, 96))	('expression', 'MPA', (35, 45))	('rat', 'Species', '10116', (19, 22))	('NCOA3', 'Gene', '8202', (91, 96))	('silencing', 'Var', (81, 90))	('mucin', 'Gene', (145, 150))	('downregulated', 'NegReg', (64, 77))
33412	28460571	The importance of mi-RNAs is underscored by high interspecies conservation, and the myriad of roles they play in the pathophysiology of multiple cancers.	('mi-RNAs', 'Var', (18, 25))	('multiple cancers', 'Disease', 'MESH:D009369', (136, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('multiple cancers', 'Disease', (136, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))
33417	28460571	In silico analysis indicated that miR-Let-7b, one of the most consistently downregulated miRs in murine model, human cell lines, and tissue samples, potentially targets KRas oncogene, NCOA3, and MUC4.	('MUC4', 'Gene', (195, 199))	('NCOA3', 'Gene', (184, 189))	('KRas', 'Gene', (169, 173))	('downregulated', 'NegReg', (75, 88))	('KRas', 'Gene', '3845', (169, 173))	('NCOA3', 'Gene', '8202', (184, 189))	('human', 'Species', '9606', (111, 116))	('miR-Let-7b', 'Var', (34, 44))	('targets', 'Reg', (161, 168))	('murine', 'Species', '10090', (97, 103))
33425	28460571	Importantly, restoration of miR-150 in PDAC cell lines resulted in decreased tumor growth, while knockdown of miR-150 promoted tumorigenicity in vivo along with reciprocal alterations in MUC4 levels in the tumors.	('rat', 'Species', '10116', (18, 21))	('rat', 'Species', '10116', (176, 179))	('decreased tumor', 'Disease', 'MESH:D009369', (67, 82))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('alterations', 'Reg', (172, 183))	('promoted', 'PosReg', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (77, 82))	('decreased tumor', 'Disease', (67, 82))	('tumors', 'Disease', (206, 212))	('MUC4 levels', 'MPA', (187, 198))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('miR-150', 'Gene', (28, 35))	('miR-150', 'Gene', '406942', (110, 117))	('knockdown', 'Var', (97, 106))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (206, 211))	('miR-150', 'Gene', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('miR-150', 'Gene', '406942', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('PDAC', 'Chemical', '-', (39, 43))
33431	28460571	Although several miRs have been demonstrated to target MUC4 and abrogate MUC4-mediated cellular processes, limited studies have tested their ability to target MUC4 in vivo in established tumors.	('MUC4', 'Protein', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('MUC4-mediated', 'MPA', (73, 86))	('abrogate', 'NegReg', (64, 72))	('rat', 'Species', '10116', (39, 42))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('miRs', 'Var', (17, 21))
33456	28460571	Transient knockdown of MUC4 expression was sufficient to activate these pathways, thereby directly implicating MUC4 as a critical target of TQ.	('activate', 'PosReg', (57, 65))	('knockdown', 'Var', (10, 19))	('TQ', 'Chemical', 'MESH:C003466', (140, 142))	('MUC4', 'Gene', (23, 27))
33468	28460571	Further, due to aberrant glycosylation and splicing, MUC4 expressed on cancer cells is likely to be distinct from that expressed on normal tissues.	('aberrant', 'Var', (16, 24))	('splicing', 'MPA', (43, 51))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('splicing', 'biological_process', 'GO:0045292', ('43', '51'))	('glycosylation', 'biological_process', 'GO:0070085', ('25', '38'))	('glycosylation', 'MPA', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (16, 38))	('MUC4', 'Gene', (53, 57))
33470	28460571	Overexpression and aberrant glycosylation of MUC4 appears to elicit MUC4-specific immune response as suggested by the presence of MUC4-specific autoantibodies in patients with colorectal cancer, and elevated levels of both Th1 and Th2 cytokines in MUC4 expressing pancreatic tumors.	('colorectal cancer', 'Disease', 'MESH:D015179', (176, 193))	('MUC4', 'Gene', (45, 49))	('Th1', 'Gene', (223, 226))	('immune response', 'biological_process', 'GO:0006955', ('82', '97'))	('colorectal cancer', 'Disease', (176, 193))	('Th1', 'Gene', '51497', (223, 226))	('pancreatic tumors', 'Disease', 'MESH:D010190', (264, 281))	('pancreatic tumors', 'Disease', (264, 281))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (19, 41))	('levels of', 'MPA', (208, 217))	('patients', 'Species', '9606', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('colorectal cancer', 'Phenotype', 'HP:0003003', (176, 193))	('MUC4', 'Gene', (248, 252))	('elevated', 'PosReg', (199, 207))	('elicit', 'Reg', (61, 67))	('glycosylation', 'biological_process', 'GO:0070085', ('28', '41'))	('MUC4-specific', 'MPA', (68, 81))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (264, 281))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('glycosylation', 'MPA', (28, 41))	('aberrant', 'Var', (19, 27))
33486	28460571	Overall, MUC4-mediated alterations augment the proliferative and metastatic capacity of PDAC cells and imply that MUC4 is a critical molecule in PDAC pathobiology.	('augment', 'PosReg', (35, 42))	('rat', 'Species', '10116', (54, 57))	('PDAC', 'Chemical', '-', (145, 149))	('rat', 'Species', '10116', (27, 30))	('alterations', 'Var', (23, 34))	('MUC4-mediated', 'Gene', (9, 22))	('PDAC', 'Chemical', '-', (88, 92))
33495	28460571	The structural and functional diversity of various MUC4 domains, and the presence of various glycoforms due to aberrant glycosylation in cancer, add further complexity in designing therapeutic strategies seeking to inhibit MUC4 function or exploit it as a target for immunotherapy.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('glycosylation', 'biological_process', 'GO:0070085', ('120', '133'))	('inhibit', 'NegReg', (215, 222))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (111, 133))	('cancer', 'Disease', (137, 143))	('aberrant', 'Var', (111, 119))	('rat', 'Species', '10116', (195, 198))	('function', 'MPA', (228, 236))
33510	28460571	Papers of special note have been highlighted as either of interest  or of considerable interest  to readers MUC4 is one of the most differentially overexpressed membranebound mucins in pancreatic cancer and functionally contributes to tumor growth, metastasis, chemoresistance, and poor survival.	('pancreatic cancer', 'Disease', (185, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('chemoresistance', 'CPA', (261, 276))	('pancreatic cancer', 'Disease', 'MESH:D010190', (185, 202))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('mucin', 'Gene', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('contributes', 'Reg', (220, 231))	('MUC4', 'Var', (108, 112))	('tumor', 'Disease', (235, 240))	('poor survival', 'CPA', (282, 295))	('metastasis', 'CPA', (249, 259))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (185, 202))	('mucin', 'Gene', '100508689', (175, 180))	('overexpressed', 'PosReg', (147, 160))
33511	28460571	Well-characterized mechanisms of MUC4 deregulation, its altered glycosylation, existence of multiple splice variants, and multiplicity of TR epitopes make it an attractive target for therapy of pancreatic cancer.	('glycosylation', 'MPA', (64, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (194, 211))	('deregulation', 'Var', (38, 50))	('altered', 'Reg', (56, 63))	('pancreatic cancer', 'Disease', 'MESH:D010190', (194, 211))	('pancreatic cancer', 'Disease', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('glycosylation', 'biological_process', 'GO:0070085', ('64', '77'))	('MUC4', 'Gene', (33, 37))
33515	26921250	Inhibition or depletion of Cdc7 in normal cells triggers a DNA origin activation checkpoint causing a reversible G1 arrest.	('DNA origin activation checkpoint', 'MPA', (59, 91))	('G1 arrest', 'MPA', (113, 122))	('depletion', 'Var', (14, 23))	('Inhibition', 'Var', (0, 10))	('Cdc7', 'Gene', (27, 31))	('Cdc7', 'Gene', '8317', (27, 31))	('triggers', 'Reg', (48, 56))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
33520	26921250	Cdc7 knockdown using siRNA in Capan-1 and PANC-1 cells resulted in marked apoptotic cell death when compared with control cells.	('apoptotic cell death', 'CPA', (74, 94))	('knockdown', 'Var', (5, 14))	('Capan-1', 'CellLine', 'CVCL:0237', (30, 37))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('74', '94'))	('Cdc7', 'Gene', '8317', (0, 4))	('Cdc7', 'Gene', (0, 4))	('PANC-1', 'CellLine', 'CVCL:0480', (42, 48))
33546	26921250	Interestingly, inactivating mutations in p53 not only disrupt the DNA origin activation checkpoint making tumours susceptible to targeting of Cdc7, but also result in increased expression of the Cdc7 anti-cancer target thus potentially increasing therapeutic efficacy.	('DNA origin activation checkpoint', 'MPA', (66, 98))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('tumours', 'Disease', (106, 113))	('expression', 'MPA', (177, 187))	('Cdc7', 'Gene', (142, 146))	('p53', 'Gene', (41, 44))	('increasing', 'PosReg', (236, 246))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('tumours', 'Disease', 'MESH:D009369', (106, 113))	('Cdc7', 'Gene', '8317', (142, 146))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', (205, 211))	('inactivating mutations', 'Var', (15, 37))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('increased', 'PosReg', (167, 176))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('Cdc7', 'Gene', (195, 199))	('Cdc7', 'Gene', '8317', (195, 199))	('disrupt', 'NegReg', (54, 61))	('p53', 'Gene', '7157', (41, 44))
33548	26921250	Notably, a strong association between high Cdc7 expression levels and mutated TP53 was observed in which 90% of mutant p53 cancer cell lines overexpressed Cdc7.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Cdc7', 'Gene', (155, 159))	('Cdc7', 'Gene', (43, 47))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('overexpressed', 'PosReg', (141, 154))	('Cdc7', 'Gene', '8317', (43, 47))	('p53', 'Gene', '7157', (119, 122))	('TP53', 'Gene', (78, 82))	('cancer', 'Disease', (123, 129))	('TP53', 'Gene', '7157', (78, 82))	('mutant', 'Var', (112, 118))	('p53', 'Gene', (119, 122))	('Cdc7', 'Gene', '8317', (155, 159))
33550	26921250	For example, PHA-767491 (Nerviano Medical Sciences, Nerviano, Italy), a dual Cdc7/Cdk9 inhibitor, has been shown to have activity by inducing apoptosis in a wide variety of cancer cell lines.	('PHA-767491', 'Var', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('activity', 'MPA', (121, 129))	('apoptosis', 'CPA', (142, 151))	('Cdc7', 'Gene', '8317', (77, 81))	('Cdc7', 'Gene', (77, 81))	('Cdk9', 'Gene', '1025', (82, 86))	('Cdk', 'molecular_function', 'GO:0004693', ('82', '85'))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Cdk9', 'Gene', (82, 86))	('inducing', 'PosReg', (133, 141))	('apoptosis', 'biological_process', 'GO:0097194', ('142', '151'))	('apoptosis', 'biological_process', 'GO:0006915', ('142', '151'))
33553	26921250	In all samples taken from 27 different patients with both favourable and unfavourable prognostic markers, PHA-767491 induced apoptosis of the CLL cells.	('patients', 'Species', '9606', (39, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('125', '134'))	('apoptosis', 'biological_process', 'GO:0006915', ('125', '134'))	('apoptosis', 'CPA', (125, 134))	('PHA-767491', 'Var', (106, 116))
33555	26921250	Importantly, 70% of pancreatic adenocarcinoma tumours have been shown to have inactivating mutations of p53, one of the highest frequencies amongst all cancers for this tumour suppressor.	('p53', 'Gene', (104, 107))	('cancers', 'Disease', (152, 159))	('pancreatic adenocarcinoma tumours', 'Disease', 'MESH:D010190', (20, 53))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('tumour', 'Disease', (169, 175))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('p53', 'Gene', '7157', (104, 107))	('tumour', 'Disease', (46, 52))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (20, 45))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('inactivating mutations', 'Var', (78, 100))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('pancreatic adenocarcinoma tumours', 'Disease', (20, 53))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
33556	26921250	Moreover, pancreatic cancers commonly harbor mutations in additional tumour suppressor genes encoding for p14ARF and p16INK4A, p15INK4B and p27Kip1; key constituent proteins encompassing all three effector arms of the DNA origin activation checkpoint.	('p15INK4B', 'Gene', '1030', (127, 135))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('harbor', 'Reg', (38, 44))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (10, 27))	('tumour', 'Disease', (69, 75))	('DNA', 'cellular_component', 'GO:0005574', ('218', '221'))	('p14ARF', 'Gene', '1029', (106, 112))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (10, 28))	('p27Kip1', 'Gene', (140, 147))	('pancreatic cancers', 'Disease', (10, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('p16INK4A', 'Gene', (117, 125))	('p15INK4B', 'Gene', (127, 135))	('p16INK4A', 'Gene', '1029', (117, 125))	('p27Kip1', 'Gene', '1027', (140, 147))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('p14ARF', 'Gene', (106, 112))	('pancreatic cancers', 'Disease', 'MESH:D010190', (10, 28))
33568	26921250	There was efficient Cdc7 mRNA knockdown in each cell line, with a mean reduction of 90% and 95% after 48 hours, in PANC-1 and Capan-1 cells respectively, when compared to transfection with the control siRNA (Supplementary Figure 2).	('PANC-1', 'CellLine', 'CVCL:0480', (115, 121))	('reduction', 'NegReg', (71, 80))	('Cdc7', 'Gene', '8317', (20, 24))	('knockdown', 'Var', (30, 39))	('Cdc7', 'Gene', (20, 24))	('Capan-1', 'CellLine', 'CVCL:0237', (126, 133))
33571	26921250	In Figure 3B and Supplementary Figure 3B, DNA histograms of the CDC7 knockdown cells show the appearance of a sub-G1 peak of cells which had less than 2C DNA content.	('DNA', 'cellular_component', 'GO:0005574', ('154', '157'))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('CDC7', 'Gene', (64, 68))	('CDC7', 'Gene', '8317', (64, 68))	('knockdown', 'Var', (69, 78))
33575	26921250	The triggering of apoptotoic cell death was confirmed by the observation that H2A.X serine 139 phosphorylation (known as gammaH2A.X), was found to be increased in the Cdc7 knockdown cells, compared with the control siRNA.	('serine 139 phosphorylation', 'MPA', (84, 110))	('H2A.X', 'Gene', '3014', (78, 83))	('H2A.X', 'Gene', (126, 131))	('cell death', 'biological_process', 'GO:0008219', ('29', '39'))	('Cdc7', 'Gene', '8317', (167, 171))	('H2A.X', 'Gene', '3014', (126, 131))	('Cdc7', 'Gene', (167, 171))	('phosphorylation', 'biological_process', 'GO:0016310', ('95', '110'))	('increased', 'PosReg', (150, 159))	('gammaH2A', 'Chemical', '-', (121, 129))	('serine', 'Chemical', 'MESH:D012694', (84, 90))	('knockdown', 'Var', (172, 181))	('H2A.X', 'Gene', (78, 83))
33579	26921250	Terminal deoxynucleotidyl transferase labelling (TUNEL) recognises nicks in the DNA molecule to which the TdT enzyme incorporates fluorescently labelled nucleotides.	('Terminal deoxynucleotidyl transferase', 'Gene', (0, 37))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('nicks', 'Var', (67, 72))	('Terminal deoxynucleotidyl transferase', 'Gene', '1791', (0, 37))	('TdT', 'molecular_function', 'GO:0003912', ('106', '109'))
33585	26921250	CDC7 knockdown with the alternative siRNA also showed efficient reduction in mRNA levels and protein analysis by western blot showed the same phenotypic pattern as with the original siRNA, with appearance of cleaved PARP-1, cleaved Caspase-3 and gammaH2A.X; confirming induction of the classical apoptotic cascade and DNA double-strand breaks.	('CDC7', 'Gene', '8317', (0, 4))	('PARP-1', 'Gene', (216, 222))	('PARP-1', 'Gene', '142', (216, 222))	('gammaH2A', 'Chemical', '-', (246, 254))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('DNA', 'cellular_component', 'GO:0005574', ('318', '321'))	('knockdown', 'Var', (5, 14))	('H2A.X', 'Gene', (251, 256))	('mRNA levels', 'MPA', (77, 88))	('H2A.X', 'Gene', '3014', (251, 256))	('reduction', 'NegReg', (64, 73))	('Caspase-3', 'Gene', '836', (232, 241))	('CDC7', 'Gene', (0, 4))	('Caspase-3', 'Gene', (232, 241))
33588	26921250	To confirm previous observations that untransformed cells would exhibit a G1 arrest in response to CDC7 knockdown, the IMR-90 human diploid fibroblast line derived from fetal lung tissue was used.	('human', 'Species', '9606', (126, 131))	('G1 arrest', 'MPA', (74, 83))	('IMR-90', 'CellLine', 'CVCL:0347', (119, 125))	('CDC7', 'Gene', (99, 103))	('CDC7', 'Gene', '8317', (99, 103))	('knockdown', 'Var', (104, 113))
33600	26921250	Phase contrast microscopy showed widespread cell death of both PANC-1 and Capan-1 cells treated with PHA-767491.	('PANC-1', 'CellLine', 'CVCL:0480', (63, 69))	('cell death', 'CPA', (44, 54))	('PHA-767491', 'Var', (101, 111))	('cell death', 'biological_process', 'GO:0008219', ('44', '54'))	('Capan-1', 'CellLine', 'CVCL:0237', (74, 81))
33601	26921250	In contrast, IMR-90 cells treated with either PHA-767491 or CDC7 siRNA exhibited normal cell morphology but a much smaller population of cells was observed compared with controls consistent with a viable G1 cell cycle arrest as observed in previous studies (Figure 4).	('cell cycle arrest', 'Phenotype', 'HP:0011018', (207, 224))	('IMR-90', 'CellLine', 'CVCL:0347', (13, 19))	('PHA-767491', 'Var', (46, 56))	('CDC7', 'Gene', (60, 64))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('207', '224'))	('CDC7', 'Gene', '8317', (60, 64))
33604	26921250	In contrast, untransformed IMR-90 cells treated with PHA-767491 showed minimal cell death with the majority of cells arrested in the G1 peak, mirroring the G1 cell cycle arrest observed with Cdc7 siRNA (Figure 5) and in keeping with previous studies.	('Cdc7', 'Gene', (191, 195))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (159, 176))	('Cdc7', 'Gene', '8317', (191, 195))	('arrested', 'Reg', (117, 125))	('PHA-767491', 'Var', (53, 63))	('IMR-90', 'CellLine', 'CVCL:0347', (27, 33))	('cell death', 'biological_process', 'GO:0008219', ('79', '89'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('159', '176'))
33608	26921250	Following CDC7 knockdown with siRNA, pancreatic adenocarcinoma cells undergo pronounced apoptotic cell death.	('apoptotic cell death', 'biological_process', 'GO:0006915', ('88', '108'))	('CDC7', 'Gene', '8317', (10, 14))	('knockdown', 'Var', (15, 24))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (37, 62))	('apoptotic cell death', 'CPA', (88, 108))	('CDC7', 'Gene', (10, 14))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (37, 62))	('pancreatic adenocarcinoma', 'Disease', (37, 62))
33610	26921250	The cell lines tested, PANC-1 and Capan-1, harbour mutations in the tumour suppressors TP53, CDKN2A, CDKN2B and CDKN1B encoding for p53, p14ARF and p16INK4A, p15INK4B and p27Kip1, key constituent proteins encompassing all three arms of the origin activation checkpoint and representing mutations commonly found in pancreatic adenocarcinoma (Figure 1).	('CDKN2A', 'Gene', (93, 99))	('mutations', 'Var', (51, 60))	('Capan-1', 'CellLine', 'CVCL:0237', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', '7157', (87, 91))	('p15INK4B', 'Gene', '1030', (158, 166))	('CDKN2A', 'Gene', '1029', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (68, 74))	('p14ARF', 'Gene', '1029', (137, 143))	('CDKN1B', 'Gene', (112, 118))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (314, 339))	('p53', 'Gene', '7157', (132, 135))	('p27Kip1', 'Gene', (171, 178))	('CDKN2B', 'Gene', (101, 107))	('p16INK4A', 'Gene', (148, 156))	('p27Kip1', 'Gene', '1027', (171, 178))	('p14ARF', 'Gene', (137, 143))	('p53', 'Gene', (132, 135))	('p16INK4A', 'Gene', '1029', (148, 156))	('TP53', 'Gene', (87, 91))	('CDKN2B', 'Gene', '1030', (101, 107))	('CDKN1B', 'Gene', '1027', (112, 118))	('PANC-1', 'CellLine', 'CVCL:0480', (23, 29))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (314, 339))	('pancreatic adenocarcinoma', 'Disease', (314, 339))	('p15INK4B', 'Gene', (158, 166))
33613	26921250	Notably the potent cancer cell specific killing observed in pancreatic cancer following Cdc7 inhibition or depletion contrasts with the stable G1 arrest observed in untransformed normal human diploid fibroblasts (IMR-90) with an intact DNA origin activation checkpoint and mirrors the G1 cell cycle arrest observed in previous studies with primary untransformed cell lines.	('DNA', 'cellular_component', 'GO:0005574', ('236', '239'))	('inhibition', 'NegReg', (93, 103))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('IMR-90', 'CellLine', 'CVCL:0347', (213, 219))	('Cdc7', 'Gene', (88, 92))	('cancer', 'Disease', (71, 77))	('Cdc7', 'Gene', '8317', (88, 92))	('cancer', 'Disease', (19, 25))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (288, 305))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('288', '305'))	('human', 'Species', '9606', (186, 191))	('pancreatic cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('depletion', 'Var', (107, 116))
33614	26921250	Moreover, we have also observed a stable reversible G1 arrest in normal (HMEpC) and immortalised (MCF10A) human mammary (HMEpC) epithelial cells following Cdc7 depletion.	('depletion', 'Var', (160, 169))	('Cdc7', 'Gene', (155, 159))	('human', 'Species', '9606', (106, 111))	('G1 arrest', 'MPA', (52, 61))	('Cdc7', 'Gene', '8317', (155, 159))	('MCF10A', 'CellLine', 'CVCL:0598', (98, 104))
33615	26921250	Taken together these data highlight the highly specific nature of the cancer-cell-specific killing following Cdc7 targeting and therefore make it a potentially powerful target in the treatment of advanced pancreatic cancer.	('targeting', 'Var', (114, 123))	('Cdc7', 'Gene', '8317', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Cdc7', 'Gene', (109, 113))	('pancreatic cancer', 'Disease', (205, 222))	('pancreatic cancer', 'Disease', 'MESH:D010190', (205, 222))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (205, 222))
33616	26921250	Interestingly, p53 inactivation not only abrogates the DNA origin activation checkpoint but also increases the Cdc7 protein expression levels of the target protein itself, thus potentially reinforcing therapeutic efficacy through a positive feedback loop.	('DNA origin activation checkpoint', 'MPA', (55, 87))	('Cdc7', 'Gene', (111, 115))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('increases', 'PosReg', (97, 106))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('inactivation', 'Var', (19, 31))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('Cdc7', 'Gene', '8317', (111, 115))	('abrogates', 'NegReg', (41, 50))
33622	26921250	Thus loss of p53 function attenuates this negative regulation of Cdc7 levels and is thus in keeping with the observation that Cdc7 levels are raised in p53 mutant tumours.	('Cdc7', 'Gene', '8317', (65, 69))	('raised', 'PosReg', (142, 148))	('tumours', 'Disease', (163, 170))	('Cdc7', 'Gene', (65, 69))	('regulation', 'biological_process', 'GO:0065007', ('51', '61'))	('tumours', 'Phenotype', 'HP:0002664', (163, 170))	('p53', 'Gene', (152, 155))	('p53', 'Gene', '7157', (13, 16))	('p53', 'Gene', '7157', (152, 155))	('tumours', 'Disease', 'MESH:D009369', (163, 170))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('loss', 'NegReg', (5, 9))	('Cdc7', 'Gene', '8317', (126, 130))	('mutant', 'Var', (156, 162))	('p53', 'Gene', (13, 16))	('Cdc7', 'Gene', (126, 130))	('attenuates', 'NegReg', (26, 36))	('negative regulation', 'MPA', (42, 61))
33624	26921250	Furthermore, targeting of Cdc7 in pancreatic cancer cell line model systems with either CDC7 siRNA or alternatively Cdc7 SMI inhibitors can induce potent cancer cell-specific killing.	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('CDC7', 'Gene', (88, 92))	('Cdc7', 'Gene', (26, 30))	('Cdc7', 'Gene', (116, 120))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('Cdc7', 'Gene', '8317', (26, 30))	('Cdc7', 'Gene', '8317', (116, 120))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('CDC7', 'Gene', '8317', (88, 92))	('inhibitors', 'Var', (125, 135))	('cancer', 'Disease', (45, 51))	('pancreatic cancer', 'Disease', (34, 51))
33630	26921250	Primary antibodies were applied at the following dilutions: Mcm2 (1:1000), geminin (1:150), H3p (1:3000) and Cdc7 (1:100).	('geminin', 'Gene', (75, 82))	('Cdc7', 'Gene', '8317', (109, 113))	('Cdc7', 'Gene', (109, 113))	('geminin', 'Gene', '51053', (75, 82))	('H3p', 'Gene', (92, 95))	('Mcm2', 'Gene', '4171', (60, 64))	('1:3000', 'Var', (97, 103))	('1:150', 'Var', (84, 89))	('Mcm2', 'Gene', (60, 64))	('H3p', 'Gene', '126961', (92, 95))
33637	26921250	The PANC-1 and Capan-1 pancreatic adenocarcinoma cell lines were selected as they represent cell line model systems representative of the majority of pancreatic cancers harbouring point mutations in the TP53 gene as well as inactivating mutations in the tumour suppressor genes CDKN2B, CDKN2A and CDKN1B.	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (23, 48))	('pancreatic cancers', 'Disease', (150, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('CDKN1B', 'Gene', (297, 303))	('point mutations', 'Var', (180, 195))	('CDKN2B', 'Gene', '1030', (278, 284))	('PANC-1', 'CellLine', 'CVCL:0480', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('TP53', 'Gene', (203, 207))	('pancreatic cancers', 'Disease', 'MESH:D010190', (150, 168))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (23, 48))	('CDKN2A', 'Gene', (286, 292))	('pancreatic adenocarcinoma', 'Disease', (23, 48))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('CDKN1B', 'Gene', '1027', (297, 303))	('inactivating mutations', 'Var', (224, 246))	('tumour', 'Disease', (254, 260))	('Capan-1', 'CellLine', 'CVCL:0237', (15, 22))	('TP53', 'Gene', '7157', (203, 207))	('CDKN2A', 'Gene', '1029', (286, 292))	('CDKN2B', 'Gene', (278, 284))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (150, 168))
33667	26695438	Nuclear Src additionally promotes the tyrosine phosphorylation of p300 in pancreatic cancer Panc-1 cells.	('tyrosine', 'Chemical', 'MESH:D014443', (38, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('tyrosine phosphorylation', 'MPA', (38, 62))	('promotes', 'PosReg', (25, 33))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('p300', 'Var', (66, 70))	('pancreatic cancer', 'Disease', (74, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('Panc-1', 'CellLine', 'CVCL:0480', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
33671	26695438	Our findings for the first time show the critical importance of nuclear Src and p300 function in the migratory properties of pancreatic cancer cells.	('migratory properties', 'CPA', (101, 121))	('p300 function', 'Var', (80, 93))	('pancreatic cancer', 'Disease', 'MESH:D010190', (125, 142))	('nuclear Src', 'Protein', (64, 75))	('pancreatic cancer', 'Disease', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))
33673	26695438	Active Src is complexed with and phosphorylates p300 in the nucleus, and the complex is bound to HMGA2 and SMYD3 genes, thereby regulating their expression to promote pancreatic tumor cell migration and invasiveness.	('invasiveness', 'CPA', (203, 215))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (167, 183))	('SMYD3', 'Gene', (107, 112))	('nucleus', 'cellular_component', 'GO:0005634', ('60', '67'))	('pancreatic tumor', 'Disease', (167, 183))	('expression', 'MPA', (145, 155))	('p300', 'Var', (48, 52))	('promote', 'PosReg', (159, 166))	('regulating', 'Reg', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('pancreatic tumor', 'Disease', 'MESH:D010190', (167, 183))	('HMGA2', 'Gene', (97, 102))	('cell migration', 'biological_process', 'GO:0016477', ('184', '198'))
33680	26695438	There are numerous reported serine/threonine phosphorylation events of p300 residues, which are also known to regulate the protein's HAT activity.	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('p300 residues', 'Var', (71, 84))	('threonine', 'Chemical', 'MESH:D013912', (35, 44))	('serine', 'Chemical', 'MESH:D012694', (28, 34))	('HAT activity', 'MPA', (133, 145))	('serine/threonine phosphorylation', 'MPA', (28, 60))	('regulate', 'Reg', (110, 118))	('phosphorylation', 'biological_process', 'GO:0016310', ('45', '60'))
33681	26695438	Initially, p300 was presumed to behave as a classical tumor suppressor due primarily to its binding to and inactivation by adenovirus E1A (E1A), as well as the discovery of rare truncating mutations in the gene that occur in both primary tumors and cell lines.	('binding', 'Interaction', (92, 99))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('54', '70'))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('inactivation', 'NegReg', (107, 119))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('binding', 'molecular_function', 'GO:0005488', ('92', '99'))	('p300', 'Var', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (238, 243))	('truncating', 'MPA', (178, 188))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('tumors', 'Disease', (238, 244))	('tumor', 'Disease', (54, 59))	('tumor suppressor', 'biological_process', 'GO:0051726', ('54', '70'))
33682	26695438	While p300 may exhibit some tumor suppressive functions under certain contexts, numerous reports to the contrary, as well as the infrequency of inactivating p300 mutations suggested that the protein is more commonly involved in oncogenic signaling.	('tumor', 'Disease', (28, 33))	('p300', 'Gene', (157, 161))	('signaling', 'biological_process', 'GO:0023052', ('238', '247'))	('protein', 'cellular_component', 'GO:0003675', ('191', '198'))	('p300', 'Var', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
33683	26695438	The role of p300 in PDAC progression is relatively unexplored, although it has been shown to be involved in c-Myc induction and gemcitabine resistance in a three-dimensional collagen environment.	('c-Myc', 'Gene', '4609', (108, 113))	('PDAC', 'Chemical', '-', (20, 24))	('collagen', 'molecular_function', 'GO:0005202', ('174', '182'))	('involved', 'Reg', (96, 104))	('gemcitabine', 'Chemical', 'MESH:C056507', (128, 139))	('c-Myc', 'Gene', (108, 113))	('PDAC', 'Disease', (20, 24))	('PDAC', 'Phenotype', 'HP:0006725', (20, 24))	('p300', 'Var', (12, 16))
33684	26695438	In this study, we demonstrate the presence of activated (pY416) Src in the nuclei of mouse embryonic fibroblasts (MEFs) overexpressing Src, PDAC cell lines, and in patient tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mouse', 'Species', '10090', (85, 90))	('activated', 'PosReg', (46, 55))	('PDAC', 'Chemical', '-', (140, 144))	('Src', 'Gene', (64, 67))	('tumor', 'Disease', (172, 177))	('patient', 'Species', '9606', (164, 171))	('pY416', 'Chemical', '-', (57, 62))	('pY416', 'Var', (57, 62))	('PDAC', 'Phenotype', 'HP:0006725', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('MEFs', 'CellLine', 'CVCL:9115', (114, 118))
33687	26695438	The regulation by Src and p300 of HMGA2 was similarly observed in a MEF model in which Src signaling is activated, but not in normal MEFs.	('regulation', 'biological_process', 'GO:0065007', ('4', '14'))	('MEFs', 'CellLine', 'CVCL:9115', (133, 137))	('p300', 'Var', (26, 30))	('Src signaling', 'MPA', (87, 100))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('HMGA2', 'Gene', (34, 39))	('activated', 'PosReg', (104, 113))
33689	26695438	These results extend our understanding of Src signaling in cancer and provide evidence that p300 cooperates with nuclear Src to promote pancreatic cancer progression and together represent an effective target for anti-invasive therapies in pancreatic cancer, a disease characterized by its high degree of invasiveness and mortality.	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('cancer', 'Disease', (147, 153))	('pancreatic cancer', 'Disease', (240, 257))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (240, 257))	('pancreatic cancer', 'Disease', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (240, 257))	('promote', 'PosReg', (128, 135))	('cancer', 'Disease', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('p300', 'Var', (92, 96))
33694	26695438	Loading equal total protein in each lane, immunoblotting analysis showed a strong enrichment of total and active Src in the three nuclear subfractions (Figure 1B, DNAse/RNAse, nuclear envelope and heparin extract), as well as enrichment of p300 in the two nucleoplasmic fractions (Figure 1B, DNase/RNase, heparin extract).	('heparin', 'Chemical', 'MESH:D006493', (197, 204))	('nuclear envelope', 'cellular_component', 'GO:0005635', ('176', '192'))	('heparin', 'Chemical', 'MESH:D006493', (305, 312))	('p300', 'Var', (240, 244))	('active Src', 'MPA', (106, 116))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))
33705	26695438	It is known that vSrc with an NLS fused to the N-terminus does not induce morphological transformation, which was confirmed in our study using the SYF-/-NLSvSrc cells, compared to NIH3T3vSrc cells, while the SYF-/-NESvSrc cells appeared morphologically transformed (Figure S3B).	('S3B', 'Gene', (273, 276))	('S3B', 'Gene', '11778', (273, 276))	('SYF-/-NLSvSrc', 'Var', (147, 160))	('NIH3T3', 'CellLine', 'CVCL:0594', (180, 186))
33708	26695438	Altogether, our results indicate that active nuclear Src is present in PDAC and MEF cells over-expressing c-Src, and further that its association with p300 is evident in both PDAC and MEF background that over-expressed active Src.	('PDAC', 'Chemical', '-', (175, 179))	('p300', 'Var', (151, 155))	('PDAC', 'Phenotype', 'HP:0006725', (71, 75))	('PDAC', 'Phenotype', 'HP:0006725', (175, 179))	('c-Src', 'Gene', (106, 111))	('c-Src', 'Gene', '6714', (106, 111))	('PDAC', 'Chemical', '-', (71, 75))
33710	26695438	Src association with p300 led us to investigate whether p300 undergoes tyrosine phosphorylation.	('phosphorylation', 'biological_process', 'GO:0016310', ('80', '95'))	('tyrosine', 'Chemical', 'MESH:D014443', (71, 79))	('p300', 'Var', (21, 25))	('p300', 'Var', (56, 60))
33711	26695438	Immunoprecipitation of p300 and Western blotting analysis for general phosphotyrosine revealed tryosine phosphorylation of p300 in the PDAC cell line, Colo-357 (Figure 3A), which was suppressed when Colo-357 cells were treated with the Src inhibitor, dasatinib (Figure 3B), suggesting tyrosine phosphorylation of p300 is dependent on Src tyrosine kinase activity.	('tyrosine', 'Chemical', 'MESH:D014443', (285, 293))	('tyrosine', 'Chemical', 'MESH:D014443', (338, 346))	('PDAC', 'Phenotype', 'HP:0006725', (135, 139))	('p300', 'Var', (123, 127))	('kinase activity', 'molecular_function', 'GO:0016301', ('347', '362'))	('Colo', 'Species', '307630', (151, 155))	('Colo', 'Species', '307630', (199, 203))	('phosphorylation', 'biological_process', 'GO:0016310', ('294', '309'))	('phosphorylation', 'biological_process', 'GO:0016310', ('104', '119'))	('tryosine', 'Chemical', '-', (95, 103))	('dasatinib', 'Chemical', 'MESH:D000069439', (251, 260))	('tryosine phosphorylation', 'MPA', (95, 119))	('PDAC', 'Chemical', '-', (135, 139))	('tyrosine', 'Chemical', 'MESH:D014443', (77, 85))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (70, 85))
33713	26695438	These results are the first to show a Src-dependent tyrosine phosphorylation of p300 in PDAC cells.	('Src-dependent tyrosine phosphorylation', 'MPA', (38, 76))	('PDAC', 'Phenotype', 'HP:0006725', (88, 92))	('tyrosine', 'Chemical', 'MESH:D014443', (52, 60))	('p300', 'Var', (80, 84))	('PDAC', 'Chemical', '-', (88, 92))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))
33717	26695438	Given that Src and p300 are associated in these cells and that p300 is tyrosine phosphorylated in a Src-dependent manner, we asked whether Src inhibition could disrupt Src or p300 association with these promoters.	('p300', 'Var', (175, 179))	('tyrosine', 'Chemical', 'MESH:D014443', (71, 79))	('association', 'Interaction', (180, 191))
33718	26695438	Inhibition of Src activity by dasatinib has no effect on the Src and p300 association with the gene promoters (Figure 4B).	('Src', 'Disease', (61, 64))	('dasatinib', 'Chemical', 'MESH:D000069439', (30, 39))	('p300', 'Var', (69, 73))
33719	26695438	By contrast, Src inhibition by dasatinib or p300 inhibition by C646 decreased both the mRNA and protein levels of HMGA2 and SMYD3 (Figure 4C).	('decreased', 'NegReg', (68, 77))	('HMGA2', 'Gene', (114, 119))	('C646', 'Var', (63, 67))	('Src', 'MPA', (13, 16))	('dasatinib', 'Chemical', 'MESH:D000069439', (31, 40))	('inhibition', 'NegReg', (17, 27))	('p300', 'Var', (44, 48))	('C646', 'Chemical', '-', (63, 67))
33721	26695438	Inhibition of Src or p300 decreased the expression of HMGA2 in SYF-Src cells, while having no effect on HMGA2 expression in the SYF+/+ or SYF-/- cells (Figure 4E, Figure S5B).	('expression', 'MPA', (40, 50))	('S5B', 'Gene', (170, 173))	('S5B', 'Gene', '66998', (170, 173))	('p300', 'Var', (21, 25))	('HMGA2', 'Gene', (54, 59))	('decreased', 'NegReg', (26, 35))
33722	26695438	Together, these data indicate that nuclear active Src in conjunction with p300 is specifically associated with HMGA2 and/or SMYD3 gene promoters and regulates their expression in a Src-kinase-dependent manner in PDAC and MEF cells.	('p300', 'Var', (74, 78))	('expression', 'MPA', (165, 175))	('PDAC', 'Phenotype', 'HP:0006725', (212, 216))	('HMGA2', 'Gene', (111, 116))	('PDAC', 'Chemical', '-', (212, 216))	('regulates', 'Reg', (149, 158))
33726	26695438	On the other hand, in soft agar studies, inhibition of Src, p300, or both suppressed anchorage-independent growth of Panc-1 cells (Figure 5A).	('p300', 'Var', (60, 64))	('suppressed', 'NegReg', (74, 84))	('anchorage-independent growth', 'CPA', (85, 113))	('agar', 'Chemical', 'MESH:D000362', (27, 31))	('Panc-1', 'CellLine', 'CVCL:0480', (117, 123))	('inhibition', 'Var', (41, 51))	('Src', 'Gene', (55, 58))
33734	26695438	Higher HMGA2 and SMYD3 expression were detected in the tumors harboring high nuclear pSrc compared to the tumors lacking active nuclear Src (Figure 6A(ii), representative data).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('SMYD3', 'Gene', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('Higher', 'PosReg', (0, 6))	('HMGA2', 'Gene', (7, 12))	('high nuclear pSrc', 'Var', (72, 89))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('expression', 'MPA', (23, 33))
33740	26695438	The role of p300 in PDAC is largely unexplored, although its function in other tumor types has begun to be described in more detail.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('PDAC', 'Chemical', '-', (20, 24))	('tumor', 'Disease', (79, 84))	('PDAC', 'Disease', (20, 24))	('PDAC', 'Phenotype', 'HP:0006725', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('p300', 'Var', (12, 16))
33741	26695438	In particular, p300 is reported to be a key mediator of oncogenic hormone receptor signaling in hormone receptor positive breast and prostate cancers whereby it promotes the expression of estrogen or androgen receptors, respectively.	('prostate cancer', 'Phenotype', 'HP:0012125', (133, 148))	('expression', 'MPA', (174, 184))	('promotes', 'PosReg', (161, 169))	('prostate cancers', 'Phenotype', 'HP:0012125', (133, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('breast and prostate cancers', 'Disease', 'MESH:D011471', (122, 149))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('p300', 'Var', (15, 19))	('androgen receptors', 'Protein', (200, 218))	('estrogen', 'Protein', (188, 196))
33743	26695438	The current studies show for the first time that p300 is involved in the migratory and metastatic behavior of pancreatic cancer cells.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('p300', 'Var', (49, 53))	('pancreatic cancer', 'Disease', (110, 127))	('pancreatic cancer', 'Disease', 'MESH:D010190', (110, 127))	('migratory', 'CPA', (73, 82))	('involved', 'Reg', (57, 65))
33746	26695438	This is consistent with the report that high nuclear pY416 Src is associated with significantly better response to tamoxifen ER antagonist and that active nuclear Src contributes to the dependency on ER signaling of the breast cancer phenotype.	('ER signaling', 'MPA', (200, 212))	('response to tamoxifen ER antagonist', 'MPA', (103, 138))	('contributes', 'Reg', (167, 178))	('pY416', 'Chemical', '-', (53, 58))	('breast cancer', 'Disease', 'MESH:D001943', (220, 233))	('high nuclear pY416 Src', 'Var', (40, 62))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('breast cancer', 'Disease', (220, 233))	('better', 'PosReg', (96, 102))	('signaling', 'biological_process', 'GO:0023052', ('203', '212'))	('breast cancer', 'Phenotype', 'HP:0003002', (220, 233))	('dependency', 'MPA', (186, 196))	('active nuclear Src', 'Var', (148, 166))	('tamoxifen', 'Chemical', 'MESH:D013629', (115, 124))
33747	26695438	While clinical trials of Src inhibitors failed to show efficacy in patients with advanced metastatic disease, present data may offer some explanation for this failure in indicating that Src and p300 participate in the migratory and invasive properties of PDAC cells rather than survival signaling.	('Src', 'Gene', (186, 189))	('PDAC', 'Chemical', '-', (255, 259))	('signaling', 'biological_process', 'GO:0023052', ('287', '296'))	('patients', 'Species', '9606', (67, 75))	('migratory', 'CPA', (218, 227))	('PDAC', 'Phenotype', 'HP:0006725', (255, 259))	('p300', 'Var', (194, 198))	('invasive properties', 'CPA', (232, 251))	('participate', 'Reg', (199, 210))
33749	26695438	Our data suggest that therapies targeting Src/p300 signaling could be efficacious early intervention options for aggressive primary tumors in which both Src and p300 are implicated in order to prevent primary tumor metastasis.	('tumor metastasis', 'Disease', 'MESH:D009362', (209, 225))	('aggressive primary tumors', 'Disease', (113, 138))	('p300', 'Var', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor metastasis', 'Disease', (209, 225))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('aggressive primary tumors', 'Disease', 'MESH:D001523', (113, 138))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
33751	26695438	The identification of HMGA2 and SMYD3 as targets of Src/p300 signaling provides additional novel mechanisms by which Src likely mediates cellular migratory and invasive properties, while also showing for the first time that p300 participates in the regulation of the migratory and invasive potential of PDAC cells.	('cellular migratory', 'CPA', (137, 155))	('mediates', 'Reg', (128, 136))	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('migratory', 'CPA', (267, 276))	('PDAC', 'Chemical', '-', (303, 307))	('regulation', 'biological_process', 'GO:0065007', ('249', '259'))	('p300', 'Var', (224, 228))	('PDAC', 'Phenotype', 'HP:0006725', (303, 307))	('invasive properties', 'CPA', (160, 179))
33754	26695438	Antibodies used were as follows: Src (B-12), p300 (C20), GAPDH (6C5), beta-Tubulin (C10), Grim19, (Santa Cruz Biotechnology, Santa Cruz, CA), Src (36D10), pY-416 Src (2101), HMGA2 (D1A7), SMYD3 (D2Q4V), Lamin A/C (#2032), Calnexin (C5C9), HDAC1 (10E2), Histone H3 (D1H2), p-TYR-100 (Cell Signaling Technology, Danvers, MA), pY418 Src (92633), p300 (507) (Novus Biologicals, Littleton, CO), HMGA2 (AF3184) (R&D Systems, Minneapolis, MN), and SMYD3 (ab16027) (Abcam, Cambridge, UK).	('Lamin A/C', 'Gene', (203, 212))	('pY418 Src (92633', 'Var', (324, 340))	('Grim19', 'Gene', '67184', (90, 96))	('HDAC1', 'Gene', (239, 244))	('MN', 'CellLine', 'CVCL:U508', (432, 434))	('Signaling', 'biological_process', 'GO:0023052', ('288', '297'))	('Calnexin', 'Gene', '12330', (222, 230))	('TYR', 'Chemical', 'MESH:D014443', (274, 277))	('C10', 'Gene', '20305', (84, 87))	('C10', 'Gene', (84, 87))	('Lamin A/C', 'Gene', '16905', (203, 212))	('Calnexin', 'Gene', (222, 230))	('HDAC1', 'Gene', '433759', (239, 244))	('Grim19', 'Gene', (90, 96))
33771	26695438	Specific antibodies used for antigen capture in IP studies were Src (B-12), p300 (C20) (Santa Cruz), and p-TYR-100 (Cell Signaling).	('p-TYR-100', 'Var', (105, 114))	('p300 (C20', 'Var', (76, 85))	('TYR', 'Chemical', 'MESH:D014443', (107, 110))	('Signaling', 'biological_process', 'GO:0023052', ('121', '130'))
33798	26506897	NCOA4 knockdown increases ferritin levels and decreases bioavailable iron as evidenced by an increase in IREB2 (iron-responsive element binding protein 2).	('NCOA4', 'Gene', (0, 5))	('iron', 'Chemical', 'MESH:D007501', (69, 73))	('NCOA4', 'Gene', '8031', (0, 5))	('ferritin levels', 'MPA', (26, 41))	('increase', 'PosReg', (93, 101))	('iron-responsive element binding', 'molecular_function', 'GO:0030350', ('112', '143'))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('increases ferritin', 'Phenotype', 'HP:0003281', (16, 34))	('iron-responsive element binding protein 2', 'Gene', (112, 153))	('decreases', 'NegReg', (46, 55))	('increases', 'PosReg', (16, 25))	('iron-responsive element binding protein 2', 'Gene', '3658', (112, 153))	('knockdown', 'Var', (6, 15))	('bioavailable iron', 'MPA', (56, 73))	('iron', 'Chemical', 'MESH:D007501', (112, 116))	('IREB2', 'Gene', '3658', (105, 110))	('IREB2', 'Gene', (105, 110))
33802	26506897	CLU-LC3B binding was mapped to LIR domain 341YNEL, and its simultaneous colocalization and direct interaction with ATG3 promotes LC3B lipidation and autolysosome maturation in mouse models of prostate cancer.	('autolysosome maturation', 'CPA', (149, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (192, 207))	('LIR', 'Var', (31, 34))	('interaction', 'Interaction', (98, 109))	('LC3B', 'Gene', (4, 8))	('promotes', 'PosReg', (120, 128))	('prostate cancer', 'Disease', 'MESH:D011471', (192, 207))	('mouse', 'Species', '10090', (176, 181))	('LC3B', 'Gene', '67443', (129, 133))	('prostate cancer', 'Disease', (192, 207))	('binding', 'molecular_function', 'GO:0005488', ('9', '16'))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('autolysosome', 'cellular_component', 'GO:0044754', ('149', '161'))	('ATG3', 'Gene', (115, 119))	('LC3B', 'Gene', '67443', (4, 8))	('LC3B', 'Gene', (129, 133))	('ATG3', 'Gene', '67841', (115, 119))	('colocalization', 'Var', (72, 86))
33803	26506897	Pharmacological inhibition of CLU in combination with AZD5363 or paclitaxel significantly delays mouse tumor growth and reduces LC3-II protein levels, suggesting concomitant autophagy suppression.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('reduces', 'NegReg', (120, 127))	('paclitaxel', 'Chemical', 'MESH:D017239', (65, 75))	('tumor', 'Disease', (103, 108))	('delays', 'NegReg', (90, 96))	('AZD5363', 'Chemical', 'MESH:C575618', (54, 61))	('suppression', 'NegReg', (184, 195))	('LC3', 'Gene', '84557', (128, 131))	('LC3', 'Gene', (128, 131))	('mouse', 'Species', '10090', (97, 102))	('autophagy', 'biological_process', 'GO:0016236', ('174', '183'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('autophagy', 'biological_process', 'GO:0006914', ('174', '183'))	('autophagy', 'CPA', (174, 183))	('inhibition', 'Var', (16, 26))
33805	26506897	The C-terminal truncated proteins result in accumulated endogenous SQSTM1, suggesting they contribute to noxious aggregate accumulation and viral pathogenesis by crippling ubiquitin-mediated selective autophagy.	('ubiquitin', 'molecular_function', 'GO:0031386', ('172', '181'))	('SQSTM1', 'Gene', (67, 73))	('ubiquitin-mediated selective', 'MPA', (172, 200))	('contribute', 'Reg', (91, 101))	('endogenous', 'MPA', (56, 66))	('C-terminal', 'Var', (4, 14))	('noxious aggregate accumulation', 'MPA', (105, 135))	('SQSTM1', 'Gene', '8878', (67, 73))	('pathogenesis', 'biological_process', 'GO:0009405', ('146', '158'))	('crippling', 'NegReg', (162, 171))	('selective autophagy', 'biological_process', 'GO:0061912', ('191', '210'))	('accumulated', 'PosReg', (44, 55))	('proteins', 'Protein', (25, 33))
33807	26506897	Dagmar Ehrnhoefer and Dale Martin of Dr. Michael Hayden's group (Center for Molecular Medicine and Therapeutics) reported that dysregulated autophagy and increased pathogenesis in Huntington disease (HD) results from a gain-of-function mutant HTT/huntingtin and a loss of wild-type HTT function, mediated by disease-related HTT proteolysis and changes to autophagy-regulating, posttranslational modifications of mutant and wild-type HTT.	('Huntington disease', 'Disease', (180, 198))	('pathogenesis', 'CPA', (164, 176))	('HTT', 'Protein', (324, 327))	('huntingtin', 'Gene', (247, 257))	('autophagy', 'biological_process', 'GO:0016236', ('140', '149'))	('HD', 'Disease', 'MESH:D006816', (200, 202))	('huntingtin', 'Gene', '3064', (247, 257))	('autophagy-regulating', 'MPA', (355, 375))	('dysregulated', 'Disease', (127, 139))	('gain-of-function', 'PosReg', (219, 235))	('proteolysis', 'biological_process', 'GO:0006508', ('328', '339'))	('posttranslational modifications', 'MPA', (377, 408))	('function', 'MPA', (286, 294))	('increased', 'PosReg', (154, 163))	('autophagy', 'biological_process', 'GO:0016236', ('355', '364'))	('mutant', 'Var', (412, 418))	('autophagy', 'biological_process', 'GO:0006914', ('140', '149'))	('mutant', 'Var', (236, 242))	('changes', 'Reg', (344, 351))	('autophagy', 'biological_process', 'GO:0006914', ('355', '364'))	('pathogenesis', 'biological_process', 'GO:0009405', ('164', '176'))	('Huntington disease', 'Disease', 'MESH:D006816', (180, 198))
33808	26506897	Myristoylation of HTT is reduced in the presence of the HD mutation, suggesting a possible mechanism by which autophagy is defective in HD patient lymphoblasts.	('reduced', 'NegReg', (25, 32))	('autophagy', 'CPA', (110, 119))	('HD', 'Disease', 'MESH:D006816', (136, 138))	('autophagy', 'biological_process', 'GO:0016236', ('110', '119'))	('HTT', 'Protein', (18, 21))	('mutation', 'Var', (59, 67))	('defective', 'NegReg', (123, 132))	('autophagy', 'biological_process', 'GO:0006914', ('110', '119'))	('HD', 'Disease', 'MESH:D006816', (56, 58))	('patient', 'Species', '9606', (139, 146))	('Myristoylation', 'MPA', (0, 14))
33809	26506897	In addition, Dr. Ehrnhoefer demonstrated that the ablation of CASP6, which is the primary caspase responsible for cleavage at D586, leads to altered levels of autophagy proteins and reduced mutant HTT levels in a mouse model of HD, suggesting a possible protective effect.	('HTT', 'Protein', (197, 200))	('mouse', 'Species', '10090', (213, 218))	('altered', 'Reg', (141, 148))	('HD', 'Disease', 'MESH:D006816', (228, 230))	('ablation', 'Var', (50, 58))	('mutant', 'MPA', (190, 196))	('autophagy', 'biological_process', 'GO:0016236', ('159', '168'))	('CASP6', 'Gene', (62, 67))	('autophagy', 'biological_process', 'GO:0006914', ('159', '168'))	('levels of', 'MPA', (149, 158))	('CASP6', 'Gene', '12368', (62, 67))	('autophagy proteins', 'CPA', (159, 177))	('reduced', 'NegReg', (182, 189))
33819	26506897	Lys05 is a previously published lysosomal inhibitor that exhibits more potent in vivo autophagy inhibition than HCQ.	('Lys05', 'Chemical', 'MESH:C573930', (0, 5))	('autophagy', 'CPA', (86, 95))	('HCQ', 'Chemical', 'MESH:D006886', (112, 115))	('autophagy', 'biological_process', 'GO:0016236', ('86', '95'))	('Lys05', 'Var', (0, 5))	('inhibition', 'NegReg', (96, 106))	('autophagy', 'biological_process', 'GO:0006914', ('86', '95'))
33824	26506897	Increasing numbers of studies identify perturbed selective autophagy of proteins, aggregates, and organelles as pathogenic mechanisms in metabolic and neurodegenerative diseases, as well as in cancer and immunity.	('perturbed', 'Var', (39, 48))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('selective autophagy', 'biological_process', 'GO:0061912', ('49', '68'))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (151, 177))	('cancer', 'Disease', (193, 199))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (151, 177))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('neurodegenerative diseases', 'Disease', (151, 177))
33859	26808546	As shown, on multivariable analysis, high interleukin 8 (IL-8) levels were associated with poor survival in both treatment groups, while higher carcinoembryonic antigen (CEA) and hypoxia induced factor 1 alpha (HIF-1alpha) levels were associated with worse survival in patients treated with erlotinib.	('HIF-1alpha', 'Gene', '3091', (211, 221))	('interleukin 8', 'Gene', '3576', (42, 55))	('IL-8', 'Gene', '3576', (57, 61))	('high', 'Var', (37, 41))	('CEA', 'Gene', (170, 173))	('higher', 'PosReg', (137, 143))	('IL-8', 'Gene', (57, 61))	('CEA', 'Gene', '1084', (170, 173))	('hypoxia', 'Disease', (179, 186))	('hypoxia', 'Disease', 'MESH:D000860', (179, 186))	('HIF-1alpha', 'Gene', (211, 221))	('carcinoembryonic antigen', 'Gene', '1084', (144, 168))	('erlotinib', 'Chemical', 'MESH:D000069347', (291, 300))	('IL-8', 'molecular_function', 'GO:0005153', ('57', '61'))	('patients', 'Species', '9606', (269, 277))	('carcinoembryonic antigen', 'Gene', (144, 168))	('interleukin 8', 'Gene', (42, 55))
33861	26808546	Significantly more patients with high IL-8, CEA, platelet derived growth factor alpha (PFGFRalpha), and mucin 1 (MUC-1) levels had stage IV metastatic disease.	('platelet derived growth factor', 'molecular_function', 'GO:0005161', ('49', '79'))	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (19, 27))	('stage IV metastatic disease', 'CPA', (131, 158))	('IL-8', 'molecular_function', 'GO:0005153', ('38', '42'))	('mucin 1', 'Gene', '4582', (104, 111))	('IL-8', 'Gene', '3576', (38, 42))	('CEA', 'Gene', (44, 47))	('MUC-1', 'Gene', (113, 118))	('IL-8', 'Gene', (38, 42))	('CEA', 'Gene', '1084', (44, 47))	('MUC-1', 'Gene', '4582', (113, 118))	('mucin 1', 'Gene', (104, 111))
33865	26808546	In the validation cohort, patients with HER2 above the median had improved survival when treated with erlotinib (median OS 8.2 vs. 5 months, HR 0.36, 95% CI 0.21-0.63, p<0.0001) whereas no significant difference between erlotinib and placebo was found from patients with HER2 2 levels lower than median (median OS 6.0 vs. 8.3 months, HR 1.28, 95% CI 0.8-2.1, p = 0.3) (Fig 3).	('HER2', 'Gene', (40, 44))	('erlotinib', 'Var', (102, 111))	('HER2', 'Gene', '2064', (40, 44))	('improved', 'PosReg', (66, 74))	('erlotinib', 'Chemical', 'MESH:D000069347', (102, 111))	('patients', 'Species', '9606', (26, 34))	('survival', 'MPA', (75, 83))	('OS', 'Chemical', '-', (311, 313))	('patients', 'Species', '9606', (257, 265))	('HER2', 'Gene', (271, 275))	('OS', 'Chemical', '-', (120, 122))	('erlotinib', 'Chemical', 'MESH:D000069347', (220, 229))	('HER2', 'Gene', '2064', (271, 275))
33866	26808546	NCIC CTG PA.3 proved its hypothesis that erlotinib plus gemcitabine results in improved OS compared to gemcitabine alone for locally advanced or metastatic PDCA, however median OS in the experimental and control arms differed by only 0.3 months (6.2 versus 5.9).	('metastatic', 'CPA', (145, 155))	('improved', 'PosReg', (79, 87))	('locally advanced', 'Disease', (125, 141))	('OS', 'Chemical', '-', (177, 179))	('gemcitabine', 'Chemical', 'MESH:C056507', (103, 114))	('erlotinib', 'Var', (41, 50))	('gemcitabine', 'Chemical', 'MESH:C056507', (56, 67))	('OS', 'Chemical', '-', (88, 90))	('erlotinib', 'Chemical', 'MESH:D000069347', (41, 50))	('PDCA', 'Phenotype', 'HP:0006725', (156, 160))
33886	25965802	However, p53 is also known to inhibit virus replication via enhanced type I interferon (IFN) antiviral responses.	('IFN', 'Gene', '3439', (88, 91))	('p53', 'Var', (9, 12))	('interferon', 'Gene', (76, 86))	('IFN', 'Gene', (88, 91))	('inhibit', 'NegReg', (30, 37))	('virus replication', 'CPA', (38, 55))	('interferon', 'Gene', '3439', (76, 86))	('enhanced', 'PosReg', (60, 68))
33888	25965802	Contrary to an expected enhancement of antiviral signaling by p53, our global analysis of gene expression in PDAC cells showed that both p53 and p53-CC dramatically inhibited type I IFN responses.	('p53-CC', 'Var', (145, 151))	('gene expression', 'biological_process', 'GO:0010467', ('90', '105'))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('IFN', 'Gene', '3439', (182, 185))	('inhibited', 'NegReg', (165, 174))	('IFN', 'Gene', (182, 185))	('p53', 'Var', (137, 140))	('PDAC', 'Chemical', '-', (109, 113))
33889	25965802	Our data suggest that this occurs through p53-mediated inhibition of the NF-kappaB pathway.	('NF-kappaB', 'Gene', (73, 82))	('inhibition', 'NegReg', (55, 65))	('p53-mediated', 'Var', (42, 54))	('NF-kappaB', 'Gene', '4790', (73, 82))
33890	25965802	Importantly, VSV-encoded p53 or p53-CC did not inhibit antiviral signaling in non-malignant human pancreatic ductal cells, which retain their resistance to all VSV recombinants.	('antiviral signaling', 'MPA', (55, 74))	('pancreatic ductal', 'Disease', 'MESH:D021441', (98, 115))	('p53-CC', 'Var', (32, 38))	('VSV', 'Species', '11276', (160, 163))	('inhibit', 'NegReg', (47, 54))	('VSV', 'Species', '11276', (13, 16))	('p53', 'Var', (25, 28))	('pancreatic ductal', 'Disease', (98, 115))	('human', 'Species', '9606', (92, 97))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))
33900	25965802	Several studies showed that in normal cells and some cancer cell lines, p53 inhibited virus replication via enhanced type I Interferon (IFN) antiviral signaling.	('Interferon', 'Gene', '3439', (124, 134))	('virus replication', 'MPA', (86, 103))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('Interferon', 'Gene', (124, 134))	('IFN', 'Gene', '3439', (136, 139))	('IFN', 'Gene', (136, 139))	('enhanced', 'PosReg', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('inhibited', 'NegReg', (76, 85))	('p53', 'Var', (72, 75))
33903	25965802	Such activities of virus-encoded p53 transgenes in cancer cells could dramatically reduce the efficacy of replicating OVs, including VSV.	('efficacy', 'MPA', (94, 102))	('replicating OVs', 'CPA', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('VSV', 'Disease', (133, 136))	('p53', 'Gene', (33, 36))	('VSV', 'Species', '11276', (133, 136))	('reduce', 'NegReg', (83, 89))	('activities', 'MPA', (5, 15))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('transgenes', 'Var', (37, 47))
33906	25965802	Specific to PDAC, TP53 gene mutations occur in more than 75% of patients and are shown to contribute to proliferation and even drive metastasis through gain of function activities.	('TP53', 'Gene', '7157', (18, 22))	('patients', 'Species', '9606', (64, 72))	('proliferation', 'CPA', (104, 117))	('TP53', 'Gene', (18, 22))	('drive', 'PosReg', (127, 132))	('metastasis', 'CPA', (133, 143))	('PDAC', 'Chemical', '-', (12, 16))	('contribute', 'Reg', (90, 100))	('mutations', 'Var', (28, 37))	('gain of function', 'PosReg', (152, 168))
33907	25965802	Previous studies have shown that exogenous delivery of p53 sensitizes PDAC to chemotherapy, treatment with adenovirus encoding p53 sensitizes PDAC to radiation, and the use of small molecules like apigenin or mouse double minute 2 homolog (MDM2) inhibitors can restore endogenous p53 function and slow PDAC proliferation.	('sensitizes', 'Reg', (59, 69))	('PDAC proliferation', 'CPA', (302, 320))	('slow', 'NegReg', (297, 301))	('PDAC', 'Chemical', '-', (142, 146))	('p53', 'Protein', (280, 283))	('restore', 'PosReg', (261, 268))	('PDAC', 'Chemical', '-', (302, 306))	('endogenous', 'MPA', (269, 279))	('mouse', 'Species', '10090', (209, 214))	('PDAC', 'Chemical', '-', (70, 74))	('MDM2', 'Gene', '17246', (240, 244))	('MDM2', 'Gene', (240, 244))	('p53', 'Var', (55, 58))	('function', 'MPA', (284, 292))	('PDAC', 'Disease', (70, 74))
33913	25965802	Surprisingly, our data show that both wt p53 and p53-CC downregulate cellular antiviral responses in a variety of PDAC cell lines, and do so through inhibition of the NF-kB pathway.	('inhibition', 'NegReg', (149, 159))	('p53-CC', 'Var', (49, 55))	('cellular antiviral responses', 'MPA', (69, 97))	('PDAC', 'Chemical', '-', (114, 118))	('downregulate', 'NegReg', (56, 68))	('NF-kB pathway', 'Pathway', (167, 180))
33923	25965802	As expected, all PDAC cell lines (but not HPDE cells) had a mutation in KRAS, as is typical for PDACs (data not shown).	('mutation', 'Var', (60, 68))	('PDAC', 'Chemical', '-', (96, 100))	('KRAS', 'Gene', (72, 76))	('KRAS', 'Gene', '3845', (72, 76))	('HPDE', 'Chemical', '-', (42, 46))	('PDAC', 'Chemical', '-', (17, 21))
33927	25965802	Selection for colonies containing VSV-XN2-DeltaM51 or HA-tagged BCR plasmids was done with 50 microg/ml of ampicillin, and GFP-p53 plasmid with 50 microg/ml of kanamycin.	('kanamycin', 'Chemical', 'MESH:D007612', (160, 169))	('ampicillin', 'Chemical', 'MESH:D000667', (107, 117))	('VSV-XN2-DeltaM51', 'Var', (34, 50))	('BCR', 'Gene', (64, 67))	('BCR', 'Gene', '613', (64, 67))	('VSV', 'Species', '11276', (34, 37))
33929	25965802	To generate VSV plasmids with eqFP650-p53, p53 sequence was first inserted into pUC57-eqFP650 plasmids, and then eqFP650-p53 was cloned into VSV-XN2-DeltaM51 plasmid.	('eqFP650-p53', 'Var', (113, 124))	('VSV', 'Species', '11276', (12, 15))	('eqFP650-p53', 'Var', (30, 41))	('p53', 'Gene', (43, 46))	('VSV', 'Species', '11276', (141, 144))
33932	25965802	To generate TP53-CC, the TP53DeltaODRD sequence from the GFP-p53 plasmid was PCR amplified using primers VG283 and VG293 and the CC sequence from the HA-tagged BCR plasmid was PCR amplified using primers VG288 and VG292.	('TP53', 'Gene', (25, 29))	('VG283', 'Var', (105, 110))	('BCR', 'Gene', (160, 163))	('VG293', 'Var', (115, 120))	('TP53', 'Gene', '7157', (12, 16))	('BCR', 'Gene', '613', (160, 163))	('TP53', 'Gene', (12, 16))	('TP53', 'Gene', '7157', (25, 29))	('VG293', 'CellLine', 'CVCL:X927', (115, 120))
33940	25965802	Following virus rescue, amplification, and purification, RNA was isolated and sequenced confirming the DeltaM51 deletion and correct transgene insertions.	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('DeltaM51', 'Var', (103, 111))	('deletion', 'Var', (112, 120))	('DeltaM51', 'DELETION', 'None', (103, 111))
33965	25965802	To analyze cellular DNA for frequent cancer mutations, the Ion AmpliSeq  Cancer Hotspot Panel v2 Kit (Life Technologies) containing 207 primer pairs was used to perform multiplex PCR for the preparation of amplicon libraries from genomic hot spot regions that are frequently mutated in human genes associated with cancer, including approximately 2800 Catalogue of Somatic Mutations in Cancer (COSMIC) mutations of 50 oncogenes and tumor suppressor genes.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('tumor suppressor', 'biological_process', 'GO:0051726', ('431', '447'))	('oncogenes', 'Gene', (417, 426))	('Cancer', 'Phenotype', 'HP:0002664', (385, 391))	('cancer', 'Disease', 'MESH:D009369', (314, 320))	('human', 'Species', '9606', (286, 291))	('Cancer', 'Disease', (385, 391))	('tumor', 'Disease', (431, 436))	('Mutations', 'Var', (372, 381))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (431, 436))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (401, 410))	('Cancer', 'Disease', 'MESH:D009369', (385, 391))	('Cancer', 'Disease', (73, 79))	('cancer', 'Disease', (314, 320))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('431', '447'))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('tumor', 'Phenotype', 'HP:0002664', (431, 436))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))	('Cancer', 'Disease', 'MESH:D009369', (73, 79))
33966	25965802	To confirm the identified p53 mutations, cellular genomic DNA corresponding to TP53 exons 5 through 9 (where a majority of TP53 mutations occur) was amplified by PCR with primers VG 268 and VG 269 (NM_000546.5, Supplemental Table 1) prior to sequencing.	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('p53', 'Gene', (26, 29))	('mutations', 'Var', (30, 39))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
33969	25965802	As the C-terminus of p53wt, the CC domain of the Bcr protein allows for formation of antiparallel tetramers.	('p53wt', 'Var', (21, 26))	('antiparallel tetramers', 'MPA', (85, 107))	('Bcr', 'Gene', '613', (49, 52))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('formation', 'MPA', (72, 81))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))	('Bcr', 'Gene', (49, 52))
33970	25965802	As a result, the chimeric p53-CC protein was shown to evade endogenous dominant-negative p53 and restore p53wt activity better than p53wt in vitro in human ductal breast epithelial, human breast adenocarcinoma, human epithelial cervical adenocarcinoma, and human non-small cell lung carcinoma cell lines.	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (188, 209))	('human', 'Species', '9606', (257, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (263, 292))	('epithelial cervical adenocarcinoma', 'Disease', 'MESH:D002277', (217, 251))	('p53wt activity', 'MPA', (105, 119))	('chimeric', 'Var', (17, 25))	('human', 'Species', '9606', (150, 155))	('human', 'Species', '9606', (182, 187))	('epithelial cervical adenocarcinoma', 'Disease', (217, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (263, 292))	('p53-CC', 'Gene', (26, 32))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (188, 209))	('non-small cell lung carcinoma', 'Disease', (263, 292))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (267, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('breast adenocarcinoma', 'Disease', (188, 209))	('evade', 'NegReg', (54, 59))	('human', 'Species', '9606', (211, 216))	('restore', 'PosReg', (97, 104))
33975	25965802	VSV M51 mutants lack neurotoxicity but retain good oncolytic abilities.	('neurotoxicity', 'Disease', (21, 34))	('VSV M51', 'Gene', (0, 7))	('oncolytic abilities', 'CPA', (51, 70))	('mutants', 'Var', (8, 15))	('neurotoxicity', 'Disease', 'MESH:D020258', (21, 34))	('VSV', 'Species', '11276', (0, 3))
33976	25965802	In addition to safety, another advantage of VSV-DeltaM51 for p53 transgene expression is that, unlike wt M protein, the DeltaM51 M does not prevent cellular gene expression in infected cells.	('gene expression', 'biological_process', 'GO:0010467', ('157', '172'))	('DeltaM51', 'Var', (48, 56))	('VSV', 'Species', '11276', (44, 47))	('DeltaM51', 'Var', (120, 128))	('DeltaM51', 'DELETION', 'None', (120, 128))	('DeltaM51', 'DELETION', 'None', (48, 56))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
33977	25965802	Therefore, VSV-DeltaM51-encoded functional p53 would be able to drive beneficial expression of p53-regulated anticancer genes.	('beneficial', 'PosReg', (70, 80))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('VSV-DeltaM51-encoded', 'Var', (11, 31))	('p53', 'Gene', (43, 46))	('VSV', 'Species', '11276', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('expression', 'MPA', (81, 91))
33981	25965802	Partial sequencing of cDNA confirmed the presence of DeltaM51 deletion as well as correct transgene insertion and sequence (Figs.	('DeltaM51', 'DELETION', 'None', (53, 61))	('DeltaM51', 'Var', (53, 61))	('transgene', 'Var', (90, 99))
33984	25965802	Suit2 cells, like PDAC cells in 75% of patients, carry a TP53 mutation.	('patients', 'Species', '9606', (39, 47))	('PDAC', 'Chemical', '-', (18, 22))	('mutation', 'Var', (62, 70))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))
33985	25965802	Specifically, Suit2 cells were reported to carry a common dominant-negative R273H mutation in TP53, which we confirmed by sequencing genomic DNA (Table 3).	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('R273H', 'Mutation', 'rs28934576', (76, 81))	('R273H', 'Var', (76, 81))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))
33988	25965802	As shown in Figure 2A, bands for the RFP-p53 fusion proteins were detected in cells infected with the VSV-p53wt, VSV-p53DeltaODRD, and VSV-p53-CC viruses.	('RFP', 'Gene', '5987', (37, 40))	('VSV-p53-CC viruses', 'Var', (135, 153))	('VSV', 'Species', '11276', (135, 138))	('detected', 'Reg', (66, 74))	('VSV-p53wt', 'Var', (102, 111))	('VSV', 'Species', '11276', (113, 116))	('VSV-p53DeltaODRD', 'Var', (113, 129))	('VSV', 'Species', '11276', (102, 105))	('RFP', 'Gene', (37, 40))
33989	25965802	As expected, p53wt and p53-CC fused to RFP appear the same size on the blot (approximately 73 kDa), while p53 with a truncated C terminus encoded by VSV-p53DeltaODRD, showed slight downshift on the blot.	('VSV-p53DeltaODRD', 'Var', (149, 165))	('RFP', 'Gene', (39, 42))	('VSV', 'Species', '11276', (149, 152))	('downshift', 'NegReg', (181, 190))	('RFP', 'Gene', '5987', (39, 42))
33991	25965802	Similar RFP-p53 nuclear localization was seen in cells infected with VSV-p53wt, VSV-p53DeltaODRD, and VSV-p53-CC.	('VSV', 'Species', '11276', (80, 83))	('VSV-p53DeltaODRD', 'Var', (80, 96))	('VSV', 'Species', '11276', (102, 105))	('RFP', 'Gene', '5987', (8, 11))	('RFP', 'Gene', (8, 11))	('VSV-p53-CC', 'Var', (102, 112))	('localization', 'biological_process', 'GO:0051179', ('24', '36'))	('VSV-p53wt', 'Var', (69, 78))	('VSV', 'Species', '11276', (69, 72))
33994	25965802	In the two viruses encoding transgenes without any NLS, VSV and VSV-p53-CC/fs, RFP localization remained cytoplasmic, as expected.	('VSV', 'Species', '11276', (56, 59))	('VSV-p53-CC/fs', 'Var', (64, 77))	('RFP', 'Gene', (79, 82))	('RFP', 'Gene', '5987', (79, 82))	('VSV', 'Species', '11276', (64, 67))	('localization', 'biological_process', 'GO:0051179', ('83', '95'))
33995	25965802	Next, we wanted to examine if VSV-encoded p53wt and p53-CC proteins were active as transcription factors in infected Suit2 cells.	('transcription', 'biological_process', 'GO:0006351', ('83', '96'))	('VSV', 'Species', '11276', (30, 33))	('p53wt', 'Var', (42, 47))	('p53-CC', 'Var', (52, 58))
34000	25965802	Figure 3 shows that the IPA predicts that the p53 signaling pathway is in the top five pathways affected for Suit2 cells infected with VSV-p53wt and VSV-p53-CC, but not for VSV-p53-CC/fs (compared to mock-treated cells) (Fig.	('VSV', 'Species', '11276', (173, 176))	('VSV-p53wt', 'Var', (135, 144))	('VSV', 'Species', '11276', (135, 138))	('affected', 'Reg', (96, 104))	('p53 signaling pathway', 'Pathway', (46, 67))	('VSV', 'Species', '11276', (149, 152))	('VSV-p53-CC', 'Var', (149, 159))
34001	25965802	Further, when comparing VSV-p53wt and VSV-p53-CC to VSV-p53-CC/fs, the p53 signaling pathway is also among the top five pathways affected (Fig.	('VSV', 'Species', '11276', (52, 55))	('VSV-p53-CC', 'Var', (38, 48))	('p53 signaling pathway', 'biological_process', 'GO:0030330', ('71', '92'))	('VSV', 'Species', '11276', (24, 27))	('VSV', 'Species', '11276', (38, 41))	('p53 signaling pathway', 'Pathway', (71, 92))
34002	25965802	Interestingly, when comparing VSV-p53wt to VSV-p53-CC, the p53 signaling pathway is not highlighted as significantly different, suggesting that the p53wt and p53-CC proteins are both active and behave similarly, at least in Suit2 cells under our experimental conditions (Fig.	('p53wt', 'Var', (148, 153))	('VSV', 'Species', '11276', (30, 33))	('VSV', 'Species', '11276', (43, 46))	('active', 'MPA', (183, 189))	('p53 signaling pathway', 'biological_process', 'GO:0030330', ('59', '80'))
34004	25965802	If virus-encoded p53wt and/or p53-CC are active, we expected them to enhance VSV cytotoxicity in cancer cells.	('cancer', 'Disease', (97, 103))	('cytotoxicity', 'Disease', (81, 93))	('VSV', 'Species', '11276', (77, 80))	('enhance', 'PosReg', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('p53-CC', 'Var', (30, 36))	('cytotoxicity', 'Disease', 'MESH:D064420', (81, 93))	('p53wt', 'Var', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
34005	25965802	Suit2 cells were mock treated or infected MOI 0.00002, 0.002, 0.1 and 1 with VSV, VSV-p53wt, VSV-p53-CC, or VSVp53-CC/fs and cell viability was examined at 1, 24, 48, and 96 h p.i.	('VSV', 'Species', '11276', (93, 96))	('VSV-p53-CC', 'Var', (93, 103))	('VSV', 'Species', '11276', (77, 80))	('VSVp53-CC/fs', 'Var', (108, 120))	('VSV', 'Species', '11276', (82, 85))	('VSV', 'Species', '11276', (108, 111))
34007	25965802	As shown in Figure 4 for MOI 0.002 and 0.00002, although no difference in cell killing between all viruses was seen at the higher MOI (a similar result was for MOI 0.1 and 1, data not shown), at the lower MOI we observed significantly more oncolysis by the VSVs expressing p53wt or p53-CC transgene, compared to VSV or VSV-p53-CC/fs (at 48 and 96 h p.i.).	('more', 'PosReg', (235, 239))	('cell killing', 'biological_process', 'GO:0001906', ('74', '86'))	('p53-CC transgene', 'Var', (282, 298))	('p53wt', 'Var', (273, 278))	('VSV', 'Species', '11276', (319, 322))	('VSV', 'Species', '11276', (312, 315))	('VSV', 'Species', '11276', (257, 260))	('oncolysis', 'CPA', (240, 249))
34008	25965802	The inability of virus-encoded p53wt and p53-CC to enhance oncotoxicity of VSV at higher MOIs may be due to strong cytotoxic effect of VSV itself masking the effect of the transgene.	('p53wt', 'Var', (31, 36))	('oncotoxicity of VSV', 'Disease', 'None', (59, 78))	('VSV', 'Species', '11276', (135, 138))	('enhance', 'PosReg', (51, 58))	('cytotoxic', 'CPA', (115, 124))	('VSV', 'Species', '11276', (75, 78))	('oncotoxicity of VSV', 'Disease', (59, 78))	('p53-CC', 'Var', (41, 47))
34010	25965802	Moreover, the virus-encoded p53wt and p53-CC enhance oncotoxicity of VSV, at least under some of our experimental conditions.	('oncotoxicity of VSV', 'Disease', (53, 72))	('enhance', 'PosReg', (45, 52))	('oncotoxicity of VSV', 'Disease', 'None', (53, 72))	('p53-CC', 'Var', (38, 44))	('p53wt', 'Var', (28, 33))
34011	25965802	Using the transcriptome profile of Suit2 cells following mock treatment or infection with VSV-p53wt, VSV-p53-CC, or VSV-p53-CC/fs, we analyzed expression levels for genes associated with type I and type II IFN signaling pathways using the Ingenuity pathway analysis.	('VSV-p53wt', 'Var', (90, 99))	('type I', 'Pathway', (187, 193))	('VSV-p53-CC', 'Var', (101, 111))	('signaling', 'biological_process', 'GO:0023052', ('210', '219'))	('expression', 'MPA', (143, 153))	('VSV', 'Species', '11276', (101, 104))	('VSV-p53-CC/fs', 'Var', (116, 129))	('IFN', 'Gene', '3439', (206, 209))	('IFN', 'Gene', (206, 209))	('VSV', 'Species', '11276', (116, 119))	('VSV', 'Species', '11276', (90, 93))
34015	25965802	However, contrary to an expected enhancement of antiviral signaling by p53, when we compare Suit2 cells infected with VSV-p53wt or VSV-p53-CC vs. cells infected with p53-CC/fs (no p53 transgene is expressed), the type I IFN signaling response was dramatically attenuated (Table 1).	('VSV', 'Species', '11276', (118, 121))	('VSV', 'Species', '11276', (131, 134))	('IFN', 'Gene', '3439', (220, 223))	('IFN', 'Gene', (220, 223))	('signaling', 'biological_process', 'GO:0023052', ('224', '233'))	('attenuated', 'NegReg', (260, 270))	('VSV-p53-CC', 'Var', (131, 141))	('signaling', 'biological_process', 'GO:0023052', ('58', '67'))
34016	25965802	Specifically, while there was a 291.10-fold increase in IFN-beta transcripts by VSV-p53-CC/fs (the recombinant VSV that does not express p53) compared to mock-treated cells, only 25.24-fold and 4.56-fold increases in IFN-beta transcript levels were observed for VSV-p53wt or VSV-p53-CC, respectively.	('IFN', 'Gene', (56, 59))	('VSV', 'Species', '11276', (262, 265))	('VSV', 'Species', '11276', (80, 83))	('VSV', 'Species', '11276', (111, 114))	('VSV', 'Species', '11276', (275, 278))	('IFN', 'Gene', '3439', (217, 220))	('increase', 'PosReg', (44, 52))	('IFN', 'Gene', '3439', (56, 59))	('IFN', 'Gene', (217, 220))	('VSV-p53-CC/fs', 'Var', (80, 93))
34017	25965802	Importantly, the transcriptome also showed that p53wt and p53-CC reduced virus-mediated expression of several key cellular antiviral proteins, including Myxovirus resistance 1 (Mx1), 2'-5'-oligoadenylate synthetase-like (OASL), Janus kinase 2 (JAK2), signal transducer and activator of transcription 1 (STAT1), and interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) (Fig.	('virus-mediated expression', 'MPA', (73, 98))	('reduced', 'NegReg', (65, 72))	('interferon', 'Gene', '3439', (315, 325))	('transcription', 'biological_process', 'GO:0006351', ('286', '299'))	('protein', 'cellular_component', 'GO:0003675', ('334', '341'))	('interferon', 'Gene', (315, 325))	('p53-CC', 'Var', (58, 64))	('JAK', 'molecular_function', 'GO:0004713', ('244', '247'))	('p53wt', 'Var', (48, 53))
34018	25965802	Also, infection with VSV-p53wt and VSV-p53-CC caused upregulation of the suppressor of cytokine signaling (SOCS1) that is known to inhibit STAT1 antiviral signaling activity.	('VSV-p53-CC', 'Var', (35, 45))	('signaling', 'biological_process', 'GO:0023052', ('96', '105'))	('SOCS1', 'Gene', (107, 112))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('upregulation', 'PosReg', (53, 65))	('VSV', 'Species', '11276', (21, 24))	('VSV-p53wt', 'Var', (21, 30))	('VSV', 'Species', '11276', (35, 38))
34019	25965802	To confirm this surprising effect of p53 inhibition of type I IFN signaling that was seen with the microarray (Table 1), Suit2 cells were mock treated or infected with VSV-p53wt, VSV-p53-CC, or VSV-p53-CC/fs at MOI 5 and total lysates were collected at 8, 12, and 18 h p.i.	('VSV-p53-CC/fs', 'Var', (194, 207))	('IFN', 'Gene', '3439', (62, 65))	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('VSV', 'Species', '11276', (194, 197))	('VSV-p53-CC', 'Var', (179, 189))	('IFN', 'Gene', (62, 65))	('p53', 'Gene', (37, 40))	('VSV', 'Species', '11276', (168, 171))	('VSV-p53wt', 'Var', (168, 177))	('VSV', 'Species', '11276', (179, 182))	('inhibition', 'NegReg', (41, 51))
34021	25965802	However, in agreement with the microarray data, in cells infected with VSV-p53wt or VSV-p53-CC, there was significantly reduced phosphorylation of STAT1, which is dependent on IFN production in infected cells.	('IFN', 'Gene', (176, 179))	('phosphorylation', 'biological_process', 'GO:0016310', ('128', '143'))	('VSV-p53-CC', 'Var', (84, 94))	('VSV', 'Species', '11276', (71, 74))	('VSV', 'Species', '11276', (84, 87))	('VSV-p53wt', 'Var', (71, 80))	('phosphorylation', 'MPA', (128, 143))	('IFN', 'Gene', '3439', (176, 179))	('reduced', 'NegReg', (120, 127))	('STAT1', 'Protein', (147, 152))
34026	25965802	Importantly, the NF-kappaB subunit RelA, known to be critical for induction of IFN-beta at early time points of infection, was downregulated by both VSV-p53 and VSV-p53-CC (Table 2).	('VSV-p53', 'Var', (149, 156))	('IFN', 'Gene', '3439', (79, 82))	('NF-kappaB', 'Gene', '4790', (17, 26))	('downregulated', 'NegReg', (127, 140))	('VSV', 'Species', '11276', (161, 164))	('NF-kappaB', 'Gene', (17, 26))	('VSV-p53-CC', 'Var', (161, 171))	('IFN', 'Gene', (79, 82))	('VSV', 'Species', '11276', (149, 152))
34028	25965802	Also, there was a 51.99-fold increase in IL-1, an NF-kappaB induced cytokine, when cells were infected with VSV-p53-CC/fs, but no change after VSV-p53wt or VSV-p53-CC infection (Table 2).	('VSV-p53-CC infection', 'Disease', 'MESH:D007239', (156, 176))	('VSV-p53-CC infection', 'Disease', (156, 176))	('VSV', 'Species', '11276', (156, 159))	('increase', 'PosReg', (29, 37))	('VSV', 'Species', '11276', (108, 111))	('IL-1', 'molecular_function', 'GO:0005149', ('41', '45'))	('IL-1', 'MPA', (41, 45))	('VSV', 'Species', '11276', (143, 146))	('NF-kappaB', 'Gene', '4790', (50, 59))	('VSV-p53-CC/fs', 'Var', (108, 121))	('NF-kappaB', 'Gene', (50, 59))
34029	25965802	This data suggests that the NF-kappaB pathway is strongly downregulated by expression of the p53 transgenes.	('transgenes', 'Var', (97, 107))	('p53', 'Gene', (93, 96))	('NF-kappaB', 'Gene', '4790', (28, 37))	('downregulated', 'NegReg', (58, 71))	('NF-kappaB', 'Gene', (28, 37))
34030	25965802	To test the hypothesis that VSV-encoded p53wt and p53-CC inhibit type I IFN responses via inhibition of NF-kappaB signaling, we conducted an experiment combining VSV infection with treatment of cells either with IKK-2 inhibitor VIII (to specifically prevent NF-kappaB activation) or JAK1/JAK2 inhibitor Ruxolitinib (to directly inhibit type I IFN-mediated signaling).	('VSV', 'Species', '11276', (162, 165))	('IKK-2', 'Gene', (212, 217))	('inhibit', 'NegReg', (57, 64))	('NF-kappaB', 'Gene', (104, 113))	('VIII', 'Gene', (228, 232))	('VSV infection', 'Disease', (162, 175))	('IFN', 'Gene', (343, 346))	('p53wt', 'Var', (40, 45))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('258', '278'))	('IFN', 'Gene', '3439', (72, 75))	('NF-kappaB', 'Gene', '4790', (104, 113))	('JAK', 'molecular_function', 'GO:0004713', ('288', '291'))	('IKK-2', 'Gene', '3551', (212, 217))	('prevent', 'NegReg', (250, 257))	('Ruxolitinib', 'Chemical', 'MESH:C540383', (303, 314))	('signaling', 'biological_process', 'GO:0023052', ('356', '365'))	('NF-kappaB', 'Gene', (258, 267))	('VIII', 'Gene', '1351', (228, 232))	('IFN', 'Gene', (72, 75))	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('NF-kappaB', 'Gene', '4790', (258, 267))	('p53-CC', 'Var', (50, 56))	('inhibit', 'NegReg', (328, 335))	('VSV infection', 'Disease', 'MESH:D007239', (162, 175))	('VSV', 'Species', '11276', (28, 31))	('IKK-2', 'molecular_function', 'GO:0008384', ('212', '217'))	('IFN', 'Gene', '3439', (343, 346))	('JAK', 'molecular_function', 'GO:0004713', ('283', '286'))
34031	25965802	Thus, if virus-encoded p53 inhibits type I IFN signaling in Suit2 cells via NF-kappaB inhibition, we would expect to see that i) IKK-2 inhibitor VIII would have a similar effect on antiviral signaling as Ruxolitinib, and that ii) the combination of IKK-2 inhibitor VIII with VSV-p53-CC/fs would produce a similar inhibiting effect on antiviral signaling as VSV-p53wt or VSV-p53-CC alone.	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('VIII', 'Gene', '1351', (145, 149))	('VIII', 'Gene', '1351', (265, 269))	('IFN', 'Gene', (43, 46))	('VSV', 'Species', '11276', (357, 360))	('inhibiting', 'NegReg', (313, 323))	('antiviral signaling', 'MPA', (334, 353))	('IKK-2', 'Gene', (249, 254))	('inhibits', 'NegReg', (27, 35))	('IKK-2', 'Gene', (129, 134))	('signaling', 'biological_process', 'GO:0023052', ('344', '353'))	('VSV', 'Species', '11276', (275, 278))	('VIII', 'Gene', (145, 149))	('VIII', 'Gene', (265, 269))	('NF-kappaB', 'Gene', (76, 85))	('p53', 'Var', (23, 26))	('Ruxolitinib', 'Chemical', 'MESH:C540383', (204, 215))	('signaling', 'biological_process', 'GO:0023052', ('191', '200'))	('IKK-2', 'molecular_function', 'GO:0008384', ('129', '134'))	('antiviral signaling', 'MPA', (181, 200))	('NF-kappaB', 'Gene', '4790', (76, 85))	('IKK-2', 'Gene', '3551', (249, 254))	('VSV', 'Species', '11276', (370, 373))	('IKK-2', 'molecular_function', 'GO:0008384', ('249', '254'))	('IKK-2', 'Gene', '3551', (129, 134))	('IFN', 'Gene', '3439', (43, 46))
34032	25965802	Cells were first mock treated or infected with VSV-p53wt, VSV-p53-CC, or VSV-p53-CC/fs at MOI 10, then mock treated (DMSO) or treated with each inhibitor for 8 h. RT-PCR results shows that, compared to mock-treated cells, there was upregulation of MxA, OAS, IFN-beta, and IkB-alpha transcripts by VSV-p53-CC/fs (Fig.	('VSV', 'Species', '11276', (73, 76))	('VSV-p53-CC/fs', 'Var', (297, 310))	('VSV', 'Species', '11276', (297, 300))	('MxA', 'MPA', (248, 251))	('upregulation', 'PosReg', (232, 244))	('IFN', 'Gene', '3439', (258, 261))	('VSV', 'Species', '11276', (58, 61))	('VSV', 'Species', '11276', (47, 50))	('OAS', 'Gene', (253, 256))	('IFN', 'Gene', (258, 261))	('DMSO', 'Chemical', 'MESH:D004121', (117, 121))	('IkB-alpha', 'Protein', (272, 281))
34033	25965802	And, consistent with the transcriptome data, there was downregulation of all these four cellular genes by VSV-p53wt and VSV-p53-CC (in comparison to VSV-p53-CC/fs).	('VSV-p53-CC', 'Var', (120, 130))	('VSV-p53wt', 'Var', (106, 115))	('VSV', 'Species', '11276', (120, 123))	('VSV', 'Species', '11276', (106, 109))	('VSV', 'Species', '11276', (149, 152))	('downregulation', 'NegReg', (55, 69))
34035	25965802	Importantly, administration of the IKK-2 inhibitor VIII inhibited upregulation of antiviral gene transcripts seen by VSV-p53-CC/fs infection, bringing down the expression levels to those induced by VSV-p53wt or VSV-p53-CC alone (Fig.	('VSV', 'Species', '11276', (211, 214))	('upregulation', 'MPA', (66, 78))	('down', 'NegReg', (151, 155))	('VIII', 'Gene', '1351', (51, 55))	('VSV', 'Species', '11276', (198, 201))	('VIII', 'Gene', (51, 55))	('IKK-2', 'Gene', '3551', (35, 40))	('IKK-2', 'molecular_function', 'GO:0008384', ('35', '40'))	('expression levels', 'MPA', (160, 177))	('VSV-p53-CC/fs', 'Var', (117, 130))	('inhibited', 'NegReg', (56, 65))	('IKK-2', 'Gene', (35, 40))	('antiviral gene', 'Gene', (82, 96))	('VSV', 'Species', '11276', (117, 120))
34036	25965802	This data suggests that type I IFN signaling in Suit2 is under direct control of NF-kappaB, and that VSV-encoded p53wt or p53-CC downregulate type I IFN responses via inhibition of NF-kappaB pathway.	('NF-kappaB', 'Gene', '4790', (81, 90))	('downregulate', 'NegReg', (129, 141))	('NF-kappaB', 'Gene', '4790', (181, 190))	('VSV', 'Species', '11276', (101, 104))	('IFN', 'Gene', '3439', (31, 34))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('NF-kappaB', 'Gene', (81, 90))	('p53-CC', 'Var', (122, 128))	('NF-kappaB', 'Gene', (181, 190))	('IFN', 'Gene', '3439', (149, 152))	('IFN', 'Gene', (31, 34))	('IFN', 'Gene', (149, 152))
34037	25965802	Next, we wanted to see if the inhibition of antiviral signaling by VSV-encoded p53 is observable in other PDAC cell lines, and if the cellular endogenous p53 status plays a role in the observed inhibition.	('signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('p53', 'Gene', (79, 82))	('VSV', 'Species', '11276', (67, 70))	('antiviral signaling', 'MPA', (44, 63))	('inhibition', 'NegReg', (30, 40))	('VSV-encoded', 'Var', (67, 78))	('PDAC', 'Chemical', '-', (106, 110))
34040	25965802	The TP53 mutations identified by Ion Ampliseq for all cell lines were independently confirmed using PCR amplification and sequencing of a region of genomic DNA between TP53 exons 5 and 9, where most p53 mutations occur (Table 3).	('TP53', 'Gene', '7157', (168, 172))	('TP53', 'Gene', (168, 172))	('TP53', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('TP53', 'Gene', '7157', (4, 8))
34041	25965802	As expected for most human PDACs, all PDAC cell lines contained mutations in the TP53 gene.	('PDAC', 'Chemical', '-', (27, 31))	('PDAC', 'Chemical', '-', (38, 42))	('human', 'Species', '9606', (21, 26))	('mutations', 'Var', (64, 73))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))	('contained', 'Reg', (54, 63))
34042	25965802	The R273H mutation for Suit2 and Capan2 is a known dominant-negative mutation, while the Y220C mutation for T3M4 is shown only to have moderate dominant-negative activity.	('R273H', 'Var', (4, 9))	('R273H', 'Mutation', 'rs28934576', (4, 9))	('Y220C', 'Mutation', 'rs121912666', (89, 94))	('Y220C', 'Var', (89, 94))
34043	25965802	For ASPC-1, we identified an early frameshift mutation (C135fs) that results in a small truncated protein product that could not be detected by Western blot analysis.	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('results in', 'Reg', (69, 79))	('C135fs', 'Mutation', 'rs1131691036', (56, 62))	('C135fs', 'Var', (56, 62))
34045	25965802	To investigate how VSV-encoded p53 expression affects antiviral signaling in these cell lines, cells were mock treated or infected with VSV-p53wt, VSV-p53-CC, or VSV-p53-CC/fs at MOI 5 and total RNA was isolated 8 h p.i.	('VSV', 'Species', '11276', (162, 165))	('affects', 'Reg', (46, 53))	('antiviral signaling', 'MPA', (54, 73))	('VSV', 'Species', '11276', (19, 22))	('RNA', 'cellular_component', 'GO:0005562', ('195', '198'))	('VSV', 'Species', '11276', (136, 139))	('VSV', 'Species', '11276', (147, 150))	('VSV-p53-CC/fs', 'Var', (162, 175))	('signaling', 'biological_process', 'GO:0023052', ('64', '73'))
34046	25965802	As was seen previously in Suit2, there was p53-mediated downregulation of transcripts associated with type I IFN as well as NF-kappaB signaling in T3M4, Capan-2, and ASPC-1 (Fig.	('p53-mediated', 'Var', (43, 55))	('IFN', 'Gene', (109, 112))	('downregulation', 'NegReg', (56, 70))	('NF-kappaB', 'Gene', '4790', (124, 133))	('transcripts associated', 'MPA', (74, 96))	('NF-kappaB', 'Gene', (124, 133))	('IFN', 'Gene', '3439', (109, 112))
34047	25965802	In particular, both p53wt and p53-CC reduced expression of the IFN-beta mRNA at 8 h p.i.	('IFN', 'Gene', '3439', (63, 66))	('expression', 'MPA', (45, 55))	('p53-CC', 'Var', (30, 36))	('IFN', 'Gene', (63, 66))	('p53wt', 'Var', (20, 25))	('reduced', 'NegReg', (37, 44))
34048	25965802	This result suggests that the observation of virus-encoded p53 effect on type I IFN signaling is not limited only to Suit2 cell line or the R273H mutation in TP53.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('effect', 'Reg', (63, 69))	('IFN', 'Gene', (80, 83))	('R273H', 'Var', (140, 145))	('R273H', 'Mutation', 'rs28934576', (140, 145))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('IFN', 'Gene', '3439', (80, 83))
34050	25965802	Importantly, expression of p53 encoded by VSV-p53wt or VSV-p53-CC did not inhibit type I IFN or NF-kappaB signaling in HPDE.	('IFN', 'Gene', '3439', (89, 92))	('HPDE', 'Chemical', '-', (119, 123))	('IFN', 'Gene', (89, 92))	('inhibit', 'NegReg', (74, 81))	('NF-kappaB', 'Gene', '4790', (96, 105))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))	('VSV', 'Species', '11276', (42, 45))	('VSV-p53-CC', 'Var', (55, 65))	('NF-kappaB', 'Gene', (96, 105))	('VSV', 'Species', '11276', (55, 58))	('VSV-p53wt', 'Var', (42, 51))
34053	25965802	The data above suggests that VSV-p53wt or VSV-p53-CC do not inhibit IFN-beta signaling in HPDE as they do in PDAC cells.	('IFN', 'Gene', '3439', (68, 71))	('VSV-p53wt', 'Var', (29, 38))	('VSV', 'Species', '11276', (29, 32))	('inhibit', 'NegReg', (60, 67))	('IFN', 'Gene', (68, 71))	('VSV-p53-CC', 'Var', (42, 52))	('PDAC', 'Chemical', '-', (109, 113))	('HPDE', 'Chemical', '-', (90, 94))	('VSV', 'Species', '11276', (42, 45))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))
34054	25965802	To further examine whether p53 transgene expression may result in the loss of oncoselectivity of VSV recombinants, the same virus stocks of VSV, VSV-p53wt, VSV-p53-CC, or VSV-p53-CC/fs were titrated on HPDE, Suit2, T3M4, Capan2, and ASPC-1 cells using plaque assay (Fig.	('VSV', 'Species', '11276', (145, 148))	('VSV', 'Species', '11276', (97, 100))	('loss', 'NegReg', (70, 74))	('VSV', 'Species', '11276', (156, 159))	('oncoselectivity', 'MPA', (78, 93))	('HPDE', 'Chemical', '-', (202, 206))	('stocks', 'Species', '3724', (130, 136))	('VSV', 'Species', '11276', (140, 143))	('VSV', 'Species', '11276', (171, 174))	('transgene', 'Var', (31, 40))	('p53', 'Gene', (27, 30))
34058	25965802	Compared to the PDAC cell lines, where Capan2 and ASPC-1 showed almost no viable cells and T3M4 and Suit2 show some resistance, the p53 transgene does not appear to increase cell killing of HPDE.	('p53', 'Var', (132, 135))	('resistance', 'MPA', (116, 126))	('cell killing', 'biological_process', 'GO:0001906', ('174', '186'))	('PDAC', 'Chemical', '-', (16, 20))	('HPDE', 'Chemical', '-', (190, 194))
34059	25965802	Even more, at MOI 10 HPDE showed only 50 percent cell viability when infected with VSV, and 75 percent cell viability when infected with VSV-p53wt, VSV-p53-CC, or VSV-p53-CC/fs (Fig.	('VSV', 'Species', '11276', (148, 151))	('VSV-p53-CC', 'Var', (148, 158))	('VSV', 'Species', '11276', (163, 166))	('VSV-p53wt', 'Var', (137, 146))	('HPDE', 'Chemical', '-', (21, 25))	('VSV', 'Species', '11276', (137, 140))	('VSV-p53-CC/fs', 'Var', (163, 176))	('VSV', 'Species', '11276', (83, 86))
34064	25965802	Our results suggest that virus-encoded p53 expression can simultaneously produce anticancer activities while assisting, rather than inhibiting, viral replication in PDAC cells.	('viral replication', 'biological_process', 'GO:0019058', ('144', '161'))	('PDAC', 'Chemical', '-', (165, 169))	('viral replication', 'CPA', (144, 161))	('assisting', 'PosReg', (109, 118))	('expression', 'Var', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('p53', 'Gene', (39, 42))	('viral replication', 'biological_process', 'GO:0008166', ('144', '161'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('viral replication', 'biological_process', 'GO:0019079', ('144', '161'))
34065	25965802	Our data is in direct contrast to previous reports that p53 enhances type I IFN signaling pathway in normal cells and some cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('IFN', 'Gene', (76, 79))	('p53', 'Var', (56, 59))	('signaling pathway', 'biological_process', 'GO:0007165', ('80', '97'))	('enhances', 'PosReg', (60, 68))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('IFN', 'Gene', '3439', (76, 79))
34069	25965802	Also, type I IFN mediated responses can be inhibited by MEK/ERK signaling, which is often upregulated in cancer cells, or by epigenetic silencing of IFN responsive transcription factors IRF7 or IRF5.	('IFN', 'Gene', '3439', (13, 16))	('inhibited', 'NegReg', (43, 52))	('IRF7', 'Gene', (186, 190))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('transcription', 'biological_process', 'GO:0006351', ('164', '177'))	('ERK', 'molecular_function', 'GO:0004707', ('60', '63'))	('IFN', 'Gene', (13, 16))	('IFN', 'Gene', '3439', (149, 152))	('IRF5', 'Gene', (194, 198))	('epigenetic silencing', 'Var', (125, 145))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('MEK/ERK signaling', 'Pathway', (56, 73))	('upregulated', 'PosReg', (90, 101))	('IFN', 'Gene', (149, 152))	('signaling', 'biological_process', 'GO:0023052', ('64', '73'))
34074	25965802	Our data suggest that VSV-encoded p53wt or p53-CC downregulate antiviral responses via inhibition of NF-kappaB.	('inhibition', 'NegReg', (87, 97))	('downregulate', 'NegReg', (50, 62))	('antiviral responses', 'MPA', (63, 82))	('VSV', 'Species', '11276', (22, 25))	('p53-CC', 'Var', (43, 49))	('NF-kappaB', 'Gene', '4790', (101, 110))	('NF-kappaB', 'Gene', (101, 110))	('p53wt', 'Var', (34, 39))
34076	25965802	Our results are in agreement with previous studies demonstrating inhibition of NF-kappaB pathway by p53 via various mechanisms, including prevention of NF-kappaB nuclear translocation through upregulation of NF-kappaB inhibitor, IkappaBalpha, competition for common transcription cofactors (p300 and cAMP response element-binding protein (CBP), and/or directly binding to NF-kappaB (RelA subunit p65) to disrupt its binding to DNA.	('inhibition', 'NegReg', (65, 75))	('NF-kappaB', 'Gene', (208, 217))	('transcription', 'biological_process', 'GO:0006351', ('266', '279'))	('binding', 'molecular_function', 'GO:0005488', ('416', '423'))	('prevention', 'NegReg', (138, 148))	('NF-kappaB', 'Gene', '4790', (152, 161))	('NF-kappaB', 'Gene', (79, 88))	('NF-kappaB', 'Gene', '4790', (208, 217))	('NF-kappaB', 'Gene', (372, 381))	('CBP', 'molecular_function', 'GO:0008140', ('339', '342'))	('binding', 'Interaction', (416, 423))	('nuclear translocation', 'MPA', (162, 183))	('NF-kappaB', 'Gene', '4790', (79, 88))	('NF-kappaB', 'Gene', '4790', (372, 381))	('binding', 'Interaction', (361, 368))	('binding', 'molecular_function', 'GO:0005488', ('361', '368'))	('DNA', 'cellular_component', 'GO:0005574', ('427', '430'))	('protein', 'cellular_component', 'GO:0003675', ('330', '337'))	('cAMP response element-binding', 'molecular_function', 'GO:0035497', ('300', '329'))	('p53', 'Gene', (100, 103))	('p300', 'Var', (291, 295))	('NF-kappaB inhibitor', 'biological_process', 'GO:0032088', ('208', '227'))	('upregulation', 'PosReg', (192, 204))	('cAMP', 'Chemical', '-', (300, 304))	('NF-kappaB', 'Gene', (152, 161))
34080	25965802	Interestingly, VSV expressing p53 (wt or p53-CC) remained attenuated in non-malignant pancreatic ductal cell line HPDE, suggesting that these novel OVs would retain their safety in vivo.	('attenuated', 'NegReg', (58, 68))	('p53', 'Var', (30, 33))	('pancreatic ductal', 'Disease', (86, 103))	('VSV', 'Species', '11276', (15, 18))	('pancreatic ductal', 'Disease', 'MESH:D021441', (86, 103))	('HPDE', 'Chemical', '-', (114, 118))	('p53-CC', 'Var', (41, 47))
34088	25965802	Significantly, a recent clinical trial using vaccinia virus encoding p53 has also shown enhanced oncolytic efficacy in clinical trials through stimulation of an antitumor immune response.	('stimulation', 'PosReg', (143, 154))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('p53', 'Var', (69, 72))	('oncolytic efficacy', 'CPA', (97, 115))	('vaccinia virus', 'Species', '10245', (45, 59))	('enhanced', 'PosReg', (88, 96))	('immune response', 'biological_process', 'GO:0006955', ('171', '186'))	('tumor', 'Disease', (165, 170))
34089	25965802	None of these previous studies has examined total gene expression in cancer cells in response to virus infection, but our data using VSV provides evidence of a new mechanism for enhanced oncolytic efficacy of viruses encoding p53 that will be important for future studies as OVs move forward in clinical application.	('virus infection', 'Disease', (97, 112))	('enhanced', 'PosReg', (178, 186))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('virus infection', 'Disease', 'MESH:D015658', (97, 112))	('VSV', 'Species', '11276', (133, 136))	('gene expression', 'biological_process', 'GO:0010467', ('50', '65'))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('p53', 'Gene', (226, 229))	('oncolytic efficacy', 'CPA', (187, 205))	('response to virus', 'biological_process', 'GO:0009615', ('85', '102'))	('viruses', 'Var', (209, 216))	('cancer', 'Disease', (69, 75))
34098	25416148	To inhibit Notch signaling in the pancreas epithelium, we crossed a mouse model of pancreatic cancer based on pancreas-specific expression of mutant Kras with a transgenic mouse that conditionally expresses a dominant negative form of the Mastermind-like 1 gene.	('mouse', 'Species', '10090', (68, 73))	('Kras', 'Gene', (149, 153))	('Kras', 'Gene', '16653', (149, 153))	('pancreatic cancer', 'Disease', (83, 100))	('Notch', 'Gene', (11, 16))	('mouse', 'Species', '10090', (172, 177))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('mutant', 'Var', (142, 148))	('inhibit', 'NegReg', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))	('Notch', 'Gene', '25496', (11, 16))
34101	25416148	As a result, in mice co-expressing mutant Kras and DNMAML, Notch signaling is inhibited specifically in the epithelium upon Cre-mediated recombination.	('Notch', 'Gene', '25496', (59, 64))	('inhibited', 'NegReg', (78, 87))	('Notch', 'Gene', (59, 64))	('mutant', 'Var', (35, 41))	('DNMAML', 'Chemical', '-', (51, 57))	('Kras', 'Gene', (42, 46))	('DNMAML', 'Gene', (51, 57))	('Kras', 'Gene', '16653', (42, 46))	('mice', 'Species', '10090', (16, 20))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))
34103	25416148	We find that DNMAML expression efficiently inhibits epithelial Notch signaling and delays PanIN formation.	('formation', 'biological_process', 'GO:0009058', ('96', '105'))	('DNMAML', 'Chemical', '-', (13, 19))	('Notch', 'Gene', (63, 68))	('DNMAML', 'Gene', (13, 19))	('PanIN formation', 'CPA', (90, 105))	('Notch', 'Gene', '25496', (63, 68))	('delays', 'NegReg', (83, 89))	('expression', 'Var', (20, 30))	('signaling', 'biological_process', 'GO:0023052', ('69', '78'))	('inhibits', 'NegReg', (43, 51))
34110	25416148	Oncogenic mutations in KRAS are widespread in human PanINs and detected in in over 90% of human PDA.	('PDA', 'Phenotype', 'HP:0006725', (96, 99))	('KRAS', 'Gene', (23, 27))	('human', 'Species', '9606', (90, 95))	('human', 'Species', '9606', (46, 51))	('mutations', 'Var', (10, 19))	('PDA', 'Disease', (96, 99))	('KRAS', 'Gene', '3845', (23, 27))	('PDA', 'Chemical', '-', (96, 99))
34120	25416148	Several studies have used genetic approaches to ablate individual Notch receptors and study the effect on pancreatic carcinogenesis.	('pancreatic carcinogenesis', 'Disease', (106, 131))	('Notch', 'Gene', '25496', (66, 71))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (106, 131))	('Notch', 'Gene', (66, 71))	('ablate', 'Var', (48, 54))
34127	25416148	Wild type mice and animals having a combination of Kras allele and/or DNMAML, but not the Cre allele were used as controls.	('mice', 'Species', '10090', (10, 14))	('DNMAML', 'Var', (70, 76))	('DNMAML', 'Chemical', '-', (70, 76))	('Kras', 'Gene', '16653', (51, 55))	('Kras', 'Gene', (51, 55))
34133	25416148	PCR cycling conditions were as follows: p48-Cre, KrasG12D, 95 C for 3 min, 95 C for 30 s, 60 C for 30 s, and 72 C for 45 s for 34 cycles, followed by 72 C for 5 min; RosaDNMAML-GFP/+, 95 C for 3 min, 95 C for 30 s, 59 C for 30 s, and 72 C for 1 min for 34 cycles, followed by 72 C for 5 min.	('p48', 'Gene', '16391', (40, 43))	('p48', 'Gene', (40, 43))	('Kras', 'Gene', (49, 53))	('Kras', 'Gene', '16653', (49, 53))	('DNMAML', 'Chemical', '-', (170, 176))	('RosaDNMAML-GFP/+', 'Var', (166, 182))
34149	25416148	Hes1 primers were acquired from Applied Biosystems; Mouse Hes1 (Mm01342805_m1), Mouse Gapdh (Mm99999915_g1).	('Mouse', 'Species', '10090', (52, 57))	('Mouse', 'Species', '10090', (80, 85))	('Gapdh', 'Gene', '14433', (86, 91))	('Gapdh', 'Gene', (86, 91))	('Hes1', 'Gene', '15205', (0, 4))	('Mm01342805_m1', 'Var', (64, 77))	('Hes1', 'Gene', '15205', (58, 62))	('Hes1', 'Gene', (0, 4))	('Hes1', 'Gene', (58, 62))	('Mm99999915_g1', 'Var', (93, 106))
34150	25416148	To block Notch signaling during pancreatic carcinogenesis, we crossed a mouse model of pancreatic cancer, based on pancreas-specific expression of mutant Kras (p48-Cre; LSL-KrasG12D; hereby referred to as KC) with a transgene expressing a Dominant-Negative form of Mastermind-like1 (DNMAML), which encodes for a truncated form of MAML1 (aa 13-74) fused to GFP, downstream of a LoxP-flanked stop cassette (Figure 1D).	('mutant', 'Var', (147, 153))	('MAML1', 'Gene', (330, 335))	('pancreatic cancer', 'Disease', (87, 104))	('Kras', 'Gene', '16653', (173, 177))	('p48', 'Gene', (160, 163))	('mouse', 'Species', '10090', (72, 77))	('Kras', 'Gene', (154, 158))	('signaling', 'biological_process', 'GO:0023052', ('15', '24'))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('p48', 'Gene', '16391', (160, 163))	('Kras', 'Gene', '16653', (154, 158))	('Notch', 'Gene', (9, 14))	('MAML1', 'Gene', '103806', (330, 335))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (32, 57))	('pancreatic carcinogenesis', 'Disease', (32, 57))	('Kras', 'Gene', (173, 177))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('Notch', 'Gene', '25496', (9, 14))	('DNMAML', 'Chemical', '-', (283, 289))
34156	25416148	Importantly, the Notch target genes were downregulated in KC;DNMAML mice compared to KC.	('mice', 'Species', '10090', (68, 72))	('KC;DNMAML', 'Var', (58, 67))	('downregulated', 'NegReg', (41, 54))	('Notch', 'Gene', (17, 22))	('DNMAML', 'Chemical', '-', (61, 67))	('Notch', 'Gene', '25496', (17, 22))
34159	25416148	In 15 week-old samples we observed a significant reduction in the number of PanINs in KC;DNMAML mice compared to KC mice (Figure 1E).	('DNMAML', 'Chemical', '-', (89, 95))	('mice', 'Species', '10090', (116, 120))	('reduction', 'NegReg', (49, 58))	('mice', 'Species', '10090', (96, 100))	('PanINs', 'Protein', (76, 82))	('KC;DNMAML', 'Var', (86, 95))
34160	25416148	Thus, inhibition of Notch signaling delayed or blocked PanIN formation.	('Notch', 'Gene', (20, 25))	('PanIN formation', 'CPA', (55, 70))	('blocked', 'NegReg', (47, 54))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))	('inhibition', 'Var', (6, 16))	('Notch', 'Gene', '25496', (20, 25))	('delayed', 'NegReg', (36, 43))	('formation', 'biological_process', 'GO:0009058', ('61', '70'))
34171	25416148	KC pancreata displayed a greater degree of disease progression with a higher proportion of PanIN1A (20%), PanIN1B (8%), and PanIN2 (1%) compared to age-matched KC;DNMAML mice (Figure 1C).	('PanIN1A', 'Gene', (91, 98))	('DNMAML', 'Chemical', '-', (163, 169))	('mice', 'Species', '10090', (170, 174))	('higher', 'PosReg', (70, 76))	('PanIN1B', 'Var', (106, 113))
34172	25416148	At 26 weeks, we observed significantly fewer PanINs and more acini in KC;DNMAML mice compared to KC.	('PanINs', 'Protein', (45, 51))	('fewer', 'NegReg', (39, 44))	('KC;DNMAML', 'Var', (70, 79))	('DNMAML', 'Chemical', '-', (73, 79))	('acini', 'CPA', (61, 66))	('mice', 'Species', '10090', (80, 84))
34174	25416148	Thus, PanINs were delayed, but their formation was not blocked, upon inhibition of epithelial Notch signaling.	('Notch', 'Gene', '25496', (94, 99))	('formation', 'biological_process', 'GO:0009058', ('37', '46'))	('delayed', 'NegReg', (18, 25))	('Notch', 'Gene', (94, 99))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('inhibition', 'Var', (69, 79))	('PanINs', 'Disease', (6, 12))
34182	25416148	To further our analysis of KC;DNMAML mice, we investigated whether inhibition of Notch signaling affected the activation of other embryonic signaling pathways that are upregulated in PanIN formation and important for their progression, such as Hedgehog and Wnt.	('inhibition', 'Var', (67, 77))	('signaling', 'biological_process', 'GO:0023052', ('87', '96'))	('activation', 'PosReg', (110, 120))	('upregulated', 'PosReg', (168, 179))	('formation', 'biological_process', 'GO:0009058', ('189', '198'))	('Notch', 'Gene', '25496', (81, 86))	('Hedgehog', 'Disease', (244, 252))	('embryonic signaling pathways', 'Pathway', (130, 158))	('DNMAML', 'Chemical', '-', (30, 36))	('signaling', 'biological_process', 'GO:0023052', ('140', '149'))	('Notch', 'Gene', (81, 86))	('mice', 'Species', '10090', (37, 41))
34185	25416148	At 15 weeks, we observed a trend towards a decrease in HES1 in KC-DNMAML samples (n >=3) when compared to KC samples, as predicted.	('decrease', 'NegReg', (43, 51))	('DNMAML', 'Chemical', '-', (66, 72))	('HES1', 'Gene', (55, 59))	('KC-DNMAML', 'Var', (63, 72))	('HES1', 'Gene', '15205', (55, 59))
34206	25416148	Similarly, KC;DNMAML developed PanINs, although they retained more acinar clusters 2 and 3 weeks after pancreatitis, compared to KC animals (Figure 4B,C).	('pancreatitis', 'Phenotype', 'HP:0001733', (103, 115))	('KC;DNMAML', 'Var', (11, 20))	('acinar clusters', 'MPA', (67, 82))	('DNMAML', 'Chemical', '-', (14, 20))	('pancreatitis', 'Disease', (103, 115))	('more', 'PosReg', (62, 66))	('PanINs', 'Disease', (31, 37))	('pancreatitis', 'Disease', 'MESH:D010195', (103, 115))
34214	25416148	Mouse models that conditionally ablate Notch receptors in the pancreas epithelium demonstrated that Notch2, but not Notch3, is critical for PanIN initiation, although Notch3 is also upregulated during PanIN/PDA development.	('Notch', 'Gene', (116, 121))	('PanIN', 'Disease', (140, 145))	('Notch', 'Gene', (100, 105))	('Notch', 'Gene', '25496', (39, 44))	('Notch3', 'Gene', '18131', (167, 173))	('Notch3', 'Gene', (116, 122))	('PDA', 'Phenotype', 'HP:0006725', (207, 210))	('ablate', 'Var', (32, 38))	('Notch', 'Gene', '25496', (116, 121))	('Notch2', 'Gene', '18129', (100, 106))	('Notch', 'Gene', (167, 172))	('Notch', 'Gene', '25496', (100, 105))	('Notch2', 'Gene', (100, 106))	('Notch', 'Gene', (39, 44))	('Notch3', 'Gene', (167, 173))	('Notch3', 'Gene', '18131', (116, 122))	('PDA', 'Chemical', '-', (207, 210))	('upregulated', 'PosReg', (182, 193))	('Mouse', 'Species', '10090', (0, 5))	('Notch', 'Gene', '25496', (167, 172))
34215	25416148	A limitation of genetic inactivation of individual Notch receptors is that they have been shown to functionally compensate for each other.	('Notch', 'Gene', (51, 56))	('genetic inactivation', 'Var', (16, 36))	('Notch', 'Gene', '25496', (51, 56))
34221	25416148	In part, this finding might be due to an escape mechanism allowing Notch signaling to be reactivated even in DNMAML expressing mice - either through transgene silencing, or possibly though sequestration of DNMAML away from the nucleus.	('mice', 'Species', '10090', (127, 131))	('silencing', 'NegReg', (159, 168))	('nucleus', 'cellular_component', 'GO:0005634', ('227', '234'))	('DNMAML', 'Chemical', '-', (206, 212))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('Notch', 'Gene', '25496', (67, 72))	('transgene', 'Var', (149, 158))	('DNMAML', 'Chemical', '-', (109, 115))	('Notch', 'Gene', (67, 72))
34246	23622130	Activated stellate cells also surround PanINs that develop in genetically engineered mice (KrasLSL-G12D/+; Pdxcre/+), and are likely to be of pancreatic origin.	('mice', 'Species', '10090', (85, 89))	('KrasLSL-G12D/+;', 'Var', (91, 106))	('pancreatic', 'Disease', 'MESH:D010195', (142, 152))	('pancreatic', 'Disease', (142, 152))	('PanINs', 'Disease', (39, 45))	('G12D', 'Mutation', 'rs121913529', (99, 103))
34254	23622130	Cyclo-oxygenase-2 is up-regulated in PaSCs exposed to the pancreatic cancer cell line PANC-1, and inhibition of cyclo-oxygenase-2 prevents PANC-1-induced proliferation of PaSC.	('pancreatic cancer', 'Disease', (58, 75))	('inhibition', 'Var', (98, 108))	('Cyclo-oxygenase-2', 'Gene', (0, 17))	('Cyclo-oxygenase-2', 'Gene', '5743', (0, 17))	('PANC-1', 'CellLine', 'CVCL:0480', (86, 92))	('PANC-1', 'CellLine', 'CVCL:0480', (139, 145))	('cyclo-oxygenase-2', 'Gene', (112, 129))	('pancreatic cancer', 'Disease', 'MESH:D010190', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('prevents', 'NegReg', (130, 138))	('oxygenase', 'molecular_function', 'GO:0016701', ('6', '15'))	('rat', 'Species', '10116', (161, 164))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (58, 75))	('cyclo-oxygenase-2', 'Gene', '5743', (112, 129))	('oxygenase', 'molecular_function', 'GO:0016701', ('118', '127'))	('up-regulated', 'PosReg', (21, 33))
34269	23622130	Hypoxia was shown to increase secretion of connective tissue growth factor (CTGF) by PaSCs, and knockdown of CTGF in PaSCs reduced cancer cell invasion under hypoxic conditions.	('knockdown', 'Var', (96, 105))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('Hypoxia', 'Disease', (0, 7))	('CTGF', 'Gene', '1490', (76, 80))	('secretion', 'biological_process', 'GO:0046903', ('30', '39'))	('CTGF', 'Gene', (76, 80))	('PaSCs reduced cancer', 'Disease', 'MESH:D009369', (117, 137))	('CTGF', 'Gene', '1490', (109, 113))	('hypoxic conditions', 'Disease', 'MESH:D009135', (158, 176))	('increase secretion of connective tissue', 'Phenotype', 'HP:0009025', (21, 60))	('CTGF', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('secretion of', 'MPA', (30, 42))	('PaSCs reduced cancer', 'Disease', (117, 137))	('connective tissue growth factor', 'Gene', '1490', (43, 74))	('connective tissue growth factor', 'Gene', (43, 74))	('increase', 'PosReg', (21, 29))	('hypoxic conditions', 'Disease', (158, 176))
34273	23622130	Reducing beta1-integrin and focal adhesion kinase activity in cancer cells using small interfering RNAs blocked the radioprotective effects of PaSCs on cancer cells.	('RNAs', 'Gene', (99, 103))	('radioprotective effects', 'CPA', (116, 139))	('small interfering', 'Var', (81, 98))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('focal adhesion kinase activity', 'molecular_function', 'GO:0004717', ('28', '58'))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('focal adhesion', 'cellular_component', 'GO:0005925', ('28', '42'))	('focal adhesion kinase activity', 'MPA', (28, 58))	('beta1-integrin', 'Gene', '3688', (9, 23))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('beta1-integrin', 'Gene', (9, 23))	('focal adhesion kinase activity', 'molecular_function', 'GO:0004715', ('28', '58'))
34298	23622130	KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdxcre/+ (KPC) mice KrasLSL-G12D/+; Trp53LSL-R172H/+ ; R26lsl-gfp/+; Pdxcre/+ (KPGC) mice Pancreas-specific type II receptor for TGFbeta (Tgfbr2) knockout mice that express activating Kras mutation (KrasLSL-G12D/+; Tgfbr2floxflox ;Ptf1acre/+).	('Kras', 'Gene', (218, 222))	('Tgfbr2', 'Gene', '21813', (172, 178))	('mice', 'Species', '10090', (189, 193))	('Trp53', 'Gene', '22059', (70, 75))	('Trp53', 'Gene', (16, 21))	('activating', 'PosReg', (207, 217))	('G12D', 'Mutation', 'rs121913529', (241, 245))	('Trp53', 'Gene', (70, 75))	('Tgfbr2', 'Gene', (172, 178))	('Tgfbr2', 'Gene', '21813', (249, 255))	('G12D', 'Mutation', 'rs121913529', (8, 12))	('KrasLSL-G12D/+;', 'Var', (233, 248))	('mice', 'Species', '10090', (49, 53))	('R172H', 'Mutation', 'p.R172H', (79, 84))	('R172H', 'Mutation', 'p.R172H', (25, 30))	('G12D', 'Mutation', 'rs121913529', (62, 66))	('mice', 'Species', '10090', (119, 123))	('Tgfbr2', 'Gene', (249, 255))	('Ptf1', 'Species', '32651', (265, 269))	('Trp53', 'Gene', '22059', (16, 21))
34328	23622130	Overexpression of VEGF in tumor tissues has been linked to poor prognosis of patients with PDAC.	('PDAC', 'Chemical', '-', (91, 95))	('VEGF', 'Protein', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('PDAC', 'Disease', (91, 95))	('PDAC', 'Phenotype', 'HP:0006725', (91, 95))	('patients', 'Species', '9606', (77, 85))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
34371	23622130	Interestingly, cultured human and rat PaSC produce acetylcholine (ACh) in response to cholecystokinin and, in turn, ACh stimulates enzyme secretion in pancreatic acinar cells cocultured with PaSCs.	('ACh', 'Chemical', 'MESH:D000109', (116, 119))	('ACh', 'Var', (116, 119))	('human', 'Species', '9606', (24, 29))	('ACh', 'Chemical', 'MESH:D000109', (66, 69))	('stimulates', 'PosReg', (120, 130))	('acetylcholine', 'MPA', (51, 64))	('acetylcholine', 'Chemical', 'MESH:D000109', (51, 64))	('enzyme secretion', 'MPA', (131, 147))	('pancreatic', 'Disease', 'MESH:D010195', (151, 161))	('secretion', 'biological_process', 'GO:0046903', ('138', '147'))	('rat', 'Species', '10116', (34, 37))	('response to cholecystokinin', 'biological_process', 'GO:0061847', ('74', '101'))	('pancreatic', 'Disease', (151, 161))
34399	23622130	In the KPC model, oral administration of IP-926, an inhibitor of Smoothened (one of the 2 transmembrane receptors in the Hh pathway), reduced PaSC activation, leading to stromal depletion, increased tumor vasculature, and improved delivery of gemcitabine to cancer cells.	('transmembrane', 'cellular_component', 'GO:0044214', ('90', '103'))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('Smoothened', 'Gene', (65, 75))	('rat', 'Species', '10116', (31, 34))	('stromal depletion', 'MPA', (170, 187))	('IP-926', 'Chemical', '-', (41, 47))	('reduced', 'NegReg', (134, 141))	('improved', 'PosReg', (222, 230))	('tumor', 'Disease', (199, 204))	('delivery of gemcitabine', 'MPA', (231, 254))	('PaSC activation', 'MPA', (142, 157))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('IP-926', 'Var', (41, 47))	('cancer', 'Disease', (258, 264))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('transmembrane', 'cellular_component', 'GO:0016021', ('90', '103'))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('gemcitabine', 'Chemical', 'MESH:C056507', (243, 254))	('increased', 'PosReg', (189, 198))
34401	23622130	In an orthotopic model of pancreatic cancer produced by injection of mice with BxPC3 cells alone or a mixture of BxPC3 and PaSCs, AZD8542 (another Smoothened inhibitor) significantly reduced tumor size, increased tumor vascularity, and reduced metastasis to liver, but only in tumors formed by a 3:1 ratio of PaSCs to cancer cells.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (318, 324))	('mice', 'Species', '10090', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('AZD8542', 'Chemical', 'MESH:C000591817', (130, 137))	('tumors', 'Disease', (277, 283))	('increased', 'PosReg', (203, 212))	('reduced', 'NegReg', (183, 190))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (26, 43))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('AZD8542', 'Var', (130, 137))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('metastasis', 'CPA', (244, 254))	('rat', 'Species', '10116', (300, 303))	('cancer', 'Disease', (37, 43))	('tumor', 'Disease', (191, 196))	('reduced', 'NegReg', (236, 243))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', (277, 282))	('pancreatic cancer', 'Disease', 'MESH:D010190', (26, 43))	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('pancreatic cancer', 'Disease', (26, 43))	('BxPC3', 'CellLine', 'CVCL:0186', (113, 118))	('BxPC3', 'CellLine', 'CVCL:0186', (79, 84))
34412	22140463	Thus, these data show that oncogenic Kras-driven PanIN originating in a non-ductal compartment can rapidly progress to PDAC when subjected to a brief inflammatory insult.	('PDAC', 'Disease', (119, 123))	('PDAC', 'Phenotype', 'HP:0006725', (119, 123))	('progress', 'PosReg', (107, 115))	('oncogenic', 'Var', (27, 36))	('PDAC', 'Chemical', '-', (119, 123))
34417	22140463	PDAC is now recognized to arise predominantly through progression of pancreatic intraepithelial neoplasia (PanIN), ranging from low- (PanIN-1A, -1B) to high-grades (PanIN-2, -3), PanIN-3 representing carcinoma in situ and the immediate precursor to ductal adenocarcinoma.	('PanIN-3', 'Var', (179, 186))	('carcinoma', 'Disease', 'MESH:D002277', (261, 270))	('PDAC', 'Chemical', '-', (0, 4))	('carcinoma', 'Disease', 'MESH:D002277', (200, 209))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (80, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('neoplasia', 'Phenotype', 'HP:0002664', (96, 105))	('pancreatic intraepithelial neoplasia', 'Disease', (69, 105))	('carcinoma', 'Disease', (261, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('pancreatic intraepithelial neoplasia', 'Disease', 'MESH:D018290', (69, 105))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (200, 217))	('PDAC', 'Disease', (0, 4))	('carcinoma', 'Disease', (200, 209))	('ductal adenocarcinoma', 'Disease', 'MESH:D044584', (249, 270))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('ductal adenocarcinoma', 'Disease', (249, 270))
34418	22140463	This histologic progression is correlated with the accumulation of genetic abnormalities of which mutations leading to the constitutive activation of KRAS are the earliest and most common (95%).	('common', 'Reg', (181, 187))	('genetic abnormalities', 'Disease', (67, 88))	('mutations', 'Var', (98, 107))	('KRAS', 'Gene', '16653', (150, 154))	('KRAS', 'Gene', (150, 154))	('genetic abnormalities', 'Disease', 'MESH:D030342', (67, 88))
34445	22140463	To test the possibility that mutated Kras activation in the Nestin lineage could lead to PDAC, a cohort of 17 2-month-old N/K mice were subjected to caerulein treatment.	('PDAC', 'Chemical', '-', (89, 93))	('lead to', 'Reg', (81, 88))	('mice', 'Species', '10090', (126, 130))	('PDAC', 'Disease', (89, 93))	('PDAC', 'Phenotype', 'HP:0006725', (89, 93))	('mutated Kras', 'Var', (29, 41))	('Kras', 'Var', (37, 41))	('caerulein', 'Chemical', 'MESH:D002108', (149, 158))
34461	22140463	In contrast, in all control animals (wild type or carrying a single mutation, Nestin-Cre, Pdx1-Cre or LSL-KrasG12D only) treated with caerulein, the pancreata appeared to be normal with occasionally residual traces of inflammation (not shown).	('mutation', 'Var', (68, 76))	('inflammation', 'biological_process', 'GO:0006954', ('218', '230'))	('caerulein', 'Chemical', 'MESH:D002108', (134, 143))	('inflammation', 'Disease', 'MESH:D007249', (218, 230))	('inflammation', 'Disease', (218, 230))
34462	22140463	Low-grade lesions in N/K pancreata showed a proliferation index of 13%+-3% similar to what is observed in P/K mice.	('mice', 'Species', '10090', (110, 114))	('proliferation index', 'CPA', (44, 63))	('N/K', 'Var', (21, 24))
34465	22140463	As observed in human PDAC samples, PanINs expressed high level of CK19, underscoring their epithelial nature, displayed mucus accumulation as shown by Muc5a expression (Fig.S3B-C), and were surrounded by collagen-rich stroma (Fig.	('PDAC', 'Chemical', '-', (21, 25))	('collagen', 'molecular_function', 'GO:0005202', ('204', '212'))	('mucus accumulation', 'MPA', (120, 138))	('PDAC', 'Phenotype', 'HP:0006725', (21, 25))	('CK19', 'Var', (66, 70))	('human', 'Species', '9606', (15, 20))	('mucus', 'cellular_component', 'GO:0070701', ('120', '125'))
34473	22140463	From a small group of 4 N/K animals treated with caerulein at later stages (4 month-old), 3 survived until age 6 months and of these, 2 displayed tumors (diameter ~5 mm) visible at the gross anatomical level.	('4 N/K', 'SUBSTITUTION', 'None', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('4 N/K', 'Var', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumors', 'Disease', (146, 152))	('caerulein', 'Chemical', 'MESH:D002108', (49, 58))
34483	22140463	These data demonstrate that N/K mice are a bona fide model of PDAC, and further support that the pancreatic Nestin lineage is the cell lineage that is mainly responsive to Kras mutation in the pancreas.	('mutation', 'Var', (177, 185))	('pancreatic', 'Disease', 'MESH:D010195', (97, 107))	('PDAC', 'Chemical', '-', (62, 66))	('pancreatic', 'Disease', (97, 107))	('mice', 'Species', '10090', (32, 36))	('Kras', 'Gene', (172, 176))	('PDAC', 'Phenotype', 'HP:0006725', (62, 66))
34490	22140463	Our data and others show that caerulein-induced AP acts as cancer promoter in PDAC mouse models, suggesting that AP, when occurring in an individual whose pancreas harbors a Kras mutation, could potentially increase PDAC risk.	('PDAC', 'Chemical', '-', (216, 220))	('PDAC', 'Phenotype', 'HP:0006725', (78, 82))	('increase', 'PosReg', (207, 215))	('AP', 'Phenotype', 'HP:0001735', (48, 50))	('caerulein', 'Chemical', 'MESH:D002108', (30, 39))	('mouse', 'Species', '10090', (83, 88))	('mutation', 'Var', (179, 187))	('Kras', 'Gene', (174, 178))	('PDAC', 'Disease', (216, 220))	('AP', 'Phenotype', 'HP:0001735', (113, 115))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('PDAC', 'Phenotype', 'HP:0006725', (216, 220))	('PDAC', 'Chemical', '-', (78, 82))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
34503	22140463	Indeed, phospho-Stat3 was shown to be directly responsible for the accelerated neoplastic progression in P/K mice following AP.	('accelerated', 'PosReg', (67, 78))	('AP', 'Phenotype', 'HP:0001735', (124, 126))	('neoplastic progression', 'CPA', (79, 101))	('mice', 'Species', '10090', (109, 113))	('phospho-Stat3', 'Var', (8, 21))
34545	21463193	By contrast, in a mouse model in which an activating K-Ras mutation is expressed in the pancreas, preinvasive pancreatic lesions are characterized by the infiltration of immune suppressor cells rather than immune effector cells, suggesting tumor immunity may be blocked from the inception of pancreatic cancer development.	('K-Ras', 'Gene', (53, 58))	('tumor', 'Disease', (240, 245))	('mouse', 'Species', '10090', (18, 23))	('pancreatic cancer', 'Disease', (292, 309))	('activating', 'PosReg', (42, 52))	('pancreatic cancer', 'Disease', 'MESH:D010190', (292, 309))	('pancreatic lesions', 'Disease', (110, 128))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('mutation', 'Var', (59, 67))	('pancreatic lesions', 'Disease', 'MESH:D010182', (110, 128))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (292, 309))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
34546	21463193	All mice with the K-Ras mutation develop pancreatic adenocarcinoma and eventually die of disease.	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (41, 66))	('pancreatic adenocarcinoma', 'Disease', (41, 66))	('mice', 'Species', '10090', (4, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (41, 66))	('develop', 'PosReg', (33, 40))	('mutation', 'Var', (24, 32))	('K-Ras', 'Gene', '16653', (18, 23))	('K-Ras', 'Gene', (18, 23))
34547	21463193	Finally, the finding that antagonism of negative T-cell regulators, such as cytotoxic T-lymphocyte-associated (CTLA) protein-4 and B- and T-lymphocyte attenuator (BTLA), can augment the antitumor immune response confirms that patients mount an immune response to their tumor.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('immune response', 'biological_process', 'GO:0006955', ('196', '211'))	('augment', 'PosReg', (174, 181))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('antagonism', 'Var', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (269, 274))	('B- and T-lymphocyte attenuator', 'Gene', '151888', (131, 161))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('tumor', 'Disease', (190, 195))	('patients', 'Species', '9606', (226, 234))	('cytotoxic T-lymphocyte-associated (CTLA) protein-4', 'Gene', '1493', (76, 126))	('immune response', 'biological_process', 'GO:0006955', ('244', '259'))	('BTLA', 'Gene', (163, 167))	('BTLA', 'Gene', '151888', (163, 167))
34571	21463193	The NewLink Genetics Corporation (IA, USA) has developed a whole-cell vaccine expressing MUC-1 modified to express alpha-gal epitopes, which is the focus of multiple clinical trials (NCT00255827, NCT00614601, NCT00569387 and NCT01072981).	('NCT01072981', 'Var', (225, 236))	('NCT00569387', 'Var', (209, 220))	('alpha-gal epitopes', 'Protein', (115, 133))	('MUC-1', 'Gene', (89, 94))	('NCT00255827', 'Var', (183, 194))	('NCT00614601', 'Var', (196, 207))	('alpha-gal', 'Chemical', '-', (115, 124))
34582	21463193	In a Phase III clinical trial, vaccination resulted in a 3-year survival advantage in vaccinated castration- resistant prostate cancer patients (31.7% survival) compared with placebo (23%).	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('survival', 'CPA', (64, 72))	('patients', 'Species', '9606', (135, 143))	('vaccinated', 'Var', (86, 96))	('prostate cancer', 'Disease', (119, 134))	('advantage', 'PosReg', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('prostate cancer', 'Disease', 'MESH:D011471', (119, 134))
34593	21463193	Currently, a similar vaccine is in a Phase I/II clinical trial in melanoma patients using DCs transfected with the mRNA of tumor cells along with that of telomerase and survivin (NCT00961844).	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('tumor', 'Disease', (123, 128))	('transfected', 'Var', (94, 105))	('survivin', 'Gene', '11799', (169, 177))	('patients', 'Species', '9606', (75, 83))	('survivin', 'Gene', (169, 177))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
34613	21463193	In a pilot vaccine study, pancreatic and colorectal patients were vaccinated with K-Ras peptides containing patient-specific mutations.	('mutations', 'Var', (125, 134))	('pancreatic', 'Disease', 'MESH:D010195', (26, 36))	('colorectal', 'Disease', 'MESH:D015179', (41, 51))	('pancreatic', 'Disease', (26, 36))	('patient', 'Species', '9606', (52, 59))	('patient', 'Species', '9606', (108, 115))	('colorectal', 'Disease', (41, 51))	('patients', 'Species', '9606', (52, 60))
34624	21463193	Remarkably, one case has been reported in which vaccination with a modified HLA-A2-restricted survivin peptide resulted in remission of liver metastasis in one individual with pancreatic cancer.	('modified', 'Var', (67, 75))	('survivin', 'Gene', '11799', (94, 102))	('liver metastasis', 'Disease', (136, 152))	('pancreatic cancer', 'Disease', (176, 193))	('pancreatic cancer', 'Disease', 'MESH:D010190', (176, 193))	('survivin', 'Gene', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (176, 193))	('liver metastasis', 'Disease', 'MESH:D009362', (136, 152))
34638	21463193	In pancreatic cancer studies, DNA vaccination has mainly been applied to murine models of cancer, though there are ongoing clinical trials in other cancers (NCT00807781, NCT00859729, NCT00471133 and NCT01064375).	('murine', 'Species', '10090', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('NCT00859729', 'Var', (170, 181))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('NCT00807781', 'Var', (157, 168))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('NCT01064375', 'Var', (199, 210))	('cancer', 'Disease', (14, 20))	('cancer', 'Disease', (148, 154))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('pancreatic cancer', 'Disease', (3, 20))	('cancers', 'Disease', (148, 155))	('NCT00471133', 'Var', (183, 194))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (90, 96))
34673	21463193	In murine studies, vaccination with SC-CEA resulted in the generation of CEA-specific T cells, reduced tumor volume and increased survival when vaccinated hCEA-transgenic mice were challenged with a CEA-expressing tumor.	('hCEA', 'Gene', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('SC', 'Species', '4932', (36, 38))	('survival', 'CPA', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', (103, 108))	('SC-CEA', 'Var', (36, 42))	('transgenic mice', 'Species', '10090', (160, 175))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('murine', 'Species', '10090', (3, 9))	('tumor', 'Disease', (214, 219))	('reduced', 'NegReg', (95, 102))	('hCEA', 'Gene', '1048', (155, 159))	('increased', 'PosReg', (120, 129))	('CEA-specific T cells', 'CPA', (73, 93))
34737	21463193	A CAR with specificity to MUC-1 has also been generated using the SM3 antibody with intracellular signaling motifs of CD28, OX40 and CD3zeta.	('CD3zeta', 'Gene', (133, 140))	('antibody', 'cellular_component', 'GO:0042571', ('70', '78'))	('intracellular', 'cellular_component', 'GO:0005622', ('84', '97'))	('OX40', 'Gene', '7293', (124, 128))	('antibody', 'cellular_component', 'GO:0019815', ('70', '78'))	('OX40', 'Gene', (124, 128))	('antibody', 'cellular_component', 'GO:0019814', ('70', '78'))	('CD28', 'Var', (118, 122))	('antibody', 'molecular_function', 'GO:0003823', ('70', '78'))	('CAR', 'cellular_component', 'GO:0005826', ('2', '5'))	('CD3zeta', 'Gene', '919', (133, 140))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))
34761	21463193	For example, MDSCs can promote Treg recruitment and maintenance through TGF-beta-dependent and -independent mechanisms.	('TGF-beta', 'Gene', '7040', (72, 80))	('MDSCs', 'Var', (13, 18))	('promote', 'PosReg', (23, 30))	('SC', 'Species', '4932', (15, 17))	('TGF-beta', 'Gene', (72, 80))	('Treg recruitment', 'CPA', (31, 47))	('maintenance', 'CPA', (52, 63))
34780	21463193	Finally, the depletion of MDSCs in murine models has been associated with improved host immune responses, resulting in delayed tumor growth, improved survival and increased efficacy of vaccine therapy.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('MDSCs', 'Gene', (26, 31))	('tumor', 'Disease', (127, 132))	('increased', 'PosReg', (163, 172))	('survival', 'CPA', (150, 158))	('depletion', 'Var', (13, 22))	('improved', 'PosReg', (141, 149))	('host immune responses', 'CPA', (83, 104))	('improved', 'PosReg', (74, 82))	('SC', 'Species', '4932', (28, 30))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('murine', 'Species', '10090', (35, 41))
34781	21463193	Elimination of MDSCs has been shown to improve antitumor responses, restore CTL and NK function, decrease tumor angiogenesis and enhance immunotherapy.	('MDSCs', 'Gene', (15, 20))	('improve', 'PosReg', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('restore', 'PosReg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('CTL', 'Protein', (76, 79))	('immunotherapy', 'CPA', (137, 150))	('angiogenesis', 'biological_process', 'GO:0001525', ('112', '124'))	('tumor', 'Disease', (51, 56))	('SC', 'Species', '4932', (17, 19))	('Elimination', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('function', 'MPA', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('decrease', 'NegReg', (97, 105))	('enhance', 'PosReg', (129, 136))	('tumor', 'Disease', (106, 111))
34785	21463193	This has obvious implications for the type of strategy that will be used; Vaccination against self-antigens has been associated with induction Tregs and MDSCs.	('associated', 'Reg', (117, 127))	('MDSCs', 'Disease', (153, 158))	('induction Tregs', 'CPA', (133, 148))	('SC', 'Species', '4932', (155, 157))	('Vaccination', 'Var', (74, 85))
34786	21463193	have reported that immunization of mice with plasmids encoding tumor antigens resulted in marked enhancement of in vivo tumor growth in a murine pulmonary metastasis model.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('enhancement', 'PosReg', (97, 108))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mice', 'Species', '10090', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('plasmids', 'Var', (45, 53))	('murine', 'Species', '10090', (138, 144))	('tumor', 'Disease', (120, 125))
34797	21463193	These studies not only demonstrated the presence of multiple mutations that can be targeted; they also showed that many of these mutations are already present in primary pancreatic cancers, and suggest vaccination after primary resection may protect against recurrence.	('pancreatic cancers', 'Disease', 'MESH:D010190', (170, 188))	('pancreatic cancers', 'Disease', (170, 188))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (170, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('mutations', 'Var', (129, 138))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (170, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))
34799	21463193	Such mutations have been identified in the past, but in the next 4-6 years we expect the sequencing of a patient's cancer (and normal cells) to be part of the diagnosis.	('cancer', 'Disease', (115, 121))	('patient', 'Species', '9606', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
34844	21037025	In tumor xenograft studies combination treatment with MORAb-009 plus chemotherapy led to a greater reduction in the growth of mesothelin expressing tumors than either MORAb-009 or chemotherapy alone.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (3, 8))	('growth', 'MPA', (116, 122))	('tumor', 'Disease', (148, 153))	('MORAb-009', 'Chemical', 'MESH:C526187', (54, 63))	('reduction', 'NegReg', (99, 108))	('MORAb-009', 'Chemical', 'MESH:C526187', (167, 176))	('MORAb-009', 'Var', (54, 63))	('mesothelin', 'Protein', (126, 136))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
34852	21037025	Other eligibility criteria included a life expectancy >= 3 months; Eastern Cooperative Oncology Group (ECOG) performance score of 0-2; adequate bone marrow, hepatic, and renal function (absolute neutrophil count >= 1.5 x 109/L; platelet count >= 100 x 109/L; hemoglobin >= 9 g/dL; serum aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase <= 5 x upper limit of normal; serum bilirubin <= 2.0 mg/dL; serum creatinine <= 2.0 mg/dL) determined <= 2 weeks before starting therapy.	('AST', 'Gene', '26503', (311, 314))	('alanine transaminase', 'MPA', (317, 337))	('aspartate transaminase', 'Gene', '26503', (287, 309))	('serum bilirubin', 'MPA', (399, 414))	('>= 100 x 109/L', 'Var', (243, 257))	('alkaline phosphatase', 'MPA', (348, 368))	('AST', 'Gene', (311, 314))	('aspartate transaminase', 'Gene', (287, 309))	('phosphatase', 'molecular_function', 'GO:0016791', ('357', '368'))	('Oncology', 'Phenotype', 'HP:0002664', (87, 95))	('serum creatinine', 'MPA', (429, 445))	('ALT', 'molecular_function', 'GO:0004021', ('339', '342'))
34926	21037025	The mean Cmax of MORAb-009 at the MTD (200 mg/m2) is significantly higher than the concentration of MORAb-009 required for ADCC against mesothelin expressing cell lines or to inhibit the mesothelin CA125 interaction in vitro.	('MORAb-009', 'Chemical', 'MESH:C526187', (17, 26))	('higher', 'PosReg', (67, 73))	('Cmax', 'MPA', (9, 13))	('MORAb-009', 'Var', (17, 26))	('MORAb-009', 'Chemical', 'MESH:C526187', (100, 109))	('ADCC', 'biological_process', 'GO:0001788', ('123', '127'))	('CA125', 'Gene', (198, 203))	('inhibit', 'NegReg', (175, 182))	('CA125', 'Gene', '94025', (198, 203))
34932	21037025	These results suggest that MORAb-009 can potentially inhibit the interaction between mesothelin and CA125 and therefore inhibit heterotypic adhesion and intra-cavitary metastasis in patients with mesothelioma and ovarian cancer.	('mesothelioma and ovarian cancer', 'Disease', 'MESH:D010051', (196, 227))	('inhibit', 'NegReg', (53, 60))	('MORAb-009', 'Chemical', 'MESH:C526187', (27, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (213, 227))	('interaction', 'Interaction', (65, 76))	('heterotypic adhesion', 'MPA', (128, 148))	('MORAb-009', 'Var', (27, 36))	('CA125', 'Gene', '94025', (100, 105))	('intra-cavitary metastasis', 'CPA', (153, 178))	('inhibit', 'NegReg', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('patients', 'Species', '9606', (182, 190))	('mesothelin', 'Protein', (85, 95))	('CA125', 'Gene', (100, 105))
34943	33670509	Several surface modifications can modulate the unique molecular structure of [60]fullerene derivatives, as well as their physicochemical properties.	('modifications', 'Var', (16, 29))	('fullerene', 'Chemical', 'MESH:D037741', (81, 90))	('modulate', 'Reg', (34, 42))
34949	33670509	Here, we describe the PANC-1 cell proliferation, migration, metabolic activity and glycolysis rate after incubations with different concentrations of Sweet-C60.	('Sweet-C60', 'Var', (150, 159))	('migration', 'CPA', (49, 58))	('PANC-1', 'CellLine', 'CVCL:0480', (22, 28))	('metabolic activity', 'CPA', (60, 78))	('Sweet-C60', 'Chemical', '-', (150, 159))	('cell proliferation', 'biological_process', 'GO:0008283', ('29', '47'))	('glycolysis rate', 'MPA', (83, 98))	('glycolysis', 'biological_process', 'GO:0006096', ('83', '93'))
34953	33670509	The [60]fullerene molecule (C60) has also become a subject of interest due to the plethora of synthetic modifications that increase its water solubility.	('water solubility', 'MPA', (136, 152))	('modifications', 'Var', (104, 117))	('water', 'Chemical', 'MESH:D014867', (136, 141))	('plethora', 'Phenotype', 'HP:0001050', (82, 90))	('increase', 'PosReg', (123, 131))	('fullerene', 'Chemical', 'MESH:D037741', (8, 17))
34970	33670509	The invasiveness and difficulty in treating pancreatic cancer are caused by many factors, such as mutations in the genes; microRNA regulation disorders; disorders in the signaling pathways, including apoptosis; the presence of cancer stem cells; epithelial-mesenchymal transition; hypoxia; and increased angiogenesis.	('microRNA regulation', 'MPA', (122, 141))	('angiogenesis', 'CPA', (304, 316))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('hypoxia', 'Disease', (281, 288))	('angiogenesis', 'biological_process', 'GO:0001525', ('304', '316'))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('genes', 'Gene', (115, 120))	('disorders', 'Reg', (153, 162))	('caused by', 'Reg', (66, 75))	('hypoxia', 'Disease', 'MESH:D000860', (281, 288))	('epithelial-mesenchymal transition', 'CPA', (246, 279))	('cancer', 'Disease', (55, 61))	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('246', '279'))	('signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('signaling pathways', 'Pathway', (170, 188))	('cancer', 'Disease', (227, 233))	('regulation', 'biological_process', 'GO:0065007', ('131', '141'))	('apoptosis', 'CPA', (200, 209))	('pancreatic cancer', 'Disease', (44, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('200', '209'))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('apoptosis', 'biological_process', 'GO:0006915', ('200', '209'))	('mutations', 'Var', (98, 107))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('increased', 'PosReg', (294, 303))
34974	33670509	It has also been reported that anti-Glut-1 antibodies may disrupt the Glut-1 transporter functions and decrease tumor growth.	('antibodies', 'Var', (43, 53))	('Glut-1', 'Gene', '6513', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Glut-1', 'Gene', '6513', (70, 76))	('Glut-1', 'Gene', (70, 76))	('tumor', 'Disease', (112, 117))	('decrease', 'NegReg', (103, 111))	('Glut-1', 'Gene', (36, 42))	('disrupt', 'NegReg', (58, 65))
34980	33670509	The study also attempted to determine the toxicity and multidirectional effects of Sweet-C60 on pancreatic cancer cells.	('pancreatic cancer', 'Disease', (96, 113))	('Sweet-C60', 'Chemical', '-', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('toxicity', 'Disease', 'MESH:D064420', (42, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('Sweet-C60', 'Var', (83, 92))	('toxicity', 'Disease', (42, 50))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))
34998	33670509	The electrophoresis was carried out at an initial voltage of 90 V, which was increased to 100 V. The proteins were transferred onto a nitrocellulose, blocked with 5% non-fat milk in a TBS-T buffer for 1.5 h and incubated with the primary antibodies against GLUT-1 (ab115730, Abcam, Cambridge, UK) and vinculin (ab129002) (Abcam, Cambridge, UK) at 4  C overnight.	('GLUT-1', 'Gene', (257, 263))	('vinculin', 'Gene', (301, 309))	('ab129002', 'Var', (311, 319))	('ab115730', 'Var', (265, 273))	('vinculin', 'Gene', '7414', (301, 309))	('GLUT-1', 'Gene', '6513', (257, 263))
35007	33670509	By analyzing the selected long-term points as depicted in Figure 2, it was determined that incubating the PANC-1 cells with the glycofullerene led to a slightly slower proliferation rate (Figure 2B).	('PANC-1', 'CellLine', 'CVCL:0480', (106, 112))	('slower', 'NegReg', (161, 167))	('glycofullerene', 'Chemical', '-', (128, 142))	('glycofullerene', 'Var', (128, 142))
35009	33670509	Conversely, the incubation with Sweet-C60 for 120 h for both doses led to a decrease in the number of cells relative to the control (Figure 2A).	('Sweet-C60', 'Chemical', '-', (32, 41))	('decrease', 'NegReg', (76, 84))	('number of cells', 'CPA', (92, 107))	('Sweet-C60', 'Var', (32, 41))
35012	33670509	Moreover, the results showed that the time required for the PANC-1 cell division after the treatment with Sweet-C60 was slightly extended.	('Sweet-C60', 'Var', (106, 115))	('cell division', 'biological_process', 'GO:0051301', ('67', '80'))	('PANC-1', 'CellLine', 'CVCL:0480', (60, 66))	('PANC-1', 'Gene', (60, 66))	('Sweet-C60', 'Chemical', '-', (106, 115))
35016	33670509	It was observed that treating the PANC-1 cells with Sweet-C60 at a dose of 0.01 mg/mL led to an insignificant increase in the metabolic activity.	('increase', 'PosReg', (110, 118))	('Sweet-C60', 'Chemical', '-', (52, 61))	('Sweet-C60', 'Var', (52, 61))	('PANC-1', 'CellLine', 'CVCL:0480', (34, 40))	('metabolic activity', 'MPA', (126, 144))
35024	33670509	After 48 h of incubation with Sweet-C60, the changes in the rate of wound healing were observed between two and four hours of measurement (in the initial phase, the rate of migration was steady at all levels).	('Sweet-C60', 'Var', (30, 39))	('Sweet-C60', 'Chemical', '-', (30, 39))	('wound healing', 'biological_process', 'GO:0042060', ('68', '81'))	('wound healing', 'CPA', (68, 81))
35028	33670509	To summarize, when the proliferation time was considered, the wound-healing assay did not provide a clear answer about the impact of Sweet-C60 on the pancreatic cancer cell migration.	('Sweet-C60', 'Var', (133, 142))	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cell migration', 'biological_process', 'GO:0016477', ('168', '182'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('wound-healing', 'biological_process', 'GO:0042060', ('62', '75'))	('Sweet-C60', 'Chemical', '-', (133, 142))	('pancreatic cancer', 'Disease', (150, 167))
35037	33670509	Interestingly, the level of the GLUT-1 protein did not change significantly during the incubation with Sweet-C60.	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('Sweet-C60', 'Chemical', '-', (103, 112))	('GLUT-1', 'Gene', '6513', (32, 38))	('Sweet-C60', 'Var', (103, 112))	('GLUT-1', 'Gene', (32, 38))
35039	33670509	What is more, after 120 h of incubation, there was a slight increase of GLUT-1 protein for the 0.01 mg/mL concentration, but there was no change of GLUT-1 in the cells that had been incubated with the 0.1 mg/mL concentration of the glycofullerene.	('GLUT-1', 'Gene', '6513', (72, 78))	('0.01 mg/mL', 'Var', (95, 105))	('GLUT-1', 'Gene', (72, 78))	('GLUT-1', 'Gene', (148, 154))	('GLUT-1', 'Gene', '6513', (148, 154))	('glycofullerene', 'Chemical', '-', (232, 246))	('increase', 'PosReg', (60, 68))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))
35048	33670509	Our previous report described the effects of Sweet-C60 on the OH-1 levels and also indicated that the induction of autophagy took place after incubating the PANC-1 cells with Sweet-C60.	('Sweet-C60', 'Var', (175, 184))	('Sweet-C60', 'Chemical', '-', (175, 184))	('effects', 'Reg', (34, 41))	('autophagy', 'CPA', (115, 124))	('Sweet-C60', 'Chemical', '-', (45, 54))	('Sweet-C60', 'Var', (45, 54))	('autophagy', 'biological_process', 'GO:0016236', ('115', '124'))	('PANC-1', 'CellLine', 'CVCL:0480', (157, 163))	('OH-1 levels', 'MPA', (62, 73))	('autophagy', 'biological_process', 'GO:0006914', ('115', '124'))
35054	33670509	Moreover, the presented data indicates that Sweet-C60 could be a promising drug delivery vehicle due to its lack of influence on cell migration, proliferation and metabolism while, at the same time, as is presented in our previous study, accumulating in the PANC-1 cells.	('Sweet-C60', 'Var', (44, 53))	('metabolism', 'biological_process', 'GO:0008152', ('163', '173'))	('metabolism', 'CPA', (163, 173))	('accumulating', 'PosReg', (238, 250))	('cell migration', 'biological_process', 'GO:0016477', ('129', '143'))	('Sweet-C60', 'Chemical', '-', (44, 53))	('PANC-1', 'CellLine', 'CVCL:0480', (258, 264))	('cell migration', 'CPA', (129, 143))
35075	32898301	3  A recent study reported that 10% of the PDAC patients carry a BRCA gene mutation which could provide an opportunity to apply screening and use targeted treatment to improve outcome.	('PDAC', 'Disease', (43, 47))	('BRCA', 'Gene', (65, 69))	('BRCA', 'Gene', '672', (65, 69))	('PDAC', 'Phenotype', 'HP:0006725', (43, 47))	('mutation', 'Var', (75, 83))	('PDAC', 'Chemical', '-', (43, 47))	('patients', 'Species', '9606', (48, 56))
35111	32898301	Initially, five derived traits were used for the model, namely CA2 (diantennary species of complex glycans in spectrum), CA4 (tetraantennary species of complex glycans in spectrum), A3FE (alpha2,6-sialylation of fucosylated triantennary glycans), A3F0L (alpha2,3-sialylation of nonfucosylated triantennary glycans) and CFa (antenna-fucosylation of complex glycans).	('glycans', 'Chemical', 'MESH:D011134', (306, 313))	('alpha2,3', 'Gene', '28923', (254, 262))	('CA2', 'Gene', (63, 66))	('A3FE', 'Var', (182, 186))	('alpha2', 'Gene', (254, 260))	('CA4', 'Gene', (121, 124))	('CA4', 'Gene', '762', (121, 124))	('alpha2', 'Gene', '170589', (254, 260))	('sialylation', 'biological_process', 'GO:0097503', ('197', '208'))	('CFa', 'Gene', (319, 322))	('glycans', 'Chemical', 'MESH:D011134', (160, 167))	('CA2', 'Gene', '760', (63, 66))	('glycans', 'Chemical', 'MESH:D011134', (237, 244))	('CFa', 'Gene', '6902', (319, 322))	('fucosylation', 'biological_process', 'GO:0036065', ('332', '344'))	('alpha2', 'Gene', (188, 194))	('F', 'Chemical', 'MESH:D005461', (249, 250))	('glycans', 'Chemical', 'MESH:D011134', (356, 363))	('alpha2', 'Gene', '170589', (188, 194))	('sialylation', 'biological_process', 'GO:0097503', ('263', '274'))	('A3F0L', 'Var', (247, 252))	('F', 'Chemical', 'MESH:D005461', (320, 321))	('glycans', 'Chemical', 'MESH:D011134', (99, 106))	('F', 'Chemical', 'MESH:D005461', (184, 185))
35112	32898301	Multiple combinations of these traits were then evaluated with regard to classification of diagnosis, resulting in a final model based on a combination of CA4, A3F0L and CFa.	('CFa', 'Gene', (170, 173))	('F', 'Chemical', 'MESH:D005461', (171, 172))	('CFa', 'Gene', '6902', (170, 173))	('F', 'Chemical', 'MESH:D005461', (162, 163))	('CA4', 'Gene', '762', (155, 158))	('A3F0L', 'Var', (160, 165))	('CA4', 'Gene', (155, 158))
35121	32898301	Both mono- and difucosylation (F and Fa, respectively) were increased for tri- and tetraantennary glycans (A3F, A4F, A3Fa, A4Fa; Table 2).	('A4F', 'Chemical', '-', (123, 126))	('difucosylation', 'MPA', (15, 29))	('A3Fa', 'Chemical', '-', (117, 121))	('glycans', 'Chemical', 'MESH:D011134', (98, 105))	('A4Fa', 'Chemical', '-', (123, 127))	('A4Fa', 'Var', (123, 127))	('F', 'Chemical', 'MESH:D005461', (119, 120))	('F', 'Chemical', 'MESH:D005461', (31, 32))	('F', 'Chemical', 'MESH:D005461', (125, 126))	('A4F', 'Var', (112, 115))	('F', 'Chemical', 'MESH:D005461', (37, 38))	('increased', 'PosReg', (60, 69))	('F', 'Chemical', 'MESH:D005461', (109, 110))	('A4F', 'Chemical', '-', (112, 115))	('mono-', 'MPA', (5, 10))	('A3F', 'Var', (107, 110))	('tetraantennary glycans', 'Protein', (83, 105))	('A3Fa', 'Var', (117, 121))	('F', 'Chemical', 'MESH:D005461', (114, 115))
35122	32898301	Also, an increase in alpha2,6-linked sialylation and a decrease in alpha2,3-linked sialylation was observed (A2F0L, A3F0L, A4F0L; Table 2).	('alpha2,3', 'Gene', '28923', (67, 75))	('A4F', 'Chemical', '-', (123, 126))	('alpha2', 'Gene', '170589', (21, 27))	('A4F0L', 'Var', (123, 128))	('alpha2', 'Gene', (67, 73))	('increase', 'PosReg', (9, 17))	('sialylation', 'biological_process', 'GO:0097503', ('83', '94'))	('decrease', 'NegReg', (55, 63))	('F', 'Chemical', 'MESH:D005461', (125, 126))	('alpha2', 'Gene', '170589', (67, 73))	('F', 'Chemical', 'MESH:D005461', (111, 112))	('alpha2', 'Gene', (21, 27))	('F', 'Chemical', 'MESH:D005461', (118, 119))	('sialylation', 'biological_process', 'GO:0097503', ('37', '48'))	('A3F0L', 'Var', (116, 121))
35147	32898301	40   We found an increase of fucosylation of triantennary and tetraantennary glycans (A3F and A4F) in PDAC patients, specifically, in glycans containing alpha 2,3-linked sialic acids (A2LF, A3LF and A4LF).	('PDAC', 'Chemical', '-', (102, 106))	('A3LF', 'Var', (190, 194))	('fucosylation', 'MPA', (29, 41))	('glycans', 'Chemical', 'MESH:D011134', (77, 84))	('PDAC', 'Disease', (102, 106))	('F', 'Chemical', 'MESH:D005461', (96, 97))	('A4F', 'Chemical', '-', (94, 97))	('F', 'Chemical', 'MESH:D005461', (202, 203))	('glycans', 'Chemical', 'MESH:D011134', (134, 141))	('PDAC', 'Phenotype', 'HP:0006725', (102, 106))	('fucosylation', 'biological_process', 'GO:0036065', ('29', '41'))	('F', 'Chemical', 'MESH:D005461', (193, 194))	('increase', 'PosReg', (17, 25))	('F', 'Chemical', 'MESH:D005461', (187, 188))	('sialic acids', 'Chemical', 'MESH:D012794', (170, 182))	('patients', 'Species', '9606', (107, 115))	('F', 'Chemical', 'MESH:D005461', (88, 89))
35177	32921958	The Syrian hamster with IL2RG gene knockout (named ZZU001) demonstrated an immune-deficient phenotype and function.	('IL2', 'molecular_function', 'GO:0005134', ('24', '27'))	('knockout', 'Var', (35, 43))	('IL2RG', 'Gene', (24, 29))	('Syrian hamster', 'Species', '10036', (4, 18))
35179	32921958	PC tissues derived from ZZU001 hamsters displayed desmoplastic reactions in the stroma and epithelial to mesenchymal transition phenotypes, whereas PC tissues derived from immune-deficient mice did not present such features.	('mice', 'Species', '10090', (189, 193))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('91', '127'))	('ZZU001', 'Var', (24, 30))	('epithelial to mesenchymal transition phenotypes', 'CPA', (91, 138))	('desmoplastic reactions in the stroma', 'CPA', (50, 86))	('hamster', 'Species', '10034', (31, 38))
35184	32921958	Here, we created a new immune-deficient Syrian hamster with interleukin 2 receptor subunit gamma (IL2RG) gene knockout and demonstrated that the IL2RG-/- Syrian hamster is a promising animal model that can faithfully recapitulate most features of human PC, notably multiple sites of metastasis.	('IL2', 'molecular_function', 'GO:0005134', ('145', '148'))	('Syrian hamster', 'Species', '10036', (40, 54))	('human', 'Species', '9606', (247, 252))	('Syrian hamster', 'Species', '10036', (154, 168))	('IL2', 'molecular_function', 'GO:0005134', ('98', '101'))	('interleukin 2 receptor subunit gamma', 'Gene', '101824015', (60, 96))	('interleukin 2 receptor subunit gamma', 'Gene', (60, 96))	('knockout', 'Var', (110, 118))	('IL2RG', 'Gene', (98, 103))
35247	32921958	As shown in Figure 1D, ZZU001 Syrian hamsters with homozygous 10 bp deletion of IL2RG had very little mRNA expression of IL2RG compared to wild type hamsters in thymus, as revealed by RT-qPCR, and no IL2RG protein expression in ZZU001 spleen was detectable by Western blotting (Figure 1E).	('hamster', 'Species', '10034', (149, 156))	('IL2', 'molecular_function', 'GO:0005134', ('80', '83'))	('Syrian hamsters', 'Species', '10036', (30, 45))	('little', 'NegReg', (95, 101))	('protein', 'cellular_component', 'GO:0003675', ('206', '213'))	('mRNA expression', 'MPA', (102, 117))	('deletion', 'Var', (68, 76))	('IL2', 'molecular_function', 'GO:0005134', ('200', '203'))	('IL2RG', 'Gene', (80, 85))	('hamster', 'Species', '10034', (37, 44))	('IL2RG', 'MPA', (121, 126))	('IL2', 'molecular_function', 'GO:0005134', ('121', '124'))
35248	32921958	Gross necropsy and microscopic analyses of ZZU001 Syrian hamsters revealed impaired lymphoid development.	('impaired lymphoid', 'Disease', (75, 92))	('Syrian hamsters', 'Species', '10036', (50, 65))	('impaired lymphoid', 'Disease', 'MESH:D060825', (75, 92))	('ZZU001', 'Var', (43, 49))
35250	32921958	The thymus of homozygous IL2RG KO hamsters was extremely hypoplastic and significantly reduced in size (Figure 2A), and consisted of an epithelial rudiment without any lymphocytes compared to WT (Figure 3A and B).	('IL2RG KO', 'Var', (25, 33))	('hypoplastic', 'Disease', 'MESH:D000741', (57, 68))	('reduced', 'NegReg', (87, 94))	('IL2', 'molecular_function', 'GO:0005134', ('25', '28'))	('hypoplastic', 'Disease', (57, 68))	('hamster', 'Species', '10034', (34, 41))
35251	32921958	The spleen of homozygous IL2RG KO hamsters was moderately decreased in size, as seen in Figure 2A.	('IL2', 'molecular_function', 'GO:0005134', ('25', '28'))	('IL2RG KO', 'Var', (25, 33))	('decreased', 'NegReg', (58, 67))	('hamster', 'Species', '10034', (34, 41))
35260	32921958	Consistent with the histology, the number of splenocytes and thymocytes was dramatically reduced in ZZU001 Syrian hamster compared with WT hamsters.	('hamster', 'Species', '10034', (114, 121))	('ZZU001', 'Var', (100, 106))	('hamster', 'Species', '10034', (139, 146))	('reduced', 'NegReg', (89, 96))	('Syrian hamster', 'Species', '10036', (107, 121))
35262	32921958	Based on these findings, it is evident that ZZU001 hamsters have a severe immune deficiency in T cell, B cell, and possibly natural killer cells.	('immune deficiency', 'Phenotype', 'HP:0002721', (74, 91))	('severe immune deficiency', 'Phenotype', 'HP:0004430', (67, 91))	('T cell', 'CPA', (95, 101))	('immune deficiency', 'Disease', 'MESH:D007153', (74, 91))	('immune deficiency', 'Disease', (74, 91))	('ZZU001', 'Var', (44, 50))	('deficiency in T cell', 'Phenotype', 'HP:0005403', (81, 101))	('hamster', 'Species', '10034', (51, 58))
35277	32921958	Of note, desmoplastic reactions that consist of extracellular matrix proteins, including collagen and fibronectin (Figure 4D) and active fibroblasts [SMA-positive staining (Figure 4D)] were readily observed in the stroma of ZZU001 hamster xenograft tumors but not in the xenograft tumors derived from B-NDG mice.	('collagen', 'molecular_function', 'GO:0005202', ('89', '97'))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('tumors', 'Disease', (281, 287))	('ZZU001', 'Var', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('B-NDG', 'Chemical', '-', (301, 306))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('hamster', 'Species', '10034', (231, 238))	('mice', 'Species', '10090', (307, 311))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('desmoplastic reactions', 'CPA', (9, 31))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('48', '68'))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('tumors', 'Disease', (249, 255))
35278	32921958	Most interestingly, the tumor cells growing in ZZU001 hamsters displayed strong vimentin positive staining, indicative of epithelial to mesenchymal transition (EMT) (Figure 4D), whereas no obviously vimentin-positive tumor cells were observed in B-NDG mice xenograft tumors (Figure 4D).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('122', '158'))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('hamster', 'Species', '10034', (54, 61))	('EMT', 'biological_process', 'GO:0001837', ('160', '163'))	('vimentin positive', 'Protein', (80, 97))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('mice', 'Species', '10090', (252, 256))	('tumor', 'Disease', (217, 222))	('vimentin', 'cellular_component', 'GO:0045099', ('80', '88'))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumors', 'Disease', (267, 273))	('vimentin', 'cellular_component', 'GO:0045098', ('199', '207'))	('B-NDG', 'Chemical', '-', (246, 251))	('tumor', 'Disease', (24, 29))	('ZZU001', 'Var', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('vimentin', 'cellular_component', 'GO:0045098', ('80', '88'))	('epithelial to mesenchymal transition', 'CPA', (122, 158))	('vimentin', 'cellular_component', 'GO:0045099', ('199', '207'))	('tumor', 'Disease', (267, 272))
35305	32921958	This study aimed to create an immune-deficient Syrian hamster by knockout of interleukin 2 (IL-2) receptor subunit gamma (IL2RG), characterize the phenotypes of IL-2RG knockout (KO) Syrian hamsters, and evaluate whether this animal can present the distinguishing features of human PC.	('Syrian hamster', 'Species', '10036', (47, 61))	('IL-2RG', 'Gene', (161, 167))	('IL-2', 'molecular_function', 'GO:0005134', ('161', '165'))	('human', 'Species', '9606', (275, 280))	('Syrian hamster', 'Species', '10036', (182, 196))	('Syrian hamsters', 'Species', '10036', (182, 197))	('IL-2RG', 'Gene', '101824015', (161, 167))	('IL2', 'molecular_function', 'GO:0005134', ('122', '125'))	('IL-2', 'molecular_function', 'GO:0005134', ('92', '96'))	('knockout', 'Var', (65, 73))	('interleukin 2', 'Gene', (77, 90))	('interleukin 2', 'Gene', '101835410', (77, 90))	('IL2RG', 'Gene', (122, 127))
35313	32921958	The comparison studies on xenografting tumors in ZZU001 and severely immune-deficient mice demonstrated that ZZU001 Syrian hamsters engrafted with human tumor cells are a promising animal model, which can recapitulate most of the features of human PC, in particular, the multiple-sites of metastasis.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('human', 'Species', '9606', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('Syrian hamsters', 'Species', '10036', (116, 131))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('mice', 'Species', '10090', (86, 90))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('ZZU001', 'Var', (109, 115))	('tumor', 'Disease', (39, 44))	('human', 'Species', '9606', (242, 247))	('tumors', 'Disease', (39, 45))
35314	32921958	PC tissues derived from ZZU001 hamsters also displayed other key features of human PC, such as desmoplastic reactions in the stroma and epithelial to mesenchymal transition phenotype, whereas PC tissues derived from immune-deficient mice did not present such features.	('epithelial to mesenchymal transition phenotype', 'CPA', (136, 182))	('mice', 'Species', '10090', (233, 237))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('136', '172'))	('ZZU001', 'Var', (24, 30))	('desmoplastic reactions in the stroma', 'CPA', (95, 131))	('hamster', 'Species', '10034', (31, 38))	('human', 'Species', '9606', (77, 82))
35326	32843618	Aberrant cell cycle machinery and loss of the CDKN2A tumor suppressor locus make CDK4/6 a potential target in pancreatic ductal adenocarcinoma (PDAC).	('PDAC', 'Chemical', '-', (144, 148))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (110, 142))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('Aberrant', 'Var', (0, 8))	('CDKN2A', 'Gene', (46, 52))	('cell cycle machinery', 'CPA', (9, 29))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('CDK', 'molecular_function', 'GO:0004693', ('81', '84'))	('cell cycle', 'biological_process', 'GO:0007049', ('9', '19'))	('CDK4/6', 'Gene', (81, 87))	('CDKN2A', 'Gene', '1029', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Aberrant cell cycle', 'Phenotype', 'HP:0011018', (0, 19))	('tumor', 'Disease', (53, 58))	('loss', 'NegReg', (34, 38))	('pancreatic ductal adenocarcinoma', 'Disease', (110, 142))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (110, 142))	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))
35332	32843618	The success in breast cancer has also yielded great insights into the mechanisms by which tumors evade the cellular homeostasis through the genetic loss or epigenetic silencing of tumor suppressor, which encodes an endogenous inhibitor of CDK4/6 (p16INK4a) to mediate cell cycle progression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('CDK', 'molecular_function', 'GO:0004693', ('239', '242'))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('cellular homeostasis', 'biological_process', 'GO:0019725', ('107', '127'))	('breast cancer', 'Disease', (15, 28))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('genetic loss', 'Disease', 'MESH:D030342', (140, 152))	('evade', 'NegReg', (97, 102))	('tumor', 'Disease', (90, 95))	('epigenetic silencing', 'Var', (156, 176))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('180', '196'))	('cellular homeostasis', 'MPA', (107, 127))	('cell cycle', 'biological_process', 'GO:0007049', ('268', '278'))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor suppressor', 'biological_process', 'GO:0051726', ('180', '196'))	('p16INK4a', 'Gene', (247, 255))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('genetic loss', 'Disease', (140, 152))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (180, 185))	('tumors', 'Disease', (90, 96))	('p16INK4a', 'Gene', '1029', (247, 255))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
35334	32843618	While it is reasonable to consider using CDK4/6i beyond breast cancer, it turns out to be challenging because of (i) unsatisfactory efficacy, (ii) drug resistance, (iii) lack of reliable biomarkers for patient selection, and (iv) toxicity.	('drug resistance', 'Phenotype', 'HP:0020174', (147, 162))	('toxicity', 'Disease', 'MESH:D064420', (230, 238))	('toxicity', 'Disease', (230, 238))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('patient', 'Species', '9606', (202, 209))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('CDK', 'molecular_function', 'GO:0004693', ('41', '44'))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('drug resistance', 'biological_process', 'GO:0009315', ('147', '162'))	('breast cancer', 'Disease', (56, 69))	('drug resistance', 'biological_process', 'GO:0042493', ('147', '162'))	('CDK4/6i', 'Var', (41, 48))
35337	32843618	These preclinical achievements serve as the basis of clinical trials in which PAL is being combined with chemotherapy (NCT02501902) and targeted therapy (e.g., mTOR inhibitor, NCT03065062; extracellular signal-regulated kinase inhibitor, NCT03454035).	('kinase inhibitor', 'biological_process', 'GO:0033673', ('220', '236'))	('mTOR', 'Gene', '2475', (160, 164))	('NCT02501902', 'Var', (119, 130))	('mTOR', 'Gene', (160, 164))	('PAL', 'Gene', '20419', (78, 81))	('extracellular', 'cellular_component', 'GO:0005576', ('189', '202'))	('PAL', 'molecular_function', 'GO:0004598', ('78', '81'))	('PAL', 'Gene', (78, 81))
35344	32843618	PAL/HCQ have been chosen given that CDK4/6i may induce cancer cell autophagy as a stress-tolerance response, evidenced by upregulation of various autophagic markers via a reactive oxygen species (ROS)-mediated mechanism.	('PAL', 'molecular_function', 'GO:0004598', ('0', '3'))	('autophagy', 'biological_process', 'GO:0006914', ('67', '76'))	('ROS', 'Chemical', 'MESH:D017382', (196, 199))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('CDK4/6i', 'Var', (36, 43))	('induce', 'PosReg', (48, 54))	('CDK', 'molecular_function', 'GO:0004693', ('36', '39'))	('autophagic markers', 'CPA', (146, 164))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (171, 194))	('stress-tolerance', 'CPA', (82, 98))	('upregulation', 'PosReg', (122, 134))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('autophagy', 'biological_process', 'GO:0016236', ('67', '76'))
35349	32843618	In addition to the effective tumor shrinkage, co-targeting CDK4/6 and autophagy results in the activation of Bcl anti-apoptotic pathway post multiple i.v.	('CDK', 'molecular_function', 'GO:0004693', ('59', '62'))	('autophagy', 'biological_process', 'GO:0006914', ('70', '79'))	('CDK4/6', 'Protein', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('autophagy', 'CPA', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('activation', 'PosReg', (95, 105))	('tumor', 'Disease', (29, 34))	('co-targeting', 'Var', (46, 58))	('Bcl anti-apoptotic pathway', 'Pathway', (109, 135))	('autophagy', 'biological_process', 'GO:0016236', ('70', '79'))
35366	32843618	The data indicated that PAL mono-treatment induced accelerated autophagy flux in PANC-1 cells without interference on autophagosome-lysosome fusion, evidenced by the presence of autolysosomes (RFP-only puncta) and near-absence of autophagosomes (both GFP and RFP puncta).	('autophagosomes', 'CPA', (230, 244))	('PAL', 'molecular_function', 'GO:0004598', ('24', '27'))	('RFP', 'Gene', '2358', (259, 262))	('PANC-1', 'Gene', '104066', (81, 87))	('lysosome', 'cellular_component', 'GO:0005764', ('132', '140'))	('autophagy', 'biological_process', 'GO:0006914', ('63', '72'))	('PAL', 'Gene', '20419', (24, 27))	('RFP', 'Gene', '2358', (193, 196))	('mono-treatment', 'Var', (28, 42))	('autophagosome', 'cellular_component', 'GO:0005776', ('118', '131'))	('PAL', 'Gene', (24, 27))	('accelerated', 'PosReg', (51, 62))	('RFP', 'Gene', (259, 262))	('autophagy flux', 'CPA', (63, 77))	('autolysosomes', 'CPA', (178, 191))	('autophagy', 'biological_process', 'GO:0016236', ('63', '72'))	('autophagosome-lysosome fusion', 'biological_process', 'GO:0061909', ('118', '147'))	('RFP', 'Gene', (193, 196))	('PANC-1', 'Gene', (81, 87))
35382	32843618	The pre-encapsulation of TEA8SOS created a pH < 5.5 inside of MSNP.	('TEA8SOS', 'Var', (25, 32))	('TEA8SOS', 'Chemical', '-', (25, 32))	('pH < 5.5 inside', 'MPA', (43, 58))	('MSNP', 'Chemical', '-', (62, 66))	('pre', 'molecular_function', 'GO:0003904', ('4', '7'))
35488	32843618	Ratiometric co-delivery of PAL/HCQ generate potent anticancer effect in subcutaneous and orthotopic PDAC models, outperforming a list of controls including free drug mixture.	('PDAC', 'Chemical', '-', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('PAL', 'molecular_function', 'GO:0004598', ('27', '30'))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('PAL/HCQ', 'Var', (27, 34))	('cancer', 'Disease', (55, 61))
35495	32843618	As a potential strategy to address the above challenges, CDK4/6i ratiometric co-delivery platform provides compartmentalized drug distribution in vivo, including the capability to maintain predetermined ratio for optimal drug synergy and toxicity reduction.	('toxicity reduction', 'Disease', (238, 256))	('CDK', 'molecular_function', 'GO:0004693', ('57', '60'))	('CDK4/6i', 'Var', (57, 64))	('toxicity reduction', 'Disease', 'MESH:D007674', (238, 256))	('compartmentalized drug distribution', 'MPA', (107, 142))
35499	32843618	Moreover, recent studies suggested that CDK4/6 inhibition may lead to augmented antitumor immunity, through activating immune surveillance and modulating tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('inhibition', 'Var', (47, 57))	('modulating', 'Reg', (143, 153))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('augmented', 'PosReg', (70, 79))	('CDK', 'molecular_function', 'GO:0004693', ('40', '43'))	('tumor', 'Disease', (84, 89))	('CDK4/6', 'Protein', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('activating', 'PosReg', (108, 118))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('immune surveillance', 'CPA', (119, 138))	('tumor', 'Disease', (154, 159))
35556	32843618	Primary antibodies included anti-phospho-Rb (1:1000, cat#8516, Cell Signaling Technology), anti-p62 (1:100, cat#ab91526, Abcam), anti-Ki67 (1:500, cat#ab15580, Abcam), anti-CC-3 (1:400, cat#9664, Cell Signaling Technology), anti-Bcl-2 (1:150, cat#ab182858, Abcam), anti-Mcl-1 (1:500, cat#ab32087, Abcam), or anti-Bcl-xL (1:500, cat#ab32370, Abcam) accordingly.	('cat', 'molecular_function', 'GO:0004096', ('147', '150'))	('phospho-Rb', 'Gene', '5925', (33, 43))	('CC-3', 'Gene', (173, 177))	('Bcl-2', 'Gene', '596', (229, 234))	('cat', 'molecular_function', 'GO:0004096', ('186', '189'))	('Bcl-xL', 'Gene', (313, 319))	('Mcl-1', 'Gene', (270, 275))	('Bcl-xL', 'Gene', '598', (313, 319))	('Signaling', 'biological_process', 'GO:0023052', ('201', '210'))	('cat', 'molecular_function', 'GO:0004096', ('53', '56'))	('phospho-Rb', 'Gene', (33, 43))	('cat#ab182858', 'Var', (243, 255))	('CC-3', 'Gene', '12367', (173, 177))	('Ki67', 'Chemical', '-', (134, 138))	('cat', 'molecular_function', 'GO:0004096', ('284', '287'))	('cat', 'molecular_function', 'GO:0004096', ('243', '246'))	('cat', 'molecular_function', 'GO:0004096', ('328', '331'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('229', '234'))	('p62', 'Gene', '8878', (96, 99))	('Signaling', 'biological_process', 'GO:0023052', ('68', '77'))	('Bcl-2', 'Gene', (229, 234))	('p62', 'Gene', (96, 99))	('Mcl-1', 'Gene', '4170', (270, 275))	('cat', 'molecular_function', 'GO:0004096', ('108', '111'))
35600	32843618	Subcutaneous PANC-1 tumor-bearing mice were randomly assigned to 4 groups, including saline, free ABT-737, co-delivery NP, and co-delivery NP + ABT-737 (n = 4).	('saline', 'Chemical', 'MESH:D012965', (85, 91))	('mice', 'Species', '10090', (34, 38))	('co-delivery', 'Var', (107, 118))	('NP + ABT-737', 'Var', (139, 151))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('PANC-1', 'Gene', '104066', (13, 19))	('ABT-737', 'Chemical', 'MESH:C501332', (144, 151))	('ABT-737', 'Chemical', 'MESH:C501332', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ABT-737', 'Gene', (98, 105))	('PANC-1', 'Gene', (13, 19))	('tumor', 'Disease', (20, 25))
35609	32843618	The slides were incubated with individual primary antibodies for 1 h including anti-phospho-Rb (1/200, cat#8516, Cell Signaling Technology), anti-Ki67 (1/100, cat#ab15580, Abcam), anti-CC-3 (1/200, cat#9664, Cell Signaling Technology), anti-Mcl-1 (1/200, cat#ab32087, Abcam), or anti-Bcl-xL (1/400, cat#ab32370, Abcam).	('cat#ab32370', 'Var', (299, 310))	('phospho-Rb', 'Gene', '5925', (84, 94))	('cat', 'molecular_function', 'GO:0004096', ('159', '162'))	('Mcl-1', 'Gene', '4170', (241, 246))	('cat', 'molecular_function', 'GO:0004096', ('198', '201'))	('Signaling', 'biological_process', 'GO:0023052', ('118', '127'))	('Bcl-xL', 'Gene', (284, 290))	('cat', 'molecular_function', 'GO:0004096', ('103', '106'))	('cat', 'molecular_function', 'GO:0004096', ('255', '258'))	('cat', 'molecular_function', 'GO:0004096', ('299', '302'))	('anti-Ki67', 'Var', (141, 150))	('Ki67', 'Chemical', '-', (146, 150))	('Mcl-1', 'Gene', (241, 246))	('Signaling', 'biological_process', 'GO:0023052', ('213', '222'))	('CC-3', 'Gene', '12367', (185, 189))	('phospho-Rb', 'Gene', (84, 94))	('Bcl-xL', 'Gene', '598', (284, 290))	('CC-3', 'Gene', (185, 189))
35626	32560530	RNAi (RNA interference)-mediated depletion of ANLN causes furrow instability in D. melanogaster S2 cells.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('depletion', 'Var', (33, 42))	('furrow instability', 'CPA', (58, 76))	('D. melanogaster', 'Species', '7227', (80, 95))	('ANLN', 'Gene', (46, 50))	('furrow', 'cellular_component', 'GO:0097610', ('58', '64'))	('causes', 'Reg', (51, 57))	('RNA interference', 'biological_process', 'GO:0016246', ('6', '22'))	('RNAi', 'biological_process', 'GO:0016246', ('0', '4'))
35627	32560530	The loss of ANLN also promotes membrane blebbing and, in cases where a relatively stable furrow forms, a loss of stability of the midbody structure that forms after furrowing in D. melanogaster.	('midbody', 'cellular_component', 'GO:0030496', ('130', '137'))	('promotes', 'PosReg', (22, 30))	('D. melanogaster', 'Species', '7227', (178, 193))	('loss', 'NegReg', (105, 109))	('stability', 'CPA', (113, 122))	('membrane', 'cellular_component', 'GO:0016020', ('31', '39'))	('furrow', 'cellular_component', 'GO:0097610', ('89', '95'))	('ANLN', 'Gene', (12, 16))	('membrane blebbing', 'CPA', (31, 48))	('membrane blebbing', 'biological_process', 'GO:0032060', ('31', '48'))	('loss', 'Var', (4, 8))
35639	32560530	ANLN was characterized as a molecule that is specifically associated with F-actin.	('F-actin', 'cellular_component', 'GO:0031941', ('74', '81'))	('F-actin', 'Gene', (74, 81))	('F-actin', 'Gene', '40444', (74, 81))	('ANLN', 'Var', (0, 4))
35641	32560530	ANLN was also described as a binding site for F-actin and amino acids 246-371 bundle actin filaments.	('binding', 'molecular_function', 'GO:0005488', ('29', '36'))	('amino acids 246-371', 'Var', (58, 77))	('F-actin', 'cellular_component', 'GO:0031941', ('46', '53'))	('binding', 'Interaction', (29, 36))	('F-actin', 'Gene', '40444', (46, 53))	('F-actin', 'Gene', (46, 53))
35648	32560530	Taken together, this suggests that ANLN could have a direct or indirect impact on actin activities both outside and inside cytokinesis events, which could be related to cancer progression.	('cancer', 'Disease', (169, 175))	('actin activities', 'MPA', (82, 98))	('ANLN', 'Var', (35, 39))	('cytokinesis', 'biological_process', 'GO:0000910', ('123', '134'))	('related', 'Reg', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('impact', 'Reg', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
35650	32560530	ANLN may indirectly impact myosin through F-actin.	('myosin', 'MPA', (27, 33))	('F-actin', 'Gene', '40444', (42, 49))	('impact', 'Reg', (20, 26))	('F-actin', 'Gene', (42, 49))	('F-actin', 'cellular_component', 'GO:0031941', ('42', '49'))	('ANLN', 'Var', (0, 4))
35661	32560530	ANLN truncation occurs in human cells without the AH domain, which was considered as a factor mediating the interaction of septins, and showed the mislocalization of the poles in the span of oscillation like the event witnessed as a lack of myosin.	('human', 'Species', '9606', (26, 31))	('ANLN truncation', 'Var', (0, 15))	('mislocalization of the poles', 'MPA', (147, 175))
35671	32560530	The half of the ANLN N-terminal of ANLN was observed not to interact with any RacGAP constructs.	('RacGAP', 'Gene', '36538', (78, 84))	('ANLN', 'Var', (35, 39))	('RacGAP', 'Gene', (78, 84))
35672	32560530	Specific RacGAP deletions to abolish Pebble or MKLP1 binding was documented without any effect on the interaction with ANLN.	('deletions', 'Var', (16, 25))	('binding', 'molecular_function', 'GO:0005488', ('53', '60'))	('MKLP1', 'Gene', (47, 52))	('RacGAP', 'Gene', (9, 15))	('Pebble', 'Gene', (37, 43))	('Pebble', 'Gene', '38879', (37, 43))	('RacGAP', 'Gene', '36538', (9, 15))	('abolish', 'NegReg', (29, 36))	('binding', 'Interaction', (53, 60))
35673	32560530	The absence of ANLN leads to a loss of connection between the spindle-associated RacGAP and the equatorial cortex and to cytokinesis failure.	('cytokinesis', 'biological_process', 'GO:0000910', ('121', '132'))	('loss', 'NegReg', (31, 35))	('spindle', 'cellular_component', 'GO:0005819', ('62', '69'))	('RacGAP', 'Gene', (81, 87))	('cytokinesis failure', 'Disease', (121, 140))	('cytokinesis failure', 'Disease', 'MESH:D006333', (121, 140))	('absence', 'Var', (4, 11))	('ANLN', 'Gene', (15, 19))	('RacGAP', 'Gene', '36538', (81, 87))	('connection', 'Interaction', (39, 49))
35675	32560530	This was also underpinned by the evidence of phosphomimetic-mutant S635D, the negative charge of D at the 635 residues which partially recovered the localization.	('S635D', 'Var', (67, 72))	('negative charge', 'MPA', (78, 93))	('S635D', 'Mutation', 'p.S635D', (67, 72))	('localization', 'MPA', (149, 161))	('localization', 'biological_process', 'GO:0051179', ('149', '161'))
35676	32560530	S635 phosphorylation helps ANLN improve the efficacy of the Rho integration with its upstream and downstream regulators, which contributes to the success of cytokinesis.	('reg', 'Gene', (109, 112))	('Rho', 'Protein', (60, 63))	('efficacy', 'MPA', (44, 52))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('cytokinesis', 'biological_process', 'GO:0000910', ('157', '168'))	('phosphorylation', 'Var', (5, 20))	('S635 phosphorylation', 'Var', (0, 20))	('improve', 'PosReg', (32, 39))	('reg', 'Gene', '5967', (109, 112))
35696	32560530	The observations have suggested that ANLN acts as the intrinsic connection between PI3K/PTEN and KDR signaling, which represents two critical transitions in carcinogenesis.	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('KDR', 'Gene', (97, 100))	('PTEN', 'Gene', (88, 92))	('ANLN', 'Var', (37, 41))	('PTEN', 'Gene', '5728', (88, 92))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('KDR', 'Gene', '3791', (97, 100))
35697	32560530	The interaction between ANLN and KDR could act as ANLN and KDR jointly as a prognostic in cancer survival, which could be applied to control triple negative breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('KDR', 'Gene', (59, 62))	('interaction', 'Interaction', (4, 15))	('KDR', 'Gene', '3791', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ANLN', 'Var', (50, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('KDR', 'Gene', (33, 36))	('KDR', 'Gene', '3791', (59, 62))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
35706	32560530	TAF10 inactivation in liver tissue was observed to dissociate TFIID complexes individually, but genes affected by TAF10 inactivation were less than 5% of the active genes.	('TFIID', 'Gene', '6908', (62, 67))	('inactivation', 'Var', (120, 132))	('TFIID', 'Gene', (62, 67))
35708	32560530	Loss of function mutations decrease the repair of DNA double-strand breaks and thereby increases the mutation frequency and the risk of cancer.	('mutation', 'CPA', (101, 109))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('increases', 'PosReg', (87, 96))	('decrease', 'NegReg', (27, 35))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('Loss of function', 'NegReg', (0, 16))	('cancer', 'Disease', (136, 142))	('repair', 'MPA', (40, 46))	('mutations', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
35710	32560530	The BRCA1 mutation is found in breast cancer in young women, which is a triple negative breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('BRCA1', 'Gene', (4, 9))	('women', 'Species', '9606', (54, 59))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('mutation', 'Var', (10, 18))	('breast cancer', 'Disease', (31, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('BRCA1', 'Gene', '672', (4, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
35712	32560530	Therefore, there is a possibility that ANLN modulates DNA repair by interacting with BRCA1 in the nucleus.	('DNA repair', 'MPA', (54, 64))	('modulates', 'Reg', (44, 53))	('DNA repair', 'biological_process', 'GO:0006281', ('54', '64'))	('BRCA1', 'Gene', (85, 90))	('interacting', 'Interaction', (68, 79))	('ANLN', 'Var', (39, 43))	('nucleus', 'cellular_component', 'GO:0005634', ('98', '105'))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('BRCA1', 'Gene', '672', (85, 90))
35718	32560530	Onset of cytokinesis (metaphase): When nuclear envelopes are broken down, ANLN moves from the nuclei to peripheral stress fibers in mammalian cells, at which ANLN might mediate these fibers' disassembly and increase the round cortex of Drosophila cells.	('broken down', 'Phenotype', 'HP:0001061', (61, 72))	('Drosophila', 'Species', '7227', (236, 246))	('increase', 'PosReg', (207, 215))	('mammalian', 'Species', '9606', (132, 141))	('metaphase', 'biological_process', 'GO:0051323', ('22', '31'))	('cytokinesis', 'biological_process', 'GO:0000910', ('9', '20'))	('ANLN', 'Var', (158, 162))	('round cortex of Drosophila cells', 'CPA', (220, 252))
35720	32560530	ANLN depletion leads to a mislocalization of F-actin, like myosin, out of the equator in Drosophila spermatocytes, which could lead to a failure in cytokinesis.	('depletion', 'Var', (5, 14))	('mislocalization', 'MPA', (26, 41))	('F-actin', 'cellular_component', 'GO:0031941', ('45', '52'))	('ANLN depletion', 'Var', (0, 14))	('Drosophila', 'Species', '7227', (89, 99))	('cytokinesis', 'biological_process', 'GO:0000910', ('148', '159'))	('cytokinesis', 'MPA', (148, 159))	('lead to', 'Reg', (127, 134))	('F-actin', 'Gene', (45, 52))	('failure', 'NegReg', (137, 144))	('F-actin', 'Gene', '40444', (45, 52))
35721	32560530	In C. elegans, ANLN (ANI-1) is associated with an asymmetry of the division plane, which plays an important role in the perturbations of contractility during cytokinesis.	('ANI-1', 'Gene', (21, 26))	('cytokinesis', 'biological_process', 'GO:0000910', ('158', '169'))	('C. elegans', 'Species', '6239', (3, 13))	('ANI-1', 'Gene', '176672', (21, 26))	('ANLN', 'Var', (15, 19))	('asymmetry of the division plane', 'CPA', (50, 81))	('associated', 'Reg', (31, 41))
35722	32560530	Metazoan ANLN coordinates contractile ring assembly and organization by crosslinking with myosin septins and F-actin in the actin-myosin ring.	('F-actin', 'Gene', '40444', (109, 116))	('F-actin', 'Gene', (109, 116))	('actin-myosin ring', 'Phenotype', 'HP:0025200', (124, 141))	('contractile ring assembly', 'biological_process', 'GO:0000915', ('26', '51'))	('F-actin', 'cellular_component', 'GO:0031941', ('109', '116'))	('crosslinking', 'Var', (72, 84))	('myosin septins', 'Protein', (90, 104))	('contractile ring', 'cellular_component', 'GO:0070938', ('26', '42'))
35723	32560530	Although actin-myosin contractility still happens in both human and Drosophila cultured cells that have been depleted of ANLN, the depletion of ANLN leads to the lateral oscillation of cleavage furrow, or its failure cannot accurately maintain at the division plane.	('lateral oscillation', 'CPA', (162, 181))	('human', 'Species', '9606', (58, 63))	('ANLN', 'Gene', (144, 148))	('Drosophila', 'Species', '7227', (68, 78))	('cleavage furrow', 'cellular_component', 'GO:0032154', ('185', '200'))	('depletion', 'Var', (131, 140))	('leads to', 'Reg', (149, 157))	('cleavage furrow', 'CPA', (185, 200))
35724	32560530	The knockdown of ANLN in human cells and Drosophila ANLN mutants caused slow and abortive furrowing as well as slow ingression.	('slow ingression', 'CPA', (111, 126))	('human', 'Species', '9606', (25, 30))	('ANLN', 'Gene', (52, 56))	('Drosophila', 'Species', '7227', (41, 51))	('mutants', 'Var', (57, 64))
35746	32560530	Evidence has shown an association between poor tumour prognosis and highly expressed ANLN in the nucleus.	('highly', 'Var', (68, 74))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('nucleus', 'cellular_component', 'GO:0005634', ('97', '104'))	('tumour', 'Disease', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
35760	32560530	For example, mutations in the ANLN gene cause kidney disease and focal segmental glomerulosclerosis, which indicate a defect in podosomal matrix adhesions.	('kidney disease', 'Phenotype', 'HP:0000112', (46, 60))	('ANLN', 'Gene', (30, 34))	('cause', 'Reg', (40, 45))	('focal segmental glomerulosclerosis', 'Disease', 'MESH:D005923', (65, 99))	('focal segmental glomerulosclerosis', 'Phenotype', 'HP:0000097', (65, 99))	('kidney disease', 'Disease', (46, 60))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (81, 99))	('mutations', 'Var', (13, 22))	('focal segmental glomerulosclerosis', 'Disease', (65, 99))	('kidney disease', 'Disease', 'MESH:D007674', (46, 60))
35762	32560530	ANLN knockdown results in abnormal adherens junctions and tight junctions in Xenopus embryos.	('adherens', 'MPA', (35, 43))	('ANLN', 'Gene', (0, 4))	('results in', 'Reg', (15, 25))	('knockdown', 'Var', (5, 14))	('tight junctions', 'CPA', (58, 73))	('Xenopus', 'Species', '8355', (77, 84))
35767	32560530	Indeed, the overexpression of ANLN in the colon cancer cell lines SW480 and HT29 actually increased cell migration and invasion, which seems to be partly related to a decrease in the expression of E-cadherin.	('cell migration', 'biological_process', 'GO:0016477', ('100', '114'))	('E-cadherin', 'Gene', (197, 207))	('cell migration', 'CPA', (100, 114))	('E-cadherin', 'Gene', '37386', (197, 207))	('colon cancer', 'Phenotype', 'HP:0003003', (42, 54))	('overexpression', 'PosReg', (12, 26))	('HT29', 'CellLine', 'CVCL:0320', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cadherin', 'molecular_function', 'GO:0008014', ('199', '207'))	('colon cancer', 'Disease', 'MESH:D015179', (42, 54))	('expression', 'MPA', (183, 193))	('ANLN', 'Var', (30, 34))	('invasion', 'CPA', (119, 127))	('increased', 'PosReg', (90, 99))	('SW480', 'CellLine', 'CVCL:0546', (66, 71))	('colon cancer', 'Disease', (42, 54))	('decrease', 'NegReg', (167, 175))	('expression', 'Species', '29278', (183, 193))	('expression', 'Species', '29278', (16, 26))
35776	32560530	Hence, we highlight the hallmarks of cancer that are impacted by ANLN (Figure 5) and discuss them as follows.	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('ANLN', 'Var', (65, 69))
35777	32560530	There is evidence showing that ANLN plays a critical role in driving cell proliferation, and the absence of ANLN could hinder cancer cells from division.	('hinder', 'NegReg', (119, 125))	('absence', 'Var', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('ANLN', 'Gene', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cell proliferation', 'CPA', (69, 87))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))
35779	32560530	The analysis with flow cytometry indicated that ANLN knockdown in MDA-MB-231 cells inhibited the cell cycle progression, with an increasing amount of cells stuck at the G2/M phase because of phosphorylation of Cdc2 and an inhibition of Cyclin D1.	('Cyclin', 'molecular_function', 'GO:0016538', ('236', '242'))	('M phase', 'biological_process', 'GO:0000279', ('172', '179'))	('phosphorylation', 'biological_process', 'GO:0016310', ('191', '206'))	('increasing', 'PosReg', (129, 139))	('inhibition', 'NegReg', (222, 232))	('cell cycle progression', 'CPA', (97, 119))	('Cdc2', 'Gene', (210, 214))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (66, 76))	('Cyclin D1', 'Gene', '595', (236, 245))	('cell cycle', 'biological_process', 'GO:0007049', ('97', '107'))	('inhibited', 'NegReg', (83, 92))	('Cyclin D1', 'Gene', (236, 245))	('ANLN knockdown', 'Var', (48, 62))	('Cdc2', 'Gene', '983', (210, 214))	('phosphorylation', 'MPA', (191, 206))
35782	32560530	ANLN deletion led to an increase in polyploidy cells along with the activation of apoptosis and DNA damage.	('increase', 'PosReg', (24, 32))	('activation of apoptosis', 'biological_process', 'GO:0006915', ('68', '91'))	('apoptosis', 'CPA', (82, 91))	('activation', 'PosReg', (68, 78))	('DNA damage', 'CPA', (96, 106))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('activation of apoptosis', 'biological_process', 'GO:0043065', ('68', '91'))	('polyploidy', 'Disease', (36, 46))	('ANLN deletion', 'Var', (0, 13))	('polyploidy', 'Disease', 'MESH:D011123', (36, 46))
35783	32560530	In pancreatic cancer, ANLN deficiency led to the expression of miR218-5p while mir-218 caused the apoptosis of pancreatic cancer cells.	('pancreatic cancer', 'Disease', (3, 20))	('apoptosis', 'CPA', (98, 107))	('expression', 'Species', '29278', (49, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (111, 128))	('expression', 'MPA', (49, 59))	('mir-218', 'Var', (79, 86))	('caused', 'Reg', (87, 93))	('pancreatic cancer', 'Disease', (111, 128))	('miR218-5p', 'Var', (63, 72))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (111, 128))	('ANLN deficiency', 'Disease', (22, 37))	('ANLN deficiency', 'Disease', 'MESH:D007153', (22, 37))
35784	32560530	ANLN was known to be involved in PI3K/PTEN signaling.	('PTEN', 'Gene', '5728', (38, 42))	('PTEN', 'Gene', (38, 42))	('signaling', 'biological_process', 'GO:0023052', ('43', '52'))	('ANLN', 'Var', (0, 4))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))
35793	32560530	In addition, the incidence of metastasis in patients with a high ANLN expression was substantially higher than that in patients with low expression.	('patients', 'Species', '9606', (44, 52))	('ANLN', 'Protein', (65, 69))	('higher', 'PosReg', (99, 105))	('high', 'Var', (60, 64))	('patients', 'Species', '9606', (119, 127))	('expression', 'Species', '29278', (70, 80))	('metastasis', 'CPA', (30, 40))	('expression', 'Species', '29278', (137, 147))
35809	32560530	The deficiency of ANLN in U2OS cells progressively induced an increase in the number and intensity of 53BP1 foci in G1 nuclei, a phenomenon that could act as a marker for an increased number of DNA damage events.	('53BP1', 'Gene', (102, 107))	('DNA', 'cellular_component', 'GO:0005574', ('194', '197'))	('ANLN', 'Gene', (18, 22))	('deficiency', 'Var', (4, 14))	('U2OS', 'CellLine', 'CVCL:0042', (26, 30))	('increase', 'PosReg', (62, 70))
35810	32560530	ANLN interacts with BRCA1, so aberrant ANLN expression might affect genome instability and mutation.	('BRCA1', 'Gene', (20, 25))	('aberrant', 'Var', (30, 38))	('mutation', 'CPA', (91, 99))	('genome instability', 'CPA', (68, 86))	('affect', 'Reg', (61, 67))	('expression', 'Species', '29278', (44, 54))	('BRCA1', 'Gene', '672', (20, 25))	('ANLN', 'Gene', (39, 43))
35812	32560530	ANLN knockdown was documented to induce polyploid hepatocytes, which induce an upregulation of the genes controlling lipid metabolism and a downregulation of the genes controlling mitochondrial oxidation.	('genes', 'MPA', (99, 104))	('ANLN', 'Gene', (0, 4))	('lipid metabolism', 'biological_process', 'GO:0006629', ('117', '133'))	('knockdown', 'Var', (5, 14))	('reg', 'Gene', (144, 147))	('reg', 'Gene', '5967', (144, 147))	('lipid', 'Chemical', 'MESH:D008055', (117, 122))	('mitochondrial oxidation', 'MPA', (180, 203))	('lipid metabolism', 'MPA', (117, 133))	('reg', 'Gene', (81, 84))	('reg', 'Gene', '5967', (81, 84))	('induce', 'Reg', (33, 39))
35827	32560530	In a study on Dalmatian dogs, the loss of ANLN caused a familial fatal acute respiratory distress syndrome, which is a disease where inflammatory mediators such as IL-8, IL-6 are suggested as the potential culprits.	('acute respiratory distress syndrome', 'Phenotype', 'HP:0011948', (71, 106))	('loss', 'Var', (34, 38))	('IL-8', 'molecular_function', 'GO:0005153', ('164', '168'))	('familial fatal acute respiratory distress syndrome', 'Disease', (56, 106))	('ANLN', 'Gene', (42, 46))	('dogs', 'Species', '9615', (24, 28))	('IL-6', 'Gene', '403985', (170, 174))	('IL-8', 'Gene', (164, 168))	('familial fatal acute respiratory distress syndrome', 'Disease', 'MESH:D012128', (56, 106))	('respiratory distress', 'Phenotype', 'HP:0002098', (77, 97))	('caused', 'Reg', (47, 53))	('IL-8', 'Gene', '403850', (164, 168))	('IL-6', 'molecular_function', 'GO:0005138', ('170', '174'))	('IL-6', 'Gene', (170, 174))
35838	32560530	Another study also suggests a critical role in the immune response through a synergy between ANLN and KDR, which have prognostic value in breast cancer survival.	('synergy', 'Var', (77, 84))	('KDR', 'Gene', '3791', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('ANLN', 'Gene', (93, 97))	('immune response', 'biological_process', 'GO:0006955', ('51', '66'))	('breast cancer', 'Disease', (138, 151))	('KDR', 'Gene', (102, 105))
35843	32560530	ANLN facilitates septin assembly to prevent pathological outfoldings of central nervous system myelin.	('central nervous system myelin', 'Disease', 'MESH:D020278', (72, 101))	('central nervous system myelin', 'Disease', (72, 101))	('septin', 'Protein', (17, 23))	('facilitates', 'PosReg', (5, 16))	('ANLN', 'Var', (0, 4))
35861	32560530	In other research, there is evidence showing that ANLN is also related to metastasis in lung adenocarcinoma (A549, PC9).	('ANLN', 'Var', (50, 54))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('PC9', 'Gene', '255738', (115, 118))	('metastasis', 'CPA', (74, 84))	('lung adenocarcinoma', 'Disease', (88, 107))	('PC9', 'Gene', (115, 118))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('related', 'Reg', (63, 70))
35864	32560530	The Cancer Genome Atlas data analysis revealed 27 mutations in 446 patients with lung adenocarcinoma, with five mutations affecting the conserved amino acids of ANLN.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('patients', 'Species', '9606', (67, 75))	('mutations', 'Var', (50, 59))	('lung adenocarcinoma', 'Disease', (81, 100))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
35868	32560530	Based on the analysis of colorectal cancer tissues, ANLN is supposed to be associated with colorectal cancer development and with a poor prognosis.	('associated with', 'Reg', (75, 90))	('ANLN', 'Var', (52, 56))	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (25, 42))	('colorectal cancer', 'Disease', (25, 42))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (25, 42))
35870	32560530	An integrated bioinformatics analysis showed that ANLN could play a role as a key candidate in cervical cancer.	('ANLN', 'Var', (50, 54))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
35876	32560530	However, some studies have shown that both total ANLN and p-ANLN expression decreased by LY294002 (Sigma-Aldrich; 20 mumol/L for 16 h), a specific inhibitor of the catalytic subunit of PI3K, which is directed at the ATP-binding site of the kinase.	('ANLN', 'MPA', (49, 53))	('LY294002', 'Var', (89, 97))	('PI3K', 'molecular_function', 'GO:0016303', ('185', '189'))	('ATP-binding', 'molecular_function', 'GO:0005524', ('216', '227'))	('p-ANLN expression', 'MPA', (58, 75))	('expression', 'Species', '29278', (65, 75))	('decreased', 'NegReg', (76, 85))	('LY294002', 'Chemical', 'MESH:C085911', (89, 97))	('ATP', 'Chemical', 'MESH:D000255', (216, 219))
35885	32560530	The mechanism of the cytotoxicity of 5-FU has been depicted to cause the misincorporation of fluoronucleotides in RNA and DNA, and the suppression of the nucleotide synthetic enzyme thymidylate synthase.	('5-FU', 'Chemical', 'MESH:D005472', (37, 41))	('misincorporation of fluoronucleotides', 'MPA', (73, 110))	('cytotoxicity', 'Disease', (21, 33))	('thymidylate synthase', 'Gene', (182, 202))	('RNA', 'cellular_component', 'GO:0005562', ('114', '117'))	('suppression', 'NegReg', (135, 146))	('thymidylate synthase', 'Gene', '7298', (182, 202))	('5-FU', 'Var', (37, 41))	('cytotoxicity', 'Disease', 'MESH:D064420', (21, 33))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))	('fluoronucleotides', 'Chemical', '-', (93, 110))
35892	32560530	In support of this idea, there has been a recent report that ANLN knockdown lowers the incidence of liver cancer but does not affect liver regeneration.	('reg', 'Gene', (139, 142))	('ANLN knockdown', 'Var', (61, 75))	('liver cancer', 'Phenotype', 'HP:0002896', (100, 112))	('liver cancer', 'Disease', 'MESH:D006528', (100, 112))	('lowers', 'NegReg', (76, 82))	('liver regeneration', 'biological_process', 'GO:0097421', ('133', '151'))	('liver cancer', 'Disease', (100, 112))	('knockdown', 'Var', (66, 75))	('reg', 'Gene', '5967', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
35908	31292535	Site-specific trends towards enrichment of MYC amplification in liver lesions, STK11 mutations in lung lesions and ATM and ARID2 mutations in abdominal lesions were seen, but were not statistically significant after false-discovery rate correction.	('ATM', 'Gene', (115, 118))	('lung lesions', 'Disease', (98, 110))	('ARID2', 'Gene', (123, 128))	('liver lesions', 'Disease', (64, 77))	('STK11', 'Gene', '6794', (79, 84))	('MYC', 'Gene', '4609', (43, 46))	('STK11', 'Gene', (79, 84))	('ATM', 'Gene', '472', (115, 118))	('false', 'biological_process', 'GO:0071878', ('216', '221'))	('STK11', 'molecular_function', 'GO:0033868', ('79', '84'))	('mutations', 'Var', (85, 94))	('ARID2', 'Gene', '196528', (123, 128))	('MYC', 'Gene', (43, 46))	('liver lesions', 'Disease', 'MESH:D017093', (64, 77))	('false', 'biological_process', 'GO:0071877', ('216', '221'))
35921	31292535	These mutations allow for a survival and growth advantage to pancreatic cancer, as demonstrated by invasive and metastatic phenotypes that are resistant to conventional treatment strategies.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('survival', 'CPA', (28, 36))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('growth advantage', 'CPA', (41, 57))	('mutations', 'Var', (6, 15))	('pancreatic cancer', 'Disease', (61, 78))
35936	31292535	The majority of tumour tissue samples (689, 97%) were sent to Foundation Medicine (Cambridge, MA) for NGS testing of cancer-related mutations.	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Disease', (16, 22))	('mutations', 'Var', (132, 141))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Disease', (117, 123))
35948	31292535	Summaries of molecular alterations (e.g., pathogenic variants, amplifications, copy-number deletions and oncogenic fusions) for individual genes were performed across patient cohorts based on the PDAC tumour site that was biopsied and tested.	('tumour', 'Disease', (201, 207))	('patient', 'Species', '9606', (167, 174))	('PDAC', 'Phenotype', 'HP:0006725', (196, 200))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('tumour', 'Disease', 'MESH:D009369', (201, 207))	('variants', 'Var', (53, 61))	('PDAC', 'Chemical', '-', (196, 200))
35960	31292535	There were several genes with modestly higher frequencies in metastatic lesions prior to multiple testing correction: MYC (more frequent in metastatic lesions, unadjusted p-value = 0.005), a cell cycle regulator whose amplification is associated with poor prognosis in pancreatic cancer, and LRP1B (more frequent in metastatic lesions, unadjusted p-value = 0.025), a tumour suppressor involved in lipid processing (Fig.	('LRP1B', 'Gene', '53353', (292, 297))	('tumour', 'Phenotype', 'HP:0002664', (367, 373))	('tumour', 'Disease', 'MESH:D009369', (367, 373))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('191', '211'))	('amplification', 'Var', (218, 231))	('pancreatic cancer', 'Disease', (269, 286))	('MYC', 'Gene', (118, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (269, 286))	('LRP1B', 'Gene', (292, 297))	('tumour', 'Disease', (367, 373))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('lipid', 'Chemical', 'MESH:D008055', (397, 402))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('191', '211'))	('metastatic', 'Disease', (316, 326))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (269, 286))	('MYC', 'Gene', '4609', (118, 121))
35965	31292535	3) included STK11, a negative regulator of mTOR signalling via AMPK, which was mutated at a higher frequency in lung lesions (unadjusted p-value = 0.0097).	('lung lesions', 'Disease', (112, 124))	('mutated', 'Var', (79, 86))	('AMPK', 'molecular_function', 'GO:0004691', ('63', '67'))	('STK11', 'Gene', '6794', (12, 17))	('STK11', 'molecular_function', 'GO:0033868', ('12', '17'))	('AMPK', 'Gene', '5562', (63, 67))	('AMPK', 'molecular_function', 'GO:0050405', ('63', '67'))	('mTOR', 'Gene', (43, 47))	('mTOR', 'Gene', '2475', (43, 47))	('STK11', 'Gene', (12, 17))	('AMPK', 'Gene', (63, 67))	('AMPK', 'molecular_function', 'GO:0047322', ('63', '67'))	('signalling', 'biological_process', 'GO:0023052', ('48', '58'))
35970	31292535	The majority of the proteins analysed occurred with similar frequencies across site-specific mutations, with the exception of increased TUBB3 and decreased PTEN expression in the liver compared with the lung (FDR-adjusted q-value < 0.1).	('mutations', 'Var', (93, 102))	('PTEN', 'Gene', (156, 160))	('expression', 'MPA', (161, 171))	('PTEN', 'Gene', '5728', (156, 160))	('decreased', 'NegReg', (146, 155))	('TUBB3', 'Gene', (136, 141))	('increased', 'PosReg', (126, 135))	('TUBB3', 'Gene', '10381', (136, 141))
35981	31292535	Actionability was defined if there was literature supporting clinical evidence of a high response rate in patients with that molecular abnormality in any cancer or a possible implication of response to therapy based on the underlying mechanism.	('nab', 'Chemical', '-', (5, 8))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('patients', 'Species', '9606', (106, 114))	('abnormality', 'Var', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
35984	31292535	In colorectal cancer, analysis of metastatic deposits revealed differences in specific mutations and protein expression, suggesting a molecular or pathway-driven treatment approach in place of, or in addition to, standard chemotherapy.	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('protein', 'Protein', (101, 108))	('colorectal cancer', 'Disease', (3, 20))	('differences', 'Reg', (63, 74))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('mutations', 'Var', (87, 96))
35988	31292535	applied whole-genome sequencing to multiple metastatic lesions from four pancreatic cancer patients and found the same driver gene mutations in every lesion.	('mutations', 'Var', (131, 140))	('patients', 'Species', '9606', (91, 99))	('pancreatic cancer', 'Disease', (73, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))
35993	31292535	This work extends previous studies by directly comparing actionable molecular mutations in both primary tumour and metastasis-derived tissues that indicate potential therapeutic intervention.	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('mutations', 'Var', (78, 87))	('nab', 'Chemical', '-', (62, 65))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('tumour', 'Disease', (104, 110))
36008	30955884	In particular, the nuclear hormone receptor RORgamma, known to drive inflammation and T-cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth, and a marked improvement in survival.	('defect', 'NegReg', (226, 232))	('T-cell differentiation', 'biological_process', 'GO:0030217', ('86', '108'))	('pancreatic cancer', 'Disease', (133, 150))	('inflammation', 'biological_process', 'GO:0006954', ('69', '81'))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('T-cell differentiation', 'CPA', (86, 108))	('RORgamma', 'Gene', '19885', (44, 52))	('pancreatic cancer', 'Disease', 'MESH:D010190', (236, 253))	('improvement', 'PosReg', (275, 286))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('nuclear hormone receptor', 'molecular_function', 'GO:0004879', ('19', '43'))	('inflammation', 'Disease', (69, 81))	('pancreatic cancer', 'Disease', (236, 253))	('survival', 'CPA', (290, 298))	('upregulated', 'PosReg', (114, 125))	('RORgamma', 'Gene', (44, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (133, 150))	('inhibition', 'Var', (197, 207))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (236, 253))	('pancreatic cancer', 'Disease', 'MESH:D010190', (133, 150))	('inflammation', 'Disease', 'MESH:D007249', (69, 81))
36022	30955884	RORgamma expression increased with progression, and its blockade via genetic or pharmacologic approaches depleted the cancer stem cell pool and profoundly inhibited human and mouse tumor propagation, in part by suppressing a super-enhancer (SE) associated oncogenic network.	('oncogenic network', 'Pathway', (256, 273))	('increased', 'PosReg', (20, 29))	('cancer', 'Disease', (118, 124))	('suppressing', 'NegReg', (211, 222))	('tumor', 'Disease', (181, 186))	('super-enhancer', 'Pathway', (225, 239))	('RORgamma', 'Gene', '19885', (0, 8))	('human', 'Species', '9606', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('RORgamma', 'Gene', (0, 8))	('expression', 'MPA', (9, 19))	('inhibited', 'NegReg', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('blockade', 'Var', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mouse', 'Species', '10090', (175, 180))	('depleted', 'NegReg', (105, 113))
36049	30955884	Among this set, inhibition of Celsr1, Celsr2 (Figure S3C-D), and Pear1/Jedi (Figure S3E) triggered apoptosis, depleted Msi+ stem cells and potently blocked cancer propagation in vitro and in vivo (Figures 3G-J, S3F-J, Table S4).	('Jedi', 'Gene', (71, 75))	('Celsr2', 'Gene', (38, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('blocked', 'NegReg', (148, 155))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('Celsr1', 'Gene', '12614', (30, 36))	('Jedi', 'Gene', '73182', (71, 75))	('Msi', 'Disease', 'None', (119, 122))	('Celsr2', 'Gene', '53883', (38, 44))	('inhibition', 'Var', (16, 26))	('apoptosis', 'CPA', (99, 108))	('Pear1', 'Gene', '73182', (65, 70))	('Pear1', 'Gene', (65, 70))	('cancer', 'Disease', (156, 162))	('Celsr1', 'Gene', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Msi', 'Disease', (119, 122))	('depleted', 'NegReg', (110, 118))
36053	30955884	Consistent with expression in stem cells, inhibition of IL10Rbeta and CSF1R led to a marked loss of sphere forming capacity and reduced stem cells (Figure 3M, N, S3N-O) in vitro and impaired tumor growth and propagation in vivo (Figure 3O-Q, Figure S3P-Q).	('IL10Rbeta', 'Gene', (56, 65))	('reduced', 'NegReg', (128, 135))	('impaired tumor growth', 'Disease', 'MESH:D006130', (182, 203))	('sphere forming capacity', 'CPA', (100, 123))	('CSF1R', 'Gene', '12978', (70, 75))	('inhibition', 'Var', (42, 52))	('CSF1', 'molecular_function', 'GO:0005011', ('70', '74'))	('loss', 'NegReg', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('IL10', 'molecular_function', 'GO:0005141', ('56', '60'))	('IL10Rbeta', 'Gene', '16154', (56, 65))	('impaired tumor growth', 'Disease', (182, 203))	('stem cells', 'CPA', (136, 146))	('CSF1R', 'Gene', (70, 75))
36065	30955884	Interestingly RORgamma levels decreased with inhibition of IL1R signaling suggesting that the upstream regulators of RORgamma in pancreatic cancer and in Th17 cells may be shared (Figure S4G).	('IL1R', 'molecular_function', 'GO:0004908', ('59', '63'))	('IL1R', 'Protein', (59, 63))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('RORgamma', 'Gene', '19885', (117, 125))	('RORgamma', 'Gene', '19885', (14, 22))	('signaling', 'biological_process', 'GO:0023052', ('64', '73'))	('inhibition', 'Var', (45, 55))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('RORgamma', 'Gene', (14, 22))	('pancreatic cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('RORgamma', 'Gene', (117, 125))	('decreased', 'NegReg', (30, 39))
36070	30955884	To define the transcriptional programs RORgamma controls in pancreatic cancer cells, we used a combination of ChIP-seq and RNA-seq and found that RORgamma knockdown led to extensive changes in transcriptional programs key to driving cancer growth: this included stem cell signals such as Wnt, BMP, and Fox (Figure 4J), and pro-tumorigenic signals such as Hmga2 (Figure 4K).	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('Hmga2', 'Gene', '15364', (355, 360))	('changes', 'Reg', (182, 189))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('knockdown', 'Var', (155, 164))	('cancer', 'Disease', (71, 77))	('RORgamma', 'Gene', (39, 47))	('tumor', 'Disease', (327, 332))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('pancreatic cancer', 'Disease', (60, 77))	('RORgamma', 'Gene', '19885', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Wnt', 'Gene', '22408;89780;22422', (288, 291))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('Wnt', 'Gene', (288, 291))	('Hmga2', 'Gene', (355, 360))	('RORgamma', 'Gene', (146, 154))	('transcriptional programs', 'MPA', (193, 217))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('cancer', 'Disease', (233, 239))	('RNA', 'cellular_component', 'GO:0005562', ('123', '126'))	('RORgamma', 'Gene', '19885', (39, 47))
36074	30955884	Mechanistically, loss of RORgamma did not markedly impact the stem cell SE landscape in two independent KPf/fC derived lines (Figure S4K-M), suggesting that it may instead bind a preexisting landscape to preferentially impact transcriptional changes.	('bind', 'Interaction', (172, 176))	('RORgamma', 'Gene', '19885', (25, 33))	('preferentially', 'PosReg', (204, 218))	('impact', 'Reg', (51, 57))	('transcriptional changes', 'MPA', (226, 249))	('RORgamma', 'Gene', (25, 33))	('impact', 'Reg', (219, 225))	('stem cell SE landscape', 'CPA', (62, 84))	('loss', 'Var', (17, 21))
36078	30955884	To assess the impact of the inhibitor in vivo, SR2211 was delivered, either alone or in combination with gemcitabine, into immunocompetent KPf/fC derived tumor bearing mice (Figures 5E, S5A).	('SR2211', 'Chemical', 'MESH:C575715', (47, 53))	('SR2211', 'Var', (47, 53))	('S5A', 'Mutation', 'rs1280426695', (186, 189))	('mice', 'Species', '10090', (168, 172))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('gemcitabine', 'Chemical', 'MESH:C056507', (105, 116))	('tumor', 'Disease', (154, 159))
36079	30955884	SR2211 significantly reduced tumor growth as a single agent (Figures 5F-G); further, while gemcitabine alone had no impact on the stem cell burden, SR2211 triggered a 3-fold depletion in CD133+ and Msi+ cells, and an 11-fold depletion of CD133+ and 6 fold depletion of Msi2+ cells in combination with gemcitabine (Figure 5H, I).	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('Msi', 'Disease', (198, 201))	('SR2211', 'Chemical', 'MESH:C575715', (0, 6))	('CD133', 'Gene', '19126', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('CD133', 'Gene', (238, 243))	('gemcitabine', 'Chemical', 'MESH:C056507', (301, 312))	('SR2211', 'Chemical', 'MESH:C575715', (148, 154))	('Msi', 'Disease', 'None', (269, 272))	('Msi', 'Disease', 'None', (198, 201))	('depletion', 'MPA', (174, 183))	('CD133', 'Gene', '19126', (238, 243))	('Msi2', 'Gene', (269, 273))	('Msi2', 'Gene', '76626', (269, 273))	('CD133', 'Gene', (187, 192))	('tumor', 'Disease', (29, 34))	('SR2211', 'Var', (148, 154))	('depletion', 'NegReg', (225, 234))	('gemcitabine', 'Chemical', 'MESH:C056507', (91, 102))	('Msi', 'Disease', (269, 272))
36080	30955884	This suggests the exciting possibility that SR2211 can eradicate chemotherapy resistant cells (Figure 5H, I).	('SR2211', 'Chemical', 'MESH:C575715', (44, 50))	('SR2211', 'Var', (44, 50))	('chemotherapy resistant cells', 'CPA', (65, 93))	('eradicate', 'NegReg', (55, 64))
36081	30955884	Finally, to assess any impact on survival, we delivered the RORgamma inhibitor into autochthonous, tumor-bearing KPf/fC mice; while none of the vehicle-treated mice were alive 25 days after the initiation of treatment, 75% of mice that received SR2211 were still alive at this point and 50% were alive even at 45 days after treatment initiation.	('tumor', 'Disease', (99, 104))	('SR2211', 'Chemical', 'MESH:C575715', (245, 251))	('mice', 'Species', '10090', (120, 124))	('mice', 'Species', '10090', (226, 230))	('SR2211', 'Var', (245, 251))	('RORgamma', 'Gene', (60, 68))	('mice', 'Species', '10090', (160, 164))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('RORgamma', 'Gene', '19885', (60, 68))
36082	30955884	SR2211 not only doubled median survival -18 days for vehicle-treated mice and 38.5 days for SR2211-treated mice- but also led to a 6-fold reduction in the risk of death (Figure 5J, HR=0.16).	('SR2211', 'Chemical', 'MESH:C575715', (92, 98))	('SR2211-treated', 'Var', (92, 106))	('SR2211', 'Chemical', 'MESH:C575715', (0, 6))	('SR2211', 'Var', (0, 6))	('mice', 'Species', '10090', (69, 73))	('mice', 'Species', '10090', (107, 111))	('doubled', 'PosReg', (16, 23))	('death', 'Disease', 'MESH:D003643', (163, 168))	('reduction', 'NegReg', (138, 147))	('death', 'Disease', (163, 168))
36083	30955884	Hmga2, identified originally from the RNA-seq as a downstream target of RORgamma, was downregulated in pancreatic epithelial cells following SR2211 delivery in vivo, suggesting effective target engagement at mid-point during treatment, although this was less apparent in end stage tumors and may explain why treated mice ultimately succumbed to disease (Figure S5B-C).	('S5B', 'Gene', (361, 364))	('tumors', 'Disease', (281, 287))	('S5B', 'Gene', '66998', (361, 364))	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('RNA', 'cellular_component', 'GO:0005562', ('38', '41'))	('SR2211', 'Var', (141, 147))	('downregulated', 'NegReg', (86, 99))	('RORgamma', 'Gene', '19885', (72, 80))	('mice', 'Species', '10090', (316, 320))	('SR2211', 'Chemical', 'MESH:C575715', (141, 147))	('RORgamma', 'Gene', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('Hmga2', 'Gene', '15364', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('Hmga2', 'Gene', (0, 5))
36088	30955884	SR2211 led to a marked depletion of the majority of large stem cell clusters within 1 week of treatment (Figures 5K-L), with no increased necrosis observed in surrounding tissues.	('depletion', 'NegReg', (23, 32))	('necrosis', 'biological_process', 'GO:0070265', ('138', '146'))	('necrosis', 'biological_process', 'GO:0008219', ('138', '146'))	('necrosis', 'Disease', (138, 146))	('necrosis', 'biological_process', 'GO:0019835', ('138', '146'))	('necrosis', 'biological_process', 'GO:0008220', ('138', '146'))	('SR2211', 'Chemical', 'MESH:C575715', (0, 6))	('SR2211', 'Var', (0, 6))	('increased necrosis', 'Phenotype', 'HP:0010885', (128, 146))	('necrosis', 'Disease', 'MESH:D009336', (138, 146))	('necrosis', 'biological_process', 'GO:0001906', ('138', '146'))
36092	30955884	Further, in chimeric mice where wild type tumors were transplanted into either wild type or RORgamma null recipients, tumors grew equivalently (Figure 6C-D), suggesting that loss of RORgamma in only the immune cells (such as Th17) and microenvironment, has no detectable impact on tumor growth.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('RORgamma', 'Gene', '19885', (182, 190))	('mice', 'Species', '10090', (21, 25))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', (281, 286))	('RORgamma', 'Gene', '19885', (92, 100))	('loss', 'Var', (174, 178))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumors', 'Disease', (118, 124))	('RORgamma', 'Gene', (182, 190))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('RORgamma', 'Gene', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('tumor', 'Disease', (118, 123))
36098	30955884	CRISPR based disruption of RORgamma led to a ~3 to 9-fold loss of colony formation in human FG PDAC cells (Figure 7A).	('RORgamma', 'Gene', '19885', (27, 35))	('colony formation in human FG PDAC cells', 'CPA', (66, 105))	('loss', 'NegReg', (58, 62))	('formation', 'biological_process', 'GO:0009058', ('73', '82'))	('disruption', 'Var', (13, 23))	('human', 'Species', '9606', (86, 91))	('RORgamma', 'Gene', (27, 35))	('PDAC', 'Chemical', '-', (95, 99))
36100	30955884	Compared to vehicle-treatment, SR2211 delivery was highly effective and tumor growth was essentially extinguished with a nearly 6-fold reduction in growth in mice receiving SR2211 (Figure 7C).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('reduction', 'NegReg', (135, 144))	('mice', 'Species', '10090', (158, 162))	('tumor', 'Disease', (72, 77))	('SR2211', 'Chemical', 'MESH:C575715', (31, 37))	('extinguished', 'NegReg', (101, 113))	('SR2211', 'Var', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('SR2211', 'Chemical', 'MESH:C575715', (173, 179))	('growth', 'MPA', (148, 154))
36103	30955884	The dependence of human pancreatic tumors on RORgamma function are exciting in light of the fact that genomic amplification of RORC occurs in ~12% of pancreatic cancer patients (Figure 7H).	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('RORC', 'Gene', (127, 131))	('genomic amplification', 'Var', (102, 123))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('RORgamma', 'Gene', '19885', (45, 53))	('pancreatic tumors', 'Disease', (24, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('pancreatic tumors', 'Disease', 'MESH:D010190', (24, 41))	('human', 'Species', '9606', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (24, 41))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (24, 40))	('patients', 'Species', '9606', (168, 176))	('RORgamma', 'Gene', (45, 53))	('pancreatic cancer', 'Disease', (150, 167))
36115	30955884	This provides additional evidence for the epigenetic and transcriptomic link to functional dependencies in cancer stem cells, and further supports previous findings that SE-linked genes may be more important for maintaining cell identity and more sensitive to perturbation.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('epigenetic', 'Var', (42, 52))	('cancer', 'Disease', (107, 113))	('cell identity', 'CPA', (224, 237))
36126	30955884	Given that inhibitors of RORgamma are currently in Phase II trials for autoimmune diseases , our findings suggest that repositioning these agents as pancreatic cancer therapies warrants further investigation.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (149, 166))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (71, 90))	('RORgamma', 'Gene', '19885', (25, 33))	('autoimmune disease', 'Phenotype', 'HP:0002960', (71, 89))	('RORgamma', 'Gene', (25, 33))	('pancreatic cancer', 'Disease', 'MESH:D010190', (149, 166))	('autoimmune diseases', 'Disease', 'MESH:D001327', (71, 90))	('inhibitors', 'Var', (11, 21))	('pancreatic cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('autoimmune diseases', 'Disease', (71, 90))
36128	30955884	The LSL-KrasG12D mouse, B6.129S4-Krastm4Tyj/J (Stock No: 008179), the p53flox/flox mouse, B6.129P2- Trp53tm1Brn/J (Stock No: 008462), and the RORgamma -knockout mouse (Stock No: 007571), were purchased from The Jackson Laboratory.	('p53', 'Gene', '22059', (102, 105))	('mouse', 'Species', '10090', (17, 22))	('p53', 'Gene', (70, 73))	('mouse', 'Species', '10090', (161, 166))	('p53', 'Gene', '22059', (70, 73))	('mouse', 'Species', '10090', (83, 88))	('Trp53', 'Gene', (100, 105))	('RORgamma', 'Gene', '19885', (142, 150))	('B6.129S4-Krastm4Tyj/J', 'Var', (24, 45))	('Trp53', 'Gene', '22059', (100, 105))	('p53', 'Gene', (102, 105))	('RORgamma', 'Gene', (142, 150))
36178	30955884	For FG and KPR172H/+C cells, 300-500 cells were resuspended in 50 microl tumorsphere media as described below, then mixed with Matrigel (BD Biosciences, 354230) at a 1:1 ratio and plated in 96-well ultra-low adhesion culture plates (Costar).	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('R172H', 'Mutation', 'p.R172H', (13, 18))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('star', 'Gene', (235, 239))	('star', 'Gene', '20845', (235, 239))	('KPR172H/+C', 'Var', (11, 21))
36192	30955884	Briefly, organoids were isolated using Cell Recovery Solution (Corning 354253), then dissociated into single cell suspensions with TrypLE Express (ThermoFisher 12604) supplemented with 25 microg/ml DNase I (Roche) and 14 microM Rho Kinase Inhibitor (Y27632, Sigma).	('Rho Kinase', 'Gene', '19878', (228, 238))	('Kinase Inhibitor', 'biological_process', 'GO:0033673', ('232', '248'))	('Y27632', 'Var', (250, 256))	('DNase I', 'molecular_function', 'GO:0004530', ('198', '205'))	('Rho Kinase', 'Gene', (228, 238))	('Y27632', 'Chemical', 'MESH:C108830', (250, 256))
36221	30955884	For NOD/SCID mice bearing flank FG tumors, mice were treated with either vehicle (5% DMSO in corn oil) or SR2211 (10 mg/kg i.p., daily) for 2.5 weeks.	('mice', 'Species', '10090', (43, 47))	('NOD', 'Gene', (4, 7))	('mice', 'Species', '10090', (13, 17))	('SCID', 'Disease', 'MESH:D053632', (8, 12))	('SCID', 'Disease', (8, 12))	('flank FG tumors', 'Disease', 'MESH:C537923', (26, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('SR2211', 'Chemical', 'MESH:C575715', (106, 112))	('SR2211', 'Var', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('DMSO', 'Chemical', 'MESH:D004121', (85, 89))	('flank FG tumors', 'Disease', (26, 41))	('NOD', 'Gene', '1822', (4, 7))
36263	30955884	Library preparation of eluted chromatin immunoprecipitated DNA fragments was performed using the NEBNext Ultra II DNA library prep kit (E7645S and E7600S- NEB) for Illumina as per the manufacturer's protocol.	('E7645S', 'Var', (136, 142))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('E7600S', 'Var', (147, 153))	('E7600S', 'SUBSTITUTION', 'None', (147, 153))	('E7645S', 'SUBSTITUTION', 'None', (136, 142))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('chromatin', 'cellular_component', 'GO:0000785', ('30', '39'))
36289	30955884	Freshly harvested tumors from two independent KPR172hC mice were subjected to mechanical and enzymatic dissociation using a Miltenyi gentleMACS Tissue Dissociator to obtain single cells.	('KPR172hC', 'Var', (46, 54))	('mice', 'Species', '10090', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
36306	30955884	To estimate the proportion of super-enhancers that are closed on RORC knockdown, divergence between each baseline condition and the corresponding KPf/fC shRorc super-enhancer list was assessed by quantifying the peak overlap and then expressing this as a proportion of the baseline list ('shared%').	('Rorc', 'Gene', (155, 159))	('Rorc', 'Gene', '19885', (155, 159))	('knockdown', 'Var', (70, 79))
36325	31334335	FoxM1 Induced Paclitaxel Resistance via Activation of the FoxM1/PHB1/RAF-MEK-ERK Pathway and Enhancement of the ABCA2 Transporter FoxM1 amplification in human pancreatic cancer predicts poor prognosis and resistance to paclitaxel.	('FoxM1', 'Gene', '2305', (130, 135))	('pancreatic cancer', 'Disease', (159, 176))	('Enhancement', 'PosReg', (93, 104))	('FoxM1', 'Gene', '2305', (58, 63))	('ABCA2', 'Gene', '20', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Induced', 'Reg', (6, 13))	('Paclitaxel', 'Chemical', 'MESH:D017239', (14, 24))	('human', 'Species', '9606', (153, 158))	('PHB1', 'Gene', (64, 68))	('FoxM1', 'Gene', '2305', (0, 5))	('FoxM1', 'Gene', (130, 135))	('ERK', 'molecular_function', 'GO:0004707', ('77', '80'))	('FoxM1', 'Gene', (58, 63))	('PHB1', 'Gene', '5245', (64, 68))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (159, 176))	('RAF', 'Gene', '22882', (69, 72))	('ERK', 'Gene', '5594', (77, 80))	('Activation', 'PosReg', (40, 50))	('Paclitaxel Resistance', 'MPA', (14, 35))	('FoxM1', 'Gene', (0, 5))	('MEK', 'Gene', '5609', (73, 76))	('ABCA2', 'Gene', (112, 117))	('amplification', 'Var', (136, 149))	('RAF', 'Gene', (69, 72))	('pancreatic cancer', 'Disease', 'MESH:D010190', (159, 176))	('MEK', 'Gene', (73, 76))	('ERK', 'Gene', (77, 80))	('paclitaxel', 'Chemical', 'MESH:D017239', (219, 229))
36329	31334335	Notably, FoxM1 conferred tumor cell resistance to paclitaxel, but knocking down PHB1 could sensitize pancreatic cancer cells to it.	('FoxM1', 'Gene', (9, 14))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (101, 118))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('knocking down', 'Var', (66, 79))	('tumor', 'Disease', (25, 30))	('pancreatic cancer', 'Disease', (101, 118))	('PHB1', 'Gene', (80, 84))	('pancreatic cancer', 'Disease', 'MESH:D010190', (101, 118))	('sensitize', 'Reg', (91, 100))	('PHB1', 'Gene', '5245', (80, 84))	('paclitaxel', 'Chemical', 'MESH:D017239', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
36334	31334335	It was regulated by FoxM1 to maintain phosphorylation of ERK1/2 in drug-resistant cells, and FoxM1 simultaneously enhanced the function of ABCA2, which collectively contributed to paclitaxel resistance.	('contributed', 'Reg', (165, 176))	('function', 'MPA', (127, 135))	('phosphorylation', 'MPA', (38, 53))	('paclitaxel resistance', 'MPA', (180, 201))	('paclitaxel', 'Chemical', 'MESH:D017239', (180, 190))	('ABCA2', 'Gene', (139, 144))	('enhanced', 'PosReg', (114, 122))	('ERK1', 'molecular_function', 'GO:0004707', ('57', '61'))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))	('FoxM1', 'Var', (93, 98))
36338	31334335	However, the common challenges for chemotherapy, such as multidrug resistance and high toxicity, also limit the use of paclitaxel.	('drug resistance', 'Phenotype', 'HP:0020174', (62, 77))	('toxicity', 'Disease', 'MESH:D064420', (87, 95))	('toxicity', 'Disease', (87, 95))	('multidrug', 'Var', (57, 66))	('paclitaxel', 'Chemical', 'MESH:D017239', (119, 129))
36343	31334335	Deregulation of FoxM1 is associated with poor prognosis in many types of human cancers, including pancreatic cancer, lung cancer, breast cancer, and so on.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (98, 115))	('lung cancer', 'Disease', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('human', 'Species', '9606', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (98, 115))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('cancers', 'Disease', (79, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('pancreatic cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('breast cancer', 'Disease', (130, 143))	('FoxM1', 'Gene', (16, 21))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
36356	31334335	In contrast, silencing of PHB1 expression sensitized ovarian cancer cells to staurosporine.	('ovarian cancer', 'Disease', 'MESH:D010051', (53, 67))	('sensitized', 'Reg', (42, 52))	('ovarian cancer', 'Disease', (53, 67))	('staurosporine', 'Chemical', 'MESH:D019311', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ovarian cancer', 'Phenotype', 'HP:0100615', (53, 67))	('PHB1', 'Gene', (26, 30))	('silencing', 'Var', (13, 22))	('PHB1', 'Gene', '5245', (26, 30))
36367	31334335	Paclitaxel-resistant cells Panc-02-PTX and A549-PTX had an elevated mitochondrial membrane potential, which was an indicator of hypersensitivity to Rhodamine 123 (Rho123).	('Panc-02-PTX', 'CellLine', 'CVCL:D627', (27, 38))	('PTX', 'Chemical', '-', (48, 51))	('PTX', 'Chemical', '-', (35, 38))	('hypersensitivity', 'Disease', (128, 144))	('hypersensitivity', 'Disease', 'MESH:D004342', (128, 144))	('A549-PTX', 'Var', (43, 51))	('Rhodamine 123', 'Chemical', 'MESH:D020112', (148, 161))	('Paclitaxel', 'Chemical', 'MESH:D017239', (0, 10))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('68', '90'))	('hypersensitivity', 'biological_process', 'GO:0002524', ('128', '144'))	('elevated', 'PosReg', (59, 67))	('mitochondrial membrane potential', 'MPA', (68, 100))	('A549', 'CellLine', 'CVCL:0023', (43, 47))
36373	31334335	To eliminate the possibility that the THR-decreased retention of Rho123 was partially due to an increase in P-gp, we tested the 4 cell lines for cross-resistance to DOX.	('DOX', 'Chemical', 'MESH:D004317', (165, 168))	('retention', 'biological_process', 'GO:0051235', ('52', '61'))	('Rho123', 'Var', (65, 71))	('P-gp', 'Gene', '283871', (108, 112))	('tested', 'Reg', (117, 123))	('P-gp', 'Gene', (108, 112))	('increase', 'PosReg', (96, 104))	('THR', 'Chemical', 'MESH:D013883', (38, 41))
36374	31334335	Aspc-1, SW1990, Panc-02, and Panc-02-PTX had virtually identical IC50 (half maximal [50%] inhibitory concentration) values of DOX (Figure S1D), which was consistent with the average intensity of DOX among the four cell lines after treatment with THR (Figures S1F and S1G).	('DOX', 'Chemical', 'MESH:D004317', (195, 198))	('DOX', 'Chemical', 'MESH:D004317', (126, 129))	('Panc-02-PTX', 'Var', (29, 40))	('THR', 'Chemical', 'MESH:D013883', (246, 249))	('DOX', 'MPA', (126, 129))	('SW1990', 'Var', (8, 14))	('Panc-02-PTX', 'CellLine', 'CVCL:D627', (29, 40))	('Panc-02', 'CellLine', 'CVCL:D627', (16, 23))	('Panc-02', 'CellLine', 'CVCL:D627', (29, 36))	('SW1990', 'CellLine', 'CVCL:1723', (8, 14))
36391	31334335	The regions in the PHB1 promoter were flanked by 4 primers, including the 169-bp site 1 (-1,725 to -1,557), 139-bp site 2 (-1,618 to -1,480), 210-bp site 3 (-895 to -686), and 210-bp site 4 (-545 to -336).	('-895 to -686', 'Var', (157, 169))	('-1,725', 'Var', (89, 95))	('-545', 'Var', (191, 195))	('PHB1', 'Gene', (19, 23))	('-1,618', 'Var', (123, 129))	('PHB1', 'Gene', '5245', (19, 23))
36393	31334335	It was consistent with the mRNA level of PHB1, when it was transfected with the increasing dosage of FoxM1 (Figure 3B), and the protein level of Bxpc-3, when it was transfected with FoxM1b or FoxM1c or treated with the increasing dosage of THR 1 (Figure 3A).	('FoxM1c', 'Var', (192, 198))	('FoxM1', 'Gene', (101, 106))	('THR 1', 'Gene', (240, 245))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('PHB1', 'Gene', (41, 45))	('mRNA level', 'MPA', (27, 37))	('PHB1', 'Gene', '5245', (41, 45))	('protein level of Bxpc-3', 'MPA', (128, 151))	('THR 1', 'Gene', '7068', (240, 245))	('FoxM1b', 'Var', (182, 188))
36402	31334335	Time course analysis revealed that exogenous overexpression of FoxM1b or FoxM1c significantly enhanced the half-life of PHB1 in HEK293T cells, from 1.49 to 6.04 and 4.81 h, respectively (Figures 3F and 3H).	('HEK293T', 'CellLine', 'CVCL:0063', (128, 135))	('3H', 'Chemical', 'MESH:D014316', (202, 204))	('PHB1', 'Gene', '5245', (120, 124))	('FoxM1b', 'Var', (63, 69))	('FoxM1c', 'Var', (73, 79))	('half-life', 'MPA', (107, 116))	('enhanced', 'PosReg', (94, 102))	('PHB1', 'Gene', (120, 124))	('overexpression', 'PosReg', (45, 59))
36406	31334335	Panc-02 transfected with FoxM1b or FoxM1c showed that PHB1 shifted from the nucleus to the cytoplasm membrane, which was consistent with the distribution of PHB1 in the Panc-02-PTX cells (Figure 4A).	('PHB1', 'Gene', '5245', (54, 58))	('FoxM1b', 'Var', (25, 31))	('FoxM1c', 'Var', (35, 41))	('PHB1', 'Gene', '5245', (157, 161))	('Panc-02-PTX', 'CellLine', 'CVCL:D627', (169, 180))	('cytoplasm', 'cellular_component', 'GO:0005737', ('91', '100'))	('Panc-02', 'CellLine', 'CVCL:D627', (0, 7))	('membrane', 'cellular_component', 'GO:0016020', ('101', '109'))	('nucleus', 'cellular_component', 'GO:0005634', ('76', '83'))	('Panc-02', 'CellLine', 'CVCL:D627', (169, 176))	('PHB1', 'Gene', (54, 58))	('PHB1', 'Gene', (157, 161))
36407	31334335	Panc-02 cell transfected with FoxM1b or FoxM1c showed that PHB1 was decreased in the nucleus and increased in the cytoplasm membrane (Figure 4B), which was consistent with the content of distribution in Panc-02 and Panc-02-PTX cells (Figure S4A).	('Panc-02', 'CellLine', 'CVCL:D627', (215, 222))	('cytoplasm', 'cellular_component', 'GO:0005737', ('114', '123'))	('PHB1', 'Gene', (59, 63))	('decreased', 'NegReg', (68, 77))	('nucleus', 'cellular_component', 'GO:0005634', ('85', '92'))	('increased', 'PosReg', (97, 106))	('membrane', 'cellular_component', 'GO:0016020', ('124', '132'))	('Panc-02', 'CellLine', 'CVCL:D627', (0, 7))	('PHB1', 'Gene', '5245', (59, 63))	('Panc-02', 'CellLine', 'CVCL:D627', (203, 210))	('Panc-02-PTX', 'CellLine', 'CVCL:D627', (215, 226))	('FoxM1c', 'Var', (40, 46))	('FoxM1b', 'Var', (30, 36))
36408	31334335	Previously, a study had shown that PHB1 directly interacted with C-RAF via the C-terminal 32 amino acids.	('interacted', 'Interaction', (49, 59))	('C-terminal 32 amino acids', 'Var', (79, 104))	('PHB1', 'Gene', (35, 39))	('PHB1', 'Gene', '5245', (35, 39))	('C-RAF', 'Gene', (65, 70))	('C-RAF', 'Gene', '5894', (65, 70))
36410	31334335	PHB1 in the membrane protein was pulled down by the C-RAF antibody and showed a significantly higher level than that of control when transfected with FoxM1b or FoxM1c in Panc-02 (Figure 4C).	('membrane', 'cellular_component', 'GO:0016020', ('12', '20'))	('PHB1', 'Gene', (0, 4))	('antibody', 'molecular_function', 'GO:0003823', ('58', '66'))	('C-RAF', 'Gene', '5894', (52, 57))	('PHB1', 'Gene', '5245', (0, 4))	('higher', 'PosReg', (94, 100))	('Panc-02', 'CellLine', 'CVCL:D627', (170, 177))	('antibody', 'cellular_component', 'GO:0042571', ('58', '66'))	('FoxM1c', 'Var', (160, 166))	('antibody', 'cellular_component', 'GO:0019815', ('58', '66'))	('C-RAF', 'Gene', (52, 57))	('antibody', 'cellular_component', 'GO:0019814', ('58', '66'))	('FoxM1b', 'Var', (150, 156))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
36414	31334335	We found that silencing PHB1 expression by transfecting Plentiv2-PHB1 (H1) plasmid strongly reduced the phosphorylation of ERK1/2 in SW1990 (Figure S3B) and overexpressing PHB1 could increase the p-ERK1/2 in Aspc-1 (Figure S3C).	('silencing', 'Var', (14, 23))	('PHB1', 'Gene', (24, 28))	('PHB1', 'Gene', (172, 176))	('SW1990', 'CellLine', 'CVCL:1723', (133, 139))	('PHB1', 'Gene', '5245', (24, 28))	('increase', 'PosReg', (183, 191))	('PHB1', 'Gene', (65, 69))	('phosphorylation', 'biological_process', 'GO:0016310', ('104', '119'))	('PHB1', 'Gene', '5245', (65, 69))	('PHB1', 'Gene', '5245', (172, 176))	('ERK1', 'molecular_function', 'GO:0004707', ('198', '202'))	('phosphorylation', 'MPA', (104, 119))	('ERK1/2', 'Protein', (123, 129))	('ERK1', 'molecular_function', 'GO:0004707', ('123', '127'))	('reduced', 'NegReg', (92, 99))	('overexpressing', 'PosReg', (157, 171))	('p-ERK1/2', 'MPA', (196, 204))
36416	31334335	Interestingly, we also found the corresponding changes of FoxM1, PHB1, and p-ERK1/2 when knocking down or overexpressing PHB1 (Figures 4E and 4F).	('ERK1', 'molecular_function', 'GO:0004707', ('77', '81'))	('changes', 'Reg', (47, 54))	('PHB1', 'Gene', (121, 125))	('PHB1', 'Gene', (65, 69))	('PHB1', 'Gene', '5245', (65, 69))	('PHB1', 'Gene', '5245', (121, 125))	('overexpressing', 'PosReg', (106, 120))	('knocking down', 'Var', (89, 102))
36424	31334335	Western blot showed that the expression of PHB1 increased as expected when Aspc-1 was transfected with FoxM1b or FoxM1c (Figure 5D).	('PHB1', 'Gene', '5245', (43, 47))	('increased', 'PosReg', (48, 57))	('FoxM1b', 'Var', (103, 109))	('PHB1', 'Gene', (43, 47))	('FoxM1c', 'Var', (113, 119))	('expression', 'MPA', (29, 39))
36425	31334335	We found that overexpression of FoxM1b or FoxM1c conferred Panc-02 resistance to paclitaxel, as indicated by the increase in IC50 compared with the control.	('FoxM1c', 'Var', (42, 48))	('conferred', 'Reg', (49, 58))	('IC50', 'MPA', (125, 129))	('Panc-02', 'CellLine', 'CVCL:D627', (59, 66))	('resistance to paclitaxel', 'MPA', (67, 91))	('paclitaxel', 'Chemical', 'MESH:D017239', (81, 91))	('FoxM1b', 'Var', (32, 38))	('increase', 'PosReg', (113, 121))	('Panc-02', 'Gene', (59, 66))	('overexpression', 'PosReg', (14, 28))
36426	31334335	Depletion of PHB1 in Panc-02 attenuated the paclitaxel resistance induced by FoxM1.	('PHB1', 'Gene', '5245', (13, 17))	('Panc-02', 'CellLine', 'CVCL:D627', (21, 28))	('paclitaxel resistance induced', 'MPA', (44, 73))	('Depletion', 'Var', (0, 9))	('attenuated', 'NegReg', (29, 39))	('paclitaxel', 'Chemical', 'MESH:D017239', (44, 54))	('PHB1', 'Gene', (13, 17))
36430	31334335	Depletion of PHB1 in the paclitaxel-resistant SW1990 cell line significantly increased drug efflux (Figure S6A).	('PHB1', 'Gene', '5245', (13, 17))	('drug efflux', 'MPA', (87, 98))	('Depletion', 'Var', (0, 9))	('efflux', 'biological_process', 'GO:0140115', ('92', '98'))	('efflux', 'biological_process', 'GO:0140352', ('92', '98'))	('SW1990', 'CellLine', 'CVCL:1723', (46, 52))	('increased', 'PosReg', (77, 86))	('paclitaxel', 'Chemical', 'MESH:D017239', (25, 35))	('PHB1', 'Gene', (13, 17))
36433	31334335	HEK293T cells were transfected with FoxM1b, FoxM1c, FoxM1b + H1, and FoxM1c + H1, which significantly altered the mRNA levels of FoxM1 and PHB1 (Figure 6A).	('mRNA levels', 'MPA', (114, 125))	('FoxM1', 'Gene', (129, 134))	('FoxM1c + H1', 'Var', (69, 80))	('PHB1', 'Gene', (139, 143))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('FoxM1b', 'Var', (36, 42))	('PHB1', 'Gene', '5245', (139, 143))	('FoxM1c', 'Var', (44, 50))	('FoxM1b + H1', 'Var', (52, 63))	('altered', 'Reg', (102, 109))
36435	31334335	Among these ABC transporter molecules, the mRNA of ABCA2 and ABCD2 were significantly upregulated in HEK293T cells when transfected with FoxM1b or FoxM1c.	('FoxM1c', 'Var', (147, 153))	('HEK293T', 'CellLine', 'CVCL:0063', (101, 108))	('ABCD2', 'Gene', '225', (61, 66))	('ABC', 'Gene', (51, 54))	('ABC', 'Gene', '10058', (61, 64))	('ABCD2', 'Gene', (61, 66))	('ABC', 'Gene', (12, 15))	('mRNA', 'MPA', (43, 47))	('ABC', 'Gene', '10058', (51, 54))	('ABC transporter', 'molecular_function', 'GO:0140359', ('12', '27'))	('upregulated', 'PosReg', (86, 97))	('ABC', 'Gene', (61, 64))	('ABC', 'Gene', '10058', (12, 15))	('FoxM1b', 'Var', (137, 143))
36436	31334335	Adversely, PHB1 depletion significantly decreased the mRNA levels of ABCA2 and ABCD2 (Figure 6B).	('PHB1', 'Gene', (11, 15))	('depletion', 'Var', (16, 25))	('ABCD2', 'Gene', '225', (79, 84))	('PHB1', 'Gene', '5245', (11, 15))	('ABCD2', 'Gene', (79, 84))	('mRNA levels', 'MPA', (54, 65))	('decreased', 'NegReg', (40, 49))	('ABCA2', 'Gene', (69, 74))
36438	31334335	We found an increase of ABCA2 in HEK293T cells when transfected with FoxM1b or FoxM1c; but, the effect was attenuated when we knocked down the PHB1.	('HEK293T', 'CellLine', 'CVCL:0063', (33, 40))	('FoxM1b', 'Var', (69, 75))	('FoxM1c', 'Var', (79, 85))	('increase', 'PosReg', (12, 20))	('PHB1', 'Gene', (143, 147))	('ABCA2', 'Gene', (24, 29))	('PHB1', 'Gene', '5245', (143, 147))
36440	31334335	Moreover, SW1990, Panc-02, and Panc-02-PTX treated with paclitaxel had elevated mRNA of ABCA2, but not ABCD2 (Figure 6E).	('mRNA', 'MPA', (80, 84))	('Panc-02-PTX', 'CellLine', 'CVCL:D627', (31, 42))	('paclitaxel', 'Chemical', 'MESH:D017239', (56, 66))	('SW1990', 'Var', (10, 16))	('Panc-02', 'CellLine', 'CVCL:D627', (31, 38))	('ABCA2', 'Gene', (88, 93))	('elevated', 'PosReg', (71, 79))	('ABCD2', 'Gene', '225', (103, 108))	('SW1990', 'CellLine', 'CVCL:1723', (10, 16))	('Panc-02', 'CellLine', 'CVCL:D627', (18, 25))	('ABCD2', 'Gene', (103, 108))
36446	31334335	In summary, overexpressing FoxM1b or FoxM1c induced the increase in PHB1 in the cell membrane and enhanced the binding of PHB1 to C-RAF, which led to paclitaxel resistance by activating the RAF/MEK/ERK pathway.	('enhanced', 'PosReg', (98, 106))	('PHB1', 'Gene', (122, 126))	('PHB1', 'Gene', '5245', (68, 72))	('increase', 'PosReg', (56, 64))	('C-RAF', 'Gene', (130, 135))	('cell membrane', 'cellular_component', 'GO:0005886', ('80', '93'))	('PHB1', 'Gene', '5245', (122, 126))	('RAF', 'Gene', '22882', (190, 193))	('FoxM1c', 'Var', (37, 43))	('MEK', 'Gene', '5609', (194, 197))	('led to', 'Reg', (143, 149))	('RAF', 'Gene', '22882', (132, 135))	('ERK', 'Gene', '5594', (198, 201))	('binding', 'molecular_function', 'GO:0005488', ('111', '118'))	('RAF', 'Gene', (190, 193))	('paclitaxel', 'Chemical', 'MESH:D017239', (150, 160))	('PHB1', 'Gene', (68, 72))	('ERK', 'molecular_function', 'GO:0004707', ('198', '201'))	('MEK', 'Gene', (194, 197))	('C-RAF', 'Gene', '5894', (130, 135))	('FoxM1b', 'Gene', (27, 33))	('RAF', 'Gene', (132, 135))	('binding', 'Interaction', (111, 118))	('ERK', 'Gene', (198, 201))	('paclitaxel resistance', 'MPA', (150, 171))	('activating', 'Reg', (175, 185))
36450	31334335	Besides, depletion of PHB1 in SW1990 induced the cells to be more sensitive to paclitaxel (Figure S6A).	('paclitaxel', 'Chemical', 'MESH:D017239', (79, 89))	('PHB1', 'Gene', '5245', (22, 26))	('depletion', 'MPA', (9, 18))	('SW1990', 'CellLine', 'CVCL:1723', (30, 36))	('more', 'PosReg', (61, 65))	('PHB1', 'Gene', (22, 26))	('SW1990', 'Var', (30, 36))	('sensitive to paclitaxel', 'MPA', (66, 89))
36451	31334335	To confirm that FoxM1b or FoxM1c increased PHB1 to promote paclitaxel drug resistance, Panc-02 cells were transfected with FoxM1b or FoxM1c, which conferred the cell resistance to Oregon Green 488 paclitaxel, while knocking down PHB1 could attenuate the effect (Figure 7C).	('PHB1', 'Gene', '5245', (43, 47))	('conferred', 'Reg', (147, 156))	('drug resistance', 'biological_process', 'GO:0042493', ('70', '85'))	('paclitaxel', 'Chemical', 'MESH:D017239', (59, 69))	('Oregon Green 488', 'Chemical', 'MESH:C436864', (180, 196))	('drug resistance', 'Phenotype', 'HP:0020174', (70, 85))	('paclitaxel drug resistance', 'MPA', (59, 85))	('paclitaxel', 'Chemical', 'MESH:D017239', (197, 207))	('drug resistance', 'biological_process', 'GO:0009315', ('70', '85'))	('Panc-02', 'CellLine', 'CVCL:D627', (87, 94))	('knocking', 'Var', (215, 223))	('promote', 'PosReg', (51, 58))	('PHB1', 'Gene', (229, 233))	('PHB1', 'Gene', (43, 47))	('PHB1', 'Gene', '5245', (229, 233))	('FoxM1c', 'Var', (133, 139))	('FoxM1b', 'Var', (123, 129))
36473	31334335	FoxM1, PHB1, and ABCA2 overexpressions were associated with a higher risk of death in univariate analysis.	('ABCA2', 'Gene', (17, 22))	('PHB1', 'Gene', (7, 11))	('PHB1', 'Gene', '5245', (7, 11))	('FoxM1', 'Gene', (0, 5))	('overexpressions', 'Var', (23, 38))
36481	31334335	We found that FoxM1b and FoxM1c directly activated the transcription of PHB1, constituting a novel signaling pathway that conferred the pancreatic cancer cell resistance to paclitaxel.	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('resistance to paclitaxel', 'MPA', (159, 183))	('FoxM1c', 'Var', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('FoxM1b', 'Var', (14, 20))	('conferred', 'PosReg', (122, 131))	('paclitaxel', 'Chemical', 'MESH:D017239', (173, 183))	('PHB1', 'Gene', (72, 76))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('transcription', 'MPA', (55, 68))	('activated', 'PosReg', (41, 50))	('PHB1', 'Gene', '5245', (72, 76))	('signaling pathway', 'biological_process', 'GO:0007165', ('99', '116'))	('pancreatic cancer', 'Disease', (136, 153))	('transcription', 'biological_process', 'GO:0006351', ('55', '68'))
36482	31334335	Our mechanistic and clinical evidence strongly suggested that deregulated FoxM1 caused abnormal PHB1 expression and critically contributed to pancreatic cancer pathogenesis and paclitaxel resistance.	('FoxM1', 'Gene', (74, 79))	('PHB1', 'Gene', (96, 100))	('pathogenesis', 'biological_process', 'GO:0009405', ('160', '172'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (142, 159))	('pancreatic cancer', 'Disease', (142, 159))	('caused abnormal', 'Reg', (80, 95))	('PHB1', 'Gene', '5245', (96, 100))	('pancreatic cancer', 'Disease', 'MESH:D010190', (142, 159))	('paclitaxel', 'Chemical', 'MESH:D017239', (177, 187))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('deregulated', 'Var', (62, 73))	('expression', 'MPA', (101, 111))	('contributed', 'Reg', (127, 138))
36506	31334335	As expected, depletion of PHB1 abolished the drug resistance, which was induced by FoxM1b or FoxM1c.	('drug resistance', 'biological_process', 'GO:0009315', ('45', '60'))	('drug resistance', 'biological_process', 'GO:0042493', ('45', '60'))	('FoxM1b', 'Var', (83, 89))	('FoxM1c', 'Var', (93, 99))	('abolished', 'NegReg', (31, 40))	('drug resistance', 'Phenotype', 'HP:0020174', (45, 60))	('depletion', 'Var', (13, 22))	('drug resistance', 'MPA', (45, 60))	('PHB1', 'Gene', (26, 30))	('PHB1', 'Gene', '5245', (26, 30))
36507	31334335	FoxM1b or FoxM1c mediated the translocation of PHB1 from the nucleus to the plasma membrane, which enhanced the interaction between PHB1 and C-RAF and contributed to an increase in the phosphorylation of ERK1/2 in the MAPK-signaling pathway.	('nucleus', 'cellular_component', 'GO:0005634', ('61', '68'))	('FoxM1c', 'Var', (10, 16))	('phosphorylation', 'biological_process', 'GO:0016310', ('185', '200'))	('translocation', 'MPA', (30, 43))	('enhanced', 'PosReg', (99, 107))	('ERK1', 'molecular_function', 'GO:0004707', ('204', '208'))	('MAPK', 'molecular_function', 'GO:0004707', ('218', '222'))	('phosphorylation', 'MPA', (185, 200))	('ERK1/2', 'Pathway', (204, 210))	('C-RAF', 'Gene', '5894', (141, 146))	('PHB1', 'Gene', (47, 51))	('plasma membrane', 'cellular_component', 'GO:0005886', ('76', '91'))	('FoxM1b', 'Var', (0, 6))	('MAPK-signaling', 'biological_process', 'GO:0000165', ('218', '232'))	('PHB1', 'Gene', (132, 136))	('MAPK-signaling pathway', 'Pathway', (218, 240))	('C-RAF', 'Gene', (141, 146))	('PHB1', 'Gene', '5245', (47, 51))	('signaling pathway', 'biological_process', 'GO:0007165', ('223', '240'))	('increase', 'PosReg', (169, 177))	('PHB1', 'Gene', '5245', (132, 136))	('interaction', 'Interaction', (112, 123))
36518	31334335	To eliminate the possibility that the decrease in Rho123 retention by THR was due to an increase in ABCB1, we tested the 4 cell lines for cross-resistance to DOX.	('THR', 'Chemical', 'MESH:D013883', (70, 73))	('decrease', 'NegReg', (38, 46))	('retention', 'biological_process', 'GO:0051235', ('57', '66'))	('ABCB1', 'Gene', (100, 105))	('Rho123', 'Var', (50, 56))	('ABCB1', 'Gene', '5243', (100, 105))	('DOX', 'Chemical', 'MESH:D004317', (158, 161))	('tested', 'Reg', (110, 116))
36524	31334335	However, in our study, HEK293T transfected with FoxM1b or FoxM1c increased the expression of ABCA2, whereas ABCC5 was not affected.	('FoxM1c', 'Var', (58, 64))	('increased', 'PosReg', (65, 74))	('ABCA2', 'Gene', (93, 98))	('FoxM1b', 'Var', (48, 54))	('expression', 'MPA', (79, 89))	('ABCC5', 'Gene', (108, 113))	('HEK293T', 'CellLine', 'CVCL:0063', (23, 30))	('HEK293T', 'Var', (23, 30))	('ABCC5', 'Gene', '10057', (108, 113))
36525	31334335	Overexpression of FoxM1 and depletion of PHB1 simultaneously reduced the protein and mRNA levels of ABCA2.	('ABCA2', 'Gene', (100, 105))	('PHB1', 'Gene', '5245', (41, 45))	('mRNA levels', 'MPA', (85, 96))	('depletion', 'Var', (28, 37))	('FoxM1', 'Gene', (18, 23))	('protein', 'MPA', (73, 80))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('reduced', 'NegReg', (61, 68))	('PHB1', 'Gene', (41, 45))
36527	31334335	Besides, treating cells with paclitaxel at the dosage of 10 nM showed that FoxM1, PHB1, ABCA2, and p-ERK1/2 were upregulated in the SW1990, Panc-02, and Panc-02-PTX cells, but not the Aspc-1 cells.	('PHB1', 'Gene', '5245', (82, 86))	('upregulated', 'PosReg', (113, 124))	('Panc-02', 'CellLine', 'CVCL:D627', (140, 147))	('Panc-02-PTX', 'CellLine', 'CVCL:D627', (153, 164))	('FoxM1', 'Gene', (75, 80))	('paclitaxel', 'Chemical', 'MESH:D017239', (29, 39))	('ABCA2', 'Gene', (88, 93))	('Panc-02', 'CellLine', 'CVCL:D627', (153, 160))	('SW1990', 'Var', (132, 138))	('ERK1', 'molecular_function', 'GO:0004707', ('101', '105'))	('SW1990', 'CellLine', 'CVCL:1723', (132, 138))	('p-ERK1/2', 'Gene', (99, 107))	('PHB1', 'Gene', (82, 86))
36532	31334335	Silencing either or both of the molecules rendered cells sensitive to paclitaxel both in vitro and in vivo.	('sensitive to paclitaxel', 'MPA', (57, 80))	('Silencing', 'Var', (0, 9))	('paclitaxel', 'Chemical', 'MESH:D017239', (70, 80))
36538	31334335	Penter-FoxM1b, Penter-FoxM1c, and PHB1-Penter were purchased from Vigene Bio (CH811655, CH825506, and CH862869, Rockville, MD, USA).	('PHB1', 'Gene', (34, 38))	('CH862869', 'Var', (102, 110))	('PHB1', 'Gene', '5245', (34, 38))	('CH811655', 'Var', (78, 86))	('CH825506', 'Var', (88, 96))
36561	31334335	For the detection of PHB1, cells were collected after transfection with FoxM1b, FoxM1c, vector, and THR (4 muM and 8 muM).	('THR', 'Chemical', 'MESH:D013883', (100, 103))	('FoxM1c', 'Var', (80, 86))	('PHB1', 'Gene', '5245', (21, 25))	('muM', 'Gene', '56925', (107, 110))	('muM', 'Gene', '56925', (117, 120))	('FoxM1b', 'Gene', (72, 78))	('muM', 'Gene', (107, 110))	('muM', 'Gene', (117, 120))	('PHB1', 'Gene', (21, 25))
36600	30819202	A growing number of studies has considerably improved our knowledge concerning the genetic and epigenetic alterations, the molecular perturbances and the precursor lesions, associated with the onset and the development of this malignancy.	('malignancy', 'Disease', 'MESH:D009369', (227, 237))	('malignancy', 'Disease', (227, 237))	('epigenetic alterations', 'Var', (95, 117))
36601	30819202	The latter consists of activating mutations in oncogenes, such as KRAS, or inactivating alterations in tumor suppressor genes, including P16, TP53, and SMAD4 or in additional genes, such as MLL3, TGFBR2, ARID1A, CDKN2a and ATM.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('TGFBR2', 'Gene', (196, 202))	('P16', 'Gene', (137, 140))	('ATM', 'Gene', '472', (223, 226))	('CDKN2a', 'Gene', (212, 218))	('SMAD4', 'Gene', '4089', (152, 157))	('MLL3', 'Gene', (190, 194))	('TP53', 'Gene', '7157', (142, 146))	('KRAS', 'Gene', '3845', (66, 70))	('inactivating alterations', 'Var', (75, 99))	('CDKN2a', 'Gene', '1029', (212, 218))	('ATM', 'Gene', (223, 226))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('103', '119'))	('activating', 'PosReg', (23, 33))	('KRAS', 'Gene', (66, 70))	('tumor', 'Disease', (103, 108))	('TGFBR2', 'Gene', '7048', (196, 202))	('tumor suppressor', 'biological_process', 'GO:0051726', ('103', '119'))	('ARID1A', 'Gene', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('SMAD4', 'Gene', (152, 157))	('TP53', 'Gene', (142, 146))	('MLL3', 'Gene', '58508', (190, 194))	('P16', 'Gene', '1029', (137, 140))	('ARID1A', 'Gene', '8289', (204, 210))	('mutations', 'Var', (34, 43))
36602	30819202	These mutations, observed in non-invasive precursor lesions known as pancreatic intraepithelial neoplasia (PanIN), accumulate and drive neoplastic transformation and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (80, 105))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('neoplasia', 'Phenotype', 'HP:0002664', (96, 105))	('pancreatic intraepithelial neoplasia', 'Disease', (69, 105))	('drive', 'PosReg', (130, 135))	('accumulate', 'PosReg', (115, 125))	('tumor', 'Disease', (166, 171))	('pancreatic intraepithelial neoplasia', 'Disease', 'MESH:D018290', (69, 105))	('neoplastic transformation', 'CPA', (136, 161))	('mutations', 'Var', (6, 15))
36678	30241340	Modulation of redox homeostasis in cancer cells has emerged as a new opportunity for tumor intervention.	('Modulation', 'Var', (0, 10))	('tumor', 'Disease', (85, 90))	('homeostasis', 'biological_process', 'GO:0042592', ('20', '31'))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Disease', (35, 41))
36682	30241340	For instance, the expression of mutant oncogenic KrasG12D is commonly present in pancreatic ductal adenocarcinoma (PDAC), resulting in an elevated basal state of the transcription factor, nuclear factor E2-related factor 2 (NRF2) to mount an antioxidant response.	('PDAC', 'Phenotype', 'HP:0006725', (115, 119))	('transcription factor', 'molecular_function', 'GO:0000981', ('166', '186'))	('NRF2', 'Gene', (224, 228))	('antioxidant response', 'MPA', (242, 262))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (81, 113))	('NRF2', 'Gene', '4780', (224, 228))	('pancreatic ductal adenocarcinoma', 'Disease', (81, 113))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (81, 113))	('KrasG12D', 'Gene', (49, 57))	('mutant', 'Var', (32, 38))	('basal state', 'MPA', (147, 158))	('elevated', 'PosReg', (138, 146))	('transcription', 'biological_process', 'GO:0006351', ('166', '179'))
36710	30241340	To distinguish the programmed cell death mode, we analyzed the expression of total poly (ADP-ribose) polymerase 1 (PARP) and cleaved PARP, wherein MSA and compounds 1 and 2 slightly increased the 89 kD cleaved fragment at 72 h (Supplementary Figure S1A).	('PARP', 'Gene', (133, 137))	('increased', 'PosReg', (182, 191))	('89 kD cleaved fragment', 'MPA', (196, 218))	('cleaved', 'Var', (125, 132))	('PARP', 'Gene', '142', (115, 119))	('poly (ADP-ribose) polymerase 1', 'Gene', '142', (83, 113))	('programmed cell death', 'biological_process', 'GO:0012501', ('19', '40'))	('PARP', 'Gene', '142', (133, 137))	('MSA', 'Chemical', 'MESH:C008493', (147, 150))	('PARP', 'Gene', (115, 119))	('poly (ADP-ribose) polymerase 1', 'Gene', (83, 113))
36738	30241340	Moreover, its knockdown has been reported to inhibit cell adhesion, migration, proliferation, and metastasis of pancreatic cancer, unveiling CD29 as a potential therapeutic target.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('CD29', 'Gene', (141, 145))	('proliferation', 'CPA', (79, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('knockdown', 'Var', (14, 23))	('CD29', 'Gene', '3688', (141, 145))	('metastasis of pancreatic cancer', 'Disease', 'MESH:D009362', (98, 129))	('cell adhesion', 'CPA', (53, 66))	('metastasis of pancreatic cancer', 'Disease', (98, 129))	('inhibit', 'NegReg', (45, 52))	('cell adhesion', 'biological_process', 'GO:0007155', ('53', '66'))	('migration', 'CPA', (68, 77))
36758	30241340	Cell detachment could be caused by CH3SeH, one of the key metabolites in Se cytotoxicity, which has been reported to cause cell detachment in different cancer cell lines, along with a decrease in CD29 expression.	('decrease', 'NegReg', (184, 192))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('CD29', 'Gene', '3688', (196, 200))	('SeH', 'molecular_function', 'GO:0033885', ('38', '41'))	('cytotoxicity', 'Disease', 'MESH:D064420', (76, 88))	('Se', 'Chemical', 'MESH:D012643', (38, 40))	('CD29', 'Gene', (196, 200))	('CH3SeH', 'Chemical', '-', (35, 41))	('CH3SeH', 'Var', (35, 41))	('Cell detachment', 'CPA', (0, 15))	('cell detachment', 'CPA', (123, 138))	('Se', 'Chemical', 'MESH:D012643', (73, 75))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('expression', 'MPA', (201, 211))	('SeH', 'molecular_function', 'GO:0004301', ('38', '41'))	('cytotoxicity', 'Disease', (76, 88))
36761	30241340	Lengthening the alkyl chain or the substitution over an arylselenol in general dramatically decreased the percentage of detached cells.	('decreased', 'NegReg', (92, 101))	('substitution', 'Var', (35, 47))	('arylselenol', 'Chemical', '-', (56, 67))
36819	30241340	IR (KBr): nu 3143 (w, C-Harom), 2961-2860 (s, C-Haliph), 1649 cm-1 (s, -C=O).	('C-Haliph', 'Disease', 'MESH:C537418', (46, 54))	('C-Haliph', 'Disease', (46, 54))	('nu 3143', 'Var', (10, 17))
36930	29954062	While this is very encouraging, we also explored if this local ablation effect could also result in immune stimulation, as was observed when NPS led to the induction of immune-mediated protection from a second tumor challenge in orthotopic mouse breast and rat liver cancer models.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('mouse', 'Species', '10090', (240, 245))	('liver cancer', 'Disease', 'MESH:D006528', (261, 273))	('liver cancer', 'Phenotype', 'HP:0002896', (261, 273))	('liver cancer', 'Disease', (261, 273))	('tumor', 'Disease', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('immune', 'MPA', (100, 106))	('rat', 'Species', '10116', (257, 260))	('local', 'Var', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
36942	29954062	Global genomic analysis has shown there are large amounts of mutations, activation of various signaling pathways and molecular heterogeneity associated with this type of cancer.	('activation', 'PosReg', (72, 82))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('signaling', 'biological_process', 'GO:0023052', ('94', '103'))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('signaling pathways', 'Pathway', (94, 112))
36955	29954062	To evaluate whether NPS ablation could induce an antitumor immune response and its potential benefit for advanced pancreatic cancer, we employed a syngeneic mouse Pan02 pancreatic cancer model to study the therapeutic efficacy of NPS for both local tumors and distant lesions in this study.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (249, 254))	('mouse', 'Species', '10090', (157, 162))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (169, 186))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('local tumor', 'Disease', 'MESH:D009364', (243, 254))	('induce', 'Reg', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('pancreatic cancer', 'Disease', 'MESH:D010190', (169, 186))	('pancreatic cancer', 'Disease', 'MESH:D010190', (114, 131))	('ablation', 'Var', (24, 32))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('immune response', 'biological_process', 'GO:0006955', ('59', '74'))	('local tumor', 'Disease', (243, 254))	('pancreatic cancer', 'Disease', (114, 131))	('pancreatic cancer', 'Disease', (169, 186))	('tumor', 'Disease', (53, 58))	('tumors', 'Disease', (249, 255))
36982	29954062	However, we did not detect the increase in the number of memory T cells including effector (CD44+ CD62L-) or central memory (CD44+ CD62L+) T cells in all tumor-free mice in the current study.	('mice', 'Species', '10090', (165, 169))	('memory', 'biological_process', 'GO:0007613', ('57', '63'))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('memory', 'biological_process', 'GO:0007613', ('117', '123'))	('CD44+ CD62L+', 'Var', (125, 137))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CD44+ CD62L-', 'Var', (92, 104))	('tumor', 'Disease', (154, 159))
36983	29954062	In spite of this, there was a population of acute effector (CD44- CD62L-) T cells that appeared to be induced in numerous NPS-treated mice in response to the re-challenge of live pancreatic tumor cells.	('mice', 'Species', '10090', (134, 138))	('CD44- CD62L-', 'Var', (60, 72))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('numerous NPS', 'Disease', (113, 125))	('pancreatic tumor', 'Disease', (179, 195))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (179, 195))	('numerous NPS', 'Disease', 'MESH:D009261', (113, 125))	('pancreatic tumor', 'Disease', 'MESH:D010190', (179, 195))
36987	29954062	Besides the above findings, we have also noticed that a prominent CD44highCD62Lhigh T cell subset was associated with tumor-bearing mice (Figure 5) but was not present in the tumor-free mice (Figure 4).	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mice', 'Species', '10090', (132, 136))	('tumor', 'Disease', (118, 123))	('mice', 'Species', '10090', (186, 190))	('CD44highCD62Lhigh', 'Var', (66, 83))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
37004	29954062	One important question is whether NPS ablation could kill cancer stem cells or whether on the contrary it may activate cancer stem cells by the selective eradication of proliferating cells.	('rat', 'Species', '10116', (176, 179))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('activate', 'PosReg', (110, 118))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('NPS', 'Gene', (34, 37))	('ablation', 'Var', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
37010	29954062	NPS induces a strong memory T cell response concomitant with the immune protection in a poorly immunogenic 4T1 breast cancer model.	('memory T cell response', 'CPA', (21, 43))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('memory', 'biological_process', 'GO:0007613', ('21', '27'))	('breast cancer', 'Disease', (111, 124))	('NPS', 'Var', (0, 3))
37058	29954062	Cells were first prepared by surface labeling of cells with anti-CD4 FITC, anti-CD8 PerCP or anti-CD25 APC, followed by intracellular nuclear staining using mAbs anti-Foxp3 PE after fixation and permeabilization.	('anti-CD25 APC', 'Var', (93, 106))	('anti-CD8 PerCP', 'Var', (75, 89))	('intracellular', 'cellular_component', 'GO:0005622', ('120', '133'))	('APC', 'cellular_component', 'GO:0005680', ('103', '106'))	('anti-CD4 FITC', 'Var', (60, 73))	('Foxp3', 'Gene', '20371', (167, 172))	('FITC', 'Chemical', 'MESH:D016650', (69, 73))	('Foxp3', 'Gene', (167, 172))
37112	28980211	Among them, patients with AMPA vs. DA were more likely to receive chemoradiation and less likely to receive chemotherapy alone (Table 1).	('AMPA', 'Chemical', '-', (26, 30))	('patients', 'Species', '9606', (12, 20))	('AMPA vs.', 'Var', (26, 34))	('chemoradiation', 'CPA', (66, 80))
37117	28980211	Patients with AMPA were more likely than those with DA to undergo pancreaticoduodenectomy.	('pancreatic', 'Disease', (66, 76))	('AMPA', 'Chemical', '-', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('pancreatic', 'Disease', 'MESH:D010195', (66, 76))	('AMPA', 'Var', (14, 18))
37153	28980211	Fourth, among patients treated with preoperative therapy, patients with AMPA were less likely than patients with DA to receive chemotherapy alone and more likely than patients with DA to receive chemoradiation.	('AMPA', 'Var', (72, 76))	('AMPA', 'Chemical', '-', (72, 76))	('patients', 'Species', '9606', (167, 175))	('less', 'NegReg', (82, 86))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (14, 22))
37156	28980211	In the field of surgery for colorectal liver metastases, previous literature has demonstrated an association between mutant KRAS and suboptimal pathologic response to preoperative chemotherapy.	('KRAS', 'Gene', (124, 128))	('mutant', 'Var', (117, 123))	('colorectal liver metastases', 'Disease', 'MESH:D009362', (28, 55))	('colorectal liver metastases', 'Disease', (28, 55))	('association', 'Interaction', (97, 108))
37157	28980211	In addition, a study on AMPA identified KRAS mutation as an independent predictor of poor prognosis following curative resection and others have suggested microsatellite instability was associated with improved survival in patients with AMPA and DA.	('AMPA', 'Chemical', '-', (24, 28))	('improved', 'PosReg', (202, 210))	('microsatellite instability', 'Var', (155, 181))	('AMPA', 'Chemical', '-', (237, 241))	('KRAS', 'Gene', (40, 44))	('survival', 'MPA', (211, 219))	('mutation', 'Var', (45, 53))	('patients', 'Species', '9606', (223, 231))
37170	29348875	HS-173 also significantly attenuated DNA damage repair by potently inhibiting ATM and DNA-PKcs, the two major kinases that respond to radiation-induced DNA double-strand breaks (DSBs), resulting in sustained DNA damage.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('DNA damage', 'MPA', (208, 218))	('HS-173', 'Chemical', 'MESH:C577242', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('208', '211'))	('DNA-PKcs', 'Gene', (86, 94))	('ATM', 'Gene', (78, 81))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))	('HS-173', 'Var', (0, 6))	('ATM', 'Gene', '472', (78, 81))	('attenuated', 'NegReg', (26, 36))	('DNA-PKcs', 'Gene', '5591', (86, 94))	('DSBs', 'Chemical', '-', (178, 182))	('inhibiting', 'NegReg', (67, 77))
37187	29348875	Inhibition of the PI3K/AKT pathway has been shown to increase radiosensitivity in various cancers including glioblastoma, non-small cell lung cancer, colorectal cancer and head and neck squamous cell carcinoma.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('radiosensitivity', 'MPA', (62, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('neck', 'cellular_component', 'GO:0044326', ('181', '185'))	('non-small cell lung cancer', 'Disease', (122, 148))	('AKT', 'Gene', (23, 26))	('glioblastoma', 'Disease', (108, 120))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (172, 209))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('increase', 'PosReg', (53, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (150, 167))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (122, 148))	('neck squamous cell carcinoma', 'Disease', (181, 209))	('colorectal cancer', 'Disease', (150, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (186, 209))	('AKT', 'Gene', '207', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (181, 209))	('Inhibition', 'Var', (0, 10))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (126, 148))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (122, 148))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (53, 78))	('PI3K', 'molecular_function', 'GO:0016303', ('18', '22'))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('glioblastoma', 'Disease', 'MESH:D005909', (108, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))
37197	29348875	Our previous studies showed that HS-173 induces apoptotic cell death in various cancer cell types.	('induces', 'Reg', (40, 47))	('HS-173', 'Var', (33, 39))	('HS-173', 'Chemical', 'MESH:C577242', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('48', '68'))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('apoptotic cell death', 'CPA', (48, 68))	('cancer', 'Disease', (80, 86))
37214	29348875	As shown in Figure 4B, HS-173 significantly attenuated radiation-induced increases in the levels of p-AKT and p-ATM, indicating that HS-173 inhibited critical components of the DNA damage response in human Miapaca-2 and PANC-1 pancreatic cancer cells.	('pancreatic cancer', 'Disease', (227, 244))	('DNA damage response', 'MPA', (177, 196))	('pancreatic cancer', 'Disease', 'MESH:D010190', (227, 244))	('ATM', 'Gene', (112, 115))	('inhibited', 'NegReg', (140, 149))	('Miapaca-2', 'CellLine', 'CVCL:0428', (206, 215))	('HS-173', 'Var', (133, 139))	('HS-173', 'Chemical', 'MESH:C577242', (23, 29))	('PANC-1', 'CellLine', 'CVCL:0480', (220, 226))	('AKT', 'Gene', '207', (102, 105))	('human', 'Species', '9606', (200, 205))	('HS-173', 'Chemical', 'MESH:C577242', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (227, 244))	('ATM', 'Gene', '472', (112, 115))	('attenuated', 'NegReg', (44, 54))	('AKT', 'Gene', (102, 105))
37215	29348875	In addition, HS-173 increased the expression of gamma-H2AX, which is frequently used as a marker for DNA double-strand breaks (DSBs) following irradiation (Figure 4C).	('increased', 'PosReg', (20, 29))	('expression', 'MPA', (34, 44))	('HS-173', 'Chemical', 'MESH:C577242', (13, 19))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))	('DSBs', 'Chemical', '-', (127, 131))	('HS-173', 'Var', (13, 19))	('gamma-H2AX', 'Protein', (48, 58))
37218	29348875	We found that HS-173 inhibited radiation-induced activation of DNA-PKcs in pancreatic cancer cells in dose-dependent manner, thereby blocking phosphorylation of the downstream substrates, KAP1, and 53BP1, a marker for DSBs (Figure 5A).	('53BP1', 'Gene', '7158', (198, 203))	('DNA-PKcs', 'Gene', (63, 71))	('KAP1', 'Gene', '1033', (188, 192))	('HS-173', 'Chemical', 'MESH:C577242', (14, 20))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('DSBs', 'Chemical', '-', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('KAP1', 'Gene', (188, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (75, 92))	('phosphorylation', 'biological_process', 'GO:0016310', ('142', '157'))	('DNA-PKcs', 'Gene', '5591', (63, 71))	('inhibited', 'NegReg', (21, 30))	('phosphorylation', 'MPA', (142, 157))	('blocking', 'NegReg', (133, 141))	('pancreatic cancer', 'Disease', (75, 92))	('pancreatic cancer', 'Disease', 'MESH:D010190', (75, 92))	('HS-173', 'Var', (14, 20))	('53BP1', 'Gene', (198, 203))
37220	29348875	Collectively, these findings indicate that HS-173 inhibits DNA-PKcs and severely impairs the DSB repair response in irradiated pancreatic cancer cells.	('pancreatic cancer', 'Disease', (127, 144))	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('HS-173', 'Var', (43, 49))	('impairs', 'NegReg', (81, 88))	('HS-173', 'Chemical', 'MESH:C577242', (43, 49))	('DSB repair response', 'MPA', (93, 112))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('DSB', 'Chemical', '-', (93, 96))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))	('DNA-PKcs', 'Gene', '5591', (59, 67))	('inhibits', 'NegReg', (50, 58))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('DNA-PKcs', 'Gene', (59, 67))
37228	29348875	As shown in Figure 6D, the combination of HS-173 and radiation significantly inhibited the phosphorylation of ATM and DNA-PKcs.	('phosphorylation', 'MPA', (91, 106))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('DNA-PKcs', 'Gene', (118, 126))	('ATM', 'Gene', '472', (110, 113))	('inhibited', 'NegReg', (77, 86))	('HS-173', 'Chemical', 'MESH:C577242', (42, 48))	('phosphorylation', 'biological_process', 'GO:0016310', ('91', '106'))	('HS-173', 'Var', (42, 48))	('ATM', 'Gene', (110, 113))	('DNA-PKcs', 'Gene', '5591', (118, 126))
37229	29348875	Consequently, the combination treatment showed a significant reduction in phosphorylation of KAP1 and 53BP1, a marker for DSB repair (Figure 6E), implying that inhibition of ATM and DNA-PKcs is sufficient to inhibit downstream signaling through KAP-1 in pancreatic tumors.	('phosphorylation', 'MPA', (74, 89))	('53BP1', 'Gene', (102, 107))	('KAP-1', 'Gene', '1033', (245, 250))	('inhibit', 'NegReg', (208, 215))	('signaling', 'biological_process', 'GO:0023052', ('227', '236'))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (254, 271))	('reduction', 'NegReg', (61, 70))	('KAP1', 'Gene', '1033', (93, 97))	('DNA-PKcs', 'Gene', '5591', (182, 190))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))	('downstream signaling', 'MPA', (216, 236))	('DSB', 'Chemical', '-', (122, 125))	('ATM', 'Gene', (174, 177))	('pancreatic tumors', 'Disease', 'MESH:D010190', (254, 271))	('pancreatic tumors', 'Disease', (254, 271))	('inhibition', 'Var', (160, 170))	('KAP1', 'Gene', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('DNA-PKcs', 'Gene', (182, 190))	('53BP1', 'Gene', '7158', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('KAP-1', 'Gene', (245, 250))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (254, 270))	('DNA', 'cellular_component', 'GO:0005574', ('182', '185'))	('ATM', 'Gene', '472', (174, 177))
37239	29348875	In particular, K-Ras mutation has been found in more than 90% of pancreatic cancer patients, which activate Ras-dependent downstream effectors pathways including PI3K signaling.	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('PI3K signaling', 'biological_process', 'GO:0014065', ('162', '176'))	('K-Ras', 'Gene', (15, 20))	('pancreatic cancer', 'Disease', (65, 82))	('activate', 'PosReg', (99, 107))	('PI3K signaling', 'Pathway', (162, 176))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutation', 'Var', (21, 29))	('PI3K', 'molecular_function', 'GO:0016303', ('162', '166'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('patients', 'Species', '9606', (83, 91))	('Ras-dependent downstream effectors pathways', 'Pathway', (108, 151))
37242	29348875	HS-173 also enhanced radiation-induced apoptosis, as evidenced by increased levels of cleaved PARP and caspase-3 as well TUNEL-positive cells.	('increased', 'PosReg', (66, 75))	('HS-173', 'Chemical', 'MESH:C577242', (0, 6))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('caspase-3', 'Gene', '836', (103, 112))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))	('PARP', 'Gene', '1302', (94, 98))	('enhanced', 'PosReg', (12, 20))	('HS-173', 'Var', (0, 6))	('PARP', 'Gene', (94, 98))	('radiation-induced apoptosis', 'CPA', (21, 48))	('caspase-3', 'Gene', (103, 112))
37243	29348875	reported that the PI3K inhibitor BEZ-235 exerted synergistic effects with chemoradiation in the treatment of non-small lung cancer harboring K-Ras mutations.	('mutations', 'Var', (147, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('BEZ-235', 'Chemical', 'MESH:C531198', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('PI3K', 'molecular_function', 'GO:0016303', ('18', '22'))	('small lung', 'Phenotype', 'HP:0002089', (113, 123))	('non-small lung cancer', 'Disease', (109, 130))	('K-Ras', 'Gene', (141, 146))	('non-small lung cancer', 'Disease', 'MESH:D002289', (109, 130))	('BEZ-235', 'Gene', (33, 40))
37252	29348875	Indeed, it has been shown that the PI3K/AKT inhibitor BEZ-235 inhibits DNA damage response proteins, including ATM and DNA-PKcs, in glioma, and the PI3K inhibitor LY294002 enhances the efficacy of radiotherapy in cervical cancer.	('glioma', 'Disease', (132, 138))	('efficacy', 'CPA', (185, 193))	('ATM', 'Gene', '472', (111, 114))	('cervical cancer', 'Disease', (213, 228))	('cervical cancer', 'Disease', 'MESH:D002583', (213, 228))	('LY294002', 'Var', (163, 171))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('DNA', 'MPA', (71, 74))	('BEZ-235', 'Chemical', 'MESH:C531198', (54, 61))	('inhibits', 'NegReg', (62, 70))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('AKT', 'Gene', '207', (40, 43))	('DNA-PKcs', 'Gene', (119, 127))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('LY294002', 'Chemical', 'MESH:C085911', (163, 171))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))	('ATM', 'Gene', (111, 114))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('PI3K', 'molecular_function', 'GO:0016303', ('148', '152'))	('BEZ-235', 'Gene', (54, 61))	('DNA damage response', 'biological_process', 'GO:0006974', ('71', '90'))	('radiotherapy', 'CPA', (197, 209))	('DNA-PKcs', 'Gene', '5591', (119, 127))	('enhances', 'PosReg', (172, 180))	('AKT', 'Gene', (40, 43))
37255	29348875	HS-173 also inhibited expression of P-KAP1, downstream target of these kinases, in irradiated pancreatic cancer cells.	('inhibited', 'NegReg', (12, 21))	('pancreatic cancer', 'Disease', (94, 111))	('KAP1', 'Gene', '1033', (38, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('HS-173', 'Var', (0, 6))	('HS-173', 'Chemical', 'MESH:C577242', (0, 6))	('KAP1', 'Gene', (38, 42))	('expression', 'MPA', (22, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (94, 111))
37257	29348875	In accord with our results, a previous study reported that the PI3K inhibitor BEZ-235 radiosensitized non-small cell lung carcinoma cells expressing oncogenic K-Ras, an effect that was correlated with higher levels of radiation-induced DNA breaks.	('DNA', 'cellular_component', 'GO:0005574', ('236', '239'))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (106, 131))	('PI3K', 'molecular_function', 'GO:0016303', ('63', '67'))	('carcinoma', 'Disease', 'MESH:D002277', (122, 131))	('BEZ-235', 'Chemical', 'MESH:C531198', (78, 85))	('carcinoma', 'Disease', (122, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (102, 131))	('oncogenic K-Ras', 'Var', (149, 164))	('BEZ-235', 'Gene', (78, 85))
37258	29348875	ZSTK474, another PI3K inhibitor, has also been shown to inhibit DNA-PKcs activity.	('DNA-PKcs', 'Gene', '5591', (64, 72))	('ZSTK474', 'Chemical', 'MESH:C510150', (0, 7))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('DNA-PKcs', 'Gene', (64, 72))	('PI3K', 'molecular_function', 'GO:0016303', ('17', '21'))	('ZSTK474', 'Var', (0, 7))	('inhibit', 'NegReg', (56, 63))
37260	29348875	Gupta et al., examining radiosensitization by the PI3K inhibitor LY294002 in bladder cancer xenograft models, reported similar results.	('LY294002', 'Var', (65, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('PI3K', 'molecular_function', 'GO:0016303', ('50', '54'))	('bladder cancer', 'Disease', (77, 91))	('LY294002', 'Chemical', 'MESH:C085911', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
37308	29180468	For example, gemcitabine has been reported to decrease circulating myeloid-derived suppressor cells and support an immune stimulatory phenotype in tumor macrophages.	('gemcitabine', 'Chemical', 'MESH:C056507', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('immune stimulatory phenotype', 'MPA', (115, 143))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('gemcitabine', 'Var', (13, 24))	('circulating myeloid-derived suppressor cells', 'CPA', (55, 99))	('decrease', 'NegReg', (46, 54))
37315	29180468	Further, preclinical in vivo studies have demonstrated that silencing Axl gene expression in PDA tumor cells blocks tumor cell invasion and enhances animal survival.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Axl gene', 'Gene', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('animal survival', 'CPA', (149, 164))	('tumor', 'Disease', (97, 102))	('enhances', 'PosReg', (140, 148))	('PDA', 'Phenotype', 'HP:0006725', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('gene expression', 'biological_process', 'GO:0010467', ('74', '89'))	('silencing', 'Var', (60, 69))	('tumor', 'Disease', (116, 121))	('blocks', 'NegReg', (109, 115))
37375	29180468	Panc265, a human PDX resistant to gemcitabine therapy, and highly aggressive in the orthotopic setting, had the highest expression of Axl (Supplementary Fig.	('gemcitabine', 'Chemical', 'MESH:C056507', (34, 45))	('expression', 'MPA', (120, 130))	('Panc265', 'CellLine', 'CVCL:J809', (0, 7))	('human', 'Species', '9606', (11, 16))	('Panc265', 'Var', (0, 7))	('Axl', 'Protein', (134, 137))
37384	29180468	The effect of BGB324 treatment on KIC tumors was consistent with the effects on Axl signaling in vitro, as BGB324 treatment substantially suppressed Akt activation in tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('KIC tumors', 'Disease', (34, 44))	('tumors', 'Disease', (38, 44))	('activation', 'PosReg', (153, 163))	('Akt', 'Gene', (149, 152))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('KIC tumors', 'Disease', 'MESH:D009369', (34, 44))	('BGB324', 'Var', (107, 113))	('BGB324', 'Chemical', 'MESH:C548378', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('Akt', 'Gene', '11651', (149, 152))	('BGB324', 'Chemical', 'MESH:C548378', (14, 20))	('suppressed', 'NegReg', (138, 148))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
37433	29180468	TBK1 has been linked to the survival of mutant Kras-expressing cells and can directly activate Akt.	('TBK1', 'molecular_function', 'GO:0008384', ('0', '4'))	('Akt', 'Gene', '11651', (95, 98))	('TBK1', 'Gene', (0, 4))	('linked', 'Reg', (14, 20))	('Akt', 'Gene', (95, 98))	('activate', 'PosReg', (86, 94))	('mutant', 'Var', (40, 46))
37435	29180468	found that the conditional deletion of TBK1 from dendritic cells resulted in T cell activation, the promotion of autoimmunity, and enhanced T cell-mediated tumor immunity.	('T cell', 'CPA', (77, 83))	('autoimmunity', 'Phenotype', 'HP:0002960', (113, 125))	('TBK1', 'molecular_function', 'GO:0008384', ('39', '43'))	('T cell activation', 'biological_process', 'GO:0042110', ('77', '94'))	('activation', 'PosReg', (84, 94))	('promotion', 'PosReg', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('autoimmunity', 'Disease', (113, 125))	('deletion', 'Var', (27, 35))	('autoimmunity', 'Disease', 'MESH:D001327', (113, 125))	('enhanced T cell', 'Phenotype', 'HP:0100828', (131, 146))	('tumor', 'Disease', (156, 161))	('enhanced', 'PosReg', (131, 139))	('TBK1', 'Gene', (39, 43))
37445	25887245	Nab-paclitaxel in combination with gemcitabine has slightly improved survival in pancreatic cancer, compared to gemcitabine alone, as demonstrated in Phase III clinical trials.	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('gemcitabine', 'Chemical', 'MESH:C056507', (112, 123))	('Nab-paclitaxel', 'Var', (0, 14))	('gemcitabine', 'Chemical', 'MESH:C056507', (35, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('improved', 'PosReg', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('pancreatic cancer', 'Disease', (81, 98))	('survival', 'MPA', (69, 77))
37463	25887245	In the nab-paclitaxel-gemcitabine group the median overall survival was 8.5 months compared to 6.7 months in the gemcitabine-alone group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001).	('gemcitabine', 'Chemical', 'MESH:C056507', (113, 124))	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (7, 21))	('nab-paclitaxel-gemcitabine', 'Var', (7, 33))	('death', 'Disease', 'MESH:D003643', (155, 160))	('death', 'Disease', (155, 160))	('gemcitabine', 'Chemical', 'MESH:C056507', (22, 33))	('overall survival', 'MPA', (51, 67))
37464	25887245	The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, compared to 3.7 months in the gemcitabine-alone group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001).	('gemcitabine', 'Chemical', 'MESH:C056507', (74, 85))	('gemcitabine', 'Chemical', 'MESH:C056507', (123, 134))	('death', 'Disease', 'MESH:D003643', (188, 193))	('death', 'Disease', (188, 193))	('nab-paclitaxel-gemcitabine', 'Var', (59, 85))	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (59, 73))
37469	25887245	These authors showed that systemic administration of the enzyme agent PEGPH20 can decrease stromal hyaluronic acid (HA) in mouse models of pancreatic cancer, reducing IFP and re-expanding the microvasculature.	('mouse', 'Species', '10090', (123, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (139, 156))	('decrease', 'NegReg', (82, 90))	('reducing', 'NegReg', (158, 166))	('HA', 'Chemical', 'MESH:D006820', (116, 118))	('pancreatic cancer', 'Disease', (139, 156))	('pancreatic cancer', 'Disease', 'MESH:D010190', (139, 156))	('PEGPH20', 'Var', (70, 77))	('PEGPH20', 'Chemical', '-', (70, 77))	('IFP', 'MPA', (167, 170))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('microvasculature', 'MPA', (192, 208))
37470	25887245	In combination with gemcitabine, PEGPH20 remodeled the tumor microenvironment and increased overall survival of mouse models with pancreatic cancer.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('PEGPH20', 'Var', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('gemcitabine', 'Chemical', 'MESH:C056507', (20, 31))	('tumor', 'Disease', (55, 60))	('remodeled', 'Reg', (41, 50))	('PEGPH20', 'Chemical', '-', (33, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (130, 147))	('increased', 'PosReg', (82, 91))	('overall survival', 'CPA', (92, 108))	('mouse', 'Species', '10090', (112, 117))	('pancreatic cancer', 'Disease', (130, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (130, 147))
37486	25887245	These results suggest why most drugs currently in clinical use, which target cancer cells in S/G2/M including nab-paclitaxel, are mostly ineffective on solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('solid tumors', 'Disease', 'MESH:D009369', (152, 164))	('S/G2', 'SUBSTITUTION', 'None', (93, 97))	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (110, 124))	('ineffective', 'NegReg', (137, 148))	('cancer cell', 'Disease', (77, 88))	('cancer cell', 'Disease', 'MESH:C538614', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('solid tumors', 'Disease', (152, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('S/G2', 'Var', (93, 97))
37488	25887245	Time-lapse FUCCI imaging demonstrated that tumor-targeting Salmonella typhimurium A1-R decoyed FUCCI-expressing cancer cells in tumors growing in nude mice to cycle from G0/G1 to S/G2/M, thereby making them sensitive to cytotoxic agents.	('sensitive', 'MPA', (207, 216))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('S/G2', 'SUBSTITUTION', 'None', (179, 183))	('Salmonella typhimurium', 'Species', '90371', (59, 81))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (128, 134))	('cancer cell', 'Disease', (112, 123))	('tumor', 'Disease', (128, 133))	('S/G2', 'Var', (179, 183))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Disease', (43, 48))	('cancer cell', 'Disease', 'MESH:C538614', (112, 123))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('nude mice', 'Species', '10090', (146, 155))
37489	25887245	The combination of Salmonella typhimurium A1-R and paclitaxel reduced tumor size compared with A1-R monotherapy or paclitaxel alone (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('paclitaxel', 'Chemical', 'MESH:D017239', (115, 125))	('paclitaxel', 'Chemical', 'MESH:D017239', (51, 61))	('Salmonella typhimurium', 'Species', '90371', (19, 41))	('tumor', 'Disease', (70, 75))	('Salmonella typhimurium A1-R', 'Var', (19, 46))	('combination', 'Interaction', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('reduced', 'NegReg', (62, 69))
37492	25887245	If tumors can be cell-cycle decoyed by an agent, it is possible that nab-paclitaxel will have more efficacy against pancreatic cancer.	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (69, 83))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('nab-paclitaxel', 'Var', (69, 83))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('cell-cycle', 'biological_process', 'GO:0007049', ('17', '27'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('pancreatic cancer', 'Disease', (116, 133))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))
37495	25887245	Cancer cells can also be selectively trapped in S/G2 by methionine depletion, such as by recombinant methioninase (rMETase) (Figure 4).	('S/G2', 'SUBSTITUTION', 'None', (48, 52))	('rMETase', 'Gene', (115, 122))	('methionine depletion', 'MPA', (56, 76))	('rMETase', 'Gene', '29252', (115, 122))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('methionine', 'Chemical', 'MESH:D008715', (56, 66))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('S/G2', 'Var', (48, 52))
37546	28638788	Important factors affecting PC include the epigenomic changes driven by DNA methylation and histone acetylation, and actions of microRNA inducing oncogenic or tumor suppressor effects.	('tumor suppressor', 'biological_process', 'GO:0051726', ('159', '175'))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('oncogenic', 'CPA', (146, 155))	('tumor suppressor', 'Gene', '7248', (159, 175))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('159', '175'))	('DNA methylation', 'biological_process', 'GO:0006306', ('72', '87'))	('histone acetylation', 'MPA', (92, 111))	('histone acetylation', 'biological_process', 'GO:0016573', ('92', '111'))	('PC', 'Phenotype', 'HP:0002894', (28, 30))	('tumor suppressor', 'Gene', (159, 175))	('DNA methylation', 'Var', (72, 87))
37549	28638788	Dysregulated expression of these molecules can increase proliferation, survival, PCSC, resistance to chemotherapy and tumor angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('survival', 'CPA', (71, 79))	('expression', 'MPA', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('PC', 'Phenotype', 'HP:0002894', (81, 83))	('proliferation', 'CPA', (56, 69))	('angiogenesis', 'biological_process', 'GO:0001525', ('124', '136'))	('tumor', 'Disease', (118, 123))	('Dysregulated', 'Var', (0, 12))	('increase', 'PosReg', (47, 55))	('PCSC', 'Disease', (81, 85))	('resistance to chemotherapy', 'CPA', (87, 113))
37556	28638788	Crosstalk among these molecules increases proliferation, survival, cancer stem cells and resistance to chemotherapy.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('proliferation', 'CPA', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('resistance to chemotherapy', 'CPA', (89, 115))	('Crosstalk', 'Var', (0, 9))	('increases', 'PosReg', (32, 41))	('survival', 'CPA', (57, 65))
37560	28638788	Risk factors for the development of PC include tobacco usage, continuous exposure to such chemicals as dyes and pesticides, family history, age, epigenetic changes, and obesity.	('obesity', 'Disease', (169, 176))	('PC', 'Phenotype', 'HP:0002894', (36, 38))	('tobacco', 'Species', '4097', (47, 54))	('obesity', 'Phenotype', 'HP:0001513', (169, 176))	('epigenetic changes', 'Var', (145, 163))	('obesity', 'Disease', 'MESH:D009765', (169, 176))
37570	28638788	The dysregulation of microRNAs is another factor involved in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('dysregulation', 'Var', (4, 17))	('cancer', 'Disease', (61, 67))	('involved', 'Reg', (49, 57))	('microRNAs', 'Protein', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
37572	28638788	Accumulating data show important relationships between dysregulated miRNAs and cancer.	('miR', 'Gene', '220972', (68, 71))	('dysregulated', 'Var', (55, 67))	('miR', 'Gene', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('relationships', 'Interaction', (33, 46))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
37591	28638788	Individuals with a high risk of developing PC can be divided into underlying gene defect, like cyclin-dependent kinase Inhibitor 2A (CDKN2A), breast cancer gene 1 and 2 (BRCA1/2), partner and localizer of BRCA2 (PALB2), and serine/threonine kinase 11 (STK11) mutations.	('STK11', 'Gene', (252, 257))	('PA', 'Phenotype', 'HP:0006725', (212, 214))	('cyclin-dependent kinase Inhibitor 2A', 'Gene', '1029', (95, 131))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('cyclin-dependent kinase Inhibitor', 'molecular_function', 'GO:0004861', ('95', '128'))	('BRCA1/2', 'Gene', (170, 177))	('breast cancer', 'Disease', (142, 155))	('PALB2', 'Gene', (212, 217))	('serine/threonine kinase 11', 'Gene', (224, 250))	('CDKN2A', 'Gene', '1029', (133, 139))	('STK11', 'Gene', '6794', (252, 257))	('PALB2', 'Gene', '79728', (212, 217))	('kinase Inhibitor', 'biological_process', 'GO:0033673', ('112', '128'))	('BRCA1/2', 'Gene', '672;675', (170, 177))	('mutations', 'Var', (259, 268))	('BRCA2', 'Gene', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('STK11', 'molecular_function', 'GO:0033868', ('252', '257'))	('cyclin-dependent kinase Inhibitor 2A', 'Gene', (95, 131))	('PC', 'Phenotype', 'HP:0002894', (43, 45))	('serine/threonine kinase 11', 'Gene', '6794', (224, 250))	('CDKN2A', 'Gene', (133, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('BRCA2', 'Gene', '675', (205, 210))
37604	28638788	Overall, CTC detection was found in 11% of PC patients and associated with poor tumor differentiation (P = 0.04), and with shorter overall survival (RR = 2.5, P = 0.01).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('CTC detection', 'Var', (9, 22))	('patients', 'Species', '9606', (46, 54))	('shorter', 'NegReg', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PC', 'Phenotype', 'HP:0002894', (43, 45))	('poor', 'NegReg', (75, 79))	('overall', 'MPA', (131, 138))	('tumor', 'Disease', (80, 85))
37605	28638788	HDAC play a major role in the regulation of gene expression via epigenetics changes.	('HDAC', 'Gene', (0, 4))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('30', '59'))	('HDAC', 'Gene', '9734', (0, 4))	('epigenetics changes', 'Var', (64, 83))
37629	28638788	PC cell lines treated with MGCD0103 showed dose dependent growth arrest, apoptosis, and induction of p21, which mediated cell cycle arrest in G2/M phase.	('growth arrest', 'Disease', 'MESH:D006323', (58, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('121', '138'))	('cell cycle arrest', 'CPA', (121, 138))	('MGCD0103', 'Var', (27, 35))	('growth arrest', 'Disease', (58, 71))	('p21', 'Gene', (101, 104))	('apoptosis', 'CPA', (73, 82))	('PC', 'Phenotype', 'HP:0002894', (0, 2))	('growth arrest', 'Phenotype', 'HP:0001510', (58, 71))	('p21', 'Gene', '644914', (101, 104))	('induction', 'Reg', (88, 97))	('MGCD0103', 'Chemical', 'MESH:C523184', (27, 35))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (121, 138))	('M phase', 'biological_process', 'GO:0000279', ('145', '152'))
37631	28638788	Many studies have found strong correlations between dysregulated microRNAs and cancer.	('correlations', 'Interaction', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('dysregulated', 'Var', (52, 64))	('microRNAs', 'Protein', (65, 74))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
37637	28638788	Furthermore, knockdown of miR21 using lentiviral vectors inhibited cell proliferation in PC derived cell lines.	('miR21', 'Gene', (26, 31))	('inhibited', 'NegReg', (57, 66))	('PC', 'Phenotype', 'HP:0002894', (89, 91))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('miR21', 'Gene', '406991', (26, 31))	('cell proliferation in', 'CPA', (67, 88))	('knockdown', 'Var', (13, 22))
37638	28638788	In addition, miR21 was found to protect PC cell from apoptosis, and its knockdown resulted in the activation of mitochondrial pathway apoptosis via the downregulation of Bcl9 (a protein involved in Wnt Pathway), upregulation of Bax, and induction of Bim.	('Bcl9', 'Gene', (170, 174))	('downregulation', 'NegReg', (152, 166))	('activation', 'PosReg', (98, 108))	('PC', 'Phenotype', 'HP:0002894', (40, 42))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('upregulation', 'PosReg', (212, 224))	('mitochondrial pathway', 'Pathway', (112, 133))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('Bax', 'Gene', (228, 231))	('induction', 'Reg', (237, 246))	('Bax', 'Gene', '581', (228, 231))	('knockdown', 'Var', (72, 81))	('apoptosis', 'biological_process', 'GO:0097194', ('134', '143'))	('Bcl9', 'Gene', '607', (170, 174))	('Bim', 'CPA', (250, 253))	('miR21', 'Gene', (13, 18))	('apoptosis', 'biological_process', 'GO:0006915', ('134', '143'))	('miR21', 'Gene', '406991', (13, 18))
37683	28638788	Furthermore, the inhibition of angiotensin-II type-1 receptor (AT1) reversed obesity-augmented desmoplasia and PC growth and improved response to 5-FU chemotherapeutic in vivo.	('AT1', 'Gene', '185', (63, 66))	('response to 5-FU chemotherapeutic', 'MPA', (134, 167))	('angiotensin-II type-1 receptor', 'Gene', '185', (31, 61))	('obesity-augmented desmoplasia', 'Disease', (77, 106))	('PC', 'Phenotype', 'HP:0002894', (111, 113))	('obesity-augmented desmoplasia', 'Disease', 'MESH:D009765', (77, 106))	('angiotensin-II type-1 receptor', 'Gene', (31, 61))	('inhibition', 'Var', (17, 27))	('improved', 'PosReg', (125, 133))	('5-FU', 'Chemical', 'MESH:D005472', (146, 150))	('obesity', 'Phenotype', 'HP:0001513', (77, 84))	('AT1', 'Gene', (63, 66))
37698	28638788	Leptin binding to its receptor triggers an activation cascade of several canonical (JAK2/STAT3, MAPK, PI-3K/AKT1) and non-canonical signaling pathways (p38MAK, JNK and AMPK).	('AMPK', 'molecular_function', 'GO:0047322', ('168', '172'))	('AKT1', 'Gene', '207', (108, 112))	('JNK', 'Gene', (160, 163))	('activation', 'PosReg', (43, 53))	('Leptin', 'Gene', (0, 6))	('PI-3K', 'molecular_function', 'GO:0016303', ('102', '107'))	('STAT3', 'Gene', '6774', (89, 94))	('JAK', 'molecular_function', 'GO:0004713', ('84', '87'))	('JNK', 'Gene', '5599', (160, 163))	('AMPK', 'Gene', '5562', (168, 172))	('Leptin', 'Gene', '3952', (0, 6))	('AKT1', 'Gene', (108, 112))	('AMPK', 'molecular_function', 'GO:0050405', ('168', '172'))	('canonical', 'Pathway', (73, 82))	('JAK2', 'Gene', '3717', (84, 88))	('binding', 'molecular_function', 'GO:0005488', ('7', '14'))	('JNK', 'molecular_function', 'GO:0004705', ('160', '163'))	('MAPK', 'molecular_function', 'GO:0004707', ('96', '100'))	('AMPK', 'Gene', (168, 172))	('p38MAK', 'Var', (152, 158))	('AMPK', 'molecular_function', 'GO:0004691', ('168', '172'))	('binding', 'Interaction', (7, 14))	('JAK2', 'Gene', (84, 88))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('STAT3', 'Gene', (89, 94))
37706	28638788	Some studies have suggested that leptin resistance could be due to abnormalities of the leptin molecule while others believe the resistance might be due to impairment of OB-R function or deficient leptin transport.	('transport', 'biological_process', 'GO:0006810', ('204', '213'))	('deficient leptin', 'Phenotype', 'HP:0003292', (187, 203))	('abnormalities', 'Var', (67, 80))	('leptin resistance', 'MPA', (33, 50))	('impairment of OB-R function', 'Disease', 'MESH:D003072', (156, 183))	('leptin transport', 'MPA', (197, 213))	('abnormalities of the leptin molecule', 'Phenotype', 'HP:0004361', (67, 103))	('deficient', 'NegReg', (187, 196))	('impairment of OB-R function', 'Disease', (156, 183))	('leptin molecule', 'Protein', (88, 103))
37740	28638788	Studies have identified that the dysregulation of HDAC, miR21, miR200, leptin, and PCSC could play important roles in PC progression.	('dysregulation', 'Var', (33, 46))	('PC', 'Phenotype', 'HP:0002894', (118, 120))	('leptin', 'Gene', (71, 77))	('miR21', 'Gene', '406991', (56, 61))	('HDAC', 'Gene', (50, 54))	('roles', 'Reg', (109, 114))	('PCSC', 'Gene', (83, 87))	('HDAC', 'Gene', '9734', (50, 54))	('miR21', 'Gene', (56, 61))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))	('PC', 'Phenotype', 'HP:0002894', (83, 85))	('play', 'Reg', (94, 98))
37772	27081079	Kaplan-Meier survival analysis indicated that overall survival of 138 resected pancreatic cancer patients with positive LN16 was similar to that of 140 patients with unresectable, locally advanced disease (p = 0.080, Figure 2).	('LN16', 'Var', (120, 124))	('pancreatic cancer', 'Disease', 'MESH:D010190', (79, 96))	('positive LN16', 'Var', (111, 124))	('pancreatic cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (79, 96))	('patients', 'Species', '9606', (152, 160))	('patients', 'Species', '9606', (97, 105))
37773	27081079	The overall survival of LN16-positive patients was significantly worse than that of LN16-negative patients (p = 0.009, Figure 2).	('LN16-positive', 'Var', (24, 37))	('worse', 'NegReg', (65, 70))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (38, 46))
37782	27081079	Kaplan-Meier analysis found that overall survival of patients with LNR < 0.25 was significantly longer than that of patients with LNR >= 0.25 in LN16-positive cohort (p < 0.001, Figure 3).	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (116, 124))	('overall survival', 'CPA', (33, 49))	('longer', 'PosReg', (96, 102))	('LNR < 0.25', 'Var', (67, 77))
37793	27081079	However, a more recent study used an imaging agent to observe the lymphatic flow pathway for pancreatic head cancer, and found that the incidence of LN16 metastatic involvement was significantly higher than the incidence of LN14 involvement.	('pancreatic head cancer', 'Disease', 'MESH:D010190', (93, 115))	('higher', 'PosReg', (195, 201))	('LN16', 'Var', (149, 153))	('head cancer', 'Phenotype', 'HP:0012288', (104, 115))	('pancreatic head cancer', 'Disease', (93, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
37816	27081079	More recently, high preoperative CA125 level was identified to be an independent risk predictor for overall survival (OS) and recurrence-free survival (RFS) in patients with resected pancreatic cancer.	('high', 'Var', (15, 19))	('patients', 'Species', '9606', (160, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (183, 200))	('high preoperative CA125 level', 'Phenotype', 'HP:0031030', (15, 44))	('CA125', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('recurrence-free survival', 'CPA', (126, 150))	('pancreatic cancer', 'Disease', 'MESH:D010190', (183, 200))	('pancreatic cancer', 'Disease', (183, 200))	('CA125', 'Gene', '94025', (33, 38))	('overall', 'Disease', (100, 107))
37817	27081079	In this study, we have found that although positive LN16 indicates an overall poor survival outcome, the subgroup of patients with CA125 < 18.62 U/ml might still benefit from surgery.	('positive', 'Var', (43, 51))	('CA125', 'Gene', (131, 136))	('patients', 'Species', '9606', (117, 125))	('CA125', 'Gene', '94025', (131, 136))	('LN16', 'Gene', (52, 56))
37823	27081079	Although LN16 involvement indicates a poor overall prognosis, metastasis to LN16 could lead to different surgical outcomes, depending on the preoperative serum CA125 levels.	('metastasis', 'Var', (62, 72))	('CA125', 'Gene', (160, 165))	('lead to', 'Reg', (87, 94))	('LN16', 'Gene', (9, 13))	('LN16', 'Gene', (76, 80))	('CA125', 'Gene', '94025', (160, 165))
37838	27081079	MUC16 and JAK2 expressions were categorized into - (score 0), + (score 1), ++ (score 2), and +++ (score 3).	('MUC16', 'Gene', '94025', (0, 5))	('JAK', 'molecular_function', 'GO:0004713', ('10', '13'))	('JAK2', 'Gene', '3717', (10, 14))	('JAK2', 'Gene', (10, 14))	('MUC16', 'Gene', (0, 5))	('+++', 'Var', (93, 96))
37857	27170998	For example, in patients with metastatic colorectal cancer the genetic analysis of the KRAS mutation and microsatellite instability is routinely performed to select those that may benefit from therapy with biological agents targeting these mutations.	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('KRAS', 'Gene', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutation', 'Var', (92, 100))	('KRAS', 'Gene', '3845', (87, 91))	('colorectal cancer', 'Disease', (41, 58))	('patients', 'Species', '9606', (16, 24))	('colorectal cancer', 'Disease', 'MESH:D015179', (41, 58))
37970	27170998	Particularly in mouse models, experimentally induced chronic pancreatitis combined with targeted expression of oncogenic mutant KrasG12V in pancreatic acini have been shown to induce PDAC formation in mouse models.	('mutant', 'Var', (121, 127))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (53, 73))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (53, 73))	('formation', 'biological_process', 'GO:0009058', ('188', '197'))	('pancreatitis', 'Phenotype', 'HP:0001733', (61, 73))	('induce', 'Reg', (176, 182))	('PDAC', 'Chemical', '-', (183, 187))	('KrasG12V', 'Gene', (128, 136))	('men', 'Species', '9606', (36, 39))	('pancreatic', 'Disease', 'MESH:D010195', (140, 150))	('chronic pancreatitis', 'Disease', (53, 73))	('mouse', 'Species', '10090', (16, 21))	('pancreatic', 'Disease', (140, 150))	('mouse', 'Species', '10090', (201, 206))	('PDAC', 'Disease', (183, 187))
38039	27082562	Patients had to have hematologic function as defined by an absolute neutrophil count (ANC) >=1500/mm3 and a platelet count >=100,000/mm3 obtained within 2 weeks before the first dose of study medication.	('Patients', 'Species', '9606', (0, 8))	('>=1500/mm3', 'Var', (91, 101))	('as', 'Chemical', 'MESH:D001151', (42, 44))	('absolute neutrophil count', 'CPA', (59, 84))
38074	27082562	Progression-free and overall survival was significantly longer in subjects with targeted treatment compared with those with conventional treatment (Figure 1A and B).	('overall survival', 'CPA', (21, 37))	('targeted treatment', 'Var', (80, 98))	('Progression-free', 'CPA', (0, 16))	('longer', 'PosReg', (56, 62))	('as', 'Chemical', 'MESH:D001151', (39, 41))
38078	27082562	Similar to progression-free survival, targeted therapy was associated with longer overall survival than conventional therapy in patients <=60 years of age (12 months vs. 5 months, respectively; P = 0.002) (Figure 3A).	('longer', 'PosReg', (75, 81))	('as', 'Chemical', 'MESH:D001151', (59, 61))	('overall survival', 'MPA', (82, 98))	('as', 'Chemical', 'MESH:D001151', (56, 58))	('patients', 'Species', '9606', (128, 136))	('targeted therapy', 'Var', (38, 54))
38092	27082562	Patients who received cetuximab, bevacizumab, and gemcitabine had longer median progression-free survival (3.53 months) and overall survival (5.41 months) than patients who only received cetuximab and bevacizumab (1.91 and 4.17 months, respectively).	('overall survival', 'CPA', (124, 140))	('patients', 'Species', '9606', (160, 168))	('bevacizumab', 'Chemical', 'MESH:D000068258', (201, 212))	('bevacizumab', 'Chemical', 'MESH:D000068258', (33, 44))	('cetuximab', 'Var', (22, 31))	('progression-free survival', 'CPA', (80, 105))	('cetuximab', 'Chemical', 'MESH:D000068818', (187, 196))	('Patients', 'Species', '9606', (0, 8))	('gemcitabine', 'Chemical', 'MESH:C056507', (50, 61))	('longer', 'PosReg', (66, 72))	('cetuximab', 'Chemical', 'MESH:D000068818', (22, 31))
38141	26716653	Similarly, tumors with low alphaSMA expression were significantly associated with higher incidence of low-grade (G1) and lower incidence of high-grade (G2-3) tumors.	('tumors', 'Disease', (158, 164))	('low-grade', 'CPA', (102, 111))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('expression', 'MPA', (36, 46))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('low', 'Var', (23, 26))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('alphaSMA', 'Gene', '11475', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('alphaSMA', 'Gene', (27, 35))
38151	26716653	In the Cox model, highly-dense stroma was confirmed as an independent prognostic parameter for OS (p = 0.001), PFS (p = 0.007), LPFS (p = 0.001) and DMFS (p = 0.002), whereas no significance was found for alphaSMA expression.	('Cox', 'Gene', '1351', (7, 10))	('alphaSMA', 'Gene', (205, 213))	('PFS', 'Disease', (111, 114))	('Cox', 'Gene', (7, 10))	('alphaSMA', 'Gene', '11475', (205, 213))	('DMFS', 'Var', (149, 153))	('DMFS', 'Chemical', '-', (149, 153))	('LPFS', 'Disease', (128, 132))
38155	26716653	Similarly, moderate and strong alphaSMA expression was associated with a less favourable outcome only in patients with stage pT1-2 tumors (OS: p = 0.016; PFS: p = 0.004; LPFS: p = 0.013; DMFS: p = 0.004), whereas no significance was detected for pT3-4 disease (Figure 3, Table 3).	('alphaSMA', 'Gene', '11475', (31, 39))	('pT1', 'Gene', '58492', (125, 128))	('patients', 'Species', '9606', (105, 113))	('pT3', 'Gene', (246, 249))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('DMFS', 'Chemical', '-', (187, 191))	('pT1', 'Gene', (125, 128))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('pT3', 'Gene', '7694', (246, 249))	('alphaSMA', 'Gene', (31, 39))	('moderate', 'Var', (11, 19))
38164	26716653	showed that high alphaSMA mRNA levels correlated with worse outcome in 109 patients that received surgery but this cohort was characterised by high heterogeneity as five different adjuvant chemotherapy regimens were administered.	('alphaSMA', 'Gene', '11475', (17, 25))	('alphaSMA', 'Gene', (17, 25))	('patients', 'Species', '9606', (75, 83))	('high', 'Var', (12, 16))
38168	26716653	In contrast to the above findings, a recent work by Kalluri and colleagues revealed improved outcome for high alphaSMA expression in 53 patients with PDAC.	('alphaSMA', 'Gene', (110, 118))	('high', 'Var', (105, 109))	('PDAC', 'Chemical', '-', (150, 154))	('outcome', 'MPA', (93, 100))	('alphaSMA', 'Gene', '11475', (110, 118))	('PDAC', 'Phenotype', 'HP:0006725', (150, 154))	('patients', 'Species', '9606', (136, 144))	('improved', 'PosReg', (84, 92))
38169	26716653	Genetic depletion of alphaSMA-positive myofibroblasts in a genetically-engineered mouse model (GEMM) of PDAC was associated with decreased ECM content and led to increased tumor progression and decreased survival.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mouse', 'Species', '10090', (82, 87))	('ECM content', 'MPA', (139, 150))	('depletion', 'Var', (8, 17))	('PDAC', 'Chemical', '-', (104, 108))	('increased', 'PosReg', (162, 171))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('PDAC', 'Phenotype', 'HP:0006725', (104, 108))	('decreased', 'NegReg', (194, 203))	('GEM', 'Chemical', '-', (95, 98))	('decreased', 'NegReg', (129, 138))	('alphaSMA', 'Gene', (21, 29))	('survival', 'CPA', (204, 212))	('alphaSMA', 'Gene', '11475', (21, 29))
38170	26716653	Stanger and colleagues reported similar findings after genetic or pharmacologic depletion of sonic hedgehog in a different GEMM that led to reduced desmoplasia associated with accelerated tumor growth and metastasis.	('tumor', 'Disease', (188, 193))	('desmoplasia', 'Disease', (148, 159))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('GEM', 'Chemical', '-', (123, 126))	('sonic hedgehog', 'Gene', (93, 107))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('desmoplasia', 'Disease', 'None', (148, 159))	('depletion', 'Var', (80, 89))	('reduced', 'NegReg', (140, 147))	('accelerated', 'PosReg', (176, 187))
38172	26716653	showed that the combination of high alphaSMA and low collagen expression, defined as activated stroma index, was associated with worse outcome but alphaSMA alone lacked a prognostic role.	('collagen expression', 'MPA', (53, 72))	('alphaSMA', 'Gene', (36, 44))	('alphaSMA', 'Gene', '11475', (36, 44))	('low', 'NegReg', (49, 52))	('low collagen expression', 'Phenotype', 'HP:0030095', (49, 72))	('alphaSMA', 'Gene', (147, 155))	('high', 'Var', (31, 35))	('collagen', 'molecular_function', 'GO:0005202', ('53', '61'))	('alphaSMA', 'Gene', '11475', (147, 155))
38239	25762644	Using data from The Cancer Genome Atlas we demonstrate that a subset of PDACs exhibits a strong pro-angiogenic signature that includes 37 genes, such as HDAC9, that are overexpressed in PDAC arising in KRC mice, which express mutated Kras and lack RB.	('pro-angiogenic signature', 'MPA', (96, 120))	('HDAC9', 'Gene', (153, 158))	('mice', 'Species', '10090', (206, 210))	('Cancer', 'Phenotype', 'HP:0002664', (20, 26))	('PDAC', 'Chemical', '-', (186, 190))	('PDAC', 'Chemical', '-', (72, 76))	('Kras', 'Gene', (234, 238))	('Kras', 'Gene', '16653', (234, 238))	('Cancer Genome Atlas', 'Disease', (20, 39))	('overexpressed', 'PosReg', (169, 182))	('PDAC', 'Phenotype', 'HP:0006725', (72, 76))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (20, 39))	('PDACs', 'Chemical', '-', (72, 77))	('RB', 'Chemical', 'MESH:D012413', (248, 250))	('PDAC', 'Phenotype', 'HP:0006725', (186, 190))	('mutated', 'Var', (226, 233))
38241	25762644	Inhibition of the type I TGF-beta receptor with SB505124 does not alter endothelial activation in vitro, but decreases pro-angiogenic gene expression and suppresses angiogenesis in vivo.	('angiogenesis', 'biological_process', 'GO:0001525', ('165', '177'))	('SB505124', 'Var', (48, 56))	('suppresses', 'NegReg', (154, 164))	('pro-angiogenic gene expression', 'MPA', (119, 149))	('SB505124', 'Chemical', 'MESH:C519132', (48, 56))	('angiogenesis', 'CPA', (165, 177))	('gene expression', 'biological_process', 'GO:0010467', ('134', '149'))	('decreases', 'NegReg', (109, 118))
38244	25762644	Thus, targeting JAK1-2 with ruxolitinib blocks a final pathway that is common to multiple pro-angiogenic factors, suppresses EC-mediated PCC proliferation, and may be useful in PDACs with a strong pro-angiogenic signature.	('blocks', 'NegReg', (40, 46))	('PDACs', 'Chemical', '-', (177, 182))	('PCC', 'Gene', (137, 140))	('PDAC', 'Phenotype', 'HP:0006725', (177, 181))	('PCC', 'cellular_component', 'GO:0120205', ('137', '140'))	('ruxolitinib', 'Chemical', 'MESH:C540383', (28, 39))	('targeting', 'Var', (6, 15))	('JAK', 'molecular_function', 'GO:0004713', ('16', '19'))	('JAK1-2', 'Gene', (16, 22))	('PCC', 'Gene', '1421', (137, 140))	('final pathway', 'Pathway', (49, 62))	('suppresses', 'NegReg', (114, 124))
38252	25762644	However, a separate GEMM-based study using KPfl/+C mice, which also express mutated Kras but have p53 haploinsufficiency, suggested that stroma depletion worsens disease, but that it is reversible by anti-angiogenesis therapy with a VEGFR2 blocking antibody.	('antibody', 'cellular_component', 'GO:0019814', ('249', '257'))	('antibody', 'molecular_function', 'GO:0003823', ('249', '257'))	('haploinsufficiency', 'Disease', 'MESH:D058495', (102, 120))	('mice', 'Species', '10090', (51, 55))	('Kras', 'Gene', (84, 88))	('Kras', 'Gene', '16653', (84, 88))	('VEGFR2', 'Gene', (233, 239))	('worsens', 'NegReg', (154, 161))	('mutated', 'Var', (76, 83))	('angiogenesis', 'biological_process', 'GO:0001525', ('205', '217'))	('antibody', 'cellular_component', 'GO:0042571', ('249', '257'))	('haploinsufficiency', 'Disease', (102, 120))	('p53', 'Gene', (98, 101))	('VEGFR2', 'Gene', '16542', (233, 239))	('disease', 'MPA', (162, 169))	('antibody', 'cellular_component', 'GO:0019815', ('249', '257'))	('p53', 'Gene', '22059', (98, 101))
38254	25762644	Although studies in certain murine models raise the possibility that VEGFR signaling may have an important role in PDAC, targeting VEGF-A either with bevacizumab, an anti-VEGF-A antibody, or with VEGF Trap, which sequesters VEGF, has failed in clinical trials in PDAC patients.	('PDAC', 'Disease', (115, 119))	('PDAC', 'Chemical', '-', (263, 267))	('PDAC', 'Phenotype', 'HP:0006725', (115, 119))	('antibody', 'molecular_function', 'GO:0003823', ('178', '186'))	('PDAC', 'Phenotype', 'HP:0006725', (263, 267))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('EGFR', 'Gene', '13649', (70, 74))	('antibody', 'cellular_component', 'GO:0042571', ('178', '186'))	('bevacizumab', 'Chemical', 'MESH:D000068258', (150, 161))	('VEGF-A', 'Gene', (131, 137))	('EGFR', 'Gene', (70, 74))	('PDAC', 'Chemical', '-', (115, 119))	('murine', 'Species', '10090', (28, 34))	('antibody', 'cellular_component', 'GO:0019815', ('178', '186'))	('targeting', 'Var', (121, 130))	('antibody', 'cellular_component', 'GO:0019814', ('178', '186'))	('patients', 'Species', '9606', (268, 276))
38260	25762644	The KRC compound mutant mice express oncogenic Kras in the pancreas which is devoid of RB due to Pdx1-driven Cre recombination (22).	('Kras', 'Gene', (47, 51))	('Pdx1', 'Gene', (97, 101))	('mice', 'Species', '10090', (24, 28))	('KRC', 'Gene', (4, 7))	('Kras', 'Gene', '16653', (47, 51))	('Pdx1', 'Gene', '18609', (97, 101))	('RB', 'Chemical', 'MESH:D012413', (87, 89))	('mutant', 'Var', (17, 23))
38265	25762644	Moreover, we show that KRC mPDACs express a pro-angiogenic gene signature that overlaps with many of the genes in the above TCGA subset, and that inhibiting JAK1-2 signaling markedly prolongs survival in this model and suppresses cancer progression in vivo, while preventing ECs from stimulating PCC growth in culture.	('prolongs', 'PosReg', (183, 191))	('PCC', 'Gene', '1421', (296, 299))	('survival', 'CPA', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('PCC', 'cellular_component', 'GO:0120205', ('296', '299'))	('suppresses', 'NegReg', (219, 229))	('PCC', 'Gene', (296, 299))	('JAK', 'molecular_function', 'GO:0004713', ('157', '160'))	('inhibiting', 'Var', (146, 156))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('PDACs', 'Chemical', '-', (28, 33))	('PDAC', 'Phenotype', 'HP:0006725', (28, 32))	('JAK1-2', 'MPA', (157, 163))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))
38295	25762644	Akin to human PDAC, which is commonly associated with a high frequency of KRAS mutations (95%) and loss of RB function, KRC mPDACs express high levels of pro-angiogenic cytokines.	('PDAC', 'Chemical', '-', (14, 18))	('PDACs', 'Chemical', '-', (125, 130))	('PDAC', 'Chemical', '-', (125, 129))	('PDAC', 'Phenotype', 'HP:0006725', (14, 18))	('RB', 'Chemical', 'MESH:D012413', (107, 109))	('human', 'Species', '9606', (8, 13))	('KRC', 'Var', (120, 123))	('mutations', 'Var', (79, 88))	('PDAC', 'Phenotype', 'HP:0006725', (125, 129))
38316	25762644	Moreover, KRC mPDACs (Figure 3C) and human PDACs are often associated with nuclear p-Smad2 and p-Smad3, indicating that canonical TGF-beta signaling pathways are active in both settings, and raising the possibility that PDAC-derived TGF-betas could promote angiogenesis.	('promote', 'PosReg', (249, 256))	('PDAC', 'Phenotype', 'HP:0006725', (15, 19))	('PDAC', 'Chemical', '-', (220, 224))	('PDACs', 'Chemical', '-', (15, 20))	('PDAC', 'Phenotype', 'HP:0006725', (43, 47))	('PDACs', 'Chemical', '-', (43, 48))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('angiogenesis', 'CPA', (257, 269))	('PDAC', 'Chemical', '-', (15, 19))	('PDAC', 'Phenotype', 'HP:0006725', (220, 224))	('angiogenesis', 'biological_process', 'GO:0001525', ('257', '269'))	('human', 'Species', '9606', (37, 42))	('PDAC', 'Chemical', '-', (43, 47))	('p-Smad3', 'Var', (95, 102))
38318	25762644	Moreover, in a syngeneic orthotopic model using KRC cells, inhibition of TGF-beta attenuates tumor growth and metastasis, and markedly prolongs survival.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('survival', 'CPA', (144, 152))	('prolongs', 'PosReg', (135, 143))	('TGF-beta', 'Gene', (73, 81))	('attenuates tumor', 'Disease', (82, 98))	('attenuates tumor', 'Disease', 'MESH:C538265', (82, 98))	('inhibition', 'Var', (59, 69))
38319	25762644	Inasmuch as blocking TGF-beta signaling suppresses tumor angiogenesis in immune-deficient orthotopic models using human PCCs, we next evaluated the consequences of TGF-beta type I receptor (TbetaRI) kinase inhibition with SB505124 on angiogenesis in a syngeneic KRC orthotopic model.	('TbetaRI', 'Gene', (190, 197))	('human', 'Species', '9606', (114, 119))	('TGF-beta type I receptor', 'Gene', '7046', (164, 188))	('angiogenesis', 'biological_process', 'GO:0001525', ('57', '69'))	('inhibition', 'NegReg', (206, 216))	('SB505124', 'Chemical', 'MESH:C519132', (222, 230))	('tumor', 'Disease', (51, 56))	('signaling', 'biological_process', 'GO:0023052', ('30', '39'))	('blocking', 'Var', (12, 20))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('suppresses', 'NegReg', (40, 50))	('PCC', 'Gene', (120, 123))	('angiogenesis', 'biological_process', 'GO:0001525', ('234', '246'))	('TbetaRI', 'Gene', '7046', (190, 197))	('PCC', 'Gene', '1421', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('TGF-beta type I receptor', 'Gene', (164, 188))	('SB505124', 'Gene', (222, 230))	('TGF-beta', 'Gene', (21, 29))
38320	25762644	Compared with vehicle-treated tumors, CD31 and CD34 immunoreactivity was attenuated in the tumors of mice treated with SB505124 a (Figure 3D), suggesting that TGF-beta signaling enhances angiogenesis in these tumors in vivo.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('SB505124 a', 'Var', (119, 129))	('mice', 'Species', '10090', (101, 105))	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('attenuated', 'NegReg', (73, 83))	('CD31', 'Protein', (38, 42))	('SB505124 a', 'Chemical', '-', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumors', 'Disease', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('angiogenesis', 'CPA', (187, 199))	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Disease', (209, 215))	('CD34 immunoreactivity', 'MPA', (47, 68))	('angiogenesis', 'biological_process', 'GO:0001525', ('187', '199'))	('enhances', 'PosReg', (178, 186))
38324	25762644	However, SB505124 failed to block the ability of KRC-derived CM to stimulate EC proliferation or migration (Figure 5F), indicating that TGF-beta does not directly enhance angiogenesis.	('migration', 'CPA', (97, 106))	('SB505124', 'Var', (9, 17))	('EC proliferation', 'CPA', (77, 93))	('SB505124', 'Chemical', 'MESH:C519132', (9, 17))
38327	25762644	SB505124 markedly suppressed the levels of all five mRNAs (Figure 3G).	('suppressed', 'NegReg', (18, 28))	('SB505124', 'Chemical', 'MESH:C519132', (0, 8))	('SB505124', 'Var', (0, 8))	('levels of all five mRNAs', 'MPA', (33, 57))
38340	25762644	Moreover, STAT3 silencing or ruxolitinib prevented KRC CM from significantly increasing Hdac9 mRNA levels (Figure 4F).	('Hdac9', 'Gene', '79221', (88, 93))	('increasing', 'PosReg', (77, 87))	('KRC CM', 'Disease', (51, 57))	('ruxolitinib', 'Chemical', 'MESH:C540383', (29, 40))	('Hdac9', 'Gene', (88, 93))	('prevented', 'NegReg', (41, 50))	('STAT3', 'Var', (10, 15))
38349	25762644	Therefore, we next used this GEMM to determine if inhibiting JAK1-2 with ruxolitinib could act to impede angiogenesis and suppress PanIN progression and mPDAC growth.	('PanIN progression', 'CPA', (131, 148))	('PDAC', 'Chemical', '-', (154, 158))	('angiogenesis', 'CPA', (105, 117))	('mPDAC growth', 'CPA', (153, 165))	('ruxolitinib', 'Chemical', 'MESH:C540383', (73, 84))	('PDAC', 'Phenotype', 'HP:0006725', (154, 158))	('angiogenesis', 'biological_process', 'GO:0001525', ('105', '117'))	('inhibiting', 'Var', (50, 60))	('impede', 'NegReg', (98, 104))	('JAK', 'molecular_function', 'GO:0004713', ('61', '64'))	('suppress', 'NegReg', (122, 130))	('JAK1-2', 'Gene', (61, 67))
38354	25762644	Remarkably, the pancreata of KRC mice receiving ruxolitinib were mostly normal, and only displayed small foci of ADM (Figure 5B) that exhibited weak p-STAT3 immunoreactivity and markedly attenuated proliferation, and were associated with few ECs (Figure 5C) in which nuclear p-STAT3 and HDAC9 immunoreactivity was markedly attenuated (Figure 5D).	('weak', 'NegReg', (144, 148))	('p-STAT3', 'MPA', (149, 156))	('ruxolitinib', 'Var', (48, 59))	('ruxolitinib', 'Chemical', 'MESH:C540383', (48, 59))	('attenuated', 'NegReg', (323, 333))	('attenuated', 'NegReg', (187, 197))	('proliferation', 'CPA', (198, 211))	('mice', 'Species', '10090', (33, 37))
38357	25762644	Therefore, ruxolitinib attenuates ADM progression to PanIN and mPDAC, while suppressing angiogenesis and markedly prolonging survival in this autochthonous model.	('ruxolitinib', 'Var', (11, 22))	('prolonging', 'NegReg', (114, 124))	('PDAC', 'Phenotype', 'HP:0006725', (64, 68))	('ruxolitinib', 'Chemical', 'MESH:C540383', (11, 22))	('angiogenesis', 'CPA', (88, 100))	('ADM', 'MPA', (34, 37))	('survival', 'CPA', (125, 133))	('PDAC', 'Chemical', '-', (64, 68))	('suppressing', 'NegReg', (76, 87))	('attenuates', 'NegReg', (23, 33))	('angiogenesis', 'biological_process', 'GO:0001525', ('88', '100'))
38358	25762644	In contrast to KRC tumors, mPDACs arising in KPC mice which express oncogenic Kras together with mutated p53, did not exhibit Hdac9 up-regulation or a pro-angiogenic gene signature that was present in KRC and human PDACs (Supplementary Figure 5A-5B).	('human', 'Species', '9606', (209, 214))	('Kras', 'Gene', (78, 82))	('Kras', 'Gene', '16653', (78, 82))	('KRC tumors', 'Disease', 'MESH:D009369', (15, 25))	('PDAC', 'Phenotype', 'HP:0006725', (215, 219))	('mutated', 'Var', (97, 104))	('KRC tumors', 'Disease', (15, 25))	('PDACs', 'Chemical', '-', (215, 220))	('regulation', 'biological_process', 'GO:0065007', ('135', '145'))	('Hdac9', 'Gene', '79221', (126, 131))	('mice', 'Species', '10090', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '22059', (105, 108))	('PDACs', 'Chemical', '-', (28, 33))	('PDAC', 'Phenotype', 'HP:0006725', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('Hdac9', 'Gene', (126, 131))
38359	25762644	Therefore, we next used this GEMM to determine whether targeting JAK1-2 with ruxolitinib suppresses PanIN progression and mPDAC growth in a GEMM lacking tumor angiogenesis.	('ruxolitinib', 'Chemical', 'MESH:C540383', (77, 88))	('PanIN progression', 'MPA', (100, 117))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('PDAC', 'Phenotype', 'HP:0006725', (123, 127))	('JAK1-2', 'Gene', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('suppresses', 'NegReg', (89, 99))	('angiogenesis', 'biological_process', 'GO:0001525', ('159', '171'))	('JAK', 'molecular_function', 'GO:0004713', ('65', '68'))	('targeting', 'Var', (55, 64))	('PDAC', 'Chemical', '-', (123, 127))
38369	25762644	However, this is a daunting task given the complexity of the molecular alterations and mutations in PDAC.	('PDAC', 'Phenotype', 'HP:0006725', (100, 104))	('PDAC', 'Chemical', '-', (100, 104))	('PDAC', 'Gene', (100, 104))	('mutations', 'Var', (87, 96))
38382	25762644	By contrast, KPC mice develop hypovascular mPDACs that have minimal blood flow, KTC mice (oncogenic Kras with deletion of the type II TGF-beta receptor) exhibit tumor angiogenesis, whereas in KPfl/+CY mice (oncogenic Kras and heterozygous p53 loss) exhibit suppressed angiogenesis.	('TGF-beta', 'Gene', (134, 142))	('Kras', 'Gene', (217, 221))	('deletion', 'Var', (110, 118))	('tumor', 'Disease', (161, 166))	('mice', 'Species', '10090', (84, 88))	('PDAC', 'Phenotype', 'HP:0006725', (44, 48))	('hypovascular', 'Disease', (30, 42))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('angiogenesis', 'biological_process', 'GO:0001525', ('167', '179'))	('mice', 'Species', '10090', (201, 205))	('p53', 'Gene', (239, 242))	('Kras', 'Gene', '16653', (217, 221))	('mice', 'Species', '10090', (17, 21))	('Kras', 'Gene', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('angiogenesis', 'biological_process', 'GO:0001525', ('268', '280'))	('hypovascular', 'Disease', 'None', (30, 42))	('PDACs', 'Chemical', '-', (44, 49))	('Kras', 'Gene', '16653', (100, 104))	('p53', 'Gene', '22059', (239, 242))
38390	25762644	By contrast, JAK1-2 inhibition with ruxolitinib or STAT3 silencing prevented PCC-derived factors from enhancing STAT3-dependent transcription, as determined in a STAT3 luciferase reporter assay.	('prevented', 'NegReg', (67, 76))	('transcription', 'biological_process', 'GO:0006351', ('128', '141'))	('enhancing', 'PosReg', (102, 111))	('STAT3', 'Gene', (51, 56))	('JAK', 'molecular_function', 'GO:0004713', ('13', '16'))	('silencing', 'Var', (57, 66))	('STAT3-dependent transcription', 'MPA', (112, 141))	('PCC', 'Gene', '1421', (77, 80))	('PCC', 'cellular_component', 'GO:0120205', ('77', '80'))	('ruxolitinib', 'Chemical', 'MESH:C540383', (36, 47))	('PCC', 'Gene', (77, 80))
38396	25762644	Oncogenic Kras has been previously shown to upregulate VEGF-A and GM-CSF expression.	('upregulate', 'PosReg', (44, 54))	('Kras', 'Gene', (10, 14))	('VEGF-A', 'Gene', (55, 61))	('expression', 'MPA', (73, 83))	('GM-CSF', 'Gene', (66, 72))	('Kras', 'Gene', '16653', (10, 14))	('Oncogenic', 'Var', (0, 9))	('GM-CSF', 'Gene', '12981', (66, 72))
38402	25762644	Moreover, when oncogenic Kras is combined with loss of p53, both EGFR and STAT3 must be suppressed to block mPDAC development, underscoring the importance of STAT3 in the earliest stages of PDAC progression.	('PDAC', 'Phenotype', 'HP:0006725', (190, 194))	('mPDAC development', 'CPA', (108, 125))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '22059', (55, 58))	('EGFR', 'Gene', (65, 69))	('EGFR', 'Gene', '13649', (65, 69))	('PDAC', 'Phenotype', 'HP:0006725', (109, 113))	('PDAC', 'Chemical', '-', (190, 194))	('Kras', 'Gene', (25, 29))	('Kras', 'Gene', '16653', (25, 29))	('loss', 'Var', (47, 51))	('PDAC', 'Chemical', '-', (109, 113))	('block', 'NegReg', (102, 107))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))
38406	25762644	Impressively, when administered at an age when mPDAC has already developed, ruxolitinib suppressed tumor angiogenesis and disease progression in KRC mice, dramatically prolonging their survival.	('tumor', 'Disease', (99, 104))	('ruxolitinib', 'Var', (76, 87))	('PDAC', 'Chemical', '-', (48, 52))	('survival', 'CPA', (185, 193))	('ruxolitinib', 'Chemical', 'MESH:C540383', (76, 87))	('prolonging', 'NegReg', (168, 178))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('mice', 'Species', '10090', (149, 153))	('angiogenesis', 'biological_process', 'GO:0001525', ('105', '117'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('suppressed', 'NegReg', (88, 98))	('PDAC', 'Phenotype', 'HP:0006725', (48, 52))	('disease progression', 'CPA', (122, 141))
38408	25762644	The current findings suggest that targeting JAK1-2 with ruxolitinib could attenuate the proliferation of PCCs and associated ECs while dampening the actions PDAC-associated inflammatory cells and inflammatory cytokines, especially in those patients whose cancers express a strong pro-angiogenic signature.	('dampening', 'NegReg', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('JAK', 'molecular_function', 'GO:0004713', ('44', '47'))	('PCC', 'Gene', (105, 108))	('actions PDAC-associated', 'MPA', (149, 172))	('PDAC', 'Phenotype', 'HP:0006725', (157, 161))	('targeting', 'Var', (34, 43))	('PCC', 'Gene', '1421', (105, 108))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('patients', 'Species', '9606', (240, 248))	('ruxolitinib', 'Chemical', 'MESH:C540383', (56, 67))	('proliferation', 'CPA', (88, 101))	('cancers', 'Disease', 'MESH:D009369', (255, 262))	('attenuate', 'NegReg', (74, 83))	('cancers', 'Disease', (255, 262))	('JAK1-2', 'Gene', (44, 50))	('PDAC', 'Chemical', '-', (157, 161))
38441	25762644	For inhibitor studies, SB505124 [2 muM], ruxolitinib [100 nM] or DMSO [0.05%] were added to control and conditioned media.	('SB505124 [', 'Var', (23, 33))	('ruxolitinib', 'Chemical', 'MESH:C540383', (41, 52))	('SB505124', 'Chemical', 'MESH:C519132', (23, 31))	('muM', 'Gene', (35, 38))	('DMSO', 'Chemical', 'MESH:D004121', (65, 69))	('muM', 'Gene', '33903', (35, 38))
38445	25762644	For inhibitors, SB505124 [2 muM], ruxolitinib [100 nM] or DMSO [0.05%] were added to the inserts and wells.	('muM', 'Gene', '33903', (28, 31))	('ruxolitinib', 'Chemical', 'MESH:C540383', (34, 45))	('SB505124', 'Chemical', 'MESH:C519132', (16, 24))	('muM', 'Gene', (28, 31))	('DMSO', 'Chemical', 'MESH:D004121', (58, 62))	('SB505124 [', 'Var', (16, 26))
38452	25762644	ECs (200,000/well) were seeded in 6-well plates, serum-starved, and media was replaced with control or conditioned media containing SB505124 [2 muM], ruxolitinib [100 nM] or DMSO [0.05%].	('muM', 'Gene', '33903', (144, 147))	('ruxolitinib', 'Chemical', 'MESH:C540383', (150, 161))	('muM', 'Gene', (144, 147))	('DMSO', 'Chemical', 'MESH:D004121', (174, 178))	('SB505124 [', 'Var', (132, 142))	('SB505124', 'Chemical', 'MESH:C519132', (132, 140))
38477	26288612	This is an important observation because it indicates that resection of an IPMN only reduces the risk of developing pancreatic cancer but does not abolish it.	('resection', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('reduces', 'NegReg', (85, 92))	('pancreatic cancer', 'Disease', (116, 133))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))
38486	26288612	It has been reported that this disease progression is associated with cumulative genetic alterations, including a number of mutations known from sporadic ductal adenocarcinoma such as KRAS and TP53.	('ductal adenocarcinoma', 'Disease', (154, 175))	('mutations', 'Var', (124, 133))	('KRAS', 'Gene', (184, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('TP53', 'Gene', '7157', (193, 197))	('KRAS', 'Gene', '3845', (184, 188))	('TP53', 'Gene', (193, 197))	('associated', 'Reg', (54, 64))	('ductal adenocarcinoma', 'Disease', 'MESH:D044584', (154, 175))
38584	25265995	Although the rest of the mutant genes are considered 'passengers', their presence and faulty interactions could, at least in principle, augment in some fashion the negative impact of 'driver' genes and, as such, contribute to the altered pathways leading to disease.	('mutant', 'Var', (25, 31))	('disease', 'Disease', (258, 265))	('faulty', 'Var', (86, 92))	('negative impact', 'MPA', (164, 179))	('interactions', 'Interaction', (93, 105))	('men', 'Species', '9606', (139, 142))	('pathways', 'Pathway', (238, 246))	('contribute', 'Reg', (212, 222))	('altered', 'Reg', (230, 237))	('augment', 'NegReg', (136, 143))
38585	25265995	Given the role these pathways normally play, their alterations can easily fuel the 'hallmarks' of cancer proposed by Hanahan and Weinberg: sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, enabling replicative immortality, inducing angiogenesis, and resisting cell death.	('death', 'Disease', 'MESH:D003643', (315, 320))	('sustaining proliferative signaling', 'MPA', (139, 173))	('inducing', 'PosReg', (273, 281))	('cancer', 'Disease', (98, 104))	('rat', 'Species', '10116', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('alterations', 'Var', (51, 62))	('rat', 'Species', '10116', (157, 160))	('metastasis', 'CPA', (227, 237))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))	('replicative immortality', 'CPA', (248, 271))	('death', 'Disease', (315, 320))	('activating', 'PosReg', (203, 213))	('growth', 'Protein', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('enabling', 'PosReg', (239, 247))	('invasion', 'CPA', (214, 222))	('cell death', 'biological_process', 'GO:0008219', ('310', '320'))	('evading', 'Var', (175, 182))	('angiogenesis', 'biological_process', 'GO:0001525', ('282', '294'))	('angiogenesis', 'CPA', (282, 294))
38586	25265995	In addition to variant genes and their associated dysfunctional pathways, deregulations stemming from sources other than protein coding genes such as those associated with microRNAs (miRNAs) and other non-coding elements or from sources other than sequence variation such as those at the epigenetic level can and do contribute to the disease phenotype.	('disease', 'Disease', (334, 341))	('variant genes', 'Var', (15, 28))	('men', 'Species', '9606', (215, 218))	('deregulations', 'MPA', (74, 87))	('contribute', 'Reg', (316, 326))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))
38609	25265995	Aberrant gene methylation is observed in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('observed', 'Reg', (29, 37))	('cancer', 'Disease', (46, 52))	('Aberrant gene methylation', 'Var', (0, 25))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))
38615	25265995	KRAS activation found in the early stages of pancreatic cancer is followed by inactivation of the cell cycle regulator CDKN2A (95%) also in the earlier stages, and inactivation of TP53 (75%) and SMAD4 (55%) in the later stages.	('SMAD4', 'Gene', '4089', (195, 200))	('pancreatic cancer', 'Disease', (45, 62))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('activation', 'PosReg', (5, 15))	('inactivation', 'Var', (164, 176))	('TP53', 'Gene', (180, 184))	('CDKN2A', 'Gene', (119, 125))	('TP53', 'Gene', '7157', (180, 184))	('inactivation', 'MPA', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('98', '118'))	('SMAD4', 'Gene', (195, 200))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))	('CDKN2A', 'Gene', '1029', (119, 125))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('98', '118'))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
38617	25265995	The inactivating mutations in PDAC involve the p16/Ink4a gene product -.	('inactivating mutations', 'Var', (4, 26))	('PDAC', 'Chemical', '-', (30, 34))	('PDAC', 'Gene', (30, 34))	('p16', 'Gene', (47, 50))	('Ink4a', 'Gene', '1029', (51, 56))	('PDAC', 'Phenotype', 'HP:0006725', (30, 34))	('Ink4a', 'Gene', (51, 56))	('p16', 'Gene', '1029', (47, 50))
38618	25265995	However, p14/Arf mutations are associated with other cancer types, and the two protein products act in connected pathways:p53 signaling promotes, as necessary, cell cycle arrest, apoptosis, or senescence and is also a negative regulator of p14/Arf expression,.	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('179', '188'))	('arrest', 'Disease', (171, 177))	('mutations', 'Var', (17, 26))	('p53', 'Gene', (122, 125))	('apoptosis', 'biological_process', 'GO:0006915', ('179', '188'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (160, 177))	('apoptosis', 'CPA', (179, 188))	('associated', 'Reg', (31, 41))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('160', '177'))	('p14', 'Gene', '1029', (240, 243))	('signaling', 'biological_process', 'GO:0023052', ('126', '135'))	('senescence', 'biological_process', 'GO:0010149', ('193', '203'))	('p14', 'Gene', '1029', (9, 12))	('cancer', 'Disease', (53, 59))	('p14', 'Gene', (240, 243))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('arrest', 'Disease', 'MESH:D006323', (171, 177))	('p14', 'Gene', (9, 12))	('senescence', 'CPA', (193, 203))	('promotes', 'PosReg', (136, 144))	('p53', 'Gene', '7157', (122, 125))
38630	25265995	Ras proteins were the first oncogenes identified in human cancers, primarily Kras with frequent activating mutations and, to a much lesser extent, mutations in the closely related Hras or Nras genes.	('Nras', 'Gene', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (107, 116))	('Nras', 'Gene', '4893', (188, 192))	('Hras', 'Gene', '3265', (180, 184))	('human', 'Species', '9606', (52, 57))	('activating', 'PosReg', (96, 106))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('Kras', 'Disease', (77, 81))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('Hras', 'Gene', (180, 184))
38631	25265995	Kras confers stem-like properties on certain cell types, Kras deletion leads to death during embryogenesis in mice, and it is in pancreatic cancer that the activating Kras mutations are the most frequent.	('embryogenesis', 'biological_process', 'GO:0009793', ('93', '106'))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('death', 'Disease', (80, 85))	('Kras', 'Gene', (57, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('embryogenesis', 'biological_process', 'GO:0009790', ('93', '106'))	('Kras', 'Gene', (167, 171))	('mice', 'Species', '10090', (110, 114))	('embryogenesis', 'biological_process', 'GO:0009792', ('93', '106'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('activating', 'PosReg', (156, 166))	('death', 'Disease', 'MESH:D003643', (80, 85))	('pancreatic cancer', 'Disease', (129, 146))	('deletion', 'Var', (62, 70))	('leads to', 'Reg', (71, 79))
38635	25265995	Aberrant DNA methylation and other epigenetic alterations are observed in many cancer types, including pancreatic cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('rat', 'Species', '10116', (50, 53))	('pancreatic cancer', 'Disease', (103, 120))	('cancer', 'Disease', (114, 120))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (103, 120))	('DNA', 'Protein', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (103, 120))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('observed', 'Reg', (62, 70))	('epigenetic alterations', 'Var', (35, 57))
38636	25265995	Epigenetic markers may provide a means for earlier detection of pancreatic cancer.	('Epigenetic markers', 'Var', (0, 18))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('pancreatic cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('pancreatic cancer', 'Disease', 'MESH:D010190', (64, 81))
38637	25265995	Pancreatic cancer may be an extreme case but it is nonetheless intriguing why so many mutations and associated altered pathways converge on this organ and its malignancy and why they do display a preferential as well as a temporal pattern.	('mutations', 'Var', (86, 95))	('pathways', 'Pathway', (119, 127))	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('malignancy', 'Disease', 'MESH:D009369', (159, 169))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('malignancy', 'Disease', (159, 169))	('converge', 'Reg', (128, 136))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
38639	25265995	A deregulated phosphatidylinositol 3-kinase-Akt pathway also contributes with loss or inactivating mutations in the Pten regulator and, to a lesser extent, amplification or activating mutations of the catalytic subunit Pik3ca.	('amplification', 'Var', (156, 169))	('loss', 'Disease', 'MESH:D015431', (78, 82))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (14, 34))	('Pten', 'Gene', '5728', (116, 120))	('deregulated', 'Reg', (2, 13))	('Pten', 'Gene', (116, 120))	('Pik3ca', 'Gene', (219, 225))	('activating', 'PosReg', (173, 183))	('Pik3ca', 'Gene', '5290', (219, 225))	('loss', 'Disease', (78, 82))	('phosphatidylinositol 3-kinase-Akt pathway', 'Pathway', (14, 55))	('inactivating', 'NegReg', (86, 98))
38640	25265995	Deletions at the p53 locus in the p53 pathway have also been seen in prostate cancer samples.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('prostate cancer', 'Disease', 'MESH:D011471', (69, 84))	('prostate cancer', 'Phenotype', 'HP:0012125', (69, 84))	('prostate cancer', 'Disease', (69, 84))	('seen', 'Reg', (61, 65))	('p53', 'Gene', (17, 20))	('Deletions', 'Var', (0, 9))	('p53', 'Gene', '7157', (17, 20))
38647	25265995	Increased phosphorylation of the receptor, expression of splice variants that do not have the ligand binding domain, mutations that allow the receptor to bind to and be activated by non-traditional ligands including antagonists, and altered expression of coregulators, steroid biosynthetic enzymes, and/or the receptor transcriptional program all contribute to testosterone-independent receptor activity -.	('mutations', 'Var', (117, 126))	('ligand', 'molecular_function', 'GO:0005488', ('94', '100'))	('phosphorylation', 'biological_process', 'GO:0016310', ('10', '25'))	('receptor activity', 'molecular_function', 'GO:0038024', ('386', '403'))	('phosphorylation', 'MPA', (10, 25))	('steroid', 'Chemical', 'MESH:D013256', (269, 276))	('Increased', 'PosReg', (0, 9))	('receptor activity', 'molecular_function', 'GO:0038023', ('386', '403'))	('contribute', 'Reg', (347, 357))	('bind', 'Interaction', (154, 158))	('testosterone', 'Chemical', 'MESH:D013739', (361, 373))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))
38649	25265995	Steroid hormones share a core biosynthetic pathway that branches into the individual steroid biosynthesis in given tissues via tissue-specific expression of terminal enzymes; in prostate cancer, changes in enzyme expression circumvent the initial testosterone depletion.	('prostate cancer', 'Phenotype', 'HP:0012125', (178, 193))	('testosterone', 'Chemical', 'MESH:D013739', (247, 259))	('circumvent', 'NegReg', (224, 234))	('expression', 'MPA', (213, 223))	('steroid', 'Chemical', 'MESH:D013256', (85, 92))	('Steroid hormones', 'Chemical', 'MESH:D013256', (0, 16))	('enzyme', 'Enzyme', (206, 212))	('prostate cancer', 'Disease', (178, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('changes', 'Var', (195, 202))	('prostate cancer', 'Disease', 'MESH:D011471', (178, 193))
38650	25265995	Gene fusion between androgen receptor-regulated genes and members of the E26 transformation-specific (ETS) family of oncogenic transcription factors is a signature feature found in ~50% of cases.	('androgen receptor', 'Gene', (20, 37))	('transcription', 'biological_process', 'GO:0006351', ('127', '140'))	('Gene fusion', 'Var', (0, 11))	('androgen receptor', 'Gene', '367', (20, 37))
38651	25265995	Fusion between the Tmprss2 gene and the Erg member of the ETS family is common in prostate cancer.	('Fusion', 'Var', (0, 6))	('Tmprss2', 'Gene', (19, 26))	('common', 'Reg', (72, 78))	('prostate cancer', 'Disease', (82, 97))	('Erg', 'Gene', (40, 43))	('Tmprss2', 'Gene', '7113', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('prostate cancer', 'Disease', 'MESH:D011471', (82, 97))	('prostate cancer', 'Phenotype', 'HP:0012125', (82, 97))	('Erg', 'Gene', '2078', (40, 43))
38652	25265995	The gene rearrangements have been mostly noticed in primary prostate cancer while the alterations/mutations of the receptor have been associated with the treatment-resistant, metastatic prostate tumors.	('noticed', 'Reg', (41, 48))	('associated', 'Reg', (134, 144))	('alterations/mutations', 'Var', (86, 107))	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))	('men', 'Species', '9606', (159, 162))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('men', 'Species', '9606', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('prostate tumors', 'Disease', 'MESH:D011471', (186, 201))	('primary prostate cancer', 'Disease', (52, 75))	('primary prostate cancer', 'Disease', 'MESH:D011471', (52, 75))	('rearrangements', 'Var', (9, 23))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('prostate tumors', 'Disease', (186, 201))	('rat', 'Species', '10116', (90, 93))
38654	25265995	Mutations in a number of other elements are being unraveled and await further investigation with respect to their role in the initiation and/or progression of prostate tumors,,.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('prostate tumors', 'Disease', 'MESH:D011471', (159, 174))	('Mutations', 'Var', (0, 9))	('prostate tumors', 'Disease', (159, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('men', 'Species', '9606', (34, 37))
38657	25265995	The main contributor in this case is an altered hypoxia-inducible factor (HIF) pathway where mutations in von Hippel-Lindau (VHL) protein render the pathway constitutively active and are found in ~90% of RCC tumors.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('RCC tumors', 'Disease', (204, 214))	('mutations', 'Var', (93, 102))	('VHL', 'Gene', (125, 128))	('found', 'Reg', (187, 192))	('VHL', 'Gene', '7428', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('von Hippel-Lindau', 'Gene', '7428', (106, 123))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('hypoxia', 'Disease', 'MESH:D000860', (48, 55))	('altered', 'Reg', (40, 47))	('RCC tumors', 'Disease', 'MESH:C538614', (204, 214))	('hypoxia', 'Disease', (48, 55))	('von Hippel-Lindau', 'Gene', (106, 123))
38662	25265995	The modified prolines are recognized by VHL which targets HIF for proteasomal degradation; the modified asparagine blocks the interaction of HIF with transcriptional activators [see Figure 3A].	('interaction', 'Interaction', (126, 137))	('proline', 'Chemical', 'MESH:D011392', (13, 20))	('modified', 'Var', (95, 103))	('VHL', 'Gene', (40, 43))	('asparagine', 'Chemical', 'MESH:D001216', (104, 114))	('VHL', 'Gene', '7428', (40, 43))	('blocks', 'NegReg', (115, 121))	('degradation', 'biological_process', 'GO:0009056', ('78', '89'))
38666	25265995	Specific mutations cataloged for the VHL gene are thought to underlie distinct morbidity and mortality phenotypes.	('mutations', 'Var', (9, 18))	('VHL', 'Gene', '7428', (37, 40))	('VHL', 'Gene', (37, 40))
38667	25265995	Mutations in components of the citric acid cycle (tricarboxylic acid or TCA cycle) create a pseudohypoxic environment that impacts on Hif modification, stabilizes the protein, and renders the pathway active, even when the VHL protein may be wild-type.	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (50, 68))	('VHL', 'Gene', (222, 225))	('impacts', 'Reg', (123, 130))	('citric acid', 'Chemical', 'MESH:D019343', (31, 42))	('renders', 'Reg', (180, 187))	('protein', 'Protein', (167, 174))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('VHL', 'Gene', '7428', (222, 225))	('Mutations', 'Var', (0, 9))	('TCA cycle', 'biological_process', 'GO:0006099', ('72', '81'))	('citric acid cycle', 'biological_process', 'GO:0006099', ('31', '48'))	('Hif modification', 'MPA', (134, 150))	('active', 'MPA', (200, 206))	('stabilizes', 'MPA', (152, 162))	('hypoxic', 'Disease', 'MESH:D000860', (98, 105))	('protein', 'cellular_component', 'GO:0003675', ('226', '233'))	('hypoxic', 'Disease', (98, 105))	('pathway', 'Pathway', (192, 199))	('TCA', 'Chemical', 'MESH:D014238', (72, 75))
38669	25265995	Also, truncating mutations in the PBRM1 gene known as BAF180 (a component of a chromatin remodeling complex) were found in ~41% of cases.	('found', 'Reg', (114, 119))	('PBRM1', 'Gene', (34, 39))	('BAF180', 'Gene', (54, 60))	('PBRM1', 'Gene', '55193', (34, 39))	('BAF180', 'Gene', '55193', (54, 60))	('truncating mutations', 'Var', (6, 26))
38670	25265995	The exact role these mutations have in the context of RCC remains to be established.	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('mutations', 'Var', (21, 30))
38673	25265995	RCC, however, is primarily a sporadic condition, where bi-allelic inactivation of VHL due to chromosomal loss, mutations, or hypermethylation accounts for much of its incidence,.	('mutations', 'Var', (111, 120))	('chromosomal loss', 'Disease', 'MESH:D015431', (93, 109))	('hypermethylation', 'Var', (125, 141))	('VHL', 'Gene', (82, 85))	('VHL', 'Gene', '7428', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('chromosomal loss', 'Disease', (93, 109))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))
38683	25265995	The DNA lesions activate the DNA damage response (DDR) system which, among a number of responses, can promote apoptosis and as such is toxic to proliferating cancer cells.	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('DNA damage response', 'biological_process', 'GO:0006974', ('29', '48'))	('apoptosis', 'biological_process', 'GO:0097194', ('110', '119'))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('apoptosis', 'biological_process', 'GO:0006915', ('110', '119'))	('promote', 'PosReg', (102, 109))	('cancer', 'Disease', (158, 164))	('rat', 'Species', '10116', (151, 154))	('apoptosis', 'CPA', (110, 119))	('lesions', 'Var', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
38696	25265995	BPA can induce rapid activation of the Erk1/2 pathway via GPER in breast cancer; it may affect various immune responses and has been implicated in the etiology of many diseases and disorders [Figure 8B].	('Erk1', 'molecular_function', 'GO:0004707', ('39', '43'))	('affect', 'Reg', (88, 94))	('BPA', 'Var', (0, 3))	('immune responses', 'CPA', (103, 119))	('BPA', 'Chemical', 'MESH:C006780', (0, 3))	('Erk1/2', 'Gene', '5595;5594', (39, 45))	('GPER', 'Gene', '2852', (58, 62))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('implicated', 'Reg', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', (66, 79))	('GPER', 'Gene', (58, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('activation', 'PosReg', (21, 31))	('Erk1/2', 'Gene', (39, 45))
38700	25265995	Deregulation of estrogen signaling is implicated in the etiology of breast cancer, and signaling is constitutively active in more than 50% of cases.	('signaling', 'biological_process', 'GO:0023052', ('87', '96'))	('estrogen signaling', 'MPA', (16, 34))	('Deregulation', 'Var', (0, 12))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('implicated', 'Reg', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))
38715	25265995	Despite the identity of altered pathways being different, constitutive signaling as well as deregulated expression of coding and non-coding genes, activation of oncogenes, and silencing of tumor suppressors are shared features.	('signaling', 'biological_process', 'GO:0023052', ('71', '80'))	('silencing', 'Var', (176, 185))	('tumor', 'Disease', (189, 194))	('deregulated', 'Var', (92, 103))	('constitutive', 'MPA', (58, 70))	('oncogenes', 'Gene', (161, 170))	('expression', 'MPA', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('activation', 'PosReg', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
38718	25265995	Why is KRAS preferentially mutated in pancreatic cancer and why does this member of Ras have the highest overall mutagenic propensities relative to the other two, closely related Ras members, HRAS and NRAS?	('pancreatic cancer', 'Disease', (38, 55))	('mutated', 'Var', (27, 34))	('mutagenic propensities', 'MPA', (113, 135))	('HRAS', 'Gene', (192, 196))	('NRAS', 'Gene', (201, 205))	('pancreatic cancer', 'Disease', 'MESH:D010190', (38, 55))	('KRAS', 'Gene', '3845', (7, 11))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('NRAS', 'Gene', '4893', (201, 205))	('preferentially', 'PosReg', (12, 26))	('HRAS', 'Gene', '3265', (192, 196))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (38, 55))	('KRAS', 'Gene', (7, 11))
38719	25265995	Differential codon usage in KRAS might underlie its higher mutagenic rate than its Ras cousins and distinct mutations may confer distinct functional behaviors upon the mutant proteins and prompt different outcomes, but they do not explain what triggers the frequency of mutations in and their association with different tissues.	('KRAS', 'Gene', (28, 32))	('KRAS', 'Gene', '3845', (28, 32))	('mutations', 'Var', (108, 117))	('mutagenic rate', 'MPA', (59, 73))	('Differential', 'Var', (0, 12))	('confer', 'Reg', (122, 128))	('rat', 'Species', '10116', (69, 72))
38720	25265995	In a similar vein, one may ask why somatic mutations in the VHL protein are primarily associated with renal cell cancer or why diminishing levels of testosterone prompt the kind of mutations that render the androgen receptor ligand-independent.	('renal cell cancer', 'Phenotype', 'HP:0005584', (102, 119))	('androgen receptor', 'Gene', (207, 224))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('VHL', 'Gene', (60, 63))	('diminishing levels of testosterone', 'Phenotype', 'HP:0040171', (127, 161))	('associated', 'Reg', (86, 96))	('VHL', 'Gene', '7428', (60, 63))	('mutations', 'Var', (43, 52))	('mutations', 'Var', (181, 190))	('androgen receptor', 'Gene', '367', (207, 224))	('renal cell cancer', 'Disease', 'MESH:C538614', (102, 119))	('renal cell cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('testosterone', 'Chemical', 'MESH:D013739', (149, 161))	('receptor ligand', 'molecular_function', 'GO:0005102', ('216', '231'))
38723	25265995	However, one is tempted to wonder whether the proneness of KRAS to mutate may in some fashion be aided or activated within a challenged pancreatic tissue milieu, perhaps further promoting its plasticity and the instantiation of mutations in other genes.	('KRAS', 'Gene', '3845', (59, 63))	('pancreatic', 'Disease', 'MESH:D010195', (136, 146))	('pancreatic', 'Disease', (136, 146))	('KRAS', 'Gene', (59, 63))	('mutate', 'Var', (67, 73))
38745	23947693	The knock-down of B7-H3 lead to matrix metalloproteinase (MMP)-2, another tumor prognostic marker cell reduced in cell level.	('MMP)-2', 'molecular_function', 'GO:0004228', ('58', '64'))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('knock-down', 'Var', (4, 14))	('B7-H3', 'Gene', (18, 23))	('tumor', 'Disease', (74, 79))
38772	23947693	Kaplan-Meier survival curves were drawn to visually compare the survival rates of 45 pancreatic cancer patients in B7-H3 (+) MMP2 (+) group, B7-H3 (+) MMP2 (-) group, B7-H3 (-) MMP2 (+) group and B7-H3 (-) MMP2 (-) group at each TNM stage.	('pancreatic cancer', 'Disease', (85, 102))	('MMP2', 'molecular_function', 'GO:0004228', ('206', '210'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('TNM', 'Gene', (229, 232))	('MMP2', 'molecular_function', 'GO:0004228', ('177', '181'))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('B7-H3 (+) MMP2', 'Var', (115, 129))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('B7-H3 (+) MMP2', 'Var', (141, 155))	('TNM', 'Gene', '10178', (229, 232))	('patients', 'Species', '9606', (103, 111))	('MMP2', 'molecular_function', 'GO:0004228', ('151', '155'))	('MMP2', 'molecular_function', 'GO:0004228', ('125', '129'))
38785	23947693	Pearson correlation coefficients analysis for B7-H3 and MMP-2 showed a significant correlations in pancreatic patients (Pearson correlation = 0.496, P = .001), the increased B7-H3 expression is correlated with higher MMP-2 in pancreatic cancer samples (Table 5).	('pancreatic', 'Disease', 'MESH:D010195', (99, 109))	('MMP-2', 'Gene', (56, 61))	('pancreatic', 'Disease', 'MESH:D010195', (226, 236))	('increased', 'PosReg', (164, 173))	('pancreatic cancer', 'Disease', 'MESH:D010190', (226, 243))	('pancreatic', 'Disease', (99, 109))	('MMP-2', 'Gene', '4313', (217, 222))	('pancreatic', 'Disease', (226, 236))	('MMP-2', 'molecular_function', 'GO:0004228', ('217', '222'))	('pancreatic cancer', 'Disease', (226, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('expression', 'MPA', (180, 190))	('higher', 'PosReg', (210, 216))	('MMP-2', 'Gene', '4313', (56, 61))	('B7-H3', 'Var', (174, 179))	('MMP-2', 'Gene', (217, 222))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (226, 243))	('MMP-2', 'molecular_function', 'GO:0004228', ('56', '61'))	('patients', 'Species', '9606', (110, 118))
38788	23947693	In patients with pancreatic cancer, the presence of B7-H3 expression has been shown to correlate with poor prognosis, Zhao et al.	('pancreatic cancer', 'Disease', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('presence', 'Var', (40, 48))	('patients', 'Species', '9606', (3, 11))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('B7-H3', 'Protein', (52, 57))
38792	23947693	In a study of 70 patients with NSCLC, B7-H3 protein expressed was associated with an increased risk for tumor metastases.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('B7-H3', 'Var', (38, 43))	('NSCLC', 'Disease', (31, 36))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('tumor metastases', 'Disease', (104, 120))	('patients', 'Species', '9606', (17, 25))	('tumor metastases', 'Disease', 'MESH:D009362', (104, 120))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))
38805	23947693	Notably, the metastasis-associated proteins, matrix metalloproteinase (MMP)-2, signal transducer and activator of transcription 3 (Stat3), and the level of secreted interleukin-8 (IL-8) were reduced in the B7-H3 knock-down cell variants.	('Stat3', 'Gene', (131, 136))	('transcription', 'biological_process', 'GO:0006351', ('114', '127'))	('interleukin-8', 'Gene', (165, 178))	('signal transducer and activator of transcription 3', 'Gene', '20848', (79, 129))	('level of', 'MPA', (147, 155))	('reduced', 'NegReg', (191, 198))	('knock-down', 'Var', (212, 222))	('Stat3', 'Gene', '20848', (131, 136))	('IL-8', 'Gene', '20309', (180, 184))	('MMP)-2', 'molecular_function', 'GO:0004228', ('71', '77'))	('interleukin-8', 'Gene', '20309', (165, 178))	('B7-H3', 'Gene', (206, 211))	('IL-8', 'molecular_function', 'GO:0005153', ('180', '184'))	('metastasis-associated proteins', 'MPA', (13, 43))	('variants', 'Var', (228, 236))	('matrix metalloproteinase', 'MPA', (45, 69))	('IL-8', 'Gene', (180, 184))
38807	23947693	This is the first report to show a correlation between the levels of B7-H3 and the levels of MMP-2 in human pancreatic tumors, and these results suggest that MMP and B7-H3 are good predictors for pancreatic TNM stage.	('pancreatic TNM', 'Disease', 'MESH:D010195', (196, 210))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('MMP', 'molecular_function', 'GO:0004235', ('158', '161'))	('MMP', 'Var', (158, 161))	('pancreatic tumors', 'Disease', 'MESH:D010190', (108, 125))	('MMP-2', 'Gene', (93, 98))	('pancreatic tumors', 'Disease', (108, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('B7-H3', 'Var', (166, 171))	('MMP-2', 'molecular_function', 'GO:0004228', ('93', '98'))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (108, 125))	('pancreatic TNM', 'Disease', (196, 210))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (108, 124))	('MMP-2', 'Gene', '4313', (93, 98))	('human', 'Species', '9606', (102, 107))
38821	22532830	In vivo, cysteamine significantly decreased metastasis in two established pancreatic tumor models, although it did not affect the size of primary tumors.	('cysteamine', 'Var', (9, 19))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('pancreatic tumor', 'Disease', (74, 90))	('decreased', 'NegReg', (34, 43))	('cysteamine', 'Chemical', 'MESH:D003543', (9, 19))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (74, 90))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('metastasis', 'CPA', (44, 54))	('tumors', 'Disease', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('pancreatic tumor', 'Disease', 'MESH:D010190', (74, 90))
38886	22532830	Cell migration was significantly inhibited at and above 0.05 mM of cysteamine in all 10 cell lines (Figure 1C and Figure S2).	('Cell migration', 'biological_process', 'GO:0016477', ('0', '14'))	('cysteamine', 'Var', (67, 77))	('Cell migration', 'CPA', (0, 14))	('cysteamine', 'Chemical', 'MESH:D003543', (67, 77))	('inhibited', 'NegReg', (33, 42))
38898	22532830	We also observed that mRNAs for two other MMPs (MMP-12 and MMP-14) showed a modest increase similar to MMP-9 in response to cysteamine treatment (Fig.	('response to cysteamine treatment', 'MPA', (112, 144))	('MMP-14', 'Var', (59, 65))	('cysteamine', 'Chemical', 'MESH:D003543', (124, 134))	('MMP-12', 'Var', (48, 54))	('MMP', 'molecular_function', 'GO:0004235', ('59', '62'))	('MMP-12', 'molecular_function', 'GO:0004234', ('48', '54'))	('MMPs', 'Gene', '17386;17390;17393;4318;17395;4321;17381;17386;4323;17387', (42, 46))	('MMPs', 'Gene', (42, 46))	('MMP-9', 'molecular_function', 'GO:0004229', ('103', '108'))
38906	22532830	In addition, two of 5 mice in the HS766T tumor model and 4 of 5 mice in MIA-PaCa2 tumor model developed ascites in their peritoneal cavity.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('MIA-PaCa2 tumor', 'Disease', 'MESH:D009369', (72, 87))	('tumor', 'Disease', (41, 46))	('HS766T', 'Var', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('MIA-PaCa2 tumor', 'Disease', (72, 87))	('ascites', 'Disease', 'MESH:D001201', (104, 111))	('ascites', 'Disease', (104, 111))	('ascites', 'Phenotype', 'HP:0001541', (104, 111))	('HS766T', 'CellLine', 'CVCL:0334', (34, 40))	('tumor', 'Disease', (82, 87))	('mice', 'Species', '10090', (22, 26))	('mice', 'Species', '10090', (64, 68))
38918	22532830	We demonstrate that cysteamine inhibits pancreatic cancer cell migration and invasion through direct inhibition of MMP enzymatic activity in vitro.	('MMP', 'molecular_function', 'GO:0004235', ('115', '118'))	('inhibition', 'NegReg', (101, 111))	('inhibits', 'NegReg', (31, 39))	('MMP', 'Gene', '17386;17390;17393;4318;17395;4321;17381;17386;4323;17387', (115, 118))	('cysteamine', 'Var', (20, 30))	('invasion', 'CPA', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('cell migration', 'biological_process', 'GO:0016477', ('58', '72'))	('MMP', 'Gene', (115, 118))	('pancreatic cancer', 'Disease', (40, 57))	('cysteamine', 'Chemical', 'MESH:D003543', (20, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (40, 57))
38923	22532830	Mice treated with cysteamine survived longer compared to control mice treated with excipient.	('survived', 'CPA', (29, 37))	('cysteamine', 'Chemical', 'MESH:D003543', (18, 28))	('mice', 'Species', '10090', (65, 69))	('Mice', 'Species', '10090', (0, 4))	('cysteamine', 'Var', (18, 28))
38924	22532830	Both in vitro and in primary tumors in vivo, MMP enzymatic activity decreased with cysteamine treatment while their expression at mRNA and protein levels did not change.	('MMP', 'Gene', '17386;17390;17393;4318;17395;4321;17381;17386;4323;17387', (45, 48))	('decreased', 'NegReg', (68, 77))	('cysteamine', 'Chemical', 'MESH:D003543', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('MMP', 'Gene', (45, 48))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('cysteamine', 'Var', (83, 93))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('MMP', 'molecular_function', 'GO:0004235', ('45', '48'))
38941	22532830	In fact in zymography assay for MMP-9, cysteamine caused a dose dependent decrease in gelatinase activity.	('decrease', 'NegReg', (74, 82))	('cysteamine', 'Var', (39, 49))	('MMP-9', 'molecular_function', 'GO:0004229', ('32', '37'))	('cysteamine', 'Chemical', 'MESH:D003543', (39, 49))	('gelatinase activity', 'MPA', (86, 105))
38945	22532830	However, it is important to point out that cysteamine inhibited enzymatic activity of MMPs, which includes all MMPs.	('inhibited', 'NegReg', (54, 63))	('cysteamine', 'Var', (43, 53))	('MMPs', 'Gene', '17386;17390;17393;4318;17395;4321;17381;17386;4323;17387', (86, 90))	('MMPs', 'Gene', (111, 115))	('cysteamine', 'Chemical', 'MESH:D003543', (43, 53))	('enzymatic activity', 'MPA', (64, 82))	('MMPs', 'Gene', '17386;17390;17393;4318;17395;4321;17381;17386;4323;17387', (111, 115))	('MMPs', 'Gene', (86, 90))
38950	22532830	During these studies, it was observed that cysteamine also had anti-carcinogenic and anti-proliferative activities in a variety of cancers.	('cysteamine', 'Var', (43, 53))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('anti-proliferative activities', 'CPA', (85, 114))	('carcinogenic', 'Disease', 'MESH:D063646', (68, 80))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('carcinogenic', 'Disease', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cysteamine', 'Chemical', 'MESH:D003543', (43, 53))
38961	21622730	MiRNA restitution was confirmed in treated xenografts by significant upregulation of the corresponding miRNA, and significant decreases in specific miRNA targets (SIRT1, CD44 and aldehyde dehydrogenase for miR34a, and KRAS2 and RREB1 for miR-143/145).	('miR-143', 'Gene', (238, 245))	('upregulation', 'PosReg', (69, 81))	('SIRT1', 'Gene', '93759', (163, 168))	('SIRT1', 'Gene', (163, 168))	('CD44', 'MPA', (170, 174))	('miR-143', 'Gene', '387161', (238, 245))	('miRNA', 'MPA', (103, 108))	('aldehyde dehydrogenase', 'MPA', (179, 201))	('decreases', 'NegReg', (126, 135))	('miR34a', 'Var', (206, 212))
38969	21622730	Misexpression of miRNAs is not merely an epiphenomenon of the neoplastic process, but deregulated miRNAs directly contribute to altered physiological states in tumor cells.	('neoplastic process', 'Phenotype', 'HP:0002664', (62, 80))	('expression', 'Species', '29278', (3, 13))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('altered', 'Reg', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('deregulated', 'Var', (86, 97))	('tumor', 'Disease', (160, 165))	('miRNAs', 'MPA', (98, 104))	('contribute', 'Reg', (114, 124))
38973	21622730	These studies have elucidated that, akin to other solid tumors, subsets of individual miRNAs (or corresponding miRNA "clusters") are either overexpressed (e.g., miR-21, miR-17-92, miR-196a, miR-200a/b, miR-221, etc.	('overexpressed', 'PosReg', (140, 153))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('miR-21', 'Var', (161, 167))	('miR-17-92', 'Var', (169, 178))	('solid tumors', 'Disease', 'MESH:D009369', (50, 62))	('solid tumors', 'Disease', (50, 62))	('miR-221', 'Var', (202, 209))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('miR-200a/b', 'Var', (190, 200))	('miR-196a', 'Var', (180, 188))
38976	21622730	Identification of aberrant miRNAs in pancreatic cancer not only provides biological insights into the pathogenesis of this neoplasm, but also forms a seedbed for establishing promising biomarkers for early detection in clinical samples.	('neoplasm', 'Phenotype', 'HP:0002664', (123, 131))	('pathogenesis', 'biological_process', 'GO:0009405', ('102', '114'))	('aberrant miRNAs', 'Var', (18, 33))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (37, 54))	('pancreatic cancer', 'Disease', (37, 54))	('neoplasm', 'Disease', (123, 131))	('miRNAs', 'Var', (27, 33))	('pancreatic cancer', 'Disease', 'MESH:D010190', (37, 54))	('clinical samples', 'Species', '191496', (219, 235))	('neoplasm', 'Disease', 'MESH:D009369', (123, 131))
38977	21622730	In light of the widespread abnormalities of miRNA expression in human cancers, modulation of deregulated miRNAs in cancer cells has also emerged as a promising therapeutic strategy.	('human', 'Species', '9606', (64, 69))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancers', 'Disease', (70, 77))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('expression', 'Species', '29278', (50, 60))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('modulation', 'Var', (79, 89))
38982	21622730	Similarly, two groups have demonstrated the therapeutic efficacy of virally administered let-7 in attenuating mutant Kras-induced lung cancer progression in both xenograft and autochthonous mouse models.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('Kras', 'Gene', '16653', (117, 121))	('mutant', 'Var', (110, 116))	('let-7', 'Gene', (89, 94))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mouse', 'Species', '10090', (190, 195))	('attenuating', 'NegReg', (98, 109))	('Kras', 'Gene', (117, 121))	('lung cancer', 'Disease', (130, 141))
39033	21622730	Thereafter, 10ng of RNA was reverse transcribed with a miRNA Reverse Transcription Kit (Applied Biosystems) using miR-34a, miR-143, and miR-145 specific RT-primers (TaqMan miRNA Assay, Applied Biosystems), as described.	('miR-34a', 'Gene', (114, 121))	('miR-145', 'Var', (136, 143))	('miR-34a', 'Gene', '723848', (114, 121))	('RNA', 'cellular_component', 'GO:0005562', ('20', '23'))	('miR-143', 'Gene', (123, 130))	('miR-143', 'Gene', '387161', (123, 130))	('Reverse Transcription', 'biological_process', 'GO:0001171', ('61', '82'))
39034	21622730	Quatitative PCR was performed using RNU6B or RNU44 as housekeeping control, and relative expression levels were calculated using the 2-DeltaDeltaCt method.	('RNU44', 'Var', (45, 50))	('RNU6B', 'Var', (36, 41))	('expression', 'Species', '29278', (89, 99))
39057	21622730	Successfully engrafted MiaPaCa-2 xenografts were treated via tail vein injection with either vehicle, "mock" nanovector, miR-34a nanovector, or mR-143/145 nanovector three times weekly, for three weeks.	('miR-34a', 'Gene', '723848', (121, 128))	('miR-34a', 'Gene', (121, 128))	('mR-143/145', 'Var', (144, 154))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (23, 32))
39060	21622730	Examination of H&E stained sections of treated xenografts demonstrated confluent sheets of necrosis in both miR-34a and miR-143/145 arms, compared to the vehicle and "mock" nanovector cohorts (Figure 2c).	('necrosis', 'Disease', 'MESH:D009336', (91, 99))	('miR-143', 'Gene', '387161', (120, 127))	('necrosis', 'biological_process', 'GO:0070265', ('91', '99'))	('necrosis', 'biological_process', 'GO:0008219', ('91', '99'))	('miR-34a', 'Gene', (108, 115))	('necrosis', 'biological_process', 'GO:0019835', ('91', '99'))	('necrosis', 'biological_process', 'GO:0008220', ('91', '99'))	('both', 'Var', (103, 107))	('miR-34a', 'Gene', '723848', (108, 115))	('and', 'Var', (116, 119))	('necrosis', 'Disease', (91, 99))	('miR-143', 'Gene', (120, 127))	('necrosis', 'biological_process', 'GO:0001906', ('91', '99'))
39069	21622730	To validate the effects of miRNA restitution, we analyzed expression levels of key targets of miR34a, miR-143, and miR145, following systemic therapy.	('expression levels', 'MPA', (58, 75))	('expression', 'Species', '29278', (58, 68))	('miR145', 'Var', (115, 121))	('miR-143', 'Gene', (102, 109))	('miR34a', 'Gene', (94, 100))	('miR-143', 'Gene', '387161', (102, 109))
39072	21622730	We observed a marked decrease in SIRT1 levels in miR-34a nanovector-treated xenografts as compared to vehicle control (Figure 4b), indicating a tangible pharmacodynamic readout of miRNA delivery.	('miR-34a', 'Gene', (49, 56))	('miR-34a', 'Gene', '723848', (49, 56))	('nanovector-treated', 'Var', (57, 75))	('SIRT1', 'Gene', '93759', (33, 38))	('SIRT1', 'Gene', (33, 38))	('decrease', 'NegReg', (21, 29))
39074	21622730	"cancer stem cells"), and that restitution of miR-34a expression depletes this subpopulation in cancers.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Disease', (1, 7))	('cancer', 'Disease', 'MESH:D009369', (1, 7))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('restitution', 'Var', (31, 42))	('miR-34a', 'Gene', (46, 53))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('miR-34a', 'Gene', '723848', (46, 53))	('expression', 'Species', '29278', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (1, 7))	('cancers', 'Disease', (96, 103))	('depletes', 'NegReg', (65, 73))
39078	21622730	In turn, mature miR-143 and miR-145 repress KRAS2 and RREB1, respectively, effectively completing the loop.	('miR-143', 'Gene', (16, 23))	('KRAS2', 'Gene', (44, 49))	('miR-143', 'Gene', '387161', (16, 23))	('repress', 'NegReg', (36, 43))	('miR-145', 'Var', (28, 35))
39094	21622730	In pancreatic cancer, these profound deleterious effects on CSCs are observed irrespective of p53 functional status, underscoring the applicability of therapeutic miR-34a restitution to a disease that harbors TP53 mutations in approximately 70% of cases.	('TP53', 'Gene', (209, 213))	('pancreatic cancer', 'Disease', (3, 20))	('miR-34a', 'Gene', (163, 170))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('miR-34a', 'Gene', '723848', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (214, 223))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))
39109	20396411	Polymorphisms in Tumour Necrosis Factor Alpha (TNFalpha) Gene in Patients with Acute Pancreatitis Proinflammatory cytokines, such as tumour necrosis factor alpha (TNFalpha), play fundamental roles in the pathogenesis of acute pancreatitis (AP).	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('Pancreatitis', 'Phenotype', 'HP:0001733', (85, 97))	('TNFalpha', 'Gene', '7124', (47, 55))	('necrosis', 'biological_process', 'GO:0008219', ('140', '148'))	('Pancreatitis', 'Disease', 'MESH:D010195', (85, 97))	('Tumour Necrosis Factor', 'Disease', 'MESH:D009336', (17, 39))	('Tumour Necrosis Factor', 'Disease', (17, 39))	('pathogenesis', 'biological_process', 'GO:0009405', ('204', '216'))	('Patients', 'Species', '9606', (65, 73))	('tumour necrosis', 'Disease', 'MESH:D009336', (133, 148))	('acute pancreatitis', 'Disease', 'MESH:D010195', (220, 238))	('AP', 'Phenotype', 'HP:0001735', (240, 242))	('Necrosis', 'biological_process', 'GO:0019835', ('24', '32'))	('alpha ', 'Gene', '7124', (156, 162))	('tumour necrosis', 'Disease', (133, 148))	('Polymorphisms', 'Var', (0, 13))	('Alpha ', 'Gene', '7124', (40, 46))	('Pancreatitis', 'Disease', (85, 97))	('necrosis', 'biological_process', 'GO:0008220', ('140', '148'))	('Necrosis', 'biological_process', 'GO:0008220', ('24', '32'))	('pancreatitis', 'Phenotype', 'HP:0001733', (226, 238))	('TNFalpha', 'Gene', '7124', (163, 171))	('acute pancreatitis', 'Disease', (220, 238))	('TNFalpha', 'Gene', (47, 55))	('Necrosis', 'biological_process', 'GO:0001906', ('24', '32'))	('Acute Pancreatitis', 'Phenotype', 'HP:0001735', (79, 97))	('Necrosis', 'biological_process', 'GO:0070265', ('24', '32'))	('necrosis', 'biological_process', 'GO:0070265', ('140', '148'))	('necrosis', 'biological_process', 'GO:0019835', ('140', '148'))	('necrosis', 'biological_process', 'GO:0001906', ('140', '148'))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (220, 238))	('alpha ', 'Gene', (156, 162))	('TNFalpha', 'Gene', (163, 171))	('Tumour', 'Phenotype', 'HP:0002664', (17, 23))	('Alpha ', 'Gene', (40, 46))	('Necrosis', 'biological_process', 'GO:0008219', ('24', '32'))
39110	20396411	The aim of this study was to determine if polymorphisms in the TNFalpha gene are associated with AP.	('TNFalpha', 'Gene', (63, 71))	('TNFalpha', 'Gene', '7124', (63, 71))	('AP', 'Phenotype', 'HP:0001735', (97, 99))	('polymorphisms', 'Var', (42, 55))	('associated', 'Reg', (81, 91))
39121	20396411	The first one at the position -238 nucleotides relative to the transcriptional start site lies within a putative regulator sequence where a G to A substitution defines two variants (TNFalpha -238 G and TNFalpha -238 A).	('TNFalpha', 'Gene', (202, 210))	('TNFalpha', 'Gene', (182, 190))	('TNFalpha', 'Gene', '7124', (202, 210))	('substitution', 'Var', (147, 159))	('TNFalpha', 'Gene', '7124', (182, 190))
39123	20396411	Although some researches have showen that SNPs of TNFalpha are associated with inflammatory diseases in pancreas, identification of an association between the polymorphisms of TNFalpha and susceptibility to AP is less clear.	('inflammatory diseases in pancreas', 'Disease', (79, 112))	('TNFalpha', 'Gene', '7124', (50, 58))	('alpha ', 'Gene', '7124', (53, 59))	('associated', 'Reg', (63, 73))	('inflammatory diseases in pancreas', 'Disease', 'MESH:D010190', (79, 112))	('TNFalpha', 'Gene', (176, 184))	('TNFalpha', 'Gene', (50, 58))	('alpha ', 'Gene', (179, 185))	('AP', 'Phenotype', 'HP:0001735', (207, 209))	('SNPs', 'Var', (42, 46))	('polymorphisms', 'Var', (159, 172))	('TNFalpha', 'Gene', '7124', (176, 184))	('alpha ', 'Gene', '7124', (179, 185))	('alpha ', 'Gene', (53, 59))
39135	20396411	The studied SNPs (TNFalpha -308 (rs1800629) and TNFalpha -238 (rs361525)) were chosen according to the following criteria: (a) minor allele frequency of 5% or greater in Caucasians, according to literature data, (b) previous epidemiologic findings indicating associations with pancreatitis and cancer susceptibility.	('TNFalpha', 'Gene', (18, 26))	('pancreatitis', 'Phenotype', 'HP:0001733', (277, 289))	('alpha ', 'Gene', '7124', (21, 27))	('TNFalpha', 'Gene', (48, 56))	('rs1800629', 'Var', (33, 42))	('cancer', 'Disease', (294, 300))	('pancreatitis', 'Disease', 'MESH:D010195', (277, 289))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('pancreatitis', 'Disease', (277, 289))	('alpha ', 'Gene', '7124', (51, 57))	('rs1800629', 'Mutation', 'rs1800629', (33, 42))	('alpha ', 'Gene', (21, 27))	('TNFalpha', 'Gene', '7124', (18, 26))	('rs361525', 'Mutation', 'rs361525', (63, 71))	('rs361525', 'Var', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('TNFalpha', 'Gene', '7124', (48, 56))	('associations', 'Interaction', (259, 271))	('alpha ', 'Gene', (51, 57))
39136	20396411	Genomic DNA was extracted from blood samples using a sodium perchlorate/chloroform extraction as described by Daly et al.. Genotypes of TNFalpha polymorphisms were determined by PCR-RFLP methods.	('chloroform', 'Chemical', 'MESH:D002725', (72, 82))	('TNFalpha', 'Gene', '7124', (136, 144))	('sodium perchlorate', 'Chemical', 'MESH:C031068', (53, 71))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('polymorphisms', 'Var', (145, 158))	('TNFalpha', 'Gene', (136, 144))
39139	20396411	For TNFalpha -308 G > A (rs1800629), primers were 5'-ATC TGG AGG AAG CGG TAG TG-3' and 5'-AAT AGG TTT TGA GGG CCA TG-3'.	('TNFalpha', 'Gene', (4, 12))	('TNFalpha', 'Gene', '7124', (4, 12))	('-308 G > A', 'Var', (13, 23))	('-308 G > A', 'SUBSTITUTION', 'None', (13, 23))	('rs1800629', 'Mutation', 'rs1800629', (25, 34))	('AAT', 'molecular_function', 'GO:0004069', ('90', '93'))	('rs1800629', 'Var', (25, 34))
39140	20396411	Digestion with NcoI produced an uncut 222-bp fragment from the mutant allele (TNFalpha -308 A), 130- and 20-bp fragments from the wild-type allele (TNFalpha -308 G).	('Digestion', 'biological_process', 'GO:0007586', ('0', '9'))	('alpha ', 'Gene', (81, 87))	('mutant', 'Var', (63, 69))	('TNFalpha', 'Gene', '7124', (78, 86))	('TNFalpha', 'Gene', (148, 156))	('alpha ', 'Gene', '7124', (81, 87))	('alpha ', 'Gene', (151, 157))	('TNFalpha', 'Gene', '7124', (148, 156))	('TNFalpha', 'Gene', (78, 86))	('alpha ', 'Gene', '7124', (151, 157))
39141	20396411	For TNFalpha -238 G > A (rs361525), primers were 5'-ATC TGG AGG AAG CGG TAG TG-3' and 5'-AGA AGA CCC CCC TCG GAA CC-3'.	('TNFalpha', 'Gene', (4, 12))	('-238 G > A', 'SUBSTITUTION', 'None', (13, 23))	('TNFalpha', 'Gene', '7124', (4, 12))	('CCC', 'cellular_component', 'GO:0030896', ('97', '100'))	('CCC', 'cellular_component', 'GO:0030896', ('101', '104'))	('rs361525', 'Mutation', 'rs361525', (25, 33))	('rs361525', 'Var', (25, 33))	('-238 G > A', 'Var', (13, 23))
39142	20396411	Digestion with MspI produced an uncut 150-bp fragment from the mutant allele (TNFalpha -238 A), 130- and 20-bp fragments from the wild-type allele (TNFalpha -238 G).	('Digestion', 'biological_process', 'GO:0007586', ('0', '9'))	('alpha ', 'Gene', (81, 87))	('mutant', 'Var', (63, 69))	('TNFalpha', 'Gene', '7124', (78, 86))	('TNFalpha', 'Gene', (148, 156))	('alpha ', 'Gene', '7124', (81, 87))	('alpha ', 'Gene', (151, 157))	('TNFalpha', 'Gene', '7124', (148, 156))	('TNFalpha', 'Gene', (78, 86))	('alpha ', 'Gene', '7124', (151, 157))
39148	20396411	Genotype distribution of two SNPs (rs1800629; rs361525) in cases and controls did not significantly differ (P > .05) and thus these polymorphisms were not associated with risk of pancreatic cancer (Table 2).	('rs1800629', 'Var', (35, 44))	('pancreatic cancer', 'Disease', 'MESH:D010190', (179, 196))	('rs361525', 'Mutation', 'rs361525', (46, 54))	('rs361525', 'Var', (46, 54))	('associated', 'Reg', (155, 165))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (179, 196))	('rs1800629', 'Mutation', 'rs1800629', (35, 44))	('pancreatic cancer', 'Disease', (179, 196))
39158	20396411	TNFalpha expression in the pancreas is increased by the onset of experimental pancreatitis, and antagonism of TNFalpha reduces the severity of local pancreatic inflammation.	('TNFalpha', 'Gene', (0, 8))	('pancreatitis', 'Disease', (78, 90))	('alpha ', 'Gene', (113, 119))	('TNFalpha', 'Gene', (110, 118))	('alpha ', 'Gene', (3, 9))	('TNFalpha', 'Gene', '7124', (0, 8))	('pancreatic inflammation', 'Phenotype', 'HP:0001733', (149, 172))	('pancreatitis', 'Phenotype', 'HP:0001733', (78, 90))	('alpha ', 'Gene', '7124', (113, 119))	('pancreatitis', 'Disease', 'MESH:D010195', (78, 90))	('increased', 'PosReg', (39, 48))	('alpha ', 'Gene', '7124', (3, 9))	('TNFalpha', 'Gene', '7124', (110, 118))	('pancreatic inflammation', 'Disease', 'MESH:D007249', (149, 172))	('antagonism', 'Var', (96, 106))	('inflammation', 'biological_process', 'GO:0006954', ('160', '172'))	('pancreatic inflammation', 'Disease', (149, 172))
39161	20396411	As to AP, identification of an association between the polymorphisms of TNFalpha and susceptibility to AP is less clear, although several SNPs in TNFalpha have been reported previously in both many forms of pancreatitis and pancreatic cancer.	('alpha ', 'Gene', '7124', (149, 155))	('pancreatitis', 'Disease', 'MESH:D010195', (207, 219))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (224, 241))	('pancreatitis', 'Disease', (207, 219))	('AP', 'Phenotype', 'HP:0001735', (103, 105))	('TNFalpha', 'Gene', (72, 80))	('alpha ', 'Gene', '7124', (75, 81))	('SNPs', 'Var', (138, 142))	('TNFalpha', 'Gene', '7124', (146, 154))	('alpha ', 'Gene', (149, 155))	('pancreatic cancer', 'Disease', 'MESH:D010190', (224, 241))	('polymorphisms', 'Var', (55, 68))	('pancreatitis', 'Phenotype', 'HP:0001733', (207, 219))	('alpha ', 'Gene', (75, 81))	('AP', 'Phenotype', 'HP:0001735', (6, 8))	('reported', 'Reg', (165, 173))	('pancreatic cancer', 'Disease', (224, 241))	('TNFalpha', 'Gene', (146, 154))	('TNFalpha', 'Gene', '7124', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
39164	20396411	On the contrary, there was no association between TNFalpha -238 polymorphism and the risk of AP (OR = 0.86; 95% CI: 0.75-1.77; P = .175) in the study (Table 2).	('AP', 'Phenotype', 'HP:0001735', (93, 95))	('TNFalpha', 'Gene', (50, 58))	('polymorphism', 'Var', (64, 76))	('TNFalpha', 'Gene', '7124', (50, 58))
39170	20396411	Similarly, we found there was no association between TNFalpha -308 polymorphism and the risk of AP (OR = 1.63; 95% CI: 1.13-4.01; P = .145) (Table 2).	('TNFalpha', 'Gene', (53, 61))	('polymorphism', 'Var', (67, 79))	('TNFalpha', 'Gene', '7124', (53, 61))	('AP', 'Phenotype', 'HP:0001735', (96, 98))
39292	33291708	Muscle loss has significant effects on patient health and quality of life.	('Muscle loss', 'Phenotype', 'HP:0003202', (0, 11))	('loss', 'NegReg', (7, 11))	('Muscle', 'Var', (0, 6))	('patient', 'Species', '9606', (39, 46))
39306	33291708	Other attributes of cancer-associated muscle wasting include enhanced autophagy, inhibition of myoblast differentiation and derangements in the renin-angiotensin system which all contribute to muscle degradation (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('autophagy', 'biological_process', 'GO:0006914', ('70', '79'))	('enhanced', 'PosReg', (61, 69))	('autophagy', 'CPA', (70, 79))	('degradation', 'biological_process', 'GO:0009056', ('200', '211'))	('muscle wasting', 'Disease', (38, 52))	('myoblast differentiation', 'CPA', (95, 119))	('inhibition', 'NegReg', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('muscle degradation', 'MPA', (193, 211))	('derangements in the renin-angiotensin system', 'Phenotype', 'HP:0000847', (124, 168))	('muscle wasting', 'Phenotype', 'HP:0003202', (38, 52))	('inhibition of myoblast differentiation', 'biological_process', 'GO:0045662', ('81', '119'))	('cancer', 'Disease', (20, 26))	('renin-angiotensin system', 'MPA', (144, 168))	('autophagy', 'biological_process', 'GO:0016236', ('70', '79'))	('derangements', 'Var', (124, 136))	('muscle wasting', 'Disease', 'MESH:D009133', (38, 52))
39323	33291708	In gastric cancer patients, a polymorphism of IL-8 was associated with cachexia.	('cachexia', 'Phenotype', 'HP:0004326', (71, 79))	('IL-8', 'Gene', (46, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('associated', 'Reg', (55, 65))	('cachexia', 'Disease', (71, 79))	('cachexia', 'Disease', 'MESH:D002100', (71, 79))	('patients', 'Species', '9606', (18, 26))	('gastric cancer', 'Disease', (3, 17))	('polymorphism', 'Var', (30, 42))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('IL-8', 'molecular_function', 'GO:0005153', ('46', '50'))
39328	33291708	TWEAK induces muscle wasting in mice.	('muscle wasting', 'Disease', 'MESH:D009133', (14, 28))	('muscle wasting', 'Disease', (14, 28))	('mice', 'Species', '10090', (32, 36))	('TWEAK', 'Var', (0, 5))	('muscle wasting', 'Phenotype', 'HP:0003202', (14, 28))
39363	33291708	TWEAK also impairs oxidative metabolism in muscle, likely by decreasing PGC1alpha expression and activation of NF-kappaB.	('PGC1alpha', 'Gene', (72, 81))	('activation', 'PosReg', (97, 107))	('decreasing', 'NegReg', (61, 71))	('expression', 'MPA', (82, 92))	('oxidative metabolism', 'biological_process', 'GO:0045333', ('19', '39'))	('PGC1alpha', 'Gene', '10891', (72, 81))	('NF-kappaB', 'Gene', '4790', (111, 120))	('impairs', 'NegReg', (11, 18))	('TWEAK', 'Var', (0, 5))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('97', '120'))	('NF-kappaB', 'Gene', (111, 120))	('oxidative metabolism in', 'MPA', (19, 42))
39364	33291708	Alterations in skeletal muscle mitochondria have been documented in the context of cancer.	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('skeletal muscle mitochondria', 'MPA', (15, 43))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('rat', 'Species', '10116', (4, 7))	('mitochondria', 'cellular_component', 'GO:0005739', ('31', '43'))	('cancer', 'Disease', (83, 89))
39383	33291708	Antagonism of ActRIIB reverses skeletal muscle loss and heart atrophy in multiple cancer cachexia models by inhibiting proteolysis and stimulating muscle stem cell growth.	('heart atrophy in multiple cancer cachexia', 'Disease', 'MESH:D006338', (56, 97))	('cell growth', 'biological_process', 'GO:0016049', ('159', '170'))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('heart atrophy in multiple cancer cachexia', 'Disease', (56, 97))	('skeletal muscle loss', 'Disease', (31, 51))	('cachexia', 'Phenotype', 'HP:0004326', (89, 97))	('Antagonism', 'Var', (0, 10))	('skeletal muscle loss', 'Disease', 'MESH:D005207', (31, 51))	('ActRIIB', 'Gene', (14, 21))	('muscle stem cell growth', 'CPA', (147, 170))	('proteolysis', 'MPA', (119, 130))	('muscle loss', 'Phenotype', 'HP:0003202', (40, 51))	('inhibiting', 'NegReg', (108, 118))	('proteolysis', 'biological_process', 'GO:0006508', ('119', '130'))	('reverses', 'NegReg', (22, 30))	('stimulating', 'PosReg', (135, 146))
39445	33291708	In mice bearing Fn14-expressing tumors, antibodies against Fn14 markedly reduce tumor-induced weight loss and extended lifespan.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('Fn14', 'Gene', (59, 63))	('weight loss', 'Disease', 'MESH:D015431', (94, 105))	('antibodies', 'Var', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mice', 'Species', '10090', (3, 7))	('lifespan', 'CPA', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (80, 85))	('weight loss', 'Disease', (94, 105))	('reduce', 'NegReg', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('weight loss', 'Phenotype', 'HP:0001824', (94, 105))	('tumors', 'Disease', (32, 38))	('tumor', 'Disease', (32, 37))	('extended', 'PosReg', (110, 118))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
39448	33291708	Inhibition of Hsp 70/90 expression abrogates tumor-induced muscle catabolism.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Hsp 70/90', 'Gene', '15511;111042', (14, 23))	('tumor', 'Disease', (45, 50))	('catabolism', 'biological_process', 'GO:0009056', ('66', '76'))	('Inhibition', 'Var', (0, 10))	('Hsp 70/90', 'Gene', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('abrogates', 'NegReg', (35, 44))
39449	33291708	Additionally, in an orthotopic pancreatic carcinoma mouse model, zinc transporter 4 (ZIP4) was shown to induce the secretion of HSP 70/90 to induce p38 mitogen-activated protein kinase (MAPK)-mediated muscle wasting.	('pancreatic', 'Disease', (31, 41))	('HSP 70/90', 'Gene', (128, 137))	('MAPK', 'molecular_function', 'GO:0004707', ('186', '190'))	('ZIP4', 'Gene', '22785', (85, 89))	('secretion', 'biological_process', 'GO:0046903', ('115', '124'))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('p38', 'Var', (148, 151))	('mitogen-activated protein kinase', 'Gene', '5609', (152, 184))	('induce', 'PosReg', (104, 110))	('ZIP4', 'Gene', (85, 89))	('muscle wasting', 'Disease', (201, 215))	('HSP 70/90', 'Gene', '15511;111042', (128, 137))	('zinc transporter 4', 'Gene', (65, 83))	('muscle wasting', 'Phenotype', 'HP:0003202', (201, 215))	('mouse', 'Species', '10090', (52, 57))	('induce', 'PosReg', (141, 147))	('muscle wasting', 'Disease', 'MESH:D009133', (201, 215))	('secretion', 'MPA', (115, 124))	('pancreatic', 'Disease', 'MESH:D010195', (31, 41))	('zinc transporter 4', 'Gene', '22785', (65, 83))	('mitogen-activated protein kinase', 'Gene', (152, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
39467	33291708	In vivo, CXCL1 impairs muscle regeneration.	('CXCL1', 'Var', (9, 14))	('impairs', 'NegReg', (15, 22))	('muscle regeneration', 'CPA', (23, 42))	('rat', 'Species', '10116', (36, 39))	('regeneration', 'biological_process', 'GO:0031099', ('30', '42'))
39482	33291708	In the murine C26 colon carcinoma model, LIF emerged as an important tumor-derived factor that induced atrophy in myotubules.	('atrophy', 'Disease', 'MESH:D001284', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('atrophy', 'Disease', (103, 110))	('myotubules', 'MPA', (114, 124))	('tumor', 'Disease', (69, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('colon carcinoma', 'Disease', (18, 33))	('murine', 'Species', '10090', (7, 13))	('LIF', 'Var', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('colon carcinoma', 'Disease', 'MESH:D003110', (18, 33))
39507	33291708	An experimental lesion in the area postrema of the brainstem lesion ablates the anorexia and the accompanying loss of muscle.	('loss', 'NegReg', (110, 114))	('anorexia', 'Phenotype', 'HP:0002039', (80, 88))	('lesion', 'Var', (16, 22))	('muscle', 'MPA', (118, 124))	('postrema of the brainstem lesion ablates the anorexia', 'Disease', 'None', (35, 88))
39508	33291708	Lesions in this area of the brainstem also attenuate TNFalpha-induced anorexia in rats (8).	('anorexia', 'Disease', 'MESH:D000855', (70, 78))	('rats', 'Species', '10116', (82, 86))	('TNFalpha-induced', 'Gene', (53, 69))	('anorexia', 'Phenotype', 'HP:0002039', (70, 78))	('anorexia', 'Disease', (70, 78))	('attenuate', 'NegReg', (43, 52))	('Lesions', 'Var', (0, 7))
39523	33291708	Blockade of ActRIIB reduces tumor size and metastasis in mice bearing the Lewis lung carcinoma; an activin receptor-like kinase inhibitor, SB-431542, has been developed but has not yet entered clinical use.	('mice', 'Species', '10090', (57, 61))	('activin', 'molecular_function', 'GO:0016915', ('99', '106'))	('tumor', 'Disease', (28, 33))	('lung carcinoma', 'Disease', (80, 94))	('lung carcinoma', 'Disease', 'MESH:D008175', (80, 94))	('Blockade', 'Var', (0, 8))	('reduces', 'NegReg', (20, 27))	('activin', 'Gene', (99, 106))	('SB-431542', 'Chemical', 'MESH:C459179', (139, 148))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('121', '137'))	('activin', 'Gene', '83729', (99, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('activin', 'molecular_function', 'GO:0005160', ('99', '106'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('ActRIIB', 'Gene', (12, 19))
39572	33199632	To generate large cohorts of experimental animals we performed orthotopic transplantation of KrasG12D + Trp53 mutant KPC (4662) cells into the pancreata of syngeneic C57BL/6 recipients as previously described.	('mutant', 'Var', (110, 116))	('Trp53', 'Gene', '22059', (104, 109))	('Trp53', 'Gene', (104, 109))	('P', 'Chemical', 'MESH:D010758', (118, 119))
39579	33199632	However, several drugs, including gemcitabine (GEM), trametinib, a MAPK/ERK kinase (MEK)-1/2 inhibitor, and PU-H71, a heat-shock protein (HSP)-90 inhibitor with specificity for tumor HSP90 variants, significantly reduced tumor growth when compared to control.	('gemcitabine', 'Chemical', 'MESH:C056507', (34, 45))	('P', 'Chemical', 'MESH:D010758', (140, 141))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('P', 'Chemical', 'MESH:D010758', (69, 70))	('P', 'Chemical', 'MESH:D010758', (108, 109))	('trametinib', 'Chemical', 'MESH:C560077', (53, 63))	('heat-shock protein (HSP)-90', 'Gene', '111042', (118, 145))	('P', 'Chemical', 'MESH:D010758', (185, 186))	('ERK kinase (MEK)-1/2', 'Gene', '26395;26396', (72, 92))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('ERK kinase (MEK)-1/2', 'Gene', (72, 92))	('ERK', 'molecular_function', 'GO:0004707', ('72', '75'))	('tumor', 'Disease', (177, 182))	('reduced', 'NegReg', (213, 220))	('PU-H71', 'Chemical', 'MESH:C526550', (108, 114))	('tumor', 'Disease', (221, 226))	('heat-shock protein (HSP)-90', 'Gene', (118, 145))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('MAPK', 'molecular_function', 'GO:0004707', ('67', '71'))	('MEK)-1', 'molecular_function', 'GO:0004708', ('84', '90'))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('variants', 'Var', (189, 197))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('GEM', 'Chemical', 'MESH:C056507', (47, 50))	('shock', 'Phenotype', 'HP:0031273', (123, 128))
39588	33199632	However, treatment of mice with either HSP90(i) + DNMT(i) or HSP90(i) + BRD4(i) combinations induced a significant body weight loss over the 2-wk treatment period, indicative of compounded drug toxicity.	('BRD4', 'Gene', (72, 76))	('HSP90(i', 'Var', (61, 68))	('mice', 'Species', '10090', (22, 26))	('DNMT', 'Gene', (50, 54))	('weight loss', 'Phenotype', 'HP:0001824', (120, 131))	('BRD4', 'Gene', '57261', (72, 76))	('DNMT', 'Gene', '13433', (50, 54))	('HSP90', 'Protein', (39, 44))	('drug toxicity', 'Disease', (189, 202))	('body weight loss', 'Disease', 'MESH:D015431', (115, 131))	('drug toxicity', 'Disease', 'MESH:D064420', (189, 202))	('body weight loss', 'Disease', (115, 131))
39589	33199632	No apparent additive drug toxicity was observed in groups of mice treated with PU-H71 + T or PU-H71 + broad-spectrum RTK(i) (SI Appendix, Fig.	('RTK', 'Gene', (117, 120))	('drug toxicity', 'Disease', 'MESH:D064420', (21, 34))	('mice', 'Species', '10090', (61, 65))	('PU-H71', 'Chemical', 'MESH:C526550', (79, 85))	('PU-H71 + T', 'Var', (79, 89))	('PU-H71', 'Chemical', 'MESH:C526550', (93, 99))	('drug toxicity', 'Disease', (21, 34))	('RTK', 'Gene', '13867', (117, 120))	('PU-H71 +', 'Var', (93, 101))
39595	33199632	In contrast, the T/P combination was highly effective at impairing tumor growth and produced a significant survival benefit, extending the median survival of mice by 1.8-fold over control (83 d vs. 46 d, P < 0.001, Fig.	('T/P combination', 'Var', (17, 32))	('impairing tumor growth', 'Disease', 'MESH:D006130', (57, 79))	('mice', 'Species', '10090', (158, 162))	('extending', 'PosReg', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('survival', 'CPA', (107, 115))	('P', 'Chemical', 'MESH:D010758', (204, 205))	('impairing tumor growth', 'Disease', (57, 79))	('P', 'Chemical', 'MESH:D010758', (19, 20))
39597	33199632	Cancer cell proliferation, as determined by Ki67 positivity, was significantly reduced in tumor tissues of mice treated with T/P combination, but not with either drug alone (Fig.	('T/P combination', 'Var', (125, 140))	('reduced', 'NegReg', (79, 86))	('P', 'Chemical', 'MESH:D010758', (127, 128))	('Ki67', 'Gene', (44, 48))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mice', 'Species', '10090', (107, 111))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Ki67', 'Gene', '17345', (44, 48))	('cell proliferation', 'biological_process', 'GO:0008283', ('7', '25'))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
39598	33199632	We also detected lower pERK immunosignal in tumor tissues treated with T and T/P combination but not in tumors treated with PU-H71 alone (Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('P', 'Chemical', 'MESH:D010758', (79, 80))	('lower', 'NegReg', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('PU-H71', 'Chemical', 'MESH:C526550', (124, 130))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('pERK immunosignal in tumor', 'Disease', 'MESH:D009369', (23, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('P', 'Chemical', 'MESH:D010758', (124, 125))	('pERK immunosignal in tumor', 'Disease', (23, 49))	('T/P combination', 'Var', (77, 92))
39601	33199632	As expected, cell growth was markedly inhibited after a 72-h exposure to each inhibitor (IC50 = 32.4 nM for trametinib and IC50 = 286 nM for PU-H71) and was further inhibited with the T/P drug combination, indicative of synergistic effect with the two-drug combination (Fig.	('PU-H71', 'Chemical', 'MESH:C526550', (141, 147))	('T/P drug', 'Var', (184, 192))	('inhibited', 'NegReg', (165, 174))	('inhibited', 'NegReg', (38, 47))	('P', 'Chemical', 'MESH:D010758', (186, 187))	('trametinib', 'Chemical', 'MESH:C560077', (108, 118))	('P', 'Chemical', 'MESH:D010758', (141, 142))	('cell growth', 'CPA', (13, 24))	('cell growth', 'biological_process', 'GO:0016049', ('13', '24'))
39605	33199632	Levels of the proapoptotic proteins PDCD4, BIM, and RIP were increased by monotherapy treatment and were further elevated with the T/P combination (Fig.	('P', 'Chemical', 'MESH:D010758', (54, 55))	('RIP', 'Gene', (52, 55))	('P', 'Chemical', 'MESH:D010758', (133, 134))	('T/P combination', 'Var', (131, 146))	('PDCD4', 'Gene', (36, 41))	('elevated', 'PosReg', (113, 121))	('RIP', 'Gene', '110628', (52, 55))	('Levels of the', 'MPA', (0, 13))	('BIM', 'Gene', (43, 46))	('increased', 'PosReg', (61, 70))	('PDCD4', 'Gene', '18569', (36, 41))	('BIM', 'Gene', '12125', (43, 46))	('P', 'Chemical', 'MESH:D010758', (36, 37))
39608	33199632	Conversely, PU-H71 alone lowered levels of pAKT and total AKT, as well their upstream activator IGFR.	('AKT', 'Gene', '11651', (44, 47))	('IGFR', 'MPA', (96, 100))	('lowered', 'NegReg', (25, 32))	('PU-H71', 'Chemical', 'MESH:C526550', (12, 18))	('PU-H71', 'Var', (12, 18))	('AKT', 'Gene', '11651', (58, 61))	('AKT', 'Gene', (44, 47))	('AKT', 'Gene', (58, 61))
39611	33199632	In similar fashion, where single agents lowered levels of p90RSK, p70S6 kinase, and pS6 that are essential for protein translation, the response to the T/P combination was more robust (Fig.	('lowered', 'NegReg', (40, 47))	('P', 'Chemical', 'MESH:D010758', (154, 155))	('pS6', 'MPA', (84, 87))	('p90RSK', 'Gene', '20112', (58, 64))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('p70S6', 'Var', (66, 71))	('protein translation', 'biological_process', 'GO:0006412', ('111', '130'))	('T/P', 'Var', (152, 155))	('p90RSK', 'Gene', (58, 64))
39616	33199632	PU-H71 treatment reduced activity and total levels of the well-established HSP90 client proteins RAF-1 and AKT, resulting in a transient reduction of pERK levels at 24 h that rebounded at later time points.	('pERK levels at 24 h', 'MPA', (150, 169))	('AKT', 'Gene', '11651', (107, 110))	('PU-H71', 'Chemical', 'MESH:C526550', (0, 6))	('PU-H71', 'Var', (0, 6))	('AKT', 'Gene', (107, 110))	('reduction', 'NegReg', (137, 146))	('RAF-1', 'Gene', '110157', (97, 102))	('RAF-1', 'Gene', (97, 102))	('HSP90', 'Protein', (75, 80))	('reduced', 'NegReg', (17, 24))	('activity', 'MPA', (25, 33))
39625	33199632	We next hypothesized that if PU-H71-mediated inhibition of PI3K/AKT/mTOR signaling has a major role in sensitizing cells to trametinib, substitution of PU-H71 with the dual PI3K/mTOR inhibitor BEZ-235 should produce a comparable effect.	('PI3K', 'molecular_function', 'GO:0016303', ('173', '177'))	('P', 'Chemical', 'MESH:D010758', (59, 60))	('sensitizing', 'MPA', (103, 114))	('PU-H71', 'Chemical', 'MESH:C526550', (152, 158))	('mTOR', 'Gene', (178, 182))	('PU-H71', 'Chemical', 'MESH:C526550', (29, 35))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('AKT', 'Gene', '11651', (64, 67))	('mTOR', 'Gene', '56717', (68, 72))	('trametinib', 'Chemical', 'MESH:C560077', (124, 134))	('AKT', 'Gene', (64, 67))	('PI3K', 'molecular_function', 'GO:0016303', ('59', '63'))	('inhibition', 'NegReg', (45, 55))	('PU-H71', 'Gene', (152, 158))	('P', 'Chemical', 'MESH:D010758', (152, 153))	('mTOR', 'Gene', '56717', (178, 182))	('BEZ-235', 'Chemical', 'MESH:C531198', (193, 200))	('substitution', 'Var', (136, 148))	('mTOR', 'Gene', (68, 72))	('P', 'Chemical', 'MESH:D010758', (29, 30))	('P', 'Chemical', 'MESH:D010758', (173, 174))
39633	33199632	Interestingly, evaluating the genetic profiles of the cell lines revealed copy number changes in AKT2 and AKT3 in the three cell lines that had the least degree of synergy with the T/P combination (SI Appendix, Fig.	('AKT2', 'Gene', (97, 101))	('AKT2', 'Gene', '11652', (97, 101))	('copy number changes', 'Var', (74, 93))	('P', 'Chemical', 'MESH:D010758', (183, 184))	('AKT3', 'Gene', (106, 110))	('AKT3', 'Gene', '23797', (106, 110))
39637	33199632	As seen in the murine KPC cells, PU-H71 treatment led to down-regulation of pRAF and effectors of the AKT/mTOR signaling axis, as well as partial reduction of pERK (Fig.	('regulation', 'biological_process', 'GO:0065007', ('62', '72'))	('down-regulation', 'NegReg', (57, 72))	('murine', 'Species', '10090', (15, 21))	('RAF', 'Gene', '387609', (77, 80))	('signaling', 'biological_process', 'GO:0023052', ('111', '120'))	('AKT', 'Gene', '11651', (102, 105))	('pERK', 'MPA', (159, 163))	('PU-H71', 'Chemical', 'MESH:C526550', (33, 39))	('P', 'Chemical', 'MESH:D010758', (33, 34))	('mTOR', 'Gene', '56717', (106, 110))	('RAF', 'Gene', (77, 80))	('mTOR', 'Gene', (106, 110))	('PU-H71', 'Var', (33, 39))	('P', 'Chemical', 'MESH:D010758', (23, 24))	('reduction', 'NegReg', (146, 155))	('AKT', 'Gene', (102, 105))
39642	33199632	Two patient-derived organoid lines from distinct patients were established in Matrigel culture, engineered to constitutively express firefly luciferase, and orthotopically transplanted into immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice.	('immunodeficient', 'Disease', 'MESH:D007153', (190, 205))	('immunodeficient', 'Disease', (190, 205))	('P', 'Chemical', 'MESH:D010758', (213, 214))	('patient', 'Species', '9606', (4, 11))	('patient', 'Species', '9606', (49, 56))	('NOD.Cg-Prkdcscid', 'Var', (206, 222))	('Il2', 'molecular_function', 'GO:0005134', ('223', '226'))	('mice', 'Species', '10090', (245, 249))	('patients', 'Species', '9606', (49, 57))
39644	33199632	After 2 wk of treatment, tumor growth across all mice receiving T/P combination was reduced by 79% comparing to vehicle-treated mice (Fig.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('mice', 'Species', '10090', (49, 53))	('reduced', 'NegReg', (84, 91))	('mice', 'Species', '10090', (128, 132))	('P', 'Chemical', 'MESH:D010758', (66, 67))	('T/P combination', 'Var', (64, 79))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
39650	33199632	We found a statistically significant increase in levels of aspartate aminotransferase (AST) levels, alanine transaminase (ALT), and alkaline phosphatase (ALP) enzymes in T/P-treated animals.	('aspartate aminotransferase', 'Gene', (59, 85))	('levels', 'MPA', (49, 55))	('alanine transaminase', 'Gene', (100, 120))	('phosphatase', 'molecular_function', 'GO:0016791', ('141', '152'))	('AST', 'Gene', (87, 90))	('P', 'Chemical', 'MESH:D010758', (172, 173))	('AST', 'Gene', '235504', (87, 90))	('ALT', 'Gene', (122, 125))	('T/P-treated', 'Var', (170, 181))	('increase', 'PosReg', (37, 45))	('alkaline phosphatase', 'MPA', (132, 152))	('alanine transaminase', 'Gene', '76282', (100, 120))	('ALT', 'molecular_function', 'GO:0004021', ('122', '125'))	('ALT', 'Gene', '76282', (122, 125))	('P', 'Chemical', 'MESH:D010758', (156, 157))	('aspartate aminotransferase', 'Gene', '235504', (59, 85))
39651	33199632	On average AST and ALT levels were 1.6-fold higher in T/P-treated animals, consistent with a grade 1 transaminitis in two of five treated animals.	('AST', 'Gene', (11, 14))	('ALT', 'Gene', (19, 22))	('AST', 'Gene', '235504', (11, 14))	('higher', 'PosReg', (44, 50))	('ALT', 'Gene', '76282', (19, 22))	('P', 'Chemical', 'MESH:D010758', (56, 57))	('T/P-treated', 'Var', (54, 65))	('ALT', 'molecular_function', 'GO:0004021', ('19', '22'))
39663	33199632	The most common oncogenic driver in PDAC is mutationally activated KRAS, detected in over 94% of PDAC patients.	('PDAC', 'Disease', (36, 40))	('PDAC', 'Phenotype', 'HP:0006725', (36, 40))	('patients', 'Species', '9606', (102, 110))	('KRAS', 'Gene', (67, 71))	('PDAC', 'Chemical', '-', (97, 101))	('mutationally activated', 'Var', (44, 66))	('PDAC', 'Chemical', '-', (36, 40))	('PDAC', 'Phenotype', 'HP:0006725', (97, 101))
39664	33199632	Thus far, therapeutic strategies to inhibit mutant KRAS variants and its effector pathways, such as the MAPK/ERK and PI3K/AKT signaling axes, have failed in PDAC, in part due to the presence of multiple compensatory and coactivated signaling pathways that contribute to cell proliferation and survival.	('PDAC', 'Phenotype', 'HP:0006725', (157, 161))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('ERK', 'Gene', '26413', (109, 112))	('AKT', 'Gene', '11651', (122, 125))	('KRAS', 'Gene', (51, 55))	('mutant', 'Var', (44, 50))	('P', 'Chemical', 'MESH:D010758', (106, 107))	('AKT signaling', 'biological_process', 'GO:0043491', ('122', '135'))	('inhibit', 'NegReg', (36, 43))	('variants', 'Var', (56, 64))	('ERK', 'molecular_function', 'GO:0004707', ('109', '112'))	('signaling', 'biological_process', 'GO:0023052', ('232', '241'))	('AKT', 'Gene', (122, 125))	('P', 'Chemical', 'MESH:D010758', (157, 158))	('P', 'Chemical', 'MESH:D010758', (117, 118))	('ERK', 'Gene', (109, 112))	('MAPK', 'molecular_function', 'GO:0004707', ('104', '108'))	('cell proliferation', 'biological_process', 'GO:0008283', ('270', '288'))	('PDAC', 'Chemical', '-', (157, 161))
39704	33115943	This increased survival results from the induction of specific antibodies to ENO1 that activate complement-dependent cytotoxicity (CDC); a decrease in tumor infiltration by regulatory T cells and myeloid-derived suppressor cells (MDSC); inhibition of migration and invasion of PDA cells; and an increase in tumor-infiltrating T cells that relocalize into tertiary lymphoid tissue.	('complement-dependent cytotoxicity', 'biological_process', 'GO:0097278', ('96', '129'))	('increased', 'PosReg', (5, 14))	('tumor', 'Disease', (307, 312))	('ENO1', 'Gene', (77, 81))	('invasion', 'CPA', (265, 273))	('inhibition', 'NegReg', (237, 247))	('survival', 'CPA', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('PDA', 'Phenotype', 'HP:0006725', (277, 280))	('decrease', 'NegReg', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('antibodies', 'Var', (63, 73))	('cytotoxicity', 'Disease', (117, 129))	('cytotoxicity', 'Disease', 'MESH:D064420', (117, 129))	('tumor', 'Disease', (151, 156))	('activate', 'PosReg', (87, 95))	('increase', 'PosReg', (295, 303))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
39707	33115943	Notably, combining ENO1 DNA vaccination with GEM treatment significantly enhanced antitumor responses and efficacy to counteract tumor progression compared with mice which were vaccinated or GEM-treated only.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mice', 'Species', '10090', (161, 165))	('efficacy', 'CPA', (106, 114))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('GEM', 'Chemical', 'MESH:C056507', (45, 48))	('tumor', 'Disease', (86, 91))	('ENO1 DNA', 'Var', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('GEM', 'Chemical', 'MESH:C056507', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('enhanced', 'PosReg', (73, 81))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
39777	33115943	Both ENO1 and GEM+ENO1 treatment induced a significant reduction of PDA lesions compared with untreated mice and GEM+ENO1 treatment further reduced tumor lesions compared with the ENO1 vaccine alone (figure 4B).	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('GEM', 'Chemical', 'MESH:C056507', (14, 17))	('reduction of PDA lesions', 'Disease', 'MESH:D051437', (55, 79))	('GEM+ENO1', 'Var', (113, 121))	('tumor lesions', 'Disease', 'MESH:D009369', (148, 161))	('mice', 'Species', '10090', (104, 108))	('tumor lesions', 'Disease', (148, 161))	('GEM', 'Chemical', 'MESH:C056507', (113, 116))	('reduction of PDA lesions', 'Disease', (55, 79))	('reduced', 'NegReg', (140, 147))	('PDA', 'Phenotype', 'HP:0006725', (68, 71))
39783	33115943	No increase in anti-K2C8 or anti-FUBP1 IgG and IFN-gamma was observed in GEM+ENO1-treated mice (data not shown).	('anti-FUBP1', 'Var', (28, 38))	('GEM', 'Chemical', 'MESH:C056507', (73, 76))	('K2C8', 'Gene', '3856', (20, 24))	('mice', 'Species', '10090', (90, 94))	('K2C8', 'Gene', (20, 24))
39784	33115943	Immunohistochemistry demonstrated that only GEM+ENO1 caused a significant increase of tumor-infiltrating CD4 and CD8 T cells (figure 4G-H and online supplemental figure 5B, C).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('GEM+ENO1', 'Var', (44, 52))	('CD8', 'Gene', (113, 116))	('tumor', 'Disease', (86, 91))	('CD8', 'Gene', '925', (113, 116))	('increase', 'PosReg', (74, 82))	('GEM', 'Chemical', 'MESH:C056507', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
39785	33115943	Compared with untreated mice, an increase of macrophage infiltration was observed in ENO1-vaccinated mice, but not in GEM or GEM+ENO1 treated mice (figure 4I and online supplemental figure 5D).	('ENO1-vaccinated', 'Var', (85, 100))	('mice', 'Species', '10090', (24, 28))	('macrophage infiltration', 'CPA', (45, 68))	('GEM', 'Chemical', 'MESH:C056507', (125, 128))	('GEM', 'Chemical', 'MESH:C056507', (118, 121))	('increase', 'PosReg', (33, 41))	('mice', 'Species', '10090', (142, 146))	('mice', 'Species', '10090', (101, 105))
39789	33115943	Depletion of CD4, but not of CD8 or B cells, completely reverted the antitumor effect of the combined treatment (figure 4L).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('CD8', 'Gene', '925', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Depletion', 'Var', (0, 9))	('tumor', 'Disease', (73, 78))	('reverted', 'NegReg', (56, 64))	('CD8', 'Gene', (29, 32))
39796	33115943	Our data showed that antigen spreading is induced by ENO1 vaccination and further increased in combination with GEM, eliciting antibody and T cell responses to G3P.	('antibody', 'cellular_component', 'GO:0019815', ('127', '135'))	('antigen spreading', 'MPA', (21, 38))	('antibody', 'cellular_component', 'GO:0019814', ('127', '135'))	('T cell responses', 'CPA', (140, 156))	('antibody', 'molecular_function', 'GO:0003823', ('127', '135'))	('eliciting', 'Reg', (117, 126))	('ENO1', 'Gene', (53, 57))	('G3P', 'Mutation', 'p.G3P', (160, 163))	('increased', 'PosReg', (82, 91))	('induced', 'Reg', (42, 49))	('GEM', 'Chemical', 'MESH:C056507', (112, 115))	('vaccination', 'Var', (58, 69))	('antibody', 'cellular_component', 'GO:0042571', ('127', '135'))	('antibody', 'MPA', (127, 135))
39800	33115943	In fact, autoantibodies to these TAA predict the patient's outcome in various malignancies.	('malignancies', 'Disease', (78, 90))	('autoantibodies', 'Var', (9, 23))	('patient', 'Species', '9606', (49, 56))	('predict', 'Reg', (37, 44))	('malignancies', 'Disease', 'MESH:D009369', (78, 90))
39826	33115943	This supports the notion that the single depletion of these subsets only partially rescues tumor growth.	('rescues', 'NegReg', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('depletion', 'Var', (41, 50))	('tumor', 'Disease', (91, 96))
39908	32899649	Molecular profiling of the biopsied liver lesion was notable for a pathogenic mutation G12V in exon 2 of the KRAS gene (by Caris Life Sciences ).	('liver lesion', 'Disease', (36, 48))	('pathogenic', 'Reg', (67, 77))	('KRAS', 'Gene', (109, 113))	('KRAS', 'Gene', '3845', (109, 113))	('liver lesion', 'Disease', 'MESH:D017093', (36, 48))	('G12V', 'Mutation', 'rs121913529', (87, 91))	('G12V in', 'Var', (87, 94))
39940	32899649	Disruption in laminar flow is a well-characterized risk factor for thrombus formation.	('thrombus', 'Disease', (67, 75))	('thrombus', 'Disease', 'MESH:D013927', (67, 75))	('formation', 'biological_process', 'GO:0009058', ('76', '85'))	('Disruption', 'Var', (0, 10))
39951	32548799	Additionally, subgroup analysis demonstrated that high MAGE-A expression was significantly associated with poor prognosis for lung, gastrointestinal, breast, and ovarian cancer in both univariate and multivariate analysis for overall survival.	('lung', 'Disease', (126, 130))	('expression', 'MPA', (62, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (162, 176))	('MAGE-A', 'Chemical', '-', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ovarian cancer', 'Disease', (162, 176))	('MAGE-A', 'Gene', (55, 61))	('ovarian cancer', 'Disease', 'MESH:D010051', (162, 176))	('breast', 'Disease', (150, 156))	('gastrointestinal', 'Disease', (132, 148))	('high', 'Var', (50, 54))
39952	32548799	Overexpression of MAGE-A subfamily members is linked to poor prognosis in multiple cancers.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('multiple cancers', 'Disease', (74, 90))	('Overexpression', 'Var', (0, 14))	('MAGE-A', 'Chemical', '-', (18, 24))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('multiple cancers', 'Disease', 'MESH:D009369', (74, 90))
39959	32548799	Molecular abnormalities (genetic and epigenetic dysregulation) plays a very important role in malignant transformation and can provide vital clinical information about cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('epigenetic dysregulation', 'Var', (37, 61))	('malignant transformation', 'CPA', (94, 118))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))
39978	32548799	High expression of MAGE-A genes is associated with poor survival outcomes in breast cancer, lung cancer, and gastric cancer.	('lung cancer', 'Disease', (92, 103))	('breast cancer', 'Disease', (77, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancer', 'Disease', (109, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('MAGE-A', 'Chemical', '-', (19, 25))
39980	32548799	Very interestingly, abnormal MAGE-A expression is more commonly detected in cancer cells that are malignant with invasive and metastatic capacity.	('abnormal', 'Var', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('detected', 'Reg', (64, 72))	('MAGE-A', 'Chemical', '-', (29, 35))	('MAGE-A', 'Gene', (29, 35))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('expression', 'MPA', (36, 46))
39981	32548799	Patients with cancer and abnormal expression of MAGE-A have a poor prognosis.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('MAGE-A', 'Protein', (48, 54))	('MAGE-A', 'Chemical', '-', (48, 54))	('abnormal expression', 'Var', (25, 44))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
40028	32548799	The association between abnormal expression of MAGE-A members and cancer is now well-established.	('MAGE-A', 'Chemical', '-', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('abnormal expression', 'Var', (24, 43))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
40037	32548799	Cancers overexpressing MAGE were more aggressive and showed the worst clinical outcomes.	('aggressive', 'CPA', (38, 48))	('Cancers', 'Disease', (0, 7))	('overexpressing', 'Var', (8, 22))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))
40040	32548799	Aberrant regulation of E3 RING ubiquitin ligases by MAGE members has been reported as contributing to tumorigenesis.	('E3 RING ubiquitin ligases', 'Protein', (23, 48))	('regulation', 'MPA', (9, 19))	('Aberrant', 'Var', (0, 8))	('contributing', 'Reg', (86, 98))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('regulation of E3', 'biological_process', 'GO:1904666', ('9', '25'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('ubiquitin', 'molecular_function', 'GO:0031386', ('31', '40'))
40044	32548799	DNA hypomethylation has been shown to induce aberrant expression of MAGE-A genes and is associated with poor survival outcomes in laryngeal squamous cell carcinoma and esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 202))	('hypomethylation', 'Var', (4, 19))	('induce', 'PosReg', (38, 44))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('MAGE-A', 'Chemical', '-', (68, 74))	('esophageal squamous cell carcinoma', 'Disease', (168, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('aberrant expression', 'MPA', (45, 64))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('0', '19'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('associated', 'Reg', (88, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('squamous cell carcinoma', 'Disease', (140, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (140, 163))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (168, 202))
40065	32548799	Overexpression of MAGE-A3 has been shown to enhance the invasive potential of thyroid cancer cells.	('thyroid cancer', 'Disease', 'MESH:D013964', (78, 92))	('MAGE-A3', 'Gene', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Overexpression', 'Var', (0, 14))	('thyroid cancer', 'Phenotype', 'HP:0002890', (78, 92))	('thyroid cancer', 'Disease', (78, 92))	('MAGE-A3', 'Gene', '4102', (18, 25))	('enhance', 'PosReg', (44, 51))
40071	32548799	Recently, MAGE-A3 overexpression has been shown to induce proliferation and migration of cervical cancer cells by modulating the EMT and Wnt signaling pathways.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('MAGE-A3', 'Gene', (10, 17))	('proliferation', 'CPA', (58, 71))	('migration', 'CPA', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('EMT', 'biological_process', 'GO:0001837', ('129', '132'))	('overexpression', 'Var', (18, 32))	('modulating', 'Reg', (114, 124))	('cancer', 'Disease', (98, 104))	('induce', 'PosReg', (51, 57))	('MAGE-A3', 'Gene', '4102', (10, 17))
40079	32548799	These findings suggest that expression of MAGE-A is associated with proliferation, inhibition of apoptosis, and chemoresistance in cancer cells.	('cancer', 'Disease', (131, 137))	('proliferation', 'CPA', (68, 81))	('inhibition', 'NegReg', (83, 93))	('MAGE-A', 'Chemical', '-', (42, 48))	('associated', 'Reg', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('83', '106'))	('chemoresistance', 'CPA', (112, 127))	('MAGE-A', 'Gene', (42, 48))	('expression', 'Var', (28, 38))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('apoptosis', 'CPA', (97, 106))
40083	32548799	For instance, MAGE-A family members (A1, A3, A6, A9, and A10) are associated with the worst clinical outcomes, with poor survival rates in lung, breast, and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	('ovarian cancer', 'Disease', 'MESH:D010051', (157, 171))	('A10', 'Var', (57, 60))	('breast', 'Disease', (145, 151))	('poor', 'NegReg', (116, 120))	('MAGE-A', 'Chemical', '-', (14, 20))	('lung', 'Disease', (139, 143))	('ovarian cancer', 'Disease', (157, 171))	('A1', 'Var', (37, 39))
40102	32490170	PAAD patients with genetic alteration of m6A regulators had worse disease-free and overall survival.	('overall survival', 'CPA', (83, 99))	('patients', 'Species', '9606', (5, 13))	('PAAD', 'Phenotype', 'HP:0006725', (0, 4))	('m6A regulators', 'Gene', (41, 55))	('genetic alteration', 'Var', (19, 37))	('worse', 'NegReg', (60, 65))
40104	32490170	Collectively, these findings can improve the understanding of m6A modifications in PAAD and potentially guide therapies in PAAD patients.	('modifications', 'Var', (66, 79))	('PAAD', 'Phenotype', 'HP:0006725', (123, 127))	('m6A', 'Protein', (62, 65))	('PAAD', 'Phenotype', 'HP:0006725', (83, 87))	('patients', 'Species', '9606', (128, 136))	('PAAD', 'Disease', (83, 87))
40111	32490170	The N6-methyladenosine (m6A) modification regulates different stages of mRNA metabolism, including maturation, folding, translation, export, and decay, and thus, consequently, drives numerous biological processes.	('mRNA metabolism', 'biological_process', 'GO:0016071', ('72', '87'))	('modification', 'Var', (29, 41))	('decay', 'MPA', (145, 150))	('export', 'MPA', (133, 139))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (4, 22))	('folding', 'MPA', (111, 118))	('mRNA metabolism', 'MPA', (72, 87))	('translation', 'MPA', (120, 131))	('maturation', 'MPA', (99, 109))	('regulates', 'Reg', (42, 51))	('drives', 'Reg', (176, 182))	('translation', 'biological_process', 'GO:0006412', ('120', '131'))
40112	32490170	m6A in mRNA has emerged as an important epitranscriptomic modification that controls cancer self-renewal and cell fate.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('controls', 'Reg', (76, 84))	('cell fate', 'CPA', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('m6A', 'Var', (0, 3))
40113	32490170	As one of the most abundant post-transcriptional modifications present in mammalian mRNA, several studies suggest that changes in m6A modification patterns are implicated in tumorigenesis, leading to various cancers, such as breast, lung, glioblastoma, and many more.	('tumor', 'Disease', (174, 179))	('glioblastoma', 'Disease', (239, 251))	('glioblastoma', 'Disease', 'MESH:D005909', (239, 251))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('lung', 'Disease', (233, 237))	('implicated', 'Reg', (160, 170))	('cancers', 'Disease', (208, 215))	('modification', 'Var', (134, 146))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('glioblastoma', 'Phenotype', 'HP:0012174', (239, 251))	('changes', 'Var', (119, 126))	('mammalian', 'Species', '9606', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('m6A', 'Protein', (130, 133))	('breast', 'Disease', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('leading to', 'Reg', (189, 199))
40116	32490170	Readers (YTHDC1-2, YTHDF1-3, and IGF2BP1-3) bind to m6A-modified mRNA and exert biological functions, such as mRNA translocation, degradation, and translation.	('IGF2BP1-3', 'Gene', (33, 42))	('YTHDF1-3', 'Gene', (19, 27))	('mRNA translocation', 'MPA', (110, 128))	('degradation', 'biological_process', 'GO:0009056', ('130', '141'))	('m6A-modified', 'Var', (52, 64))	('bind', 'Interaction', (44, 48))	('translation', 'MPA', (147, 158))	('degradation', 'MPA', (130, 141))	('translation', 'biological_process', 'GO:0006412', ('147', '158'))	('YTHDC1-2', 'Gene', (9, 17))	('YTHDF1-3', 'Gene', '54915;51441;253943', (19, 27))	('IGF2BP1-3', 'Gene', '10642;10644;10643', (33, 42))	('YTHDC1-2', 'Gene', '91746;64848', (9, 17))
40117	32490170	Whereas a previous study found that m6A writer METTL3 could promote chemo- and radioresistance in PAAD cells, one recent study discovered that several hypomethylated genes correlated with poor overall survival of PAAD patients.	('promote', 'PosReg', (60, 67))	('METTL3', 'Gene', (47, 53))	('PAAD', 'Phenotype', 'HP:0006725', (98, 102))	('patients', 'Species', '9606', (218, 226))	('poor', 'NegReg', (188, 192))	('correlated with', 'Reg', (172, 187))	('PAAD', 'Phenotype', 'HP:0006725', (213, 217))	('m6A writer', 'Var', (36, 46))
40125	32490170	From 149 TCGA PAAD cases analyzed, the m6A writer gene VIRMA (6.7%) demonstrated the highest frequency of genetic alteration (mutations and/or copy number variations [CNVs]), followed by HAKAI (4%), YTHDF3 (3.4%), IGF2BP1 (3.4%), and ALKBH5 (2.7%) (Figure 1A; Table 1).	('YTHDF3', 'Gene', (199, 205))	('ALKBH5', 'Gene', (234, 240))	('IGF2BP1', 'Gene', (214, 221))	('m6A writer', 'Gene', (39, 49))	('HAKAI', 'Gene', (187, 192))	('genetic', 'MPA', (106, 113))	('YTHDF3', 'Gene', '253943', (199, 205))	('PAAD', 'Phenotype', 'HP:0006725', (14, 18))	('IGF2BP1', 'Gene', '10642', (214, 221))	('copy number variations', 'Var', (143, 165))	('ALKBH5', 'Gene', '54890', (234, 240))	('HAKAI', 'Gene', '79872', (187, 192))
40126	32490170	Next, we explored the relationship between genetic alterations of m6A regulators and clinicopathological features of PAAD patients.	('genetic alterations', 'Var', (43, 62))	('patients', 'Species', '9606', (122, 130))	('PAAD', 'Phenotype', 'HP:0006725', (117, 121))	('m6A regulators', 'Gene', (66, 80))	('PAAD', 'Disease', (117, 121))
40127	32490170	The results demonstrated that PAAD patients with/without genetic alterations of m6A regulators had no significantly distinct features, including age, gender, pathological stage, histological grade, or TNM stage (Table 2).	('m6A regulators', 'Gene', (80, 94))	('PAAD', 'Phenotype', 'HP:0006725', (30, 34))	('genetic alterations', 'Var', (57, 76))	('patients', 'Species', '9606', (35, 43))
40141	32490170	Regulators or inhibitors of m6A modifications may provide the potential therapeutic strategies for cancers.	('m6A', 'Gene', (28, 31))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('modifications', 'Var', (32, 45))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
40142	32490170	The methylation modification of m6A has been proven to be reversible through the regulation of methyltransferase (writers), demethylase (erasers), and proteins that recognize m6A modification (readers).	('regulation', 'biological_process', 'GO:0065007', ('81', '91'))	('m6A', 'Gene', (32, 35))	('methyltransferase', 'Enzyme', (95, 112))	('demethylase', 'Gene', (124, 135))	('m6A', 'Var', (175, 178))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('demethylase', 'Gene', '8932', (124, 135))
40144	32490170	The YTH domain can recognize m6A through a conserved aromatic cage, and another two proteins:FMR1 and LRPPRC:"read" this modification.	('LRPPRC', 'Gene', '10128', (102, 108))	('FMR1', 'Gene', '2332', (93, 97))	('FMR1', 'Gene', (93, 97))	('m6A', 'Var', (29, 32))	('LRPPRC', 'Gene', (102, 108))
40152	32490170	Besides, small ubiquitin-like modifier (SUMO)ylation of METTL3 is of importance for the promotion of tumor growth at lysine residues K177, K211, K212, and K215 in non-small cell lung carcinoma (NSCLC).	('K215', 'Var', (155, 159))	('promotion', 'PosReg', (88, 97))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (167, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (163, 192))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('non-small cell lung carcinoma', 'Disease', (163, 192))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('NSCLC', 'Disease', (194, 199))	('K177', 'Var', (133, 137))	('K211', 'Var', (139, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('K212', 'Var', (145, 149))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (163, 192))	('tumor', 'Disease', (101, 106))	('METTL3', 'Gene', (56, 62))	('ubiquitin', 'molecular_function', 'GO:0031386', ('15', '24'))	('lysine', 'Chemical', 'MESH:D008239', (117, 123))
40157	32490170	Deletion of METTL3 could impair the EMT of cancer cells both in vitro and in vivo.	('METTL3', 'Gene', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('impair', 'NegReg', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('EMT', 'biological_process', 'GO:0001837', ('36', '39'))	('Deletion', 'Var', (0, 8))
40158	32490170	However, m6A modification is multifaceted in the cancer environment.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('m6A', 'Var', (9, 12))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))
40161	32490170	As for m6A erasers, the silencing of ALKBH5 inhibits cancer growth and invasion by disturbing EMT and angiogenesis-related transcripts, including transforming growth factor (TGF)-beta signaling pathway genes.	('ALKBH5', 'Gene', '54890', (37, 43))	('EMT', 'biological_process', 'GO:0001837', ('94', '97'))	('signaling pathway', 'biological_process', 'GO:0007165', ('184', '201'))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('ALKBH5', 'Gene', (37, 43))	('disturbing', 'Reg', (83, 93))	('angiogenesis', 'biological_process', 'GO:0001525', ('102', '114'))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('transforming growth factor (TGF)-beta', 'Gene', '7039', (146, 183))	('inhibits', 'NegReg', (44, 52))	('angiogenesis-related', 'CPA', (102, 122))	('silencing', 'Var', (24, 33))
40166	32490170	In both YTHDF2 knockout hematopoietic stem and progenitor cells and YTHDF2 knockdown human umbilical cord hematopoietic stem cells, these mRNAs were stable and facilitated hematopoietic stem-cell expansion while knocking down one of the key targets of YTHDF2: Tal1 mRNA, which partially rescued the phenotype.	('knocking', 'Var', (212, 220))	('Tal1', 'Gene', '6886', (260, 264))	('YTHDF2', 'Gene', '51441', (68, 74))	('facilitated', 'PosReg', (160, 171))	('YTHDF2', 'Gene', (8, 14))	('YTHDF2', 'Gene', (252, 258))	('Tal1', 'Gene', (260, 264))	('YTHDF2', 'Gene', (68, 74))	('hematopoietic stem-cell expansion', 'CPA', (172, 205))	('YTHDF2', 'Gene', '51441', (8, 14))	('YTHDF2', 'Gene', '51441', (252, 258))	('human', 'Species', '9606', (85, 90))	('cell expansion', 'biological_process', 'GO:0016049', ('191', '205'))
40167	32490170	Collectively, these studies corroborate the functional importance of m6A modifications, such as METTL3, METTL14, FTO, and YTHDF2, and they provide profound insights into development and maintenance of AML and self-renewal of leukemia stem/initiation cells through the downstream MYC and Tal1 pathways.	('modifications', 'Var', (73, 86))	('AML', 'Phenotype', 'HP:0004808', (201, 204))	('AML', 'Disease', (201, 204))	('FTO', 'Gene', '79068', (113, 116))	('Tal1', 'Gene', (287, 291))	('MYC', 'Gene', (279, 282))	('YTHDF2', 'Gene', (122, 128))	('FTO', 'Gene', (113, 116))	('METTL14', 'Gene', (104, 111))	('m6A', 'Gene', (69, 72))	('self-renewal', 'CPA', (209, 221))	('MYC', 'Gene', '4609', (279, 282))	('leukemia', 'Phenotype', 'HP:0001909', (225, 233))	('YTHDF2', 'Gene', '51441', (122, 128))	('METTL3', 'Gene', (96, 102))	('Tal1', 'Gene', '6886', (287, 291))	('leukemia', 'Disease', (225, 233))	('leukemia', 'Disease', 'MESH:D007938', (225, 233))	('AML', 'Disease', 'MESH:D015470', (201, 204))
40168	32490170	The above information demonstrates that m6A modification can target multiple genes participating in various critical biological processes, such as transcription, cell proliferation, and cancer-related pathways.	('modification', 'Var', (44, 56))	('target', 'Reg', (61, 67))	('transcription', 'biological_process', 'GO:0006351', ('147', '160'))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cell proliferation', 'CPA', (162, 180))	('transcription', 'CPA', (147, 160))	('m6A', 'Var', (40, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('162', '180'))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
40169	32490170	In similar studies on glioma and clear cell renal cell carcinoma, m6A regulator alterations were correlated with a poorer prognosis and an indication that novel therapeutic strategies for m6A RNA methylation should be further explored in the treatment of cancer.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('alterations', 'Var', (80, 91))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (33, 64))	('clear cell renal cell carcinoma', 'Disease', (33, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('glioma', 'Disease', (22, 28))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (33, 64))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (44, 64))	('RNA', 'cellular_component', 'GO:0005562', ('192', '195'))	('m6A regulator', 'Gene', (66, 79))	('cancer', 'Disease', (255, 261))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('RNA methylation', 'biological_process', 'GO:0001510', ('192', '207'))	('glioma', 'Disease', 'MESH:D005910', (22, 28))
40171	32490170	Among upregulated genes, according to previous reports, Cadherin EGF LAG Seven-Pass G-Type Receptor 3 (CELSR3) is epigenetically dysregulated in 84% of small intestinal neuroendocrine tumors (SINETs).	('EGF', 'molecular_function', 'GO:0005154', ('65', '68'))	('small intestinal neuroendocrine tumors', 'Disease', (152, 190))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('SINET', 'Chemical', '-', (192, 197))	('Cadherin EGF LAG Seven-Pass G-Type Receptor 3', 'Gene', (56, 101))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (169, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('CELSR3', 'Gene', '1951', (103, 109))	('epigenetically dysregulated', 'Var', (114, 141))	('CELSR3', 'Gene', (103, 109))	('small intestinal neuroendocrine tumors', 'Disease', 'MESH:D018358', (152, 190))	('Cadherin EGF LAG Seven-Pass G-Type Receptor 3', 'Gene', '1951', (56, 101))	('Cadherin', 'molecular_function', 'GO:0008014', ('56', '64'))
40173	32490170	Epigenetic changes in GAD1 expression facilitates cancer metastasis by altering glutamate metabolism in the microenvironment of metastatic brain cancer.	('cancer', 'Disease', (145, 151))	('facilitates', 'PosReg', (38, 49))	('cancer', 'Disease', (50, 56))	('glutamate metabolism', 'MPA', (80, 100))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('brain cancer', 'Phenotype', 'HP:0030692', (139, 151))	('altering', 'Reg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('brain cancer', 'Disease', (139, 151))	('glutamate', 'Chemical', 'MESH:D018698', (80, 89))	('glutamate metabolism', 'biological_process', 'GO:0006536', ('80', '100'))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('brain cancer', 'Disease', 'MESH:D001932', (139, 151))	('GAD1', 'Gene', '2571', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('Epigenetic changes', 'Var', (0, 18))	('GAD1', 'Gene', (22, 26))
40178	32490170	In addition, EGF-TGF-beta interactions could increase pancreatic cell invasion, which could be blocked by erlotinib and SB505124, a type I TGF-beta receptor inhibitor.	('pancreatic cell invasion', 'CPA', (54, 78))	('interactions', 'Interaction', (26, 38))	('EGF', 'Gene', (13, 16))	('SB505124', 'Chemical', 'MESH:C519132', (120, 128))	('erlotinib', 'Chemical', 'MESH:D000069347', (106, 115))	('EGF', 'molecular_function', 'GO:0005154', ('13', '16'))	('EGF', 'Gene', '1950', (13, 16))	('SB505124', 'Var', (120, 128))	('increase', 'PosReg', (45, 53))
40180	32490170	According to studies, TNNT1 is overexpressed in breast cancer and leiomyosarcoma; PPFIA3 is methylated in most gastric cancer samples, whereas barely methylated in normal samples, suggesting m6A writers could outperform erasers during such carcinogenesis.	('m6A writers', 'Var', (191, 202))	('gastric cancer', 'Disease', 'MESH:D013274', (111, 125))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (66, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (66, 80))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('TNNT1', 'Gene', (22, 27))	('breast cancer', 'Disease', (48, 61))	('leiomyosarcoma', 'Disease', (66, 80))	('TNNT1', 'Gene', '7138', (22, 27))	('PPFIA3', 'Gene', (82, 88))	('PPFIA3', 'Gene', '8541', (82, 88))	('gastric cancer', 'Disease', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
40181	32490170	Third, rather than make comparisons between normal and cancer groups and use a conventional pathological staging system to sub group patients, we have developed a novel method to stratify PAAD patients by their m6A regulator alteration status, offering a new perspective to identify heterogeneities among PAAD patients.	('patients', 'Species', '9606', (310, 318))	('patients', 'Species', '9606', (193, 201))	('PAAD', 'Phenotype', 'HP:0006725', (188, 192))	('alteration', 'Var', (225, 235))	('PAAD', 'Phenotype', 'HP:0006725', (305, 309))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('PAAD', 'Disease', (188, 192))	('patients', 'Species', '9606', (133, 141))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
40192	30618016	However, their aberrant overexpression and glycosylation in various malignancies facilitate oncogenic events from inception to metastasis.	('malignancies', 'Disease', (68, 80))	('oncogenic events', 'CPA', (92, 108))	('overexpression', 'PosReg', (24, 38))	('aberrant', 'Var', (15, 23))	('facilitate', 'PosReg', (81, 91))	('glycosylation', 'biological_process', 'GO:0070085', ('43', '56'))	('glycosylation', 'Var', (43, 56))	('malignancies', 'Disease', 'MESH:D009369', (68, 80))
40215	30618016	Aberrantly high levels of mucins on cancer cells create steric hindrance and mask the detection of tumor-associated antigens (TAAs) and prevent specific and non-specific lysis of the tumor cells by immune cells.	('tumor', 'Disease', (99, 104))	('prevent', 'NegReg', (136, 143))	('Aberrantly', 'Var', (0, 10))	('lysis', 'biological_process', 'GO:0019835', ('170', '175'))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('mucin', 'Gene', (26, 31))	('cancer', 'Disease', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('mask', 'NegReg', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (183, 188))	('detection', 'MPA', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mucin', 'Gene', '100508689', (26, 31))	('steric', 'MPA', (56, 62))
40218	30618016	A study demonstrating the induction of strong antibody responses in mice using naked MUC4 peptides and Thomson-Friedenrich (T) and sialyl-Tn (sTn) glyco-peptide antigens shows the significance of aberrantly glycosylated backbone as tumor-associated glycopeptide antigens.	('mice', 'Species', '10090', (68, 72))	('antibody', 'cellular_component', 'GO:0019815', ('46', '54'))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('antibody', 'cellular_component', 'GO:0019814', ('46', '54'))	('antibody', 'molecular_function', 'GO:0003823', ('46', '54'))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', (232, 237))	('antibody', 'cellular_component', 'GO:0042571', ('46', '54'))	('aberrantly', 'Var', (196, 206))
40221	30618016	Aberrant overexpression and glycosylation patterns of tumor-associated mucins have been implicated in immunomodulation.	('mucin', 'Gene', (71, 76))	('overexpression', 'PosReg', (9, 23))	('glycosylation patterns', 'MPA', (28, 50))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('glycosylation', 'biological_process', 'GO:0070085', ('28', '41'))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mucin', 'Gene', '100508689', (71, 76))	('tumor', 'Disease', (54, 59))
40232	30618016	Moreover, the formation of extracellular mucinous matrix by aberrantly glycosylated mucin masks various receptors on the cell surface, hence obstructing ligand-receptor or cellular interactions.	('mucin', 'Gene', (84, 89))	('ligand-receptor', 'Interaction', (153, 168))	('receptors', 'Protein', (104, 113))	('mucin', 'Gene', '100508689', (41, 46))	('cell surface', 'cellular_component', 'GO:0009986', ('121', '133'))	('masks', 'NegReg', (90, 95))	('extracellular', 'cellular_component', 'GO:0005576', ('27', '40'))	('ligand', 'molecular_function', 'GO:0005488', ('153', '159'))	('mucin', 'Gene', '100508689', (84, 89))	('obstructing', 'NegReg', (141, 152))	('aberrantly glycosylated', 'Var', (60, 83))	('mucin', 'Gene', (41, 46))	('formation', 'biological_process', 'GO:0009058', ('14', '23'))
40233	30618016	For instance, membrane-bound MUC1 and MUC16 have been reported to suppress TLR-mediated innate immune activation at the ocular surface, inhibiting secretion of pro-inflammatory cytokines, such as IL-6, IL-8, and TNF-alpha, in human corneal epithelial cells.	('inhibiting', 'NegReg', (136, 146))	('human', 'Species', '9606', (226, 231))	('suppress', 'NegReg', (66, 74))	('membrane', 'cellular_component', 'GO:0016020', ('14', '22'))	('TLR-mediated', 'Gene', (75, 87))	('IL-8', 'Gene', '3576', (202, 206))	('IL-6', 'Gene', (196, 200))	('IL-8', 'Gene', (202, 206))	('secretion of pro-inflammatory cytokines', 'MPA', (147, 186))	('IL-6', 'molecular_function', 'GO:0005138', ('196', '200'))	('IL-8', 'molecular_function', 'GO:0005153', ('202', '206'))	('secretion', 'biological_process', 'GO:0046903', ('147', '156'))	('IL-6', 'Gene', '3569', (196, 200))	('MUC16', 'Var', (38, 43))
40238	30618016	When the ability of mucins to elicit adaptive immune response was tested using glycosylated and non-glycosylated OVA-MUC1 fusion peptides, GalNac O-glycosylation resulted in increased helper T-cell immune response and production of MUC1-specific antibodies through MHC class II presentation in HLA-A2 transgenic mice.	('GalNac', 'Chemical', '-', (139, 145))	('mucin', 'Gene', '100508689', (20, 25))	('O-glycosylation', 'Var', (146, 161))	('HLA-A', 'Gene', '3105', (294, 299))	('adaptive immune response', 'biological_process', 'GO:0002250', ('37', '61'))	('transgenic mice', 'Species', '10090', (301, 316))	('mucin', 'Gene', (20, 25))	('HLA-A', 'Gene', (294, 299))	('immune response', 'biological_process', 'GO:0006955', ('198', '213'))	('glycosylation', 'biological_process', 'GO:0070085', ('148', '161'))	('helper T-cell immune response', 'CPA', (184, 213))	('O-glyco', 'Chemical', '-', (146, 153))	('increased', 'PosReg', (174, 183))	('MUC1-specific', 'Protein', (232, 245))
40241	30618016	The TR region of MUC1 contains three predominant cleavage sites: Thr3-Ser4, Gly13-Ser14, and His20-Gly1.	('Ser', 'cellular_component', 'GO:0005790', ('70', '73'))	('Gly1', 'Gene', (76, 80))	('Thr3-Ser4', 'Var', (65, 74))	('Ser', 'cellular_component', 'GO:0005790', ('82', '85'))	('Gly1', 'Gene', '390816', (76, 80))	('Ser4', 'Chemical', '-', (70, 74))	('Gly1', 'Gene', (99, 103))	('His20', 'Chemical', '-', (93, 98))	('MUC1', 'Gene', (17, 21))	('Ser14', 'Chemical', '-', (82, 87))	('Gly1', 'Gene', '390816', (99, 103))	('Thr3', 'Chemical', '-', (65, 69))	('Gly13', 'Chemical', '-', (76, 81))
40242	30618016	However, O-linked glycosylation at either Thr3 or Ser4 sites renders MUC1 glycoforms unavailable for proteolytic processing by DCs, probably due to cleavage site masking.	('Ser4', 'Gene', (50, 54))	('glycosylation', 'biological_process', 'GO:0070085', ('18', '31'))	('O-linked glycosylation', 'Var', (9, 31))	('Ser4', 'Chemical', '-', (50, 54))	('Thr3', 'Chemical', '-', (42, 46))	('Ser', 'cellular_component', 'GO:0005790', ('50', '53'))	('unavailable', 'NegReg', (85, 96))
40249	30618016	Together, these studies demonstrate that the aberrant expression and glycosylation of cancer-associated mucins modulate both innate and adaptive immune effector functions, enabling cancer cell survival.	('modulate', 'Reg', (111, 119))	('adaptive immune effector functions', 'CPA', (136, 170))	('enabling', 'PosReg', (172, 180))	('innate', 'CPA', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mucin', 'Gene', '100508689', (104, 109))	('aberrant expression', 'Var', (45, 64))	('glycosylation', 'biological_process', 'GO:0070085', ('69', '82'))	('glycosylation', 'MPA', (69, 82))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('mucin', 'Gene', (104, 109))	('cancer', 'Disease', (86, 92))
40255	30618016	Thus, deletion of the mucl gene produces strong TLR4-and TLR5-mediated DC responses.	('TLR5', 'Gene', '7100', (57, 61))	('mucl', 'Gene', (22, 26))	('TLR5', 'Gene', (57, 61))	('TLR4', 'Gene', (48, 52))	('deletion', 'Var', (6, 14))	('TLR4', 'Gene', '7099', (48, 52))
40262	30618016	An improved antibody response has been observed in the case of peptide modifications with alpha-GalNAc, due to saccharide-mediated structural changes in the MUC1 peptide backbone.	('improved', 'PosReg', (3, 11))	('antibody', 'cellular_component', 'GO:0042571', ('12', '20'))	('alpha-GalNAc', 'Protein', (90, 102))	('antibody', 'cellular_component', 'GO:0019814', ('12', '20'))	('antibody', 'cellular_component', 'GO:0019815', ('12', '20'))	('alpha-GalNAc', 'Chemical', '-', (90, 102))	('peptide modifications', 'Var', (63, 84))	('antibody', 'molecular_function', 'GO:0003823', ('12', '20'))	('antibody response', 'CPA', (12, 29))	('saccharide', 'Chemical', 'MESH:D002241', (111, 121))
40267	30618016	Aberrant glycosylation leads to the expression of T, sTn, sLea, and sLex structures on tumor-associated mucins, which contribute to the metastatic ability of several tumor types.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('tumor', 'Disease', (87, 92))	('mucin', 'Gene', '100508689', (104, 109))	('tumor', 'Disease', (166, 171))	('glycosylation', 'biological_process', 'GO:0070085', ('9', '22'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mucin', 'Gene', (104, 109))	('glycosylation', 'MPA', (9, 22))	('leads to', 'Reg', (23, 31))
40272	30618016	A recent study demonstrated that MUC4 further enhances the survival and extravasation of the disseminated tumor cells by physically interacting with platelets and immune cells, such as macrophages and hematopoietic progenitors.	('interacting', 'Interaction', (132, 143))	('enhances', 'PosReg', (46, 54))	('extravasation', 'CPA', (72, 85))	('survival', 'CPA', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('MUC4', 'Var', (33, 37))	('tumor', 'Disease', (106, 111))
40274	30618016	Loss of MUC2 stimulates increased IL-6 production by tumor-associated macrophages, which in turn leads to increased STAT3 signaling and epithelial-to-mesenchymal transition in colon cancer cells.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('MUC2', 'Gene', '4583', (8, 12))	('colon cancer', 'Phenotype', 'HP:0003003', (176, 188))	('IL-6 production', 'biological_process', 'GO:0032635', ('34', '49'))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('136', '172'))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('epithelial-to-mesenchymal transition', 'CPA', (136, 172))	('MUC2', 'Gene', (8, 12))	('STAT3', 'Gene', (116, 121))	('increased', 'PosReg', (106, 115))	('colon cancer', 'Disease', 'MESH:D015179', (176, 188))	('IL-6', 'Gene', '3569', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('STAT3', 'Gene', '6774', (116, 121))	('IL-6', 'Gene', (34, 38))	('IL-6', 'molecular_function', 'GO:0005138', ('34', '38'))	('Loss', 'Var', (0, 4))	('increased', 'PosReg', (24, 33))	('colon cancer', 'Disease', (176, 188))	('increased IL-6', 'Phenotype', 'HP:0030783', (24, 38))	('tumor', 'Disease', (53, 58))
40275	30618016	MUC5AC leads to the suppression of anti-tumor function of neutrophils, promoting enhanced in vivo tumor growth and metastasis.	('suppression', 'NegReg', (20, 31))	('MUC5AC', 'Var', (0, 6))	('enhanced', 'PosReg', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (40, 45))
40277	30618016	MUC5AC silencing significantly increases IL-8 production and neutrophil activation in pancreatic cancer cells.	('neutrophil activation', 'biological_process', 'GO:0042119', ('61', '82'))	('pancreatic cancer', 'Disease', (86, 103))	('increases', 'PosReg', (31, 40))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('IL-8', 'Gene', '3576', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('IL-8', 'Gene', (41, 45))	('IL-8 production', 'biological_process', 'GO:0032637', ('41', '56'))	('MUC5AC', 'Protein', (0, 6))	('neutrophil activation', 'CPA', (61, 82))	('silencing', 'Var', (7, 16))	('IL-8', 'molecular_function', 'GO:0005153', ('41', '45'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
40280	30618016	MUC16 also inhibits formation of immune synapses between tumor and NK cells.	('formation of immune synapses', 'CPA', (20, 48))	('inhibits', 'NegReg', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('MUC16', 'Var', (0, 5))	('tumor', 'Disease', (57, 62))	('formation', 'biological_process', 'GO:0009058', ('20', '29'))
40283	30618016	Overexpression of MUC1 in various malignancies is associated with increased tumor cell invasion and metastasis.	('increased', 'PosReg', (66, 75))	('malignancies', 'Disease', 'MESH:D009369', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('malignancies', 'Disease', (34, 46))	('Overexpression', 'Var', (0, 14))	('MUC1', 'Gene', (18, 22))	('metastasis', 'CPA', (100, 110))
40286	30618016	Altered glycosylation of mucins generates new epitopes that form the basis of monoclonal antibody (mAb) based diagnosis and targeted therapy.	('glycosylation', 'MPA', (8, 21))	('epitopes', 'MPA', (46, 54))	('mucin', 'Gene', '100508689', (25, 30))	('antibody', 'cellular_component', 'GO:0019815', ('89', '97'))	('antibody', 'cellular_component', 'GO:0019814', ('89', '97'))	('Altered', 'Var', (0, 7))	('antibody', 'molecular_function', 'GO:0003823', ('89', '97'))	('glycosylation', 'biological_process', 'GO:0070085', ('8', '21'))	('mucin', 'Gene', (25, 30))	('antibody', 'cellular_component', 'GO:0042571', ('89', '97'))
40295	30618016	Alternatively, an anti-idiotypic monoclonal antibody (abagovomab) against oregovomab, mirroring CA125 in phase I or II clinical trial developed anti-anti-idiotypic antibodies (Ab3) and MUC16 antibodies and the patients with Ab3 showed better survival.	('CA125', 'Gene', (96, 101))	('antibody', 'cellular_component', 'GO:0042571', ('44', '52'))	('antibody', 'molecular_function', 'GO:0003823', ('44', '52'))	('anti-anti-idiotypic', 'Var', (144, 163))	('CA125', 'Gene', '94025', (96, 101))	('antibody', 'cellular_component', 'GO:0019815', ('44', '52'))	('patients', 'Species', '9606', (210, 218))	('antibody', 'cellular_component', 'GO:0019814', ('44', '52'))	('oregovomab', 'Chemical', 'MESH:C107428', (74, 84))	('survival', 'CPA', (242, 250))	('better', 'PosReg', (235, 241))
40300	30618016	Moreover, the phase III clinical trials following treatment with radiolabeled HMFG1 in ovarian cancer patients failed to reach endpoints of increased time to relapse or patient survival.	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('patient', 'Species', '9606', (102, 109))	('patients', 'Species', '9606', (102, 110))	('HMFG1', 'Gene', (78, 83))	('ovarian cancer', 'Disease', 'MESH:D010051', (87, 101))	('patient', 'Species', '9606', (169, 176))	('radiolabeled', 'Var', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ovarian cancer', 'Disease', (87, 101))
40314	30618016	Phase I clinical trial of a 3A-MMAE conjugate DMUC5754A in unresectable ovarian and pancreatic cancer patients revealed minimal cytotoxicity and anti-tumor activity for MUC16-expressing tumors.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('DMUC5754A', 'Var', (46, 55))	('cytotoxicity', 'Disease', 'MESH:D064420', (128, 140))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (84, 101))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('patients', 'Species', '9606', (102, 110))	('ovarian and pancreatic cancer', 'Disease', 'MESH:D010195', (72, 101))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cytotoxicity', 'Disease', (128, 140))	('tumor', 'Disease', (150, 155))
40328	30618016	In addition, studies in xenograft models and pancreatic cancer patients showed that, when combined with gemcitabine, 90Y-PAM4-based RIT prolonged survival and increased tumor regression.	('prolonged', 'PosReg', (136, 145))	('pancreatic cancer', 'Disease', (45, 62))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('90Y-PAM4-based', 'Var', (117, 131))	('gemcitabine', 'Chemical', 'MESH:C056507', (104, 115))	('increased', 'PosReg', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))	('tumor', 'Disease', (169, 174))	('patients', 'Species', '9606', (63, 71))	('survival', 'CPA', (146, 154))	('90Y-PAM4', 'Chemical', '-', (117, 125))
40345	30618016	TG4010, a recombinant virus vaccine encoding MUC1 and IL-2, induced reasonable MUC1-specific CD4+ and CD8+ T cell activity in a phase II clinical trial for metastatic renal clear-cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('CD8', 'Gene', (102, 105))	('renal clear-cell carcinoma', 'Disease', 'MESH:C538614', (167, 193))	('CD8', 'Gene', '925', (102, 105))	('renal clear-cell carcinoma', 'Disease', (167, 193))	('CD4', 'Gene', (93, 96))	('TG4010', 'Var', (0, 6))	('CD4', 'Gene', '920', (93, 96))	('IL-2', 'Gene', '3558', (54, 58))	('IL-2', 'molecular_function', 'GO:0005134', ('54', '58'))	('IL-2', 'Gene', (54, 58))
40346	30618016	Furthermore, TG4010 did not cause significant adverse events, while eliciting promising clinical responses when tested in patients with various cancers, including lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('TG4010', 'Var', (13, 19))	('lung cancer', 'Disease', (163, 174))	('patients', 'Species', '9606', (122, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
40366	30618016	Aberrant glycosylation and extensive splicing of carcinoma mucins result in the generation of cancer-specific B- and T-cell epitopes, providing opportunities for vaccine design.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('splicing', 'MPA', (37, 45))	('Aberrant', 'Var', (0, 8))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('mucin', 'Gene', (59, 64))	('carcinoma', 'Disease', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('glycosylation', 'biological_process', 'GO:0070085', ('9', '22'))	('splicing', 'biological_process', 'GO:0045292', ('37', '45'))	('result in', 'Reg', (66, 75))	('mucin', 'Gene', '100508689', (59, 64))	('glycosylation', 'MPA', (9, 22))	('carcinoma', 'Disease', 'MESH:D009369', (49, 58))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
40382	31273306	Taken together, these results indicate that aberrant expression of KS is predictive of pancreatic cancer progression and metastasis and may serve as a novel prognostic biomarker for pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('metastasis', 'CPA', (121, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (182, 199))	('pancreatic cancer', 'Disease', (87, 104))	('progression', 'CPA', (105, 116))	('pancreatic cancer', 'Disease', (182, 199))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('KS', 'Chemical', 'MESH:D007632', (67, 69))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (182, 199))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('aberrant expression', 'Var', (44, 63))
40387	31273306	In tissues, KS chains can be either N- or O-linked to the proteoglycan core protein.	('O-linked', 'Var', (42, 50))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('KS chains', 'Protein', (12, 21))	('KS', 'Chemical', 'MESH:D007632', (12, 14))	('core', 'cellular_component', 'GO:0019013', ('71', '75'))	('proteoglycan', 'molecular_function', 'GO:0005203', ('58', '70'))
40393	31273306	Dysregulation of KS biosynthesis has been associated with numerous diseased conditions, including macular degeneration and keratoconus, amyotrophic lateral sclerosis, Alzheimer's diseases, and mucopolysaccharidosis IV.	('KS', 'Chemical', 'MESH:D007632', (17, 19))	('biosynthesis', 'biological_process', 'GO:0009058', ('20', '32'))	('macular degeneration', 'Phenotype', 'HP:0000608', (98, 118))	('amyotrophic lateral sclerosis', 'Disease', (136, 165))	('associated', 'Reg', (42, 52))	('keratoconus', 'Disease', (123, 134))	('Dysregulation', 'Var', (0, 13))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (136, 165))	('keratoconus', 'Phenotype', 'HP:0000563', (123, 134))	('mucopolysaccharidosis IV', 'Disease', (193, 217))	('mucopolysaccharidosis IV', 'Disease', 'MESH:D009085', (193, 217))	('macular degeneration', 'Disease', (98, 118))	("Alzheimer's diseases", 'Disease', (167, 187))	("Alzheimer's diseases", 'Disease', 'MESH:D000544', (167, 187))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (136, 165))
40394	31273306	In addition, several studies have reported that aberrant expression of KS is highly associated with malignant conditions such as Burkitt's lymphoma, astrocytic tumors, glioblastoma, and in human embryonic cancer cells.	('lymphoma', 'Phenotype', 'HP:0002665', (139, 147))	('embryonic cancer', 'Disease', 'MESH:D009373', (195, 211))	('aberrant expression', 'Var', (48, 67))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('associated', 'Reg', (84, 94))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (129, 147))	('embryonic cancer', 'Disease', (195, 211))	('human', 'Species', '9606', (189, 194))	('astrocytic tumors', 'Disease', (149, 166))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (129, 147))	('KS', 'Chemical', 'MESH:D007632', (71, 73))	("Burkitt's lymphoma", 'Disease', (129, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (168, 180))	('astrocytic tumors', 'Disease', 'MESH:D001254', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('glioblastoma', 'Disease', (168, 180))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (168, 180))	('embryonic cancer', 'Phenotype', 'HP:0002898', (195, 211))
40407	31273306	In addition to this, we also observed the correlation of aberrant expression of KS with increase risk and reduced overall patients' survival.	('patients', 'Species', '9606', (122, 130))	('reduced', 'NegReg', (106, 113))	('KS', 'Chemical', 'MESH:D007632', (80, 82))	('aberrant expression', 'Var', (57, 76))
40419	31273306	In general, positive KS expression was observed in 21 (60%) of 35 pancreatic tumor specimens and has significantly higher probability to be in stage III/IV compared to patients with KS negative staining (95 vs. 57.1, p value = 0.01).	('pancreatic tumor', 'Phenotype', 'HP:0002894', (66, 82))	('KS', 'Chemical', 'MESH:D007632', (182, 184))	('pancreatic tumor', 'Disease', 'MESH:D010190', (66, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('patients', 'Species', '9606', (168, 176))	('pancreatic tumor', 'Disease', (66, 82))	('positive KS expression', 'Var', (12, 34))	('KS', 'Chemical', 'MESH:D007632', (21, 23))
40422	31273306	Kaplan-Meier analysis showed that positive KS level is associated with a shorter median survival of 5.9 months compared to 12.5 months with negative KS expression and is significantly predictive of overall survival in patients (Fig.	('median survival', 'MPA', (81, 96))	('patients', 'Species', '9606', (218, 226))	('KS', 'Chemical', 'MESH:D007632', (149, 151))	('positive', 'Var', (34, 42))	('shorter', 'NegReg', (73, 80))	('overall', 'MPA', (198, 205))	('predictive', 'Reg', (184, 194))	('KS', 'Chemical', 'MESH:D007632', (43, 45))
40437	31273306	Dysregulation of glycosyltransferases expression that are involved in KS biosynthesis mediates aberrant KS expression in numerous pathophysiological conditions including cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancers', 'Disease', (170, 177))	('Dysregulation', 'Var', (0, 13))	('KS', 'Chemical', 'MESH:D007632', (70, 72))	('KS', 'Chemical', 'MESH:D007632', (104, 106))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('biosynthesis', 'biological_process', 'GO:0009058', ('73', '85'))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('glycosyltransferases', 'Enzyme', (17, 37))	('aberrant', 'Var', (95, 103))
40453	31273306	Aberrant expression of KS results in numerous pathophysiological conditions including cancers.	('Aberrant expression', 'Var', (0, 19))	('results in', 'Reg', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('KS', 'Chemical', 'MESH:D007632', (23, 25))
40457	31273306	We showed for the first time the correlation of aberrant KS expression with pancreatic cancer progression and metastasis and with worse overall patient survival status.	('metastasis', 'CPA', (110, 120))	('pancreatic cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('patient', 'Species', '9606', (144, 151))	('aberrant', 'Var', (48, 56))	('KS', 'Chemical', 'MESH:D007632', (57, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (76, 93))	('KS expression', 'Protein', (57, 70))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))
40466	31273306	These features are mainly caused by genetic and epigenetic dysregulation of glycosyltransferase genes and the tumor microenvironment, which results in increased cell proliferation, cell cycle progression, EMT, angiogenesis, and immune evasion.	('increased', 'PosReg', (151, 160))	('cell proliferation', 'biological_process', 'GO:0008283', ('161', '179'))	('EMT', 'CPA', (205, 208))	('epigenetic dysregulation', 'Var', (48, 72))	('caused', 'Reg', (26, 32))	('EMT', 'biological_process', 'GO:0001837', ('205', '208'))	('cell cycle progression', 'CPA', (181, 203))	('cell proliferation', 'CPA', (161, 179))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('immune evasion', 'CPA', (228, 242))	('genetic', 'Var', (36, 43))	('immune evasion', 'biological_process', 'GO:0042783', ('228', '242'))	('cell cycle', 'biological_process', 'GO:0007049', ('181', '191'))	('immune evasion', 'biological_process', 'GO:0051842', ('228', '242'))	('glycosyltransferase genes', 'Gene', (76, 101))	('angiogenesis', 'biological_process', 'GO:0001525', ('210', '222'))	('tumor', 'Disease', (110, 115))	('angiogenesis', 'CPA', (210, 222))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
40469	31273306	Previously, we have reported that aberrant O-glycophenotype directly induces oncogenic features with enhanced cell growth and invasion in pancreatic cancer cells, and is critical during tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('pancreatic cancer', 'Disease', (138, 155))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('aberrant', 'Var', (34, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (138, 155))	('tumor', 'Disease', (186, 191))	('induces', 'Reg', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('O-glycophenotype', 'Protein', (43, 59))	('enhanced', 'PosReg', (101, 109))	('cell growth', 'biological_process', 'GO:0016049', ('110', '121'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))	('oncogenic', 'Disease', (77, 86))	('cell growth', 'CPA', (110, 121))
40470	31273306	Interestingly, studies have shown that O-glycopeptide epitopes with truncated O-glycan and a short peptide sequence have cancer-specific antigens properties and can be targeted by drug-loaded antibodies and T cell-engaging immunotherapies.	('truncated', 'Var', (68, 77))	('O-glycan', 'Chemical', '-', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('O-glycopeptide', 'Protein', (39, 53))	('O-glycan', 'Protein', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
40487	31273306	95% of pancreatic cancers carry activating mutations in KRAS, and up to 70% have mutated p53 tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('p53', 'Gene', '7157', (89, 92))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (7, 25))	('KRAS', 'Gene', (56, 60))	('tumor', 'Disease', (93, 98))	('KRAS', 'Gene', '3845', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('mutated', 'Var', (81, 88))	('p53', 'Gene', (89, 92))	('pancreatic cancers', 'Disease', 'MESH:D010190', (7, 25))	('pancreatic cancers', 'Disease', (7, 25))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (7, 24))	('tumor suppressor', 'biological_process', 'GO:0051726', ('93', '109'))	('activating', 'PosReg', (32, 42))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('93', '109'))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
40490	31273306	In this study, we demonstrated that a higher-level expression of B3GNT5 mRNA in KRAS and p53 mutated highly metastatic FG, T3M-4, and HPAF pancreatic cancer cell lines (Fig.	('KRAS', 'Gene', (80, 84))	('mutated', 'Var', (93, 100))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (139, 156))	('HPAF pancreatic cancer', 'Disease', 'MESH:D010190', (134, 156))	('KRAS', 'Gene', '3845', (80, 84))	('p53', 'Gene', (89, 92))	('highly metastatic FG', 'CPA', (101, 121))	('B3GNT5', 'Gene', (65, 71))	('HPAF pancreatic cancer', 'Disease', (134, 156))	('p53', 'Gene', '7157', (89, 92))	('B3GNT5', 'Gene', '84002', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
40491	31273306	Further, B3GNT5 mRNA expression was also increased in human primary pancreatic tumors which carry activating KRAS mutations in approximately 93% of patient cohort (Fig.	('human', 'Species', '9606', (54, 59))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (68, 85))	('B3GNT5', 'Gene', '84002', (9, 15))	('increased', 'PosReg', (41, 50))	('mutations', 'Var', (114, 123))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (68, 84))	('KRAS', 'Gene', (109, 113))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('KRAS', 'Gene', '3845', (109, 113))	('pancreatic tumors', 'Disease', 'MESH:D010190', (68, 85))	('patient', 'Species', '9606', (148, 155))	('pancreatic tumors', 'Disease', (68, 85))	('B3GNT5', 'Gene', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('activating', 'PosReg', (98, 108))
40492	31273306	Interestingly, gain of function mutation in B3GNT2 has been reported to be associated with increased tumorigenic potential in cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('gain of function', 'PosReg', (15, 31))	('B3GNT2', 'Gene', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('B3GNT2', 'Gene', '10678', (44, 50))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('increased', 'PosReg', (91, 100))	('mutation', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
40493	31273306	Moreover, transfer of a sulfate residue to position 6 of GlcNAc residues in KS by CHST2/6/7 has been reported to activate p38 MAPK-PI3K cell survival signaling pathway axis and reduced radiation induced apoptosis in Burkitt's Lymphoma cells.	('KS', 'Chemical', 'MESH:D007632', (76, 78))	('reduced', 'NegReg', (177, 184))	('CHST2/6/7', 'Gene', (82, 91))	('signaling pathway', 'biological_process', 'GO:0007165', ('150', '167'))	('MAPK', 'molecular_function', 'GO:0004707', ('126', '130'))	('GlcNAc', 'Chemical', 'MESH:D000117', (57, 63))	('radiation induced apoptosis', 'CPA', (185, 212))	('p38', 'Gene', (122, 125))	('activate', 'PosReg', (113, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('CHST2/6/7', 'Gene', '9435;4166;56548', (82, 91))	("Burkitt's Lymphoma", 'Disease', 'MESH:D002051', (216, 234))	('PI3K', 'molecular_function', 'GO:0016303', ('131', '135'))	('p38', 'Gene', '1432', (122, 125))	('transfer', 'Var', (10, 18))	('sulfate', 'Chemical', 'MESH:D013431', (24, 31))	("Burkitt's Lymphoma", 'Disease', (216, 234))	('Lymphoma', 'Phenotype', 'HP:0002665', (226, 234))
40494	31273306	Therefore, it is predicted that mutations might contribute to the differential expression of KS specific glycosyltransferase genes and aberrant sulfation of KS, thereby leading to pancreatic cancer growth and metastasis.	('KS specific', 'Gene', (93, 104))	('leading to', 'Reg', (169, 179))	('expression', 'MPA', (79, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (180, 197))	('growth', 'CPA', (198, 204))	('pancreatic cancer', 'Disease', (180, 197))	('KS', 'Chemical', 'MESH:D007632', (93, 95))	('sulfation', 'biological_process', 'GO:0051923', ('144', '153'))	('mutations', 'Var', (32, 41))	('contribute', 'Reg', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('aberrant', 'Var', (135, 143))	('metastasis', 'CPA', (209, 219))	('KS', 'Chemical', 'MESH:D007632', (157, 159))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (180, 197))
40498	31273306	Overall, the results of this study support the concept that aberrant expression of KS contributes to aggressive nature of pancreatic tumors and their early metastases (Fig.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('pancreatic tumors', 'Disease', (122, 139))	('aberrant expression', 'Var', (60, 79))	('metastases', 'Disease', (156, 166))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (122, 139))	('KS', 'Chemical', 'MESH:D007632', (83, 85))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (122, 138))	('contributes', 'Reg', (86, 97))	('metastases', 'Disease', 'MESH:D009362', (156, 166))	('pancreatic tumors', 'Disease', 'MESH:D010190', (122, 139))	('aggressive nature', 'CPA', (101, 118))
40528	31273306	Analysis and interpretation of data: P.D.L., P.P.P., N.R., B.S., F.Y., F.Q.	('B.S.', 'Var', (59, 63))	('F.Y.', 'Var', (65, 69))	('P.P.P', 'Disease', 'MESH:C000656865', (45, 50))	('P.D.L.', 'Var', (37, 43))	('P.P.P', 'Disease', (45, 50))	('N.R.', 'Var', (53, 57))
40529	31273306	Critical revision of the manuscript for important intellectual content: P.D.L., P.P.P., N.R., B.S., P.M.G., F.Y., F.Q.	('P.D.L.', 'Var', (72, 78))	('B.S.', 'Var', (94, 98))	('F.Y.', 'Var', (108, 112))	('P.P.P', 'Disease', 'MESH:C000656865', (80, 85))	('P.M.G.', 'Var', (100, 106))	('P.P.P', 'Disease', (80, 85))	('N.R.', 'Var', (88, 92))
40532	29696628	Because pharmacologic or genetic inhibition of YAP1 suppresses tumor progression and increases the drug sensitivity, targeting YAP1 may open a fertile avenue for a novel therapeutic approach in relevant cancers.	('inhibition', 'Var', (33, 43))	('tumor', 'Disease', (63, 68))	('YAP1', 'Gene', (47, 51))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('drug sensitivity', 'Phenotype', 'HP:0020174', (99, 115))	('drug sensitivity', 'MPA', (99, 115))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('increases', 'PosReg', (85, 94))	('suppresses', 'NegReg', (52, 62))	('YAP1', 'Gene', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
40537	29696628	The Hippo pathway is considered as a tumor suppressor pathway, since the component of this pathway plays a key role in regulating organ size by inhibiting cell proliferation, promoting apoptosis and regulating stem/progenitor cell expansion, and mutations or downregulations of this pathway components lead to organ overgrowth.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('apoptosis', 'biological_process', 'GO:0006915', ('185', '194'))	('overgrowth', 'Phenotype', 'HP:0001548', (316, 326))	('rat', 'Species', '10116', (167, 170))	('mutations', 'Var', (246, 255))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('stem/progenitor cell expansion', 'CPA', (210, 240))	('cell expansion', 'biological_process', 'GO:0016049', ('226', '240'))	('cell proliferation', 'biological_process', 'GO:0008283', ('155', '173'))	('inhibiting', 'NegReg', (144, 154))	('apoptosis', 'CPA', (185, 194))	('lead to', 'Reg', (302, 309))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))	('promoting', 'PosReg', (175, 184))	('organ overgrowth', 'CPA', (310, 326))	('regulating', 'Reg', (199, 209))	('cell proliferation', 'CPA', (155, 173))	('tumor', 'Disease', (37, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('downregulations', 'NegReg', (259, 274))	('apoptosis', 'biological_process', 'GO:0097194', ('185', '194'))
40538	29696628	Dephosphorylated YAP1 due to inactivated Hippo signaling accumulates in the nucleus, and YAP1 in the nucleus upregulates the transcription factors that regulate the expression of genes associated with cell proliferation, reprogramming, stemness, epithelial-mesenchymal transition (EMT) and anti-apoptosis.	('cell proliferation', 'biological_process', 'GO:0008283', ('201', '219'))	('stemness', 'Disease', 'MESH:D020295', (236, 244))	('YAP1', 'Var', (89, 93))	('stemness', 'Disease', (236, 244))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('246', '279'))	('anti-apoptosis', 'biological_process', 'GO:0043066', ('290', '304'))	('EMT', 'biological_process', 'GO:0001837', ('281', '284'))	('upregulates', 'PosReg', (109, 120))	('expression', 'MPA', (165, 175))	('transcription', 'MPA', (125, 138))	('reprogramming', 'CPA', (221, 234))	('transcription', 'biological_process', 'GO:0006351', ('125', '138'))	('rat', 'Species', '10116', (213, 216))	('nucleus', 'cellular_component', 'GO:0005634', ('76', '83'))	('Hippo signaling', 'biological_process', 'GO:0035329', ('41', '56'))	('cell proliferation', 'CPA', (201, 219))	('epithelial-mesenchymal transition', 'CPA', (246, 279))	('nucleus', 'cellular_component', 'GO:0005634', ('101', '108'))
40542	29696628	Because YAP1 inhibition suppresses tumor progression and recovers drug-sensitivities in pre-clinical setting, YAP1 could be an attractive therapeutic target.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('drug-sensitivities', 'MPA', (66, 84))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('pre', 'molecular_function', 'GO:0003904', ('88', '91'))	('clinical', 'Species', '191496', (92, 100))	('inhibition', 'Var', (13, 23))	('tumor', 'Disease', (35, 40))	('suppresses', 'NegReg', (24, 34))	('recovers', 'PosReg', (57, 65))	('YAP1', 'Gene', (8, 12))
40562	29696628	Inhibition of YAP1 decreased cancer cell proliferation, colony formation, invasiveness and motility.	('formation', 'biological_process', 'GO:0009058', ('63', '72'))	('colon', 'Disease', 'MESH:D015179', (56, 61))	('cancer', 'Disease', (29, 35))	('invasiveness', 'Disease', (74, 86))	('YAP1', 'Gene', (14, 18))	('cell proliferation', 'biological_process', 'GO:0008283', ('36', '54'))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('colon', 'Disease', (56, 61))	('motility', 'CPA', (91, 99))	('Inhibition', 'Var', (0, 10))	('decreased', 'NegReg', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('invasiveness', 'Disease', 'MESH:D009362', (74, 86))	('rat', 'Species', '10116', (48, 51))
40572	29696628	Conversely, beta-catenin upregulates YAP1 by binding to DNA enhancer element of Yap1, and knockdown of beta-catenin led to decreased YAP1 expression.	('knockdown', 'Var', (90, 99))	('binding', 'Interaction', (45, 52))	('decreased', 'NegReg', (123, 132))	('beta-catenin', 'Gene', (103, 115))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('beta-catenin', 'Gene', (12, 24))	('beta-catenin', 'Gene', '1499', (103, 115))	('binding', 'molecular_function', 'GO:0005488', ('45', '52'))	('expression', 'MPA', (138, 148))	('beta-catenin', 'Gene', '1499', (12, 24))	('upregulates', 'PosReg', (25, 36))	('YAP1', 'Gene', (37, 41))	('Yap1', 'Gene', (80, 84))	('YAP1', 'Gene', (133, 137))
40576	29696628	YAP1 expression substitutes for oncogenic KRAS in KRAS mutant colon and pancreatic cancer cell lines.	('KRAS', 'Gene', (42, 46))	('colon', 'Disease', 'MESH:D015179', (62, 67))	('YAP1', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (42, 46))	('pancreatic cancer', 'Disease', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (72, 89))	('KRAS', 'Gene', (50, 54))	('mutant', 'Var', (55, 61))	('colon', 'Disease', (62, 67))	('KRAS', 'Gene', '3845', (50, 54))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))
40581	29696628	In a recent study, pancreatic tumor initiation was studied in Yap1/Taz disrupted KRas mutant mice.	('pancreatic tumor', 'Phenotype', 'HP:0002894', (19, 35))	('pancreatic tumor initiation', 'Disease', 'MESH:D010190', (19, 46))	('mutant', 'Var', (86, 92))	('KRas', 'Gene', (81, 85))	('pancreatic tumor initiation', 'Disease', (19, 46))	('mice', 'Species', '10090', (93, 97))	('KRas', 'Gene', '16653', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
40589	29696628	MiR-138 and miR-497 suppress YAP1 directly to decrease cancer cell proliferation, invasion, migration and tumor growth respectively.	('miR-497', 'Gene', '574456', (12, 19))	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('rat', 'Species', '10116', (95, 98))	('MiR-138', 'Chemical', '-', (0, 7))	('invasion', 'CPA', (82, 90))	('decrease', 'NegReg', (46, 54))	('MiR-138', 'Var', (0, 7))	('rat', 'Species', '10116', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('migration', 'CPA', (92, 101))	('YAP1', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('suppress', 'NegReg', (20, 28))	('miR-497', 'Gene', (12, 19))	('cancer', 'Disease', (55, 61))	('tumor', 'Disease', (106, 111))
40591	29696628	Although several known oncogenes are activated by oncogenic mutation in the coding region, YAP1 mutation is rare in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('mutation', 'Var', (60, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('NSCLC', 'Disease', (116, 121))	('YAP1', 'Gene', (91, 95))
40592	29696628	Whole-genome sequencing data of 1312 patients revealed 1.1% germline R331W missense mutation of YAP1 in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (104, 123))	('R331W missense', 'Var', (69, 83))	('patients', 'Species', '9606', (37, 45))	('YAP1', 'Gene', (96, 100))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (104, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('R331W', 'Mutation', 'rs193100333', (69, 74))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (104, 123))
40596	29696628	In contrast, some studies reported anti-tumorigenic roles of YAP1: (i) Knockdown of YAP1 suppressed anoikis, increased migration and invasiveness of breast cancer cells and enhanced tumor growth in mice; (ii) In clinical samples, YAP1 expression was positively correlated with estrogen receptor (ER) negative patients, while it was inversely correlated with ER positive patients; and (iii) Low YAP1 mRNA expression was an independent poor prognostic factor for the luminal A subtype.	('anoikis', 'biological_process', 'GO:0043276', ('100', '107'))	('invasiveness of breast cancer', 'Disease', 'MESH:D001943', (133, 162))	('suppressed', 'NegReg', (89, 99))	('Low', 'NegReg', (390, 393))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('increased', 'PosReg', (109, 118))	('clinical samples', 'Species', '191496', (212, 228))	('migration', 'CPA', (119, 128))	('mRNA expression', 'MPA', (399, 414))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('YAP1', 'Gene', (230, 234))	('patients', 'Species', '9606', (370, 378))	('invasiveness of breast cancer', 'Disease', (133, 162))	('luminal A', 'Disease', (465, 474))	('tumor', 'Disease', (40, 45))	('enhanced', 'PosReg', (173, 181))	('YAP1', 'Gene', (84, 88))	('tumor', 'Disease', (182, 187))	('anoikis', 'CPA', (100, 107))	('YAP1', 'Gene', (394, 398))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('rat', 'Species', '10116', (122, 125))	('mice', 'Species', '10090', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('patients', 'Species', '9606', (309, 317))	('Knockdown', 'Var', (71, 80))
40603	29696628	In our study, high YAP1 expression was associated with increased mesenchymal markers including vimentin and Snail.	('Snail', 'Gene', (108, 113))	('vimentin', 'cellular_component', 'GO:0045099', ('95', '103'))	('expression', 'MPA', (24, 34))	('vimentin', 'cellular_component', 'GO:0045098', ('95', '103'))	('increased', 'PosReg', (55, 64))	('mesenchymal markers', 'CPA', (65, 84))	('vimentin', 'Protein', (95, 103))	('high', 'Var', (14, 18))	('Snail', 'Gene', '6615', (108, 113))	('YAP1', 'Gene', (19, 23))
40607	29696628	In NSCLC, YAP1 directly interacts with OCT4 followed by SOX2 upregulation to facilitate self-renewal and vascular mimicry of CSCs, while depletion of YAP1 lowered the expression of core embryonic stem cell factors such as SOX2, OCT4 and NANOG.	('core', 'cellular_component', 'GO:0019013', ('181', '185'))	('OCT4', 'Gene', '5460', (39, 43))	('expression', 'MPA', (167, 177))	('depletion', 'Var', (137, 146))	('OCT4', 'Gene', '5460', (228, 232))	('interacts', 'Interaction', (24, 33))	('OCT4', 'Gene', (39, 43))	('YAP1', 'Gene', (150, 154))	('SOX2', 'Gene', '6657', (56, 60))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('SOX2', 'Gene', (56, 60))	('OCT4', 'Gene', (228, 232))	('upregulation', 'PosReg', (61, 73))	('SOX2', 'Gene', (222, 226))	('SOX2', 'Gene', '6657', (222, 226))	('NSCLC', 'Disease', (3, 8))	('self-renewal', 'CPA', (88, 100))	('vascular mimicry of', 'CPA', (105, 124))	('NANOG', 'Gene', '79923', (237, 242))	('lowered', 'NegReg', (155, 162))	('NANOG', 'Gene', (237, 242))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('facilitate', 'PosReg', (77, 87))
40615	29696628	As YAP1 signaling pathway has been consistently associated with the occurrence of intrinsic or acquired resistance to chemotherapeutic agents in several malignancies, inhibition of YAP1 signaling may synergistically enhance the efficacy of chemotherapeutic agents.	('signaling pathway', 'biological_process', 'GO:0007165', ('8', '25'))	('enhance', 'PosReg', (216, 223))	('YAP1', 'Gene', (3, 7))	('malignancies', 'Disease', (153, 165))	('YAP1', 'Gene', (181, 185))	('associated', 'Reg', (48, 58))	('inhibition', 'Var', (167, 177))	('signaling', 'biological_process', 'GO:0023052', ('186', '195'))	('malignancies', 'Disease', 'MESH:D009369', (153, 165))
40622	29696628	In summary, YAP1 expression may decrease the therapeutic efficacy of numerous anti-cancer drugs, and the combination of conventional drugs with YAP1 inhibitor may suppress malignant tumors more effectively.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('therapeutic', 'MPA', (45, 56))	('suppress', 'NegReg', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('decrease the therapeutic efficacy', 'Phenotype', 'HP:0020173', (32, 65))	('malignant tumors', 'Disease', (172, 188))	('expression', 'Var', (17, 27))	('YAP1', 'Gene', (12, 16))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('malignant tumors', 'Disease', 'MESH:D018198', (172, 188))	('decrease', 'NegReg', (32, 40))	('cancer', 'Disease', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
40624	29696628	Inhibition of YAP1 by genetic silencing or verteporfin can increase the sensitivity of cisplatin, erlotinib and gefitinib in different cancer types.	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('cancer', 'Disease', (135, 141))	('YAP1', 'Gene', (14, 18))	('Inhibition', 'NegReg', (0, 10))	('genetic silencing', 'Var', (22, 39))	('sensitivity', 'MPA', (72, 83))	('erlotinib', 'Chemical', 'MESH:D000069347', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('verteporfin', 'Chemical', 'MESH:D000077362', (43, 54))	('gefitinib', 'Chemical', 'MESH:D000077156', (112, 121))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('increase', 'PosReg', (59, 67))
40637	29696628	Conversely, p53 activation stimulates both innate and adaptive immunity, while p53 inactivation alters the immune landscape of the TME towards pro-tumor inflammation, and p53 reactivation changes the TME to promote antitumor immunity.	('inflammation', 'biological_process', 'GO:0006954', ('153', '165'))	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('activation stimulates', 'PosReg', (16, 37))	('promote', 'PosReg', (207, 214))	('tumor', 'Disease', (147, 152))	('p53', 'Gene', '7157', (79, 82))	('inactivation', 'Var', (83, 95))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('innate', 'CPA', (43, 49))	('tumor inflammation', 'Disease', 'MESH:D007249', (147, 165))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (12, 15))	('alters', 'Reg', (96, 102))	('adaptive immunity', 'CPA', (54, 71))	('tumor inflammation', 'Disease', (147, 165))	('p53', 'Gene', '7157', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('immune landscape', 'MPA', (107, 123))	('p53', 'Gene', (12, 15))	('reactivation', 'Var', (175, 187))	('p53', 'Gene', (171, 174))
40638	29696628	Since various molecules induce immunosuppression in the TME, it is understandable that manipulation of those molecules may facilitate immune-responsive TME and will suppress cancer progression and enhance the efficacy of IO agents.	('IO agents', 'CPA', (221, 230))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('immune-responsive TME', 'MPA', (134, 155))	('enhance', 'PosReg', (197, 204))	('IO', 'Chemical', '-', (221, 223))	('manipulation', 'Var', (87, 99))	('immunosuppression', 'MPA', (31, 48))	('suppress', 'NegReg', (165, 173))	('facilitate', 'PosReg', (123, 133))
40650	29696628	In a recent study, it was found that YAP1 directly recruits M2 macrophages for liver carcinogenesis, and YAP1 activates tumor-initiating cells for the recruitment of M2 macrophages from the very beginning of tumor formation.	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('formation', 'biological_process', 'GO:0009058', ('214', '223'))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (79, 99))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('YAP1', 'Var', (105, 109))	('YAP1', 'Gene', (37, 41))	('liver carcinogenesis', 'Disease', (79, 99))	('tumor', 'Disease', (120, 125))
40652	29696628	A more recent study showed that YAP1 directly upregulates CCL2 in hepatocytes to enhance the infiltration of macrophages for the cancer formation, and macrophage ablation of Ccl2 in mice significantly reduced hepatic inflammation and HCC development.	('reduced hepatic inflammation', 'Phenotype', 'HP:0001410', (201, 229))	('mice', 'Species', '10090', (182, 186))	('cancer', 'Disease', (129, 135))	('reduced', 'NegReg', (201, 208))	('YAP1', 'Gene', (32, 36))	('Ccl2', 'Gene', '20296', (174, 178))	('ablation', 'Var', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('hepatic inflammation', 'Phenotype', 'HP:0012115', (209, 229))	('inflammation', 'biological_process', 'GO:0006954', ('217', '229'))	('Ccl', 'molecular_function', 'GO:0044101', ('174', '177'))	('upregulates', 'PosReg', (46, 57))	('CCL2', 'Gene', (58, 62))	('infiltration of macrophages', 'MPA', (93, 120))	('rat', 'Species', '10116', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('HCC', 'Gene', '619501', (234, 237))	('HCC', 'Phenotype', 'HP:0001402', (234, 237))	('hepatic inflammation', 'Disease', (209, 229))	('enhance', 'PosReg', (81, 88))	('CCL', 'molecular_function', 'GO:0044101', ('58', '61'))	('hepatic inflammation', 'Disease', 'MESH:D007249', (209, 229))	('HCC', 'Gene', (234, 237))	('Ccl2', 'Gene', (174, 178))	('formation', 'biological_process', 'GO:0009058', ('136', '145'))
40654	29696628	MDSCs represent a phenotypically heterogeneous cell population of immature myeloid cells, and they facilitate tumor progression by suppressing effector T-cell activities, especially CD8+ cytotoxic T-cells.	('MDSCs', 'Var', (0, 5))	('CD8', 'Gene', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('CD8', 'Gene', '925', (182, 185))	('effector T-cell activities', 'CPA', (143, 169))	('facilitate', 'PosReg', (99, 109))	('suppressing', 'NegReg', (131, 142))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
40663	29696628	In KRAS mutant pancreatic cancer, YAP1 upregulates cytokines (e.g., IL-6 and IL-1alpha) and COX2 which mediates prostaglandin E2 (PGE2) synthesis to promote inflammation.	('YAP1', 'Gene', (34, 38))	('IL-1', 'molecular_function', 'GO:0005149', ('77', '81'))	('pancreatic cancer', 'Disease', (15, 32))	('IL-6', 'Gene', '3569', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('inflammation', 'Disease', (157, 169))	('PGE2', 'Chemical', 'MESH:D015232', (130, 134))	('COX2', 'Gene', (92, 96))	('KRAS', 'Gene', '3845', (3, 7))	('IL-6', 'Gene', (68, 72))	('mutant', 'Var', (8, 14))	('IL-1alpha', 'Gene', (77, 86))	('KRAS', 'Gene', (3, 7))	('promote', 'PosReg', (149, 156))	('inflammation', 'biological_process', 'GO:0006954', ('157', '169'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (15, 32))	('synthesis', 'biological_process', 'GO:0009058', ('136', '145'))	('COX2', 'Gene', '4513', (92, 96))	('upregulates', 'PosReg', (39, 50))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (112, 128))	('IL-6', 'molecular_function', 'GO:0005138', ('68', '72'))	('inflammation', 'Disease', 'MESH:D007249', (157, 169))	('pancreatic cancer', 'Disease', 'MESH:D010190', (15, 32))	('IL-1alpha', 'Gene', '3552', (77, 86))
40687	29696628	In addition to these anti-cancerous effects, YAP1 inhibition may modulate immunosuppressive to immunoresponsive TME by inhibiting recruitment of MDSCs, activating effector T-cells activities and enhancing the sensitivity to IO agents.	('enhancing', 'PosReg', (195, 204))	('inhibition', 'Var', (50, 60))	('cancer', 'Disease', (26, 32))	('inhibiting', 'NegReg', (119, 129))	('YAP1', 'Gene', (45, 49))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('recruitment', 'MPA', (130, 141))	('immunosuppressive to immunoresponsive TME', 'MPA', (74, 115))	('IO', 'Chemical', '-', (224, 226))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('effector', 'CPA', (163, 171))	('activating', 'PosReg', (152, 162))	('modulate', 'Reg', (65, 73))	('sensitivity to IO agents', 'MPA', (209, 233))
40688	29696628	Although further mechanistic and preclinical studies are needed, YAP1 inhibitory therapy in combination with anti-cancerous drugs has a potential to be a novel therapeutic strategy.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('inhibitory therapy', 'Var', (70, 88))	('YAP1', 'Gene', (65, 69))	('clinical', 'Species', '191496', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rat', 'Species', '10116', (174, 177))	('cancer', 'Disease', (114, 120))
40698	30455857	Diabetic nude mice treated with streptozotocin (STZ) exhibited larger tumors and were more likely to develop liver metastasis than control mice.	('larger', 'PosReg', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('streptozotocin', 'Var', (32, 46))	('nude mice', 'Species', '10090', (9, 18))	('STZ', 'Chemical', 'MESH:D013311', (48, 51))	('mice', 'Species', '10090', (14, 18))	('Diabetic', 'Disease', 'MESH:D003920', (0, 8))	('tumors', 'Disease', (70, 76))	('develop', 'PosReg', (101, 108))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mice', 'Species', '10090', (139, 143))	('streptozotocin', 'Chemical', 'MESH:D013311', (32, 46))	('Diabetic', 'Disease', (0, 8))	('liver metastasis', 'Disease', 'MESH:D009362', (109, 125))	('liver metastasis', 'Disease', (109, 125))
40710	30455857	Our previous studies found that high glucose levels could promote pancreatic cancer proliferation and invasion as well as epithelial-mesenchymal transition (EMT) and metastasis.	('high', 'Var', (32, 36))	('epithelial-mesenchymal transition', 'CPA', (122, 155))	('pancreatic cancer', 'Disease', (66, 83))	('metastasis', 'CPA', (166, 176))	('promote', 'PosReg', (58, 65))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('122', '155'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (66, 83))	('invasion', 'CPA', (102, 110))	('high glucose', 'Phenotype', 'HP:0003074', (32, 44))	('EMT', 'biological_process', 'GO:0001837', ('157', '160'))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (66, 83))
40796	30455857	To confirm that high glucose-inducedHIF-1alpha influences the invasive and migratory abilities of pancreatic cancer cells, we used HIF-1alpha siRNA to knock down HIF-1alpha.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (98, 115))	('high glucose', 'Phenotype', 'HP:0003074', (16, 28))	('knock', 'Var', (151, 156))	('pancreatic cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('glucose', 'Chemical', 'MESH:D005947', (21, 28))	('pancreatic cancer', 'Disease', 'MESH:D010190', (98, 115))	('influences', 'Reg', (47, 57))
40797	30455857	We found that the increased BxPC-3 cell invasion and migration in the presence of high glucose was significantly inhibited by the HIF-1alpha knockdown (Fig.	('knockdown', 'Var', (141, 150))	('BxPC-3 cell invasion', 'CPA', (28, 48))	('increased', 'PosReg', (18, 27))	('glucose', 'Chemical', 'MESH:D005947', (87, 94))	('inhibited', 'NegReg', (113, 122))	('migration', 'CPA', (53, 62))	('high glucose', 'Phenotype', 'HP:0003074', (82, 94))	('HIF-1alpha', 'Gene', (130, 140))	('BxPC-3', 'CellLine', 'CVCL:0186', (28, 34))
40843	29727019	Specifically, immunofluorescence staining showed that BMJ decreases protein expression/nuclear localization of CSC-associated transcription factors SOX2, OCT4 and NANOG, and CSC marker CD44.	('BMJ', 'Var', (54, 57))	('BMJ', 'Chemical', '-', (54, 57))	('decreases', 'NegReg', (58, 67))	('SOX2', 'Gene', (148, 152))	('expression/nuclear localization', 'MPA', (76, 107))	('CD44', 'Gene', '960', (185, 189))	('CSC-associated transcription', 'Gene', (111, 139))	('protein expression/nuclear', 'MPA', (68, 94))	('CD44', 'Gene', (185, 189))	('OCT4', 'Gene', (154, 158))
40856	29727019	PDACs are the most commonly occurring form of PanC (90%), with mutated KRAS expressed in >= 95% of cases.	('mutated', 'Var', (63, 70))	('PDAC', 'Chemical', '-', (0, 4))	('PanC', 'Phenotype', 'HP:0002894', (46, 50))	('PanC', 'Disease', (46, 50))	('KRAS', 'Gene', (71, 75))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('KRAS', 'Gene', '3845', (71, 75))	('PDACs', 'Disease', (0, 5))
40868	29727019	Regarding PanC, our published studies have shown promising anticancer activity of BMJ against PanC cells in both culture and nude mice xenografts, via Adenosine monophosphate-activated protein kinase (AMPK) modulation, together with its efficacy in gemcitabine-resistant PanC cells.	('PanC', 'Phenotype', 'HP:0002894', (271, 275))	('AMPK', 'molecular_function', 'GO:0050405', ('201', '205'))	('PanC', 'Phenotype', 'HP:0002894', (10, 14))	('gemcitabine', 'Chemical', 'MESH:C056507', (249, 260))	('AMPK', 'Gene', (201, 205))	('AMPK', 'molecular_function', 'GO:0004691', ('201', '205'))	('cancer', 'Disease', (63, 69))	('BMJ', 'Var', (82, 85))	('nude mice', 'Species', '10090', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('AMPK', 'molecular_function', 'GO:0047322', ('201', '205'))	('PanC', 'Phenotype', 'HP:0002894', (94, 98))	('modulation', 'Var', (207, 217))	('Adenosine', 'MPA', (151, 160))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('BMJ', 'Chemical', '-', (82, 85))	('AMPK', 'Gene', '5563', (201, 205))	('PanC', 'Disease', (94, 98))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
40927	29727019	Chemoresistance in PanC might result from extreme desmoplasia, hypovasculariztion, aberrant activity of membrane transporters/drug efflux pumps and drug metabolizing enzymes and mostly, the CSCs.	('hypovasculariztion', 'Disease', (63, 81))	('result from', 'Reg', (30, 41))	('hypovasculariztion', 'Disease', 'None', (63, 81))	('membrane', 'cellular_component', 'GO:0016020', ('104', '112'))	('extreme desmoplasia', 'Disease', (42, 61))	('efflux', 'biological_process', 'GO:0140115', ('131', '137'))	('membrane transporters/drug efflux pumps', 'MPA', (104, 143))	('efflux', 'biological_process', 'GO:0140352', ('131', '137'))	('drug', 'Enzyme', (148, 152))	('PanC', 'Phenotype', 'HP:0002894', (19, 23))	('PanC', 'Disease', (19, 23))	('extreme desmoplasia', 'Disease', 'MESH:C563475', (42, 61))	('aberrant activity', 'Var', (83, 100))
40938	29727019	BMJ also strongly induced cell death (with increasing concentration and treatment time) in PANC1 and AsPC1 cells; cell death was induced by BMJ in MiaPaCa2 cells at 24 hours (even though the untreated controls showed higher percentage of dead cells compared to other PanC cells) (Fig.	('PANC1', 'CellLine', 'CVCL:0480', (91, 96))	('AsPC1', 'CellLine', 'CVCL:0152', (101, 106))	('BMJ', 'Chemical', '-', (0, 3))	('BMJ', 'Var', (140, 143))	('PanC', 'Phenotype', 'HP:0002894', (267, 271))	('BMJ', 'Chemical', '-', (140, 143))	('MiaPaCa2', 'CellLine', 'CVCL:0428', (147, 155))	('cell death', 'biological_process', 'GO:0008219', ('114', '124'))	('cell death', 'CPA', (114, 124))	('cell death', 'biological_process', 'GO:0008219', ('26', '36'))
40976	29727019	Together, these findings suggested that BMJ effectively downregulates the protein expression of the CSC associated transcription factors in both cell culture and animal xenografts, thus signifying its possible efficacy as a novel PanC chemotherapeutic.	('BMJ', 'Var', (40, 43))	('PanC', 'Phenotype', 'HP:0002894', (230, 234))	('BMJ', 'Chemical', '-', (40, 43))	('transcription', 'biological_process', 'GO:0006351', ('115', '128'))	('downregulates', 'NegReg', (56, 69))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('CSC associated transcription factors', 'Gene', (100, 136))	('protein expression', 'MPA', (74, 92))
40986	29727019	Furthermore, purified fractions of bitter melon methanolic extract containing monogalactosyl diacylglycerol (MGDG, a glycoglycerolipid) also displayed DNA polymerase inhibition-mediated growth inhibitory effects in lung, leukemia, colon, cervical and stomach cancer cells; however, no such effects were observed in normal cells.	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))	('growth inhibitory effects', 'CPA', (186, 211))	('inhibition-mediated', 'NegReg', (166, 185))	('DNA polymerase', 'Enzyme', (151, 165))	('stomach cancer', 'Disease', (251, 265))	('leukemia', 'Phenotype', 'HP:0001909', (221, 229))	('lung', 'Disease', (215, 219))	('colon', 'Disease', 'MESH:D015179', (231, 236))	('monogalactosyl', 'Var', (78, 92))	('leukemia', 'Disease', 'MESH:D007938', (221, 229))	('stomach cancer', 'Disease', 'MESH:D013274', (251, 265))	('leukemia', 'Disease', (221, 229))	('colon', 'Disease', (231, 236))	('monogalactosyl diacylglycerol', 'Chemical', 'MESH:C009909', (78, 107))	('stomach cancer', 'Phenotype', 'HP:0012126', (251, 265))	('glycoglycerolipid', 'Chemical', 'MESH:C015903', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('bitter melon', 'Species', '3673', (35, 47))	('MGDG', 'Chemical', 'MESH:C009909', (109, 113))	('methanolic', 'Chemical', '-', (48, 58))
40999	29727019	Targeting these CSC genes responsible for stemness has been reported to diminish the tumorigenic potential and enhance sensitivity to chemotherapeutic agents by altering core CSC properties.	('diminish', 'NegReg', (72, 80))	('tumor', 'Disease', (85, 90))	('altering', 'Reg', (161, 169))	('sensitivity to chemotherapeutic agents', 'MPA', (119, 157))	('core', 'cellular_component', 'GO:0019013', ('170', '174'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('enhance', 'PosReg', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('core CSC properties', 'MPA', (170, 189))	('Targeting', 'Var', (0, 9))
41005	29727019	Lastly, translational relevance of BMJ was confirmed in vivo utilizing MiaPaCa2 xenografts where BMJ administration (via oral gavage) also caused a significant reduction in PanC-CSC associated transcription factors as examined by immunohistochemical staining of SOX2, OCT4, NANOG and PDX1, thus verifying the results noted from our in vitro studies.	('reduction', 'NegReg', (160, 169))	('BMJ', 'Chemical', '-', (97, 100))	('PanC-CSC associated transcription factors', 'Gene', (173, 214))	('MiaPaCa2', 'CellLine', 'CVCL:0428', (71, 79))	('PanC', 'Phenotype', 'HP:0002894', (173, 177))	('BMJ', 'Var', (97, 100))	('transcription', 'biological_process', 'GO:0006351', ('193', '206'))	('BMJ', 'Chemical', '-', (35, 38))
41007	29727019	The effects observed in vitro were further corroborated in mouse xenograft tissue samples showing a decrease in PanC-CSC associated regulatory molecules in BMJ treated samples compared to controls.	('BMJ', 'Chemical', '-', (156, 159))	('mouse', 'Species', '10090', (59, 64))	('decrease', 'NegReg', (100, 108))	('PanC-CSC associated regulatory molecules', 'MPA', (112, 152))	('BMJ', 'Var', (156, 159))	('PanC', 'Phenotype', 'HP:0002894', (112, 116))
41056	30055578	Patients with initial liver recurrence were more likely to have a positive margin resection compared to lung recurrence cohort, however, this difference was not statistically significant (87% vs 77%, P = 0.148).	('liver', 'Disease', (22, 27))	('Patients', 'Species', '9606', (0, 8))	('positive', 'Var', (66, 74))
41081	30055578	Current evidence suggests that tissue hypoxia could be one of the important drivers of these genetic rearrangements that yields to multi-clonal expansion and activation of the metastasis process.	('yields to', 'Reg', (121, 130))	('metastasis process', 'CPA', (176, 194))	('hypoxia', 'Disease', 'MESH:D000860', (38, 45))	('activation', 'PosReg', (158, 168))	('hypoxia', 'Disease', (38, 45))	('multi-clonal expansion', 'Var', (131, 153))
41154	29324681	Individuals with Lynch syndrome and certain other genetic syndromes, as well as BRCA1 and BRCA2 mutation carriers, are also at an increased risk.	('Lynch syndrome', 'Disease', 'MESH:D003123', (17, 31))	('BRCA2', 'Gene', (90, 95))	('BRCA1', 'Gene', '672', (80, 85))	('mutation', 'Var', (96, 104))	('BRCA2', 'Gene', '675', (90, 95))	('BRCA1', 'Gene', (80, 85))	('Lynch syndrome', 'Disease', (17, 31))
41197	29324681	It results from inactivation of the tumor suppressor gene MEN-1, has autosomal dominant transmission and the penetrance is almost 100% with age.	('tumor suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('MEN-1', 'Gene', '4221', (58, 63))	('MEN-1', 'Gene', (58, 63))	('inactivation', 'Var', (16, 28))	('results from', 'Reg', (3, 15))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
41205	29324681	Mutation of the MEN-1 gene is the most common genetic alteration found in pancreatic neuroendocrine carcinomas (PNC), but with distinctly different frequencies between them; PPoma is present in 18-44% of the cases.	('PP', 'Gene', '5539', (174, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('MEN-1', 'Gene', '4221', (16, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (85, 109))	('Mutation', 'Var', (0, 8))	('pancreatic neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (74, 110))	('pancreatic neuroendocrine carcinomas', 'Disease', (74, 110))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (85, 110))	('MEN-1', 'Gene', (16, 21))
41207	29324681	The fact that mutations in MEN-1 are found in non-functioning PNC is not surprising when considering that non-functioning PNC are common in patients with multiple endocrine neoplasia type 1 (MEN-1) and higher morbidity and mortality are associated with MEN-1, not to mention that the average life expectancy for patients with these tumors was lower than that of patients with MEN-1 who did not present with PNC tumors.	('MEN-1', 'Gene', (191, 196))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (163, 182))	('multiple endocrine neoplasia type 1', 'Gene', '4221', (154, 189))	('multiple endocrine neoplasia type 1', 'Gene', (154, 189))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('MEN-1', 'Gene', '4221', (376, 381))	('tumor', 'Phenotype', 'HP:0002664', (411, 416))	('patients', 'Species', '9606', (362, 370))	('tumors', 'Phenotype', 'HP:0002664', (332, 338))	('tumors', 'Phenotype', 'HP:0002664', (411, 417))	('PNC tumors', 'Disease', 'MESH:D009369', (407, 417))	('MEN-1', 'Gene', '4221', (27, 32))	('MEN-1', 'Gene', (376, 381))	('patients', 'Species', '9606', (140, 148))	('mutations', 'Var', (14, 23))	('tumors', 'Disease', (332, 338))	('lower', 'NegReg', (343, 348))	('tumors', 'Disease', (411, 417))	('patients', 'Species', '9606', (312, 320))	('PNC tumors', 'Disease', (407, 417))	('MEN-1', 'Gene', (27, 32))	('MEN-1', 'Gene', '4221', (253, 258))	('MEN-1', 'Gene', '4221', (191, 196))	('tumors', 'Disease', 'MESH:D009369', (332, 338))	('tumors', 'Disease', 'MESH:D009369', (411, 417))	('neoplasia', 'Phenotype', 'HP:0002664', (173, 182))	('men', 'Species', '9606', (267, 270))	('MEN-1', 'Gene', (253, 258))
41210	29324681	This syndrome is characterized by inactivating mutations of the VHL gene (3p25) encoding the elonginprotein.	('VHL', 'Gene', '7428', (64, 67))	('VHL', 'Gene', (64, 67))	('inactivating mutations', 'Var', (34, 56))
41287	29324681	With the identification of the MEN-1 gene and mutations causing this syndrome, it was believed that it would be possible to identify the mutations associated with the malignancy of the pancreatic tumors and to identify patients at high risk of developing metastatic disease.	('malignancy of the pancreatic tumors', 'Disease', (167, 202))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('mutations', 'Var', (46, 55))	('associated', 'Reg', (147, 157))	('malignancy of the pancreatic tumors', 'Disease', 'MESH:D010190', (167, 202))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (185, 202))	('mutations', 'Var', (137, 146))	('MEN-1', 'Gene', '4221', (31, 36))	('MEN-1', 'Gene', (31, 36))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
41301	29324681	Thus, the cytoreduction of hepatic metastases with palliative intent to control symptoms increases median survival by 3-4 times, as well as providing excellent symptom control.	('median survival', 'MPA', (99, 114))	('symptom', 'MPA', (160, 167))	('cytoreduction', 'Var', (10, 23))	('hepatic metastases', 'Disease', (27, 45))	('hepatic metastases', 'Disease', 'MESH:D009362', (27, 45))	('increases', 'PosReg', (89, 98))
41331	29324681	There are currently three radioactive compounds with different characteristics: 111-In-octreotide, 90-Y-octreotide and 177-Lu-octeotate.	('177-Lu-octeotate', 'Var', (119, 135))	('111-In-octreotide', 'Chemical', 'MESH:C094279', (80, 97))	('177-Lu-octeotate', 'Chemical', '-', (119, 135))	('90-Y-octreotide', 'Chemical', '-', (99, 114))	('111-In-octreotide', 'Var', (80, 97))
41332	29324681	111-In-octreotide has a lower tissue penetration, but in a small study with 16 patients (most with carcinoids) it showed a clinical benefit in 70% of the cases, for at least six months after the last application.	('carcinoid', 'Phenotype', 'HP:0100570', (99, 108))	('carcinoids', 'Phenotype', 'HP:0100570', (99, 109))	('111-In-octreotide', 'Var', (0, 17))	('benefit', 'PosReg', (132, 139))	('patients', 'Species', '9606', (79, 87))	('111-In-octreotide', 'Chemical', 'MESH:C094279', (0, 17))
41334	29324681	90-Y-octreotide has higher energy and, therefore, greater tissue penetration.	('90-Y-octreotide', 'Var', (0, 15))	('higher', 'PosReg', (20, 26))	('energy', 'MPA', (27, 33))	('greater', 'PosReg', (50, 57))	('tissue penetration', 'CPA', (58, 76))	('90-Y-octreotide', 'Chemical', '-', (0, 15))
41339	29324681	It is already fully accepted that the development of cancer involves the accumulation of genetic alterations.	('men', 'Species', '9606', (45, 48))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('genetic alterations', 'Var', (89, 108))
41373	29593283	CD103+ cDC1s are known to cross-present antigen to activate CD8+ T cells and secrete factors that attract T cells into the tumor.	('n', 'Chemical', 'MESH:D009584', (74, 75))	('attract', 'PosReg', (98, 105))	('tumor', 'Disease', (123, 128))	('C', 'Chemical', 'MESH:D002244', (9, 10))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('CD8', 'Gene', '925', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('activate', 'PosReg', (51, 59))	('n', 'Chemical', 'MESH:D009584', (18, 19))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('n', 'Chemical', 'MESH:D009584', (21, 22))	('n', 'Chemical', 'MESH:D009584', (115, 116))	('CD103+', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('CD8', 'Gene', (60, 63))
41374	29593283	Furthermore, CD103+ cDC1s are important for transporting antigen into the draining lymph nodes (LNs), supporting T-cell activation and expansion.	('n', 'Chemical', 'MESH:D009584', (132, 133))	('n', 'Chemical', 'MESH:D009584', (139, 140))	('cDC1s', 'Gene', (20, 25))	('T-cell activation', 'CPA', (113, 130))	('CD103+', 'Var', (13, 19))	('supporting', 'PosReg', (102, 112))	('n', 'Chemical', 'MESH:D009584', (66, 67))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('n', 'Chemical', 'MESH:D009584', (89, 90))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('n', 'Chemical', 'MESH:D009584', (143, 144))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('T-cell activation', 'biological_process', 'GO:0042110', ('113', '130'))	('expansion', 'CPA', (135, 144))	('C', 'Chemical', 'MESH:D002244', (22, 23))	('C', 'Chemical', 'MESH:D002244', (13, 14))
41375	29593283	Given these functions, it is understandable that CD103+ cDC1s have been implicated in initiation and maintenance of CD8+ T-cell responses against tumors.	('n', 'Chemical', 'MESH:D009584', (19, 20))	('n', 'Chemical', 'MESH:D009584', (98, 99))	('CD8', 'Gene', (116, 119))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('C', 'Chemical', 'MESH:D002244', (58, 59))	('n', 'Chemical', 'MESH:D009584', (142, 143))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('implicated', 'Reg', (72, 82))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('CD8', 'Gene', '925', (116, 119))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('cDC1s', 'Gene', (56, 61))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('n', 'Chemical', 'MESH:D009584', (84, 85))	('CD103+', 'Var', (49, 55))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('n', 'Chemical', 'MESH:D009584', (4, 5))	('n', 'Chemical', 'MESH:D009584', (133, 134))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('tumors', 'Disease', (146, 152))	('n', 'Chemical', 'MESH:D009584', (107, 108))
41377	29593283	In patients, intratumoral CD141+ cDC1 numbers correlate with better outcomes in many types of solid tumors, including breast cancer (BC).	('better', 'PosReg', (61, 67))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('rat', 'Species', '10116', (16, 19))	('tumor', 'Disease', (100, 105))	('CD141+', 'Var', (26, 32))	('solid tumors', 'Disease', (94, 106))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('tumor', 'Disease', (18, 23))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('C', 'Chemical', 'MESH:D002244', (26, 27))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('breast cancer', 'Disease', (118, 131))	('n', 'Chemical', 'MESH:D009584', (8, 9))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('solid tumors', 'Disease', 'MESH:D009369', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('patients', 'Species', '9606', (3, 11))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('C', 'Chemical', 'MESH:D002244', (134, 135))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('BC', 'Phenotype', 'HP:0003002', (133, 135))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('cDC1', 'Gene', (33, 37))	('n', 'Chemical', 'MESH:D009584', (115, 116))
41383	29593283	This interruption reduces the systemic cDC1 pool, negatively impacting CD8+ T-cell immunity and correlating with poor patient outcome.	('n', 'Chemical', 'MESH:D009584', (16, 17))	('n', 'Chemical', 'MESH:D009584', (50, 51))	('CD8', 'Gene', '925', (71, 74))	('C', 'Chemical', 'MESH:D002244', (41, 42))	('negatively impacting', 'NegReg', (50, 70))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('n', 'Chemical', 'MESH:D009584', (93, 94))	('n', 'Chemical', 'MESH:D009584', (6, 7))	('reduces', 'NegReg', (18, 25))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('systemic cDC1 pool', 'MPA', (30, 48))	('C', 'Chemical', 'MESH:D002244', (71, 72))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('patient', 'Species', '9606', (118, 125))	('interruption', 'Var', (5, 17))	('CD8', 'Gene', (71, 74))
41394	29593283	Patient populations showed a decrease in CD141+ cDC1s and CD1c+ cDC2s (Fig.	('CD1c', 'Gene', '911', (58, 62))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('C', 'Chemical', 'MESH:D002244', (66, 67))	('C', 'Chemical', 'MESH:D002244', (41, 42))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('n', 'Chemical', 'MESH:D009584', (17, 18))	('CD1c', 'Gene', (58, 62))	('C', 'Chemical', 'MESH:D002244', (50, 51))	('CD141+', 'Var', (41, 47))	('decrease', 'NegReg', (29, 37))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('Patient', 'Species', '9606', (0, 7))	('C', 'Chemical', 'MESH:D002244', (58, 59))
41396	29593283	1a, CD141+ cDC1s are rare in the BM but are dramatically reduced in BC and PDAC patients.	('C', 'Chemical', 'MESH:D002244', (69, 70))	('patients', 'Species', '9606', (80, 88))	('BC', 'Phenotype', 'HP:0003002', (68, 70))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('CD141+ cDC1s', 'Var', (4, 16))	('PDAC', 'Disease', (75, 79))	('PDAC', 'Phenotype', 'HP:0006725', (75, 79))	('C', 'Chemical', 'MESH:D002244', (78, 79))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('n', 'Chemical', 'MESH:D009584', (66, 67))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('reduced', 'NegReg', (57, 64))	('C', 'Chemical', 'MESH:D002244', (4, 5))	('C', 'Chemical', 'MESH:D002244', (13, 14))
41404	29593283	Previous studies have shown that CD141+ cDC1 numbers and functions in the tumor are predictive of patient outcome, prompting us to assess whether changes in CD141+ cDC1s in the BM prior to treatment or resection were also predictive of response to therapy.	('patient', 'Species', '9606', (98, 105))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('cDC1s', 'Gene', (164, 169))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('tumor', 'Disease', (74, 79))	('n', 'Chemical', 'MESH:D009584', (241, 242))	('n', 'Chemical', 'MESH:D009584', (210, 211))	('C', 'Chemical', 'MESH:D002244', (42, 43))	('CD141+ cDC1s', 'Gene', (157, 169))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('C', 'Chemical', 'MESH:D002244', (33, 34))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('changes', 'Var', (146, 153))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('C', 'Chemical', 'MESH:D002244', (166, 167))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('C', 'Chemical', 'MESH:D002244', (157, 158))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('n', 'Chemical', 'MESH:D009584', (171, 172))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('n', 'Chemical', 'MESH:D009584', (196, 197))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (155, 156))
41407	29593283	Notably, CD1c+ cDC2 numbers were not predictive of pCR, suggesting the predictive nature is specific to the CD141+ cDC1 subset (Supplementary Fig.	('C', 'Chemical', 'MESH:D002244', (17, 18))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('C', 'Chemical', 'MESH:D002244', (52, 53))	('C', 'Chemical', 'MESH:D002244', (117, 118))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('C', 'Chemical', 'MESH:D002244', (9, 10))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('CD1c', 'Gene', '911', (9, 13))	('n', 'Chemical', 'MESH:D009584', (20, 21))	('C', 'Chemical', 'MESH:D002244', (108, 109))	('CD141+ cDC1', 'Var', (108, 119))	('CD1c', 'Gene', (9, 13))
41416	29593283	In contrast to cDC1s, Ly6G+Ly6C+CSF1R+ immature granulocytes and Ly6G+CSF1R- mature granulocytes expand in the BM (Fig.	('n', 'Chemical', 'MESH:D009584', (1, 2))	('C', 'Chemical', 'MESH:D002244', (17, 18))	('Ly6C', 'Gene', '17067', (27, 31))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('Ly6G', 'Chemical', '-', (65, 69))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('CSF1', 'molecular_function', 'GO:0005011', ('70', '74'))	('CSF1', 'molecular_function', 'GO:0005011', ('32', '36'))	('C', 'Chemical', 'MESH:D002244', (30, 31))	('n', 'Chemical', 'MESH:D009584', (101, 102))	('Ly6G', 'Chemical', '-', (22, 26))	('Ly6C', 'Gene', (27, 31))	('Ly6G+CSF1R-', 'Var', (65, 76))
41426	29593283	To determine if changes in cDC1 progenitors result in systemic alterations in the pool of available cDCs, we analyzed circulating pre-DCs.	('changes', 'Var', (16, 23))	('pre', 'molecular_function', 'GO:0003904', ('130', '133'))	('n', 'Chemical', 'MESH:D009584', (19, 20))	('rat', 'Species', '10116', (67, 70))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('C', 'Chemical', 'MESH:D002244', (29, 30))	('C', 'Chemical', 'MESH:D002244', (135, 136))	('pool of available cDCs', 'MPA', (82, 104))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('C', 'Chemical', 'MESH:D002244', (102, 103))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('cDC1', 'Gene', (27, 31))	('alterations', 'Reg', (63, 74))
41431	29593283	These changes in the pool of circulating pre-DCs correlated with reduced numbers of CD103+ cDC1s in the uninvolved LNs of tumor-bearing mice (Fig.	('n', 'Chemical', 'MESH:D009584', (15, 16))	('CD103+', 'Var', (84, 90))	('mice', 'Species', '10090', (136, 140))	('C', 'Chemical', 'MESH:D002244', (93, 94))	('reduced', 'NegReg', (65, 72))	('n', 'Chemical', 'MESH:D009584', (98, 99))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('n', 'Chemical', 'MESH:D009584', (73, 74))	('C', 'Chemical', 'MESH:D002244', (84, 85))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('n', 'Chemical', 'MESH:D009584', (133, 134))	('pre', 'molecular_function', 'GO:0003904', ('41', '44'))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('tumor', 'Disease', (122, 127))	('n', 'Chemical', 'MESH:D009584', (9, 10))
41443	29593283	To verify that the reduced number of cDC1s in the poly I:C plug was due to a decreased pool of circulating pre-DCs rather than changes in recruitment cytokines, we measured recruitment of CD103+ cDC1s to a matrigel plug containing the recruitment factor C-C motif chemokine ligand 4 (Ccl4), which is known to be downregulated in some tumor types.	('n', 'Chemical', 'MESH:D009584', (156, 157))	('n', 'Chemical', 'MESH:D009584', (304, 305))	('n', 'Chemical', 'MESH:D009584', (130, 131))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('pool', 'MPA', (87, 91))	('ligand', 'molecular_function', 'GO:0005488', ('274', '280'))	('CD103+', 'Var', (188, 194))	('C-C motif chemokine ligand 4', 'Gene', (254, 282))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('n', 'Chemical', 'MESH:D009584', (327, 328))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('n', 'Chemical', 'MESH:D009584', (271, 272))	('C', 'Chemical', 'MESH:D002244', (112, 113))	('n', 'Chemical', 'MESH:D009584', (278, 279))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('C', 'Chemical', 'MESH:D002244', (256, 257))	('C', 'Chemical', 'MESH:D002244', (254, 255))	('n', 'Chemical', 'MESH:D009584', (301, 302))	('n', 'Chemical', 'MESH:D009584', (222, 223))	('Ccl4', 'Gene', '20303', (284, 288))	('poly I:C', 'Chemical', 'MESH:D011070', (50, 58))	('tumor', 'Disease', (334, 339))	('Ccl4', 'Gene', (284, 288))	('n', 'Chemical', 'MESH:D009584', (182, 183))	('n', 'Chemical', 'MESH:D009584', (244, 245))	('C', 'Chemical', 'MESH:D002244', (39, 40))	('pre', 'molecular_function', 'GO:0003904', ('107', '110'))	('n', 'Chemical', 'MESH:D009584', (125, 126))	('decreased', 'NegReg', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (334, 339))	('n', 'Chemical', 'MESH:D009584', (228, 229))	('rat', 'Species', '10116', (115, 118))	('C-C motif chemokine ligand 4', 'Gene', '20303', (254, 282))	('n', 'Chemical', 'MESH:D009584', (226, 227))	('n', 'Chemical', 'MESH:D009584', (315, 316))	('C', 'Chemical', 'MESH:D002244', (197, 198))	('Ccl', 'molecular_function', 'GO:0044101', ('284', '287'))	('C', 'Chemical', 'MESH:D002244', (284, 285))	('C', 'Chemical', 'MESH:D002244', (188, 189))
41444	29593283	Again, we saw a defect in CD103+ cDC1s recruited to the Ccl4-containing matrigel plug in tumor-bearing mice (Supplementary Fig.	('n', 'Chemical', 'MESH:D009584', (67, 68))	('Ccl', 'molecular_function', 'GO:0044101', ('56', '59'))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('C', 'Chemical', 'MESH:D002244', (26, 27))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('tumor', 'Disease', (89, 94))	('cDC1s', 'Gene', (33, 38))	('Ccl4', 'Gene', '20303', (56, 60))	('C', 'Chemical', 'MESH:D002244', (56, 57))	('CD103+', 'Var', (26, 32))	('Ccl4', 'Gene', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('mice', 'Species', '10090', (103, 107))	('n', 'Chemical', 'MESH:D009584', (4, 5))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
41451	29593283	We found that CD45.1+ MPs transferred into tumor-bearing mice differentiated into fewer CDPs, pre-DCs, and cDC1s in the BM, but more granulocytes in both the BM and blood (Fig.	('CDPs', 'CPA', (88, 92))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('tumor', 'Disease', (43, 48))	('pre', 'molecular_function', 'GO:0003904', ('94', '97'))	('C', 'Chemical', 'MESH:D002244', (99, 100))	('n', 'Chemical', 'MESH:D009584', (114, 115))	('CD45.1+ MPs', 'Var', (14, 25))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('fewer', 'NegReg', (82, 87))	('C', 'Chemical', 'MESH:D002244', (88, 89))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('CDPs', 'Chemical', '-', (88, 92))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (6, 7))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('mice', 'Species', '10090', (57, 61))	('C', 'Chemical', 'MESH:D002244', (14, 15))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('C', 'Chemical', 'MESH:D002244', (109, 110))	('n', 'Chemical', 'MESH:D009584', (162, 163))	('n', 'Chemical', 'MESH:D009584', (69, 70))
41482	29593283	To determine if either of these cytokines was necessary to alter cDC differentiation, we neutralized both GCSF and IL-6 in the context of PyMT-B6 tumors.	('C', 'Chemical', 'MESH:D002244', (107, 108))	('PyMT-B6 tumors', 'Disease', 'MESH:D026681', (138, 152))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('C', 'Chemical', 'MESH:D002244', (67, 68))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('GCSF', 'Gene', (106, 110))	('neutralized', 'Var', (89, 100))	('n', 'Chemical', 'MESH:D009584', (112, 113))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('n', 'Chemical', 'MESH:D009584', (89, 90))	('IL-6', 'Gene', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('IL-6', 'molecular_function', 'GO:0005138', ('115', '119'))	('IL-6', 'Gene', '16193', (115, 119))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('PyMT-B6 tumors', 'Disease', (138, 152))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('n', 'Chemical', 'MESH:D009584', (76, 77))
41483	29593283	As above, the presence of PyMT-B6 tumors reduced BM pre-DC and CD24+ cDC1 and blood pre-DC numbers while increasing granulocytes in both tissues.	('blood pre-DC numbers', 'MPA', (78, 98))	('n', 'Chemical', 'MESH:D009584', (19, 20))	('n', 'Chemical', 'MESH:D009584', (60, 61))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (130, 131))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('n', 'Chemical', 'MESH:D009584', (106, 107))	('PyMT-B6 tumors', 'Disease', 'MESH:D026681', (26, 40))	('BM pre-DC', 'MPA', (49, 58))	('reduced BM', 'Phenotype', 'HP:0045082', (41, 51))	('reduced', 'NegReg', (41, 48))	('pre', 'molecular_function', 'GO:0003904', ('84', '87'))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('C', 'Chemical', 'MESH:D002244', (63, 64))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('presence', 'Var', (14, 22))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('C', 'Chemical', 'MESH:D002244', (71, 72))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('increasing', 'PosReg', (105, 115))	('pre', 'molecular_function', 'GO:0003904', ('52', '55'))	('PyMT-B6 tumors', 'Disease', (26, 40))	('granulocytes in', 'MPA', (116, 131))	('CD24+ cDC1', 'MPA', (63, 73))
41484	29593283	After treatment with GCSF-neutralizing antibody, we observed that pre-DCs and CD24+ cDC1s in the BM and pre-DCs in the blood were restored to levels in tumor-free mice.	('cDC1s', 'Gene', (84, 89))	('antibody', 'molecular_function', 'GO:0003823', ('39', '47'))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('tumor-free', 'Disease', (152, 162))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('antibody', 'cellular_component', 'GO:0042571', ('39', '47'))	('pre', 'molecular_function', 'GO:0003904', ('104', '107'))	('tumor-free', 'Disease', 'MESH:D000072662', (152, 162))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('mice', 'Species', '10090', (163, 167))	('antibody', 'cellular_component', 'GO:0019815', ('39', '47'))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('pre', 'molecular_function', 'GO:0003904', ('66', '69'))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('C', 'Chemical', 'MESH:D002244', (78, 79))	('C', 'Chemical', 'MESH:D002244', (71, 72))	('CD24+', 'Var', (78, 83))	('n', 'Chemical', 'MESH:D009584', (101, 102))	('antibody', 'cellular_component', 'GO:0019814', ('39', '47'))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('C', 'Chemical', 'MESH:D002244', (22, 23))	('C', 'Chemical', 'MESH:D002244', (109, 110))
41486	29593283	Additionally, GCSF neutralization reduced immature granulocytes in the BM and granulocytes in the blood, as expected.	('n', 'Chemical', 'MESH:D009584', (19, 20))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('reduced', 'NegReg', (34, 41))	('neutralization', 'Var', (19, 33))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('immature granulocytes in the', 'CPA', (42, 70))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('n', 'Chemical', 'MESH:D009584', (65, 66))
41487	29593283	Neutralization of GCSF was also sufficient to increase CD8+ T cells in the tumor (Fig.	('GCSF', 'Gene', (18, 22))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('increase', 'PosReg', (46, 54))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('CD8', 'Gene', (55, 58))	('Neutralization', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('CD8', 'Gene', '925', (55, 58))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('tumor', 'Disease', (75, 80))
41488	29593283	Although IL-6 neutralization reduced immature granulocytes and inflammatory monocytes as previously described, it did not reverse tumor-induced reductions in pre-DCs or CD24+ cDC1s in the BM (Supplementary Fig.	('n', 'Chemical', 'MESH:D009584', (156, 157))	('n', 'Chemical', 'MESH:D009584', (60, 61))	('IL-6', 'Gene', '16193', (9, 13))	('C', 'Chemical', 'MESH:D002244', (163, 164))	('pre', 'molecular_function', 'GO:0003904', ('158', '161'))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('tumor', 'Disease', (130, 135))	('n', 'Chemical', 'MESH:D009584', (200, 201))	('n', 'Chemical', 'MESH:D009584', (137, 138))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('CD24+', 'Var', (169, 174))	('immature granulocytes', 'MPA', (37, 58))	('C', 'Chemical', 'MESH:D002244', (169, 170))	('C', 'Chemical', 'MESH:D002244', (177, 178))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('n', 'Chemical', 'MESH:D009584', (152, 153))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('IL-6', 'molecular_function', 'GO:0005138', ('9', '13'))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('n', 'Chemical', 'MESH:D009584', (182, 183))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('n', 'Chemical', 'MESH:D009584', (118, 119))	('IL-6', 'Gene', (9, 13))	('reduced', 'NegReg', (29, 36))	('neutralization', 'Var', (14, 28))
41491	29593283	We found that changes in BM progenitor numbers in tumor-free mice dosed with GCSF mice paralleled those observed in tumor-bearing mice.	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('n', 'Chemical', 'MESH:D009584', (114, 115))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('mice', 'Species', '10090', (61, 65))	('n', 'Chemical', 'MESH:D009584', (17, 18))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('BM progenitor numbers', 'CPA', (25, 46))	('tumor', 'Disease', (50, 55))	('mice', 'Species', '10090', (82, 86))	('mice', 'Species', '10090', (130, 134))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (6, 7))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('tumor-free', 'Disease', (50, 60))	('GCSF', 'Var', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (116, 121))	('tumor-free', 'Disease', 'MESH:D000072662', (50, 60))
41493	29593283	As expected, GCSF increased immature granulocytes in the BM and granulocytes in the blood (Fig.	('n', 'Chemical', 'MESH:D009584', (19, 20))	('increased', 'PosReg', (18, 27))	('n', 'Chemical', 'MESH:D009584', (67, 68))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('immature granulocytes', 'CPA', (28, 49))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('GCSF', 'Var', (13, 17))
41508	29593283	By contrast, tumor tissues from PyMT-B6 and KPC models had higher Csf3 levels compared to normal mammary and pancreas tissues (Fig.	('tumor', 'Disease', (13, 18))	('Csf3', 'Gene', '12985', (66, 70))	('C', 'Chemical', 'MESH:D002244', (66, 67))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('higher', 'PosReg', (59, 65))	('n', 'Chemical', 'MESH:D009584', (106, 107))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('PyMT-B6', 'Var', (32, 39))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('Csf3', 'Gene', (66, 70))	('KPC models', 'Var', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
41512	29593283	Additionally, although GCSF was expressed in both tumor and stroma, tumor levels of GCSF were considerably higher than stroma levels in most cases.	('tumor', 'Disease', (68, 73))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('n', 'Chemical', 'MESH:D009584', (134, 135))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('GCSF', 'Var', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('higher', 'PosReg', (107, 113))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('tumor', 'Disease', (50, 55))
41514	29593283	To directly test if tumor-derived GCSF was responsible for impaired cDC development, we deleted the Csf3 gene using CRISPR CAS9 in the PyMT-B6 cell line (PyMT-B6 GCSFKO).	('C', 'Chemical', 'MESH:D002244', (100, 101))	('C', 'Chemical', 'MESH:D002244', (163, 164))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('CAS', 'cellular_component', 'GO:0005650', ('123', '126'))	('Csf3', 'Gene', (100, 104))	('C', 'Chemical', 'MESH:D002244', (123, 124))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('deleted', 'Var', (88, 95))	('I', 'Chemical', 'MESH:D007455', (118, 119))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('Csf3', 'Gene', '12985', (100, 104))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('n', 'Chemical', 'MESH:D009584', (107, 108))	('tumor', 'Disease', (20, 25))
41515	29593283	Both BM and blood profiling showed pre-DCs and cDC1 populations were recovered and immature granulocytes were reduced in PyMT-B6 GCSFKO tumor-bearing mice relative to PyMT-B6 tumor-bearing controls (Fig.	('mice', 'Species', '10090', (150, 154))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('immature granulocytes', 'CPA', (83, 104))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('GCSFKO', 'Var', (129, 135))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('tumor', 'Disease', (136, 141))	('n', 'Chemical', 'MESH:D009584', (191, 192))	('tumor', 'Disease', (175, 180))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('reduced', 'NegReg', (110, 117))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('PyMT-B6 GCSFKO', 'Var', (121, 135))	('C', 'Chemical', 'MESH:D002244', (40, 41))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('pre', 'molecular_function', 'GO:0003904', ('35', '38'))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('n', 'Chemical', 'MESH:D009584', (186, 187))
41537	29593283	Furthermore, IRF8 expression was, again, downregulated in progenitors from PyMT-B6 tumor-bearing mice but was not downregulated in progenitors from PyMT-B6 GCSFKO mice (Supplementary Fig.	('tumor', 'Disease', (83, 88))	('downregulated', 'NegReg', (41, 54))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('n', 'Chemical', 'MESH:D009584', (177, 178))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('IRF8', 'Gene', (13, 17))	('expression', 'MPA', (18, 28))	('mice', 'Species', '10090', (163, 167))	('n', 'Chemical', 'MESH:D009584', (56, 57))	('PyMT-B6', 'Var', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mice', 'Species', '10090', (97, 101))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('n', 'Chemical', 'MESH:D009584', (94, 95))
41544	29593283	However, IRF8 overexpression rendered MPs insensitive to GCSF, and their cDC1 differentiation was comparable to Flt3L-alone conditions (Fig.	('cDC1 differentiation', 'CPA', (73, 93))	('n', 'Chemical', 'MESH:D009584', (132, 133))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('overexpression', 'Var', (14, 28))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('IRF8', 'Gene', (9, 13))	('n', 'Chemical', 'MESH:D009584', (64, 65))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('C', 'Chemical', 'MESH:D002244', (75, 76))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('C', 'Chemical', 'MESH:D002244', (58, 59))
41549	29593283	We observed reduced recruitment of CD103+ cDC1s to the secondary tumor site and draining LNs of primary tumor-bearing mice (Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('C', 'Chemical', 'MESH:D002244', (44, 45))	('mice', 'Species', '10090', (118, 122))	('tumor', 'Disease', (65, 70))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('cDC1s', 'Gene', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('recruitment', 'MPA', (20, 31))	('CD103+', 'Var', (35, 41))	('tumor', 'Disease', (104, 109))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('n', 'Chemical', 'MESH:D009584', (84, 85))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('n', 'Chemical', 'MESH:D009584', (77, 78))	('reduced', 'NegReg', (12, 19))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('n', 'Chemical', 'MESH:D009584', (115, 116))
41553	29593283	In these knockouts, we observed reduced numbers of tumor-specific CD8+ T cells comparable to the primary tumor-bearing mice.	('n', 'Chemical', 'MESH:D009584', (1, 2))	('mice', 'Species', '10090', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('knockouts', 'Var', (9, 18))	('reduced', 'NegReg', (32, 39))	('tumor', 'Disease', (51, 56))	('CD8', 'Gene', (66, 69))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('CD8', 'Gene', '925', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
41559	29593283	Ly6G-depletion did not reverse the defect in BM pre-DCs and cDC1s and did not recover IRF8 expression in BM progenitors (Supplementary Fig.	('IRF8', 'Gene', (86, 90))	('expression', 'MPA', (91, 101))	('n', 'Chemical', 'MESH:D009584', (74, 75))	('n', 'Chemical', 'MESH:D009584', (19, 20))	('n', 'Chemical', 'MESH:D009584', (67, 68))	('Ly6G', 'Chemical', '-', (0, 4))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('C', 'Chemical', 'MESH:D002244', (62, 63))	('pre', 'molecular_function', 'GO:0003904', ('48', '51'))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('C', 'Chemical', 'MESH:D002244', (53, 54))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('not', 'NegReg', (74, 77))	('Ly6G-depletion', 'Var', (0, 14))
41560	29593283	To show that immature granulocytes were not mediating CD8+ T-cell suppression beyond the loss of cDC1s in this model, we neutralized Ly6G in the context of the secondary tumor experiment described above.	('n', 'Chemical', 'MESH:D009584', (82, 83))	('Ly6G', 'Var', (133, 137))	('tumor', 'Disease', (170, 175))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('C', 'Chemical', 'MESH:D002244', (99, 100))	('n', 'Chemical', 'MESH:D009584', (184, 185))	('CD8', 'Gene', '925', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('neutralized Ly6G', 'Var', (121, 137))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('Ly6G', 'Chemical', '-', (133, 137))	('CD8', 'Gene', (54, 57))	('n', 'Chemical', 'MESH:D009584', (164, 165))	('C', 'Chemical', 'MESH:D002244', (54, 55))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('n', 'Chemical', 'MESH:D009584', (139, 140))
41566	29593283	Also, we neutralized Ly6G in IRF8-/- mice and measured PyMT-mCh-OVA tumor growth and found tumors grew at similar rates (Fig.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('Ly6G', 'Var', (21, 25))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('tumor', 'Disease', (91, 96))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('tumor', 'Disease', (68, 73))	('n', 'Chemical', 'MESH:D009584', (88, 89))	('mice', 'Species', '10090', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('neutralized Ly6G', 'Var', (9, 25))	('OVA tumor', 'Phenotype', 'HP:0100615', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Disease', (91, 97))	('rat', 'Species', '10116', (114, 117))	('Ly6G', 'Chemical', '-', (21, 25))	('PyMT-mCh-OVA', 'Chemical', '-', (55, 67))	('mCh', 'molecular_function', 'GO:0043881', ('60', '63'))
41567	29593283	These findings suggest that the loss of IRF8 can promote tumor growth by suppressing cDC1s rather than solely through the expansion of granulocytes.	('C', 'Chemical', 'MESH:D002244', (87, 88))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('n', 'Chemical', 'MESH:D009584', (130, 131))	('rat', 'Species', '10116', (91, 94))	('cDC1s', 'Gene', (85, 90))	('IRF8', 'Gene', (40, 44))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('loss', 'Var', (32, 36))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('promote', 'PosReg', (49, 56))	('suppressing', 'NegReg', (73, 84))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('n', 'Chemical', 'MESH:D009584', (101, 102))	('tumor', 'Disease', (57, 62))	('n', 'Chemical', 'MESH:D009584', (8, 9))
41569	29593283	Our data suggest that exposure to tumor-derived GCSF can impair BM progenitors in their ability to generate cDC1s.	('rat', 'Species', '10116', (103, 106))	('GCSF', 'Var', (48, 52))	('ability', 'MPA', (88, 95))	('tumor', 'Disease', (34, 39))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('C', 'Chemical', 'MESH:D002244', (110, 111))	('BM progenitors', 'CPA', (64, 78))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('n', 'Chemical', 'MESH:D009584', (101, 102))	('impair', 'NegReg', (57, 63))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
41573	29593283	We also observed that combined treatment with Flt3L and anti-GCSF IgGs did not further upregulate pre-DC or cDC numbers in tumor-free mice (Fig.	('C', 'Chemical', 'MESH:D002244', (62, 63))	('n', 'Chemical', 'MESH:D009584', (53, 54))	('n', 'Chemical', 'MESH:D009584', (112, 113))	('mice', 'Species', '10090', (134, 138))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('tumor-free', 'Disease', 'MESH:D000072662', (123, 133))	('C', 'Chemical', 'MESH:D002244', (110, 111))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('C', 'Chemical', 'MESH:D002244', (103, 104))	('pre', 'molecular_function', 'GO:0003904', ('98', '101'))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor-free', 'Disease', (123, 133))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('I', 'Chemical', 'MESH:D007455', (66, 67))	('anti-GCSF', 'Var', (56, 65))
41580	29593283	In tumor-bearing mice, in which IRF8 is downregulated, neutralizing GCSF restores IRF8 levels to tumor-free mouse conditions in BM progenitors.	('n', 'Chemical', 'MESH:D009584', (43, 44))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('tumor-free', 'Disease', (97, 107))	('tumor-free', 'Disease', 'MESH:D000072662', (97, 107))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('tumor', 'Disease', (3, 8))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('restores', 'PosReg', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mice', 'Species', '10090', (17, 21))	('downregulated', 'NegReg', (40, 53))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('mouse', 'Species', '10090', (108, 113))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('IRF8 levels', 'MPA', (82, 93))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('GCSF', 'Gene', (68, 72))	('neutralizing', 'Var', (55, 67))
41581	29593283	Importantly, neutralizing GCSF also increased IRF8 levels in pre-DCs (Fig.	('C', 'Chemical', 'MESH:D002244', (27, 28))	('C', 'Chemical', 'MESH:D002244', (66, 67))	('n', 'Chemical', 'MESH:D009584', (37, 38))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('I', 'Chemical', 'MESH:D007455', (46, 47))	('IRF8 levels', 'MPA', (46, 57))	('neutralizing', 'Var', (13, 25))	('pre', 'molecular_function', 'GO:0003904', ('61', '64'))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('increased', 'PosReg', (36, 45))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('GCSF', 'Gene', (26, 30))
41586	29593283	When Flt3L was combined with anti-GCSF IgGs, tumor infiltration of CD103+ cDC1s, but not CD11b+ cDC2s, were increased by more than twofold and this increase correlated with substantially more CD8+ T cells.	('C', 'Chemical', 'MESH:D002244', (76, 77))	('tumor', 'Disease', (45, 50))	('n', 'Chemical', 'MESH:D009584', (3, 4))	('rat', 'Species', '10116', (57, 60))	('C', 'Chemical', 'MESH:D002244', (67, 68))	('C', 'Chemical', 'MESH:D002244', (98, 99))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('CD103+', 'Var', (67, 73))	('CD8', 'Gene', (192, 195))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('increased', 'PosReg', (108, 117))	('I', 'Chemical', 'MESH:D007455', (39, 40))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('C', 'Chemical', 'MESH:D002244', (192, 193))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('more', 'PosReg', (187, 191))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('n', 'Chemical', 'MESH:D009584', (179, 180))	('n', 'Chemical', 'MESH:D009584', (140, 141))	('n', 'Chemical', 'MESH:D009584', (20, 21))	('CD8', 'Gene', '925', (192, 195))	('n', 'Chemical', 'MESH:D009584', (52, 53))
41587	29593283	Together, these data show that GCSF neutralization supports Flt3L-mediated expansion and mobilization of cDC1 and suggest this activity is facilitated in part by restoring IRF8 expression and commitment to the cDC1 lineage.	('C', 'Chemical', 'MESH:D002244', (212, 213))	('C', 'Chemical', 'MESH:D002244', (107, 108))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('neutralization', 'Var', (36, 50))	('n', 'Chemical', 'MESH:D009584', (217, 218))	('expression', 'MPA', (177, 187))	('n', 'Chemical', 'MESH:D009584', (200, 201))	('n', 'Chemical', 'MESH:D009584', (169, 170))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('Flt3L-mediated', 'Gene', (60, 74))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('n', 'Chemical', 'MESH:D009584', (152, 153))	('cDC1', 'Gene', (105, 109))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('n', 'Chemical', 'MESH:D009584', (189, 190))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('IRF8', 'Gene', (172, 176))	('commitment', 'CPA', (192, 202))	('restoring', 'PosReg', (162, 171))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('mobilization', 'MPA', (89, 101))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('n', 'Chemical', 'MESH:D009584', (186, 187))
41588	29593283	Given these results, we hypothesized Flt3L+anti-GCSF IgGs would bolster cDC-based immunotherapeutic strategies in established tumors.	('bolster', 'PosReg', (64, 71))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('tumors', 'Disease', (126, 132))	('n', 'Chemical', 'MESH:D009584', (112, 113))	('I', 'Chemical', 'MESH:D007455', (53, 54))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('Flt3L+anti-GCSF', 'Var', (37, 52))	('n', 'Chemical', 'MESH:D009584', (4, 5))	('C', 'Chemical', 'MESH:D002244', (74, 75))	('rat', 'Species', '10116', (102, 105))	('cDC-based immunotherapeutic strategies', 'CPA', (72, 110))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
41592	29593283	By contrast, survival was extended in mice treated with anti-GCSF IgGs+Flt3L+poly I:C+anti-PD1 IgGs compared with mice treated with vehicle alone or Flt3L+poly I:C+anti-PD1 IgGs (Fig.	('n', 'Chemical', 'MESH:D009584', (36, 37))	('mice', 'Species', '10090', (38, 42))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('extended', 'PosReg', (26, 34))	('anti-GCSF IgGs+Flt3L+poly', 'Var', (56, 81))	('poly I:C', 'Chemical', 'MESH:D011070', (155, 163))	('survival', 'CPA', (13, 21))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('I', 'Chemical', 'MESH:D007455', (95, 96))	('I', 'Chemical', 'MESH:D007455', (160, 161))	('IgGs+Flt3L+poly I:C+anti-PD1 IgGs', 'Var', (66, 99))	('poly I:C', 'Chemical', 'MESH:D011070', (77, 85))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('I', 'Chemical', 'MESH:D007455', (173, 174))	('n', 'Chemical', 'MESH:D009584', (165, 166))	('n', 'Chemical', 'MESH:D009584', (143, 144))	('mice', 'Species', '10090', (114, 118))	('IgGs+Flt3L+poly', 'Var', (66, 81))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('I', 'Chemical', 'MESH:D007455', (82, 83))	('I', 'Chemical', 'MESH:D007455', (66, 67))
41604	29593283	This is an important finding because IRF8 expression in progenitors as early as the hematopoietic stem cell primes transcriptional networks and influences lineage bias towards cDC and cDC1 fate.	('influences', 'Reg', (144, 154))	('cDC1 fate', 'CPA', (184, 193))	('C', 'Chemical', 'MESH:D002244', (186, 187))	('n', 'Chemical', 'MESH:D009584', (18, 19))	('transcriptional networks', 'MPA', (115, 139))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('n', 'Chemical', 'MESH:D009584', (145, 146))	('C', 'Chemical', 'MESH:D002244', (178, 179))	('n', 'Chemical', 'MESH:D009584', (9, 10))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('expression', 'Var', (42, 52))	('primes', 'PosReg', (108, 114))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('IRF8', 'Gene', (37, 41))	('n', 'Chemical', 'MESH:D009584', (181, 182))	('n', 'Chemical', 'MESH:D009584', (157, 158))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('lineage bias towards cDC', 'CPA', (155, 179))	('n', 'Chemical', 'MESH:D009584', (118, 119))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('n', 'Chemical', 'MESH:D009584', (131, 132))
41618	29593283	Given cDC1 differentiation is interrupted in cancer, our study shows that there is no longer a sufficient supply of cDC1 progenitors available to populate new and persistent sites of inflammation, such as sites of tumor outgrowth and metastasis, and that this lack of cDC1s is detrimental to anti-tumor CD8+ T-cell responses.	('n', 'Chemical', 'MESH:D009584', (194, 195))	('n', 'Chemical', 'MESH:D009584', (43, 44))	('detrimental', 'NegReg', (277, 288))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('n', 'Chemical', 'MESH:D009584', (18, 19))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('n', 'Chemical', 'MESH:D009584', (320, 321))	('tumor', 'Disease', (297, 302))	('n', 'Chemical', 'MESH:D009584', (231, 232))	('n', 'Chemical', 'MESH:D009584', (184, 185))	('n', 'Chemical', 'MESH:D009584', (88, 89))	('inflammation', 'biological_process', 'GO:0006954', ('183', '195'))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('CD8', 'Gene', (303, 306))	('n', 'Chemical', 'MESH:D009584', (247, 248))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('n', 'Chemical', 'MESH:D009584', (25, 26))	('inflammation', 'Disease', 'MESH:D007249', (183, 195))	('n', 'Chemical', 'MESH:D009584', (160, 161))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('C', 'Chemical', 'MESH:D002244', (303, 304))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('lack', 'Var', (260, 264))	('C', 'Chemical', 'MESH:D002244', (8, 9))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumor', 'Disease', (214, 219))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('C', 'Chemical', 'MESH:D002244', (270, 271))	('cancer', 'Disease', (45, 51))	('n', 'Chemical', 'MESH:D009584', (293, 294))	('inflammation', 'Disease', (183, 195))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('C', 'Chemical', 'MESH:D002244', (118, 119))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('n', 'Chemical', 'MESH:D009584', (284, 285))	('n', 'Chemical', 'MESH:D009584', (4, 5))	('n', 'Chemical', 'MESH:D009584', (171, 172))	('n', 'Chemical', 'MESH:D009584', (83, 84))	('cDC1s', 'Gene', (268, 273))	('CD8', 'Gene', '925', (303, 306))	('n', 'Chemical', 'MESH:D009584', (155, 156))
41621	29593283	Others have shown that the number of CD141+ cDC1s in the tumor, especially in balance with immune-suppressive myeloid cells, is an important indicator of chemotherapy response and outcome in patients.	('n', 'Chemical', 'MESH:D009584', (82, 83))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('n', 'Chemical', 'MESH:D009584', (177, 178))	('cDC1s', 'Gene', (44, 49))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('n', 'Chemical', 'MESH:D009584', (142, 143))	('tumor', 'Disease', (57, 62))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('CD141+', 'Var', (37, 43))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('n', 'Chemical', 'MESH:D009584', (189, 190))	('patients', 'Species', '9606', (191, 199))	('C', 'Chemical', 'MESH:D002244', (37, 38))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('n', 'Chemical', 'MESH:D009584', (172, 173))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('n', 'Chemical', 'MESH:D009584', (196, 197))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('n', 'Chemical', 'MESH:D009584', (76, 77))
41623	29593283	These data suggest tumor-induced alteration in myeloid differentiation, and specifically cDC1 development occurring in the BM, may also impact patient response to therapy and predict patient outcome.	('n', 'Chemical', 'MESH:D009584', (156, 157))	('n', 'Chemical', 'MESH:D009584', (148, 149))	('n', 'Chemical', 'MESH:D009584', (42, 43))	('patient', 'Species', '9606', (183, 190))	('tumor', 'Disease', (19, 24))	('C', 'Chemical', 'MESH:D002244', (91, 92))	('patient', 'Species', '9606', (143, 150))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('impact', 'Reg', (136, 142))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('n', 'Chemical', 'MESH:D009584', (73, 74))	('alteration', 'Var', (33, 43))	('rat', 'Species', '10116', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('predict', 'Reg', (175, 182))	('n', 'Chemical', 'MESH:D009584', (188, 189))	('n', 'Chemical', 'MESH:D009584', (172, 173))	('myeloid differentiation', 'CPA', (47, 70))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (69, 70))	('cDC1 development', 'Gene', (89, 105))
41629	29593283	Others have also shown that Flt3L treatment or colony-stimulating factor 1 (CSF1) neutralization expands cDC1 numbers in the tumor and increases response to both chemotherapies and immunotherapies.	('n', 'Chemical', 'MESH:D009584', (132, 133))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('C', 'Chemical', 'MESH:D002244', (107, 108))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('C', 'Chemical', 'MESH:D002244', (76, 77))	('n', 'Chemical', 'MESH:D009584', (185, 186))	('n', 'Chemical', 'MESH:D009584', (178, 179))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('response', 'MPA', (145, 153))	('colony-stimulating factor 1', 'Gene', (47, 74))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('neutralization', 'Var', (82, 96))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('CSF1', 'Gene', (76, 80))	('expands', 'PosReg', (97, 104))	('n', 'Chemical', 'MESH:D009584', (150, 151))	('CSF1', 'Gene', '12977', (76, 80))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('increases', 'PosReg', (135, 144))	('cDC1', 'Gene', (105, 109))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('colony-stimulating factor 1', 'Gene', '12977', (47, 74))	('n', 'Chemical', 'MESH:D009584', (101, 102))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('tumor', 'Disease', (125, 130))	('CSF1', 'molecular_function', 'GO:0005011', ('76', '80'))	('n', 'Chemical', 'MESH:D009584', (21, 22))
41631	29593283	Here, we neutralized GCSF to increase BM cDC1 differentiation, which was able to further increase the efficacy of Flt3L by refining the IRF8-mediated cDC1 differentiation program.	('n', 'Chemical', 'MESH:D009584', (169, 170))	('n', 'Chemical', 'MESH:D009584', (53, 54))	('BM cDC1 differentiation', 'CPA', (38, 61))	('n', 'Chemical', 'MESH:D009584', (60, 61))	('n', 'Chemical', 'MESH:D009584', (30, 31))	('increase BM', 'Phenotype', 'HP:0031418', (29, 40))	('neutralized', 'Var', (9, 20))	('increase', 'PosReg', (29, 37))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('C', 'Chemical', 'MESH:D002244', (43, 44))	('C', 'Chemical', 'MESH:D002244', (152, 153))	('C', 'Chemical', 'MESH:D002244', (22, 23))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('n', 'Chemical', 'MESH:D009584', (162, 163))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('n', 'Chemical', 'MESH:D009584', (9, 10))
41674	29593283	For anti-Ly6G IgG-treated arm, anti-Ly6G IgGs treatment, as described below, was started 1 day prior to implantation of the PyMT-mCh-OVA tumor.	('n', 'Chemical', 'MESH:D009584', (53, 54))	('tumor', 'Disease', (137, 142))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('OVA tumor', 'Phenotype', 'HP:0100615', (133, 142))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('n', 'Chemical', 'MESH:D009584', (109, 110))	('I', 'Chemical', 'MESH:D007455', (14, 15))	('PyMT-mCh-OVA', 'Chemical', '-', (124, 136))	('mCh', 'molecular_function', 'GO:0043881', ('129', '132'))	('anti-Ly6G', 'Var', (4, 13))	('Ly6G', 'Chemical', '-', (36, 40))	('I', 'Chemical', 'MESH:D007455', (41, 42))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('Ly6G', 'Chemical', '-', (9, 13))	('n', 'Chemical', 'MESH:D009584', (115, 116))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('anti-Ly6G', 'Var', (31, 40))
41678	29593283	For anti-Ly6G IgG-treated arm, anti-Ly6G IgGs, as described below, was started 1 day prior to implantation of the matrigel plug.	('n', 'Chemical', 'MESH:D009584', (32, 33))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('n', 'Chemical', 'MESH:D009584', (99, 100))	('anti-Ly6G', 'Var', (4, 13))	('Ly6G', 'Chemical', '-', (36, 40))	('I', 'Chemical', 'MESH:D007455', (41, 42))	('Ly6G', 'Chemical', '-', (9, 13))	('I', 'Chemical', 'MESH:D007455', (14, 15))	('anti-Ly6G', 'Var', (31, 40))
41737	29593283	Cells were stained and analyzed as described for flow cytometry, identifying the progeny of isolated progenitors by CD45.2 positivity.	('n', 'Chemical', 'MESH:D009584', (15, 16))	('n', 'Chemical', 'MESH:D009584', (74, 75))	('positivity', 'Var', (123, 133))	('n', 'Chemical', 'MESH:D009584', (106, 107))	('n', 'Chemical', 'MESH:D009584', (20, 21))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('CD45.2', 'Gene', (116, 122))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('C', 'Chemical', 'MESH:D002244', (0, 1))
41764	29593283	Mice were treated with 200 mug anti-PD1 IgGs (clone RMP1-14, BioXCell) every 3 days by intraperitoneal injection.	('n', 'Chemical', 'MESH:D009584', (88, 89))	('n', 'Chemical', 'MESH:D009584', (98, 99))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('C', 'Chemical', 'MESH:D002244', (65, 66))	('anti-PD1', 'Var', (31, 39))	('RMP1', 'Gene', (52, 56))	('I', 'Chemical', 'MESH:D007455', (40, 41))	('mug', 'molecular_function', 'GO:0043739', ('27', '30'))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('Mice', 'Species', '10090', (0, 4))	('n', 'Chemical', 'MESH:D009584', (104, 105))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('RMP1', 'Gene', '104168', (52, 56))
41793	29593283	T.M.N, W.G.H., R.C.F., D.C.L., C.M., K.N.W., and R.L.A.	('C', 'Chemical', 'MESH:D002244', (17, 18))	('C', 'Chemical', 'MESH:D002244', (31, 32))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('D.C.L.', 'Var', (23, 29))	('R.C.F.', 'Var', (15, 21))	('C.M.', 'Var', (31, 35))	('C', 'Chemical', 'MESH:D002244', (25, 26))	('K.N.W.', 'Var', (37, 43))
41804	19996307	Accumulating evidence indicates that genomic deletion of the EBF1 gene contributes to the pathogenesis, drug resistance and relapse of B-progenitor acute lymphoblastic leukemia (ALL).	('genomic deletion', 'Var', (37, 53))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (148, 176))	('B-progenitor', 'CPA', (135, 147))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('ALL', 'Phenotype', 'HP:0006721', (178, 181))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (148, 176))	('drug resistance', 'biological_process', 'GO:0009315', ('104', '119'))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('EBF1', 'Gene', (61, 65))	('acute lymphoblastic leukemia', 'Disease', (148, 176))	('drug resistance', 'biological_process', 'GO:0042493', ('104', '119'))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (154, 176))	('B-progenitor acute lymphoblastic leukemia', 'Phenotype', 'HP:0004812', (135, 176))	('pathogenesis', 'biological_process', 'GO:0009405', ('90', '102'))	('contributes', 'Reg', (71, 82))	('drug resistance', 'MPA', (104, 119))
41805	19996307	Epigenetic silencing and genomic deletion of the EBF3 locus in chromosome 10q are very frequent in glioblastoma (GBM).	('glioblastoma', 'Disease', (99, 111))	('GBM', 'Phenotype', 'HP:0012174', (113, 116))	('EBF3', 'Gene', (49, 53))	('glioblastoma', 'Disease', 'MESH:D005909', (99, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('genomic deletion', 'Var', (25, 41))	('Epigenetic silencing', 'Var', (0, 20))	('frequent', 'Reg', (87, 95))
41808	19996307	These missense mutations occur in the DNA-binding domain or the conserved IPT/TIG domain, suggesting that they might disrupt the functions of these two proteins.	('missense mutations', 'Var', (6, 24))	('disrupt', 'NegReg', (117, 124))	('occur', 'Reg', (25, 30))	('IPT', 'Gene', (74, 77))	('TIG', 'Chemical', '-', (78, 81))	('functions', 'MPA', (129, 138))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('IPT', 'Gene', '54802', (74, 77))	('DNA-binding', 'molecular_function', 'GO:0003677', ('38', '49'))
41810	19996307	Therefore, EBFs represent new tumor suppressors whose inactivation blocks normal development and contributes to tumorigenesis of diverse types of human cancer.	('tumor', 'Disease', (112, 117))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('contributes to', 'Reg', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('EBFs', 'Chemical', '-', (11, 15))	('normal development', 'CPA', (74, 92))	('human', 'Species', '9606', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('EBFs', 'Gene', (11, 15))	('tumor', 'Disease', (30, 35))	('inactivation', 'Var', (54, 66))	('blocks', 'NegReg', (67, 73))
41813	19996307	Several recent large-scale sequencing studies have confirmed the high prevalence of mutations of these genes across diverse cancer types.	('mutations', 'Var', (84, 93))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
41814	19996307	These common mutations are believed to be the driving force in tumorigenesis.	('tumor', 'Disease', (63, 68))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
41815	19996307	One surprising discovery from these studies is that, in addition to a few frequently mutated genes, specific tumors display low-frequency mutations in a diverse array of genes.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (138, 147))
41818	19996307	Regardless, the diversity of genes with low-frequency mutations in different tumors reflects the notorious complexity of cancer.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
41819	19996307	Low frequency cancer-specific mutations have been observed in genes encoding two members of the early B-cell factors (EBF, or Olfactory neuronal transcription factor-1, Olf-1) in glioblastoma (GBM) and pancreatic cancer.	('transcription', 'biological_process', 'GO:0006351', ('145', '158'))	('glioblastoma', 'Disease', 'MESH:D005909', (179, 191))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (202, 219))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('glioblastoma', 'Disease', (179, 191))	('Olf-1', 'Gene', '1879', (169, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('cancer', 'Disease', (213, 219))	('GBM', 'Phenotype', 'HP:0012174', (193, 196))	('Olf-1', 'Gene', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('pancreatic cancer', 'Disease', 'MESH:D010190', (202, 219))	('mutations', 'Var', (30, 39))	('Olfactory neuronal transcription factor-1', 'Gene', '1879', (126, 167))	('cancer', 'Disease', (14, 20))	('pancreatic cancer', 'Disease', (202, 219))	('transcription factor', 'molecular_function', 'GO:0000981', ('145', '165'))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Olfactory neuronal transcription factor-1', 'Gene', (126, 167))	('cancer', 'Disease', 'MESH:D009369', (213, 219))
41821	19996307	found that the EBF3 locus on the human chromosome 10q is deleted or methylated in brain tumors.	('methylated', 'Var', (68, 78))	('brain tumors', 'Phenotype', 'HP:0030692', (82, 94))	('brain tumors', 'Disease', 'MESH:D001932', (82, 94))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('brain tumors', 'Disease', (82, 94))	('EBF3', 'Gene', (15, 19))	('human', 'Species', '9606', (33, 38))	('brain tumor', 'Phenotype', 'HP:0030692', (82, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
41823	19996307	Furthermore, deletion of the EBF1 locus occurs in B-progenitor acute lymphoblastic leukemia (ALL).	('occurs', 'Reg', (40, 46))	('EBF1', 'Gene', (29, 33))	('B-progenitor acute lymphoblastic leukemia', 'Phenotype', 'HP:0004812', (50, 91))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (63, 91))	('leukemia', 'Phenotype', 'HP:0001909', (83, 91))	('acute lymphoblastic leukemia', 'Disease', (63, 91))	('deletion', 'Var', (13, 21))	('ALL', 'Phenotype', 'HP:0006721', (93, 96))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (63, 91))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (69, 91))
41826	19996307	Here, we introduce the structure and function of the EBF family of transcription factors, and will focus on the emerging evidence of their genetic and epigenetic inactivation in cancers as well as discuss the potential mechanisms by which these factors function in tumor suppression.	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', (265, 270))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('epigenetic inactivation', 'Var', (151, 174))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('transcription', 'biological_process', 'GO:0006351', ('67', '80'))	('function', 'Reg', (253, 261))	('EBF', 'Gene', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (265, 270))
41839	19996307	Mutation of any of the four Zn2+-binding residues to alanine abolishes the DNA-binding activity of EBF1.	('DNA-binding', 'molecular_function', 'GO:0003677', ('75', '86'))	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('Zn2+', 'Chemical', 'MESH:D015032', (28, 32))	('abolishes', 'NegReg', (61, 70))	('Mutation', 'Var', (0, 8))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('DNA-binding', 'Interaction', (75, 86))	('alanine', 'Chemical', 'MESH:D000409', (53, 60))	('EBF1', 'Gene', (99, 103))
41868	19996307	Interestingly, siRNA-mediated knockdown of the Mi-2beta subunit of the Mi-2/NuRD repression/remodeling complex appears to potentiate EBF1- and Pax5-mediated gene activation, suggesting the involvement of the Mi-2/NuRD silencing complex in EBF1-mediated gene repression (Fig.	('potentiate', 'PosReg', (122, 132))	('Mi-2beta', 'Gene', (47, 55))	('knockdown', 'Var', (30, 39))	('Mi-2beta', 'Gene', '1108', (47, 55))	('activation', 'PosReg', (162, 172))	('EBF1-', 'Gene', (133, 138))
41872	19996307	Targeted inactivation of Ebf2 results in reduced bone mass.	('reduced', 'NegReg', (41, 48))	('reduced bone mass', 'Phenotype', 'HP:0004349', (41, 58))	('Ebf2', 'Gene', '64641', (25, 29))	('Ebf2', 'Gene', (25, 29))	('inactivation', 'Var', (9, 21))	('bone mass', 'CPA', (49, 58))
41876	19996307	Ectopic expression of Ebf1 in the preadipocyte cell line 3T3-L1 fibroblasts or mouse embryonic fibroblasts induces adipogenesis.	('mouse', 'Species', '10090', (79, 84))	('3T3-L1', 'CellLine', 'CVCL:0123', (57, 63))	('Ebf1', 'Gene', (22, 26))	('adipogenesis', 'biological_process', 'GO:0060612', ('115', '127'))	('adipogenesis', 'MPA', (115, 127))	('Ectopic expression', 'Var', (0, 18))	('induces', 'Reg', (107, 114))	('adipogenesis', 'biological_process', 'GO:0045444', ('115', '127'))
41880	19996307	For example, mouse EBF2 appears to act earlier than EBF1 or EBF3, and in Xenopus, EBF3 promotes differentiation of specific neuronal subtypes.	('mouse', 'Species', '10090', (13, 18))	('differentiation', 'CPA', (96, 111))	('Xenopus', 'Species', '8355', (73, 80))	('EBF3', 'Var', (82, 86))	('promotes', 'PosReg', (87, 95))
41883	19996307	EBF2 is expressed in the embryonic CNS, and targeted inactivation of Ebf2 has revealed roles for EBF2 in peripheral nerve morphogenesis, migration of hormone-producing neurons, and projection of olfactory neurons.	('EBF2', 'Gene', (97, 101))	('Ebf2', 'Gene', '64641', (69, 73))	('morphogenesis', 'biological_process', 'GO:0009653', ('122', '135'))	('projection of olfactory neurons', 'CPA', (181, 212))	('migration', 'CPA', (137, 146))	('roles', 'Reg', (87, 92))	('rat', 'Species', '10116', (140, 143))	('Ebf2', 'Gene', (69, 73))	('inactivation', 'Var', (53, 65))	('peripheral nerve morphogenesis', 'CPA', (105, 135))
41891	19996307	One consequence of the 10q loss is the deletion of the Pten locus in 10q22, a well-established genetic defect during gliomagenesis.	('glioma', 'Disease', (117, 123))	('genetic defect', 'Disease', (95, 109))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('deletion', 'Var', (39, 47))	('genetic defect', 'Disease', 'MESH:D030342', (95, 109))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('Pten', 'Gene', '5728', (55, 59))	('Pten', 'Gene', (55, 59))	('loss', 'NegReg', (27, 31))
41895	19996307	However, hypermethylation of the Pten promoter occurs mostly in low-grade glioma and secondary GBMs.	('Pten', 'Gene', '5728', (33, 37))	('GBM', 'Phenotype', 'HP:0012174', (95, 98))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('secondary GBMs', 'Disease', (85, 99))	('occurs', 'Reg', (47, 53))	('Pten', 'Gene', (33, 37))	('hypermethylation', 'Var', (9, 25))	('glioma', 'Disease', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
41898	19996307	A genome-wide screen using integrated genomic and epigenetic analyses revealed that the EBF3 locus at chromosome 10q26.3 is biallelically altered by methylation or deletion in the majority of high-grade brain tumors.	('brain tumors', 'Disease', (203, 215))	('methylation', 'biological_process', 'GO:0032259', ('149', '160'))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('rat', 'Species', '10116', (32, 35))	('altered', 'Reg', (138, 145))	('EBF3', 'Gene', (88, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('102', '112'))	('methylation', 'Var', (149, 160))	('brain tumors', 'Disease', 'MESH:D001932', (203, 215))	('brain tumors', 'Phenotype', 'HP:0030692', (203, 215))	('deletion', 'Var', (164, 172))	('brain tumor', 'Phenotype', 'HP:0030692', (203, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
41899	19996307	The EBF3 gene was found to be inactivated in 50% of grade II, 83% of grade III, and 90% of grade IV brain tumors by deletion, or promoter hypermethylation of the EBF3 locus.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('EBF3', 'Gene', (162, 166))	('promoter hypermethylation', 'Var', (129, 154))	('brain tumors', 'Phenotype', 'HP:0030692', (100, 112))	('deletion', 'Var', (116, 124))	('EBF3 gene', 'Gene', (4, 13))	('brain tumors', 'Disease', 'MESH:D001932', (100, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('brain tumors', 'Disease', (100, 112))	('inactivated', 'NegReg', (30, 41))	('brain tumor', 'Phenotype', 'HP:0030692', (100, 111))
41905	19996307	Since Pten inactivation alone is not sufficient to cause gliomas, and the loss of Pten is almost invariably associated with the loss of EBF3, it is tempting to speculate that genomic deletion of EBF3 might facilitate gliomagenesis when Pten is also lost.	('Pten', 'Gene', '5728', (236, 240))	('Pten', 'Gene', (236, 240))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('glioma', 'Disease', (217, 223))	('EBF3', 'Gene', (195, 199))	('glioma', 'Disease', 'MESH:D005910', (217, 223))	('glioma', 'Disease', (57, 63))	('Pten', 'Gene', (82, 86))	('Pten', 'Gene', '5728', (82, 86))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('loss', 'NegReg', (128, 132))	('glioma', 'Phenotype', 'HP:0009733', (217, 223))	('loss', 'Var', (74, 78))	('gliomas', 'Disease', (57, 64))	('EBF3', 'Gene', (136, 140))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('facilitate', 'PosReg', (206, 216))	('Pten', 'Gene', '5728', (6, 10))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('Pten', 'Gene', (6, 10))
41909	19996307	Remarkably, large-scale sequencing of all coding exons in tumors and their normal tissue counterparts has detected tumor-specific mutations of the EBF3 gene in GBM and pancreatic cancer.	('EBF3', 'Gene', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('pancreatic cancer', 'Disease', 'MESH:D010190', (168, 185))	('GBM', 'Phenotype', 'HP:0012174', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('pancreatic cancer', 'Disease', (168, 185))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Disease', (115, 120))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('GBM', 'Disease', (160, 163))	('mutations', 'Var', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (168, 185))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
41910	19996307	In a primary tumor of a 32-year-old male GBM patient, a missense mutation was found.	('tumor', 'Disease', (13, 18))	('GBM', 'Phenotype', 'HP:0012174', (41, 44))	('missense mutation', 'Var', (56, 73))	('patient', 'Species', '9606', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
41911	19996307	It results in the change of amino acid residue from W to C at position 265 (W265C) of EBF3.	('W265C', 'Var', (76, 81))	('EBF3', 'Gene', (86, 90))	('amino acid residue', 'MPA', (28, 46))	('change', 'Reg', (18, 24))	('W265C', 'SUBSTITUTION', 'None', (76, 81))
41912	19996307	A missense mutation of EBF3 (R243W) was also discovered in a pancreatic ductal adenocarcinoma that metastasized to the lung from a 59-year-old male patient.	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('R243W', 'Mutation', 'p.R243W', (29, 34))	('pancreatic ductal adenocarcinoma', 'Disease', (61, 93))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (61, 93))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (61, 93))	('EBF3', 'Gene', (23, 27))	('patient', 'Species', '9606', (148, 155))	('R243W', 'Var', (29, 34))
41917	19996307	Epigenetic silencing of the EBF3 locus occurs in colon, liver, and head and neck squamous cell carcinoma.	('occurs', 'Reg', (39, 45))	('colon', 'Disease', 'MESH:D015179', (49, 54))	('EBF3', 'Gene', (28, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('neck squamous cell carcinoma', 'Disease', (76, 104))	('colon', 'Disease', (49, 54))	('Epigenetic silencing', 'Var', (0, 20))	('liver', 'Disease', (56, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('neck', 'cellular_component', 'GO:0044326', ('76', '80'))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (76, 104))
41930	19996307	For example, the B-progenitor leukemias contain several well-known genomic translocations such as t(9;22)[BCR-ABL1], t(1;19)[TCF3-PBX1], t(12;21)[ETV6-RUNX1], and the rearrangements of MLL (myeloid/lymphoid or mixed-lineage leukemia).	('RUNX1', 'Gene', '861', (151, 156))	('TCF3', 'Gene', '6929', (125, 129))	('leukemia', 'Disease', (224, 232))	('PBX1', 'Gene', (130, 134))	('MLL', 'Gene', (185, 188))	('leukemia', 'Disease', 'MESH:D007938', (224, 232))	('MLL', 'Gene', '4297', (185, 188))	('ETV6', 'Gene', '2120', (146, 150))	('PBX1', 'Gene', '5087', (130, 134))	('myeloid/lymphoid', 'Disease', (190, 206))	('leukemias', 'Disease', 'MESH:D007938', (30, 39))	('t(9;22)[', 'Var', (98, 106))	('myeloid/lymphoid', 'Disease', 'MESH:D023981', (190, 206))	('leukemias', 'Phenotype', 'HP:0001909', (30, 39))	('leukemia', 'Phenotype', 'HP:0001909', (30, 38))	('ETV6', 'Gene', (146, 150))	('leukemias', 'Disease', (30, 39))	('leukemia', 'Disease', (30, 38))	('leukemia', 'Disease', 'MESH:D007938', (30, 38))	('leukemia', 'Phenotype', 'HP:0001909', (224, 232))	('TCF3', 'Gene', (125, 129))	('rearrangements', 'Var', (167, 181))	('RUNX1', 'Gene', (151, 156))
41931	19996307	Translocation or deletion of Pax5 in B-cell precursor ALL results in reduced or abolished expression of EBF1 and other factors involved in B-lymphocyte development, thereby preventing B-cell maturation.	('ALL', 'Phenotype', 'HP:0006721', (54, 57))	('cell maturation', 'biological_process', 'GO:0048469', ('186', '201'))	('reduced', 'NegReg', (69, 76))	('B-cell maturation', 'CPA', (184, 201))	('lymphocyte development', 'biological_process', 'GO:0030098', ('141', '163'))	('preventing', 'NegReg', (173, 183))	('abolished', 'NegReg', (80, 89))	('expression', 'MPA', (90, 100))	('deletion', 'Var', (17, 25))	('rat', 'Species', '10116', (195, 198))	('EBF1', 'Gene', (104, 108))	('Pax5', 'Gene', (29, 33))
41932	19996307	Deletions of other key genes in the B-cell maturation pathway, such as TCF3 (encoding the human E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS), are also frequent events in ALL.	('IKZF1', 'Gene', (114, 119))	('IKZF3', 'Gene', '22806', (133, 138))	('ALL', 'Phenotype', 'HP:0006721', (177, 180))	('AIOLOS', 'Gene', (140, 146))	('IKAROS', 'Gene', '10320', (121, 127))	('AIOLOS', 'Gene', '22806', (140, 146))	('EBF1', 'Gene', (102, 106))	('rat', 'Species', '10116', (47, 50))	('human', 'Species', '9606', (90, 95))	('LEF1', 'Gene', '51176', (108, 112))	('cell maturation', 'biological_process', 'GO:0048469', ('38', '53'))	('IKZF1', 'Gene', '10320', (114, 119))	('IKZF3', 'Gene', (133, 138))	('TCF3', 'Gene', '6929', (71, 75))	('IKAROS', 'Gene', (121, 127))	('LEF1', 'Gene', (108, 112))	('Deletions', 'Var', (0, 9))	('TCF3', 'Gene', (71, 75))
41933	19996307	It is striking that 82% of the patients with BCR-ABL1-like disease harbor deletions in these genes.	('patients', 'Species', '9606', (31, 39))	('deletions', 'Var', (74, 83))	('BCR-ABL1-like disease', 'Disease', (45, 66))
41934	19996307	It was shown previously that Ebf1+/- heterozygous mice have a 50% reduction of fraction B (now termed pro-B) cells.	('Ebf1+/-', 'Var', (29, 36))	('fraction B', 'MPA', (79, 89))	('mice', 'Species', '10090', (50, 54))	('reduction', 'NegReg', (66, 75))
41935	19996307	Since the expression of EBF1 mRNA was detected in ALL cells with monoallelic deletion, EBF1 might be a haploinsufficient tumor suppressor.	('haploinsufficient tumor', 'Disease', (103, 126))	('detected', 'Reg', (38, 46))	('ALL', 'Phenotype', 'HP:0006721', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('121', '137'))	('expression', 'MPA', (10, 20))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (103, 126))	('monoallelic deletion', 'Var', (65, 85))	('EBF1', 'Gene', (24, 28))	('tumor suppressor', 'biological_process', 'GO:0051726', ('121', '137'))
41938	19996307	Taken together, these recent findings demonstrate that genomic lesions of the EBF1 gene contribute to the pathogenesis, drug resistance and disease relapse of ALL.	('drug resistance', 'biological_process', 'GO:0042493', ('120', '135'))	('contribute', 'Reg', (88, 98))	('drug resistance', 'CPA', (120, 135))	('drug resistance', 'Phenotype', 'HP:0020174', (120, 135))	('EBF1', 'Gene', (78, 82))	('disease relapse', 'CPA', (140, 155))	('genomic lesions', 'Var', (55, 70))	('ALL', 'Phenotype', 'HP:0006721', (159, 162))	('drug resistance', 'biological_process', 'GO:0009315', ('120', '135'))	('pathogenesis', 'biological_process', 'GO:0009405', ('106', '118'))	('rat', 'Species', '10116', (45, 48))
41939	19996307	In mouse B-cell lymphomas, retroviral insertions occur frequently in two genetic loci: Evi3 (ecotropic viral integration site 3 encoding Evi3, also known as EHZF, Zfp521 or ZNF521), and Ebfaz (encoding EBF-associated zinc finger protein, EBFAZ, also known as OAZ, Zfp423, or ZNF423).	('ZNF423', 'Gene', '94187', (275, 281))	('OAZ', 'Gene', (259, 262))	('EHZF', 'Gene', (157, 161))	('ZNF521', 'Gene', (173, 179))	('lymphomas', 'Disease', (16, 25))	('ZNF521', 'Gene', '225207', (173, 179))	('Evi3', 'Gene', (87, 91))	('retroviral', 'Var', (27, 37))	('EHZF', 'Gene', '25925', (157, 161))	('Zfp521', 'Gene', '225207', (163, 169))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (9, 25))	('lymphoma', 'Phenotype', 'HP:0002665', (16, 24))	('EBFAZ', 'Gene', '94187', (238, 243))	('EBFAZ', 'Gene', (238, 243))	('rat', 'Species', '10116', (114, 117))	('ZNF423', 'Gene', (275, 281))	('mouse', 'Species', '10090', (3, 8))	('protein', 'cellular_component', 'GO:0003675', ('229', '236'))	('Zfp521', 'Gene', (163, 169))	('OAZ', 'Gene', '18245', (259, 262))	('lymphomas', 'Disease', 'MESH:D008223', (16, 25))	('Ebfaz', 'Gene', (186, 191))	('lymphomas', 'Phenotype', 'HP:0002665', (16, 25))
41944	19996307	Interestingly, Viral integration at the Evi3 or Ebfaz sites appears mutually exclusive, suggesting that both Zfp521 and Zfp423 act in the same pathway during the development of B cell tumors.	('Zfp521', 'Gene', (109, 115))	('B cell tumors', 'Disease', (177, 190))	('Zfp423', 'Var', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('rat', 'Species', '10116', (26, 29))	('Zfp521', 'Gene', '225207', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('B cell tumors', 'Disease', 'MESH:D016393', (177, 190))	('act', 'Reg', (127, 130))
41945	19996307	Studies suggest that overexpression of Zfp423 and Zfp521 in B-cell leukemias and lymphomas represses EBF1 target genes that suppress leukemogenesis in B cells.	('Zfp423', 'Var', (39, 45))	('suppress', 'NegReg', (124, 132))	('leukemogenesis', 'Disease', (133, 147))	('Zfp521', 'Gene', '225207', (50, 56))	('lymphomas', 'Phenotype', 'HP:0002665', (81, 90))	('leukemias', 'Phenotype', 'HP:0001909', (67, 76))	('lymphoma', 'Phenotype', 'HP:0002665', (81, 89))	('leukemias', 'Disease', (67, 76))	('overexpression', 'PosReg', (21, 35))	('lymphomas', 'Disease', (81, 90))	('lymphomas', 'Disease', 'MESH:D008223', (81, 90))	('Zfp521', 'Gene', (50, 56))	('leukemia', 'Phenotype', 'HP:0001909', (67, 75))	('represses', 'NegReg', (91, 100))	('leukemias', 'Disease', 'MESH:D007938', (67, 76))	('EBF1 target genes', 'Gene', (101, 118))
41947	19996307	Similarly, its expression is particularly high in leukemias with rearrangements of the MLL gene.	('high', 'Reg', (42, 46))	('leukemias', 'Phenotype', 'HP:0001909', (50, 59))	('leukemias', 'Disease', (50, 59))	('rearrangements', 'Var', (65, 79))	('MLL', 'Gene', '4297', (87, 90))	('expression', 'MPA', (15, 25))	('leukemias', 'Disease', 'MESH:D007938', (50, 59))	('MLL', 'Gene', (87, 90))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))
41950	19996307	At the molecular level, Zfp521 and Zfp423 are highly similar to each other, each containing 30 Kruppel-type zinc fingers.	('Zfp521', 'Gene', '225207', (24, 30))	('Zfp521', 'Gene', (24, 30))	('Zfp423', 'Var', (35, 41))
41954	19996307	This evidence, along with the finding that siRNA-mediated down-regulation of Mi-2beta subunit of the Mi-2/NuRD complex enhances EBF1-mediated transcriptional activation, suggests that Zfp521 and Zfp423 might recruit this corepressor complex to suppress EBF1 target genes (Fig.	('Zfp521', 'Gene', '225207', (184, 190))	('regulation', 'biological_process', 'GO:0065007', ('63', '73'))	('NuRD complex', 'cellular_component', 'GO:0016581', ('106', '118'))	('Zfp423', 'Var', (195, 201))	('Zfp521', 'Gene', (184, 190))	('EBF1-mediated', 'Gene', (128, 141))	('Mi-2beta', 'Gene', (77, 85))	('enhances', 'PosReg', (119, 127))	('EBF1', 'Gene', (253, 257))	('Mi-2beta', 'Gene', '1108', (77, 85))	('down-regulation', 'NegReg', (58, 73))	('suppress', 'NegReg', (244, 252))	('transcriptional activation', 'MPA', (142, 168))
41958	19996307	Overexpression of ID proteins can induce malignant transformation and was indeed observed in several types of cancer including colon, prostate, and lung cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('induce', 'Reg', (34, 40))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', (153, 159))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('colon', 'Disease', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('observed', 'Reg', (81, 89))	('prostate', 'Disease', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', (148, 159))	('Overexpression', 'Var', (0, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('colon', 'Disease', 'MESH:D015179', (127, 132))	('malignant transformation', 'CPA', (41, 65))
41960	19996307	Additionally, genomic loss of the EBF1 locus or other EBF genes appears to occur in solid malignancies.	('malignancies', 'Disease', (90, 102))	('genomic loss', 'Var', (14, 26))	('EBF', 'Gene', (54, 57))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('EBF1', 'Gene', (34, 38))
41963	19996307	detected a cancer-specific somatic missense mutation in a primary ductal adenocarcinoma of the pancreas in a 60-year-old female patient.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('missense mutation', 'Var', (35, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('cancer', 'Disease', (11, 17))	('ductal adenocarcinoma of the pancreas', 'Disease', (66, 103))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('patient', 'Species', '9606', (128, 135))	('ductal adenocarcinoma of the pancreas', 'Disease', 'MESH:D021441', (66, 103))
41964	19996307	This mutation causes the amino acid substitution of arginine for glutamine at position 242, which lies within the DBD of EBF1 (R242Q, Fig.	('DBD', 'Chemical', '-', (114, 117))	('arginine', 'MPA', (52, 60))	('causes', 'Reg', (14, 20))	('R242Q', 'Mutation', 'rs768597902', (127, 132))	('arginine for glutamine at position 242', 'Mutation', 'rs768597902', (52, 90))	('R242Q', 'Var', (127, 132))
41965	19996307	It is noteworthy that the R242Q mutation of EBF1 and the R243W mutation of EBF3 affect two consecutive arginine residues within the well-conserved DBD of the EBF family.	('affect', 'Reg', (80, 86))	('R243W', 'Var', (57, 62))	('EBF1', 'Gene', (44, 48))	('R243W', 'Mutation', 'p.R243W', (57, 62))	('R242Q', 'Var', (26, 31))	('R242Q', 'Mutation', 'rs768597902', (26, 31))	('DBD', 'Chemical', '-', (147, 150))	('arginine', 'Chemical', 'MESH:D001120', (103, 111))	('EBF3', 'Gene', (75, 79))
41966	19996307	Thus, these mutations might impair the normal functions of EBFs.	('EBFs', 'Chemical', '-', (59, 63))	('normal functions', 'MPA', (39, 55))	('mutations', 'Var', (12, 21))	('impair', 'NegReg', (28, 34))
41971	19996307	Inactivation of EBF genes blocks normal development pathways, which results in the accumulation and expansion of undifferentiated progenitor cells, leading to tumorigenesis.	('blocks', 'NegReg', (26, 32))	('expansion', 'CPA', (100, 109))	('normal development', 'CPA', (33, 51))	('leading to', 'Reg', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('results in', 'Reg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('Inactivation', 'Var', (0, 12))	('EBF genes', 'Gene', (16, 25))
41972	19996307	Therefore, EBF inactivation due to genomic deletion, epigenetic silencing, or somatic point mutations might have causal roles in the tumorigenesis of several types of cancer including leukemia, GBM, and pancreatic cancer.	('cancer', 'Disease', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('GBM', 'Disease', (194, 197))	('leukemia', 'Disease', 'MESH:D007938', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('leukemia', 'Disease', (184, 192))	('cancer', 'Disease', (214, 220))	('pancreatic cancer', 'Disease', 'MESH:D010190', (203, 220))	('roles', 'Reg', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('epigenetic silencing', 'Var', (53, 73))	('pancreatic cancer', 'Disease', (203, 220))	('GBM', 'Phenotype', 'HP:0012174', (194, 197))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('genomic deletion', 'Var', (35, 51))	('tumor', 'Disease', (133, 138))	('inactivation', 'NegReg', (15, 27))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('EBF', 'Gene', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (203, 220))	('leukemia', 'Phenotype', 'HP:0001909', (184, 192))
41977	19996307	Tissue-specific inactivation of the Ebf genes in mice will allow the establishment of mouse tumor models to probe specific roles of EBFs in the development of different types of cancer.	('Ebf', 'Gene', '13591', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('mouse', 'Species', '10090', (86, 91))	('EBFs', 'Chemical', '-', (132, 136))	('mice', 'Species', '10090', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('inactivation', 'Var', (16, 28))	('cancer', 'Disease', (178, 184))	('Ebf', 'Gene', (36, 39))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Disease', (92, 97))
41981	19996307	Such studies will establish molecular basis for EBF proteins in tumor suppression and will provide clues for designing rational therapy for patients with specific types of cancer containing abnormalities in the EBF pathways.	('tumor', 'Disease', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('rat', 'Species', '10116', (119, 122))	('abnormalities', 'Var', (190, 203))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('EBF pathways', 'Pathway', (211, 223))	('patients', 'Species', '9606', (140, 148))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('cancer', 'Disease', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
42027	28602029	The number of infiltrating CD8+ lymphocytes were significantly higher in HLA-DR positive PDA tissues than in HLA-DR negative PDA tissues (HLA-DR negative: mean n = 226 +- 51 vs. HLA-DR positive: mean n = 361 +- 39, P = 0.042; Fig.	('PDA', 'Phenotype', 'HP:0006725', (89, 92))	('PDA', 'Chemical', '-', (125, 128))	('HLA-DR', 'Gene', (73, 79))	('CD8', 'Gene', (27, 30))	('PDA', 'Disease', (89, 92))	('CD8', 'Gene', '925', (27, 30))	('PDA', 'Chemical', '-', (89, 92))	('PDA', 'Phenotype', 'HP:0006725', (125, 128))	('higher', 'PosReg', (63, 69))	('positive', 'Var', (80, 88))
42048	28602029	When patients were divided into four groups according to PD-L1 and HLA class I expression, negative PD-L1 expression and high HLA class I expression by PDA (n = 12) was associated with a significant better recurrence-free survival (P < 0.001; Fig.	('PDA', 'Chemical', '-', (152, 155))	('patients', 'Species', '9606', (5, 13))	('better', 'PosReg', (199, 205))	('PD-L1', 'Gene', '29126', (100, 105))	('expression', 'MPA', (106, 116))	('PD-L1', 'Gene', (57, 62))	('recurrence-free survival', 'CPA', (206, 230))	('PD-L1', 'Gene', '29126', (57, 62))	('negative', 'NegReg', (91, 99))	('PDA', 'Phenotype', 'HP:0006725', (152, 155))	('high', 'Var', (121, 125))	('PD-L1', 'Gene', (100, 105))
42069	28602029	In line with the findings, correlation between CD4+ and CD8+ T-cell infiltration was detected in PDA patients, but not that between CD8+ T-cell infiltration and Foxp3+ Treg, suggesting the effector CD4+ T cell may infiltrate into the TME of PDA associated with CD8+ T-cell infiltration, irrespective of Treg infiltration.	('patients', 'Species', '9606', (101, 109))	('PDA', 'Chemical', '-', (97, 100))	('PDA', 'Phenotype', 'HP:0006725', (241, 244))	('Foxp3', 'Gene', '50943', (161, 166))	('CD8', 'Gene', (261, 264))	('PDA', 'Disease', (241, 244))	('CD8', 'Gene', '925', (261, 264))	('PDA', 'Phenotype', 'HP:0006725', (97, 100))	('CD8', 'Gene', (56, 59))	('PDA', 'Chemical', '-', (241, 244))	('CD8', 'Gene', (132, 135))	('CD8', 'Gene', '925', (56, 59))	('CD4+ T', 'Var', (198, 204))	('CD8', 'Gene', '925', (132, 135))	('infiltrate', 'CPA', (214, 224))	('Foxp3', 'Gene', (161, 166))
42083	28602029	Therefore, it is possible that the IFN-gamma-STAT1 axis induced by CD4+ or CD8+ T cells, or macrophage-producing IL-6-STAT3 axis, might serve as the primary mechanism of PD-L1 expression by PDA cells and Tregs infiltration into the TME 29, 30.	('PD-L1', 'Gene', (170, 175))	('IFN-gamma', 'Gene', '3458', (35, 44))	('STAT1', 'Gene', (45, 50))	('IFN-gamma', 'Gene', (35, 44))	('PDA', 'Chemical', '-', (190, 193))	('IL-6', 'Gene', (113, 117))	('CD8', 'Gene', '925', (75, 78))	('PD-L1', 'Gene', '29126', (170, 175))	('STAT3', 'Gene', '6774', (118, 123))	('IL-6', 'Gene', '3569', (113, 117))	('STAT1', 'Gene', '6772', (45, 50))	('STAT3', 'Gene', (118, 123))	('IL-6', 'molecular_function', 'GO:0005138', ('113', '117'))	('PDA', 'Phenotype', 'HP:0006725', (190, 193))	('CD8', 'Gene', (75, 78))	('CD4+', 'Var', (67, 71))
42124	26871953	Decreased TUSC3 Promotes Pancreatic Cancer Proliferation, Invasion and Metastasis Pancreatic cancer is an aggressive disease with dismal prognosis.	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (25, 42))	('Decreased', 'Var', (0, 9))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('aggressive disease', 'Disease', 'MESH:D001523', (106, 124))	('TUSC3', 'Gene', (10, 15))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (82, 99))	('Metastasis', 'CPA', (71, 81))	('aggressive disease', 'Disease', (106, 124))	('Pancreatic Cancer', 'Disease', (25, 42))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (25, 42))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (82, 99))	('TUSC3', 'Gene', '7991', (10, 15))	('Pancreatic cancer', 'Disease', (82, 99))	('Promotes', 'PosReg', (16, 24))
42148	26871953	Further study showed its low expression results from TUSC3 promoter hypermethylation and the methylation status of the TUSC3 promoter has a significant and independent influence on progression free and overall survival for ovarian cancer patients.	('TUSC3', 'Gene', (119, 124))	('progression', 'Disease', (181, 192))	('patients', 'Species', '9606', (238, 246))	('ovarian cancer', 'Phenotype', 'HP:0100615', (223, 237))	('ovarian cancer', 'Disease', 'MESH:D010051', (223, 237))	('low', 'NegReg', (25, 28))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('influence', 'Reg', (168, 177))	('TUSC3', 'Gene', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('hypermethylation', 'Var', (68, 84))	('expression', 'MPA', (29, 39))	('overall survival', 'CPA', (202, 218))	('ovarian cancer', 'Disease', (223, 237))	('methylation', 'Var', (93, 104))
42149	26871953	As early as in 2005, homozygous and heterozygous deletion of TUSC3 gene was discovered in pancreatic cancer cell lines and specimens with genomic array-based studies.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('men', 'Species', '9606', (128, 131))	('pancreatic cancer', 'Disease', (90, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('deletion', 'Var', (49, 57))	('TUSC3', 'Gene', (61, 66))
42204	26871953	The tumor stage is defined as T1N0M0 in 8 patients (6.84%), T2N0M0 in 20 patients (17.09%), T3N0M0 in 24 patients (20.51%), T1N1M0 in 9 patients (7.69%), T2N1M0 in 18 patients (15.38%), T3N1M0 in 21 patients (17.95%), T4N0M0 in 2 patients (1.71%), T4N1M0 in 4 patients (3.42%), T2-3N0M1 in 5 patients (4.27%) and T1-4N1M1 in 6 patients (5.13%).	('tumor', 'Disease', (4, 9))	('N', 'Chemical', 'MESH:D009584', (188, 189))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('N', 'Chemical', 'MESH:D009584', (220, 221))	('T2N1M0', 'Var', (154, 160))	('N', 'Chemical', 'MESH:D009584', (282, 283))	('patients', 'Species', '9606', (292, 300))	('T3N0M0', 'Var', (92, 98))	('N', 'Chemical', 'MESH:D009584', (156, 157))	('N', 'Chemical', 'MESH:D009584', (250, 251))	('T3N1M0', 'Var', (186, 192))	('T4N1M0', 'Var', (248, 254))	('patients', 'Species', '9606', (260, 268))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('T2N0M0', 'Var', (60, 66))	('patients', 'Species', '9606', (105, 113))	('T1N1M0', 'Var', (124, 130))	('N', 'Chemical', 'MESH:D009584', (317, 318))	('patients', 'Species', '9606', (42, 50))	('patients', 'Species', '9606', (73, 81))	('patients', 'Species', '9606', (327, 335))	('N', 'Chemical', 'MESH:D009584', (32, 33))	('T4N0M0', 'Var', (218, 224))	('patients', 'Species', '9606', (167, 175))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('patients', 'Species', '9606', (230, 238))	('patients', 'Species', '9606', (136, 144))	('T1-4N1M1', 'Var', (313, 321))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('patients', 'Species', '9606', (199, 207))	('T2-3N0M1', 'Var', (278, 286))	('N', 'Chemical', 'MESH:D009584', (94, 95))
42214	26871953	Univariate analysis identified high tumor stage (stage I+II vs III vs IV P<0.001), high serum CA199 level (CA199<300IU/ml vs CA199>=00IU/ml, p = 0.034), no administration of chemotherapy (chemotherapy vs no treatment, p = 0.025), and decreased TUSC3 expression level (p = 0.015) as poor prognostic factors for RFS in this study cohort.	('CA199', 'Chemical', '-', (125, 130))	('decreased', 'NegReg', (234, 243))	('CA199', 'Chemical', '-', (94, 99))	('CA199>=00IU/ml', 'Var', (125, 139))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('RFS', 'Disease', (310, 313))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('CA199', 'Chemical', '-', (107, 112))	('TUSC3 expression level', 'MPA', (244, 266))	('tumor', 'Disease', (36, 41))	('serum CA199 level', 'MPA', (88, 105))	('men', 'Species', '9606', (212, 215))
42223	26871953	In this pair of cell model, it was demonstrated that TUSC3 expression of AsPC-1 mu is higher than that of AsPC-1 (Fig 4A), suggesting that TUSC3 is regulated by NF-kappaB activity.	('AsPC-1', 'CellLine', 'CVCL:0152', (73, 79))	('NF-kappaB', 'Gene', '4790', (161, 170))	('NF-kappaB', 'Gene', (161, 170))	('expression', 'MPA', (59, 69))	('higher', 'PosReg', (86, 92))	('AsPC-1', 'CellLine', 'CVCL:0152', (106, 112))	('AsPC-1', 'Var', (73, 79))
42228	26871953	It was demonstrated previously that L3.6pl exhibits higher NF-kappaB activity than Colo357.	('L3.6pl', 'Var', (36, 42))	('NF-kappaB', 'Gene', (59, 68))	('higher', 'PosReg', (52, 58))	('NF-kappaB', 'Gene', '4790', (59, 68))
42229	26871953	And interestingly, TUSC3 expression is higher in Colo357 than in L3.6pl both at mRNA and protein level (Fig 4C).	('higher', 'PosReg', (39, 45))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('expression', 'MPA', (25, 35))	('TUSC3', 'Gene', (19, 24))	('Colo357', 'Var', (49, 56))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
42231	26871953	To study the tumor suppressive function of TUSC3, shRNAs were designed to knockdown the expression of TUSC3 in in vitro pancreatic cancer model.	('N', 'Chemical', 'MESH:D009584', (53, 54))	('tumor', 'Disease', (13, 18))	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('knockdown', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('TUSC3', 'Gene', (102, 107))	('pancreatic cancer', 'Disease', (120, 137))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
42233	26871953	Both mRNA and protein levels were detected to confirm the efficiency of silencing (Fig 5A and 5B).	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('silencing', 'Var', (72, 81))	('mRNA and', 'MPA', (5, 13))
42238	26871953	Then, Matrigel based assay was used to analyze the effects of TUSC3 knockdown on migration and extracellular matrix (ECM) invasion of pancreatic cancer cells.	('pancreatic cancer', 'Disease', 'MESH:D010190', (134, 151))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('95', '115'))	('TUSC3', 'Gene', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (134, 151))	('knockdown', 'Var', (68, 77))	('migration', 'CPA', (81, 90))	('pancreatic cancer', 'Disease', (134, 151))
42241	26871953	Five weeks after injection of Colo357 shRNA2 and Colo357 shRNA3 cells, all of the mice became sick and were sacrificed.	('mice', 'Species', '10090', (82, 86))	('Colo357', 'Var', (30, 37))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('Colo357', 'Var', (49, 56))
42243	26871953	Then the liver metastases were weighted and compared with t-text, Colo357 shRNA2 vs Colo357 Scramble (p = 0.0444), Colo357 shRNA3 vs Colo357 Scramble (p = 0.0443).	('metastases', 'Disease', (15, 25))	('N', 'Chemical', 'MESH:D009584', (77, 78))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('Colo357 shRNA3', 'Var', (115, 129))	('metastases', 'Disease', 'MESH:D009362', (15, 25))
42245	26871953	Compared with samples from mice injected with TUSC3 scramble cell lines, those from TUSC3 shRNA2 and TUSC3 shRNA3 show decreased expression levels of TUSC3 both with IHC (S1 Fig) and at mRNA level (S2 Fig).	('decreased', 'NegReg', (119, 128))	('mice', 'Species', '10090', (27, 31))	('N', 'Chemical', 'MESH:D009584', (188, 189))	('N', 'Chemical', 'MESH:D009584', (93, 94))	('expression levels', 'MPA', (129, 146))	('TUSC3', 'Gene', (150, 155))	('TUSC3 shRNA3', 'Var', (101, 113))	('N', 'Chemical', 'MESH:D009584', (110, 111))
42256	26871953	Previously, TUSC3 down-regulation has been demonstrated due to homozygous and heterozygous deletion in prostate cancer, promoter hypermethylation in ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('regulation', 'biological_process', 'GO:0065007', ('23', '33'))	('deletion', 'Var', (91, 99))	('ovarian cancer', 'Disease', (149, 163))	('prostate cancer', 'Disease', 'MESH:D011471', (103, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (149, 163))	('TUSC3', 'Gene', (12, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (149, 163))	('down-regulation', 'NegReg', (18, 33))	('promoter', 'MPA', (120, 128))	('prostate cancer', 'Disease', (103, 118))
42259	26871953	For example, early study showed TUSC3 is not hypermethylated in colorectal carcinoma, however hypermethylation is the major mechanism for TUSC3 down-regulation in ovarian cancer and even carries a prognostic value.	('TUSC3', 'Gene', (138, 143))	('ovarian cancer', 'Disease', (163, 177))	('hypermethylation', 'Var', (94, 110))	('colorectal carcinoma', 'Disease', (64, 84))	('down-regulation', 'NegReg', (144, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (163, 177))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (64, 84))	('ovarian cancer', 'Disease', 'MESH:D010051', (163, 177))	('regulation', 'biological_process', 'GO:0065007', ('149', '159'))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
42263	26871953	Loss of TUSC3 can destabilize the rough ER system and induce inflation of the cisternae system and alters ER stress response signaling in prostate cancer and ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('prostate cancer', 'Disease', 'MESH:D011471', (138, 153))	('prostate cancer', 'Phenotype', 'HP:0012125', (138, 153))	('prostate cancer', 'Disease', (138, 153))	('alters', 'Reg', (99, 105))	('ER stress response signaling', 'MPA', (106, 134))	('rough ER system', 'MPA', (34, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (158, 172))	('ER stress response', 'biological_process', 'GO:0034976', ('106', '124'))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('destabilize', 'NegReg', (18, 29))	('Loss', 'Var', (0, 4))	('induce', 'Reg', (54, 60))	('rough ER', 'cellular_component', 'GO:0005791', ('34', '42'))	('inflation', 'MPA', (61, 70))	('ovarian cancer', 'Disease', (158, 172))	('TUSC3', 'Gene', (8, 13))
42267	26871953	Later on, it was discovered that TUSC3 mRNA down-regulation originates from hypermethylation of its promoter, and the methylation status has a prognostic value in ovarian cancer.	('regulation', 'biological_process', 'GO:0065007', ('49', '59'))	('ovarian cancer', 'Disease', (163, 177))	('hypermethylation', 'Var', (76, 92))	('down-regulation', 'NegReg', (44, 59))	('methylation', 'biological_process', 'GO:0032259', ('118', '129'))	('TUSC3', 'Gene', (33, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (163, 177))	('ovarian cancer', 'Disease', 'MESH:D010051', (163, 177))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
42282	25914189	Subsequently, we found that TPX2 siRNA effectively suppressed the proliferation of pancreatic cancer cells in culture, and the direct injection of TPX2 siRNA into subcutaneously implanted pancreatic cancer cells in nude mice revealed antiproliferative effects.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('pancreatic cancer', 'Disease', (83, 100))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (188, 205))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('suppressed', 'NegReg', (51, 61))	('TPX2', 'Var', (147, 151))	('nude mice', 'Species', '10090', (215, 224))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('antiproliferative effects', 'CPA', (234, 259))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))	('pancreatic cancer', 'Disease', (188, 205))	('pancreatic cancer', 'Disease', 'MESH:D010190', (188, 205))
42284	25914189	Among 56 angiogenesis-related factors examined using angiogenesis arrays, the average protein levels of insulin-like growth factor-binding protein-3 (IGFBP-3) were significantly higher in TPX2 siRNA-treated tumors than in the Control siRNA-treated tumors.	('insulin-like growth factor-binding protein-3', 'Gene', '3486', (104, 148))	('tumors', 'Disease', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Disease', (207, 213))	('protein levels', 'MPA', (86, 100))	('insulin-like growth factor-binding protein-3', 'Gene', (104, 148))	('angiogenesis', 'biological_process', 'GO:0001525', ('53', '65'))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('IGFBP-3', 'Gene', (150, 157))	('angiogenesis', 'biological_process', 'GO:0001525', ('9', '21'))	('IGFBP-3', 'Gene', '3486', (150, 157))	('TPX2', 'Var', (188, 192))	('higher', 'PosReg', (178, 184))	('insulin-like growth factor-binding protein', 'cellular_component', 'GO:0017052', ('104', '146'))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('insulin-like growth factor-binding', 'molecular_function', 'GO:0005520', ('104', '138'))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))
42285	25914189	Moreover, we demonstrated that CD34-positive microvessels were significantly reduced in tumors treated with TPX2 siRNA compared to tumors that treated with Control siRNA.	('CD34', 'Gene', '947', (31, 35))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('reduced', 'NegReg', (77, 84))	('TPX2 siRNA', 'Var', (108, 118))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('CD34', 'Gene', (31, 35))
42290	25914189	Although several chemotherapeutic regimens using molecular targeting drugs have shown some benefit for the prognosis of pancreatic cancer patients, the impact of these drugs remains unsatisfactory.	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('molecular targeting drugs', 'Var', (49, 74))	('patients', 'Species', '9606', (138, 146))	('pancreatic cancer', 'Disease', (120, 137))
42296	25914189	Aberrant expression of TPX2 leads to improper spindle assembly and chromosomal instability, and these processes might be partly responsible for carcinogenesis.	('Aberrant expression', 'Var', (0, 19))	('chromosomal instability', 'CPA', (67, 90))	('spindle assembly', 'biological_process', 'GO:0051225', ('46', '62'))	('leads to', 'Reg', (28, 36))	('carcinogenesis', 'Disease', 'MESH:D063646', (144, 158))	('TPX2', 'Gene', (23, 27))	('carcinogenesis', 'Disease', (144, 158))	('spindle', 'cellular_component', 'GO:0005819', ('46', '53'))	('improper spindle assembly', 'CPA', (37, 62))	('chromosomal instability', 'Phenotype', 'HP:0040012', (67, 90))	('responsible', 'Reg', (128, 139))
42341	25914189	Real-time RT-PCR demonstrated that the expression of the TPX2 gene was strongly knocked down by TPX2 -siRNAs in the three selected pancreatic cancer cell lines, KLM1, KP4, and Panc1 (Fig.1E).	('knocked down', 'NegReg', (80, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('Panc1', 'CellLine', 'CVCL:0480', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('pancreatic cancer', 'Disease', (131, 148))	('TPX2 gene', 'Gene', (57, 66))	('TPX2', 'Var', (96, 100))	('expression', 'MPA', (39, 49))
42345	25914189	The proliferation of the tumor was significantly lower in mice treated with TPX2 siRNA than in mice treated with PBS or Control siRNA (Fig.3A).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mice', 'Species', '10090', (95, 99))	('tumor', 'Disease', (25, 30))	('PBS', 'Chemical', '-', (113, 116))	('mice', 'Species', '10090', (58, 62))	('TPX2 siRNA', 'Var', (76, 86))	('lower', 'NegReg', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
42346	25914189	The expression of TPX2 protein was lower in the tumors treated with TPX2 siRNA-2 than in those treated with PBS or Control siRNA (Fig.3B).	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('expression', 'MPA', (4, 14))	('TPX2', 'Var', (68, 72))	('lower', 'NegReg', (35, 40))	('protein', 'Protein', (23, 30))	('TPX2', 'Gene', (18, 22))	('PBS', 'Chemical', '-', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
42347	25914189	The average proportion of TPX2-positive cells in the randomly selected high-power fields was significantly lower in the tumors treated with TPX2 siRNA-2 compared to that in tumors treated with PBS or Control siRNA (Fig.3C).	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('PBS', 'Chemical', '-', (193, 196))	('lower', 'NegReg', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('TPX2', 'Var', (140, 144))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
42348	25914189	In addition, the number of Ki67-positive cell in tumor treated with TPX2 siRNA was lower than that in tumor treated with PBS or Control siRNA.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('PBS', 'Chemical', '-', (121, 124))	('Ki67-positive', 'Protein', (27, 40))	('TPX2 siRNA', 'Var', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (49, 54))	('lower', 'NegReg', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
42351	25914189	Among 56 angiogenesis-related factors, the average protein levels of insulin-like growth factor-binding protein-3 (IGFBP-3) were significantly higher in the TPX2 siRNA-treated tumors than the Control siRNA-treated tumors (Fig.4A).	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('IGFBP-3', 'Gene', (115, 122))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('higher', 'PosReg', (143, 149))	('tumors', 'Disease', (214, 220))	('IGFBP-3', 'Gene', '3486', (115, 122))	('insulin-like growth factor-binding', 'molecular_function', 'GO:0005520', ('69', '103'))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))	('angiogenesis', 'biological_process', 'GO:0001525', ('9', '21'))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('insulin-like growth factor-binding protein-3', 'Gene', '3486', (69, 113))	('TPX2', 'Var', (157, 161))	('insulin-like growth factor-binding protein', 'cellular_component', 'GO:0017052', ('69', '111'))	('protein levels', 'MPA', (51, 65))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('insulin-like growth factor-binding protein-3', 'Gene', (69, 113))	('tumors', 'Disease', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))
42353	25914189	In the immunohistochemical analysis, the average proportion of IGFBP-3-positive cells in randomly selected high-power fields was significantly higher in the tumors treated with TPX2 siRNA compared to that in tumors treated with PBS or Control siRNA (Fig.4B).	('TPX2 siRNA', 'Var', (177, 187))	('PBS', 'Chemical', '-', (228, 231))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('IGFBP-3', 'Gene', (63, 70))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('higher', 'PosReg', (143, 149))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('IGFBP-3', 'Gene', '3486', (63, 70))
42354	25914189	Additionally, the average number of microvessels stained with CD34 was significantly lower in tumors treated with TPX2 siRNA than that in tumors treated with PBS or Control siRNA (Fig.4B).	('lower', 'NegReg', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('CD34', 'Gene', '947', (62, 66))	('PBS', 'Chemical', '-', (158, 161))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Disease', (94, 100))	('TPX2 siRNA', 'Var', (114, 124))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('CD34', 'Gene', (62, 66))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
42358	25914189	That treated with both IGFBP3 siRNA and TPX2 siRNA were lower than in untreated cells, but were higher than in cells treated with TPX2 siRNA.	('TPX2', 'Var', (40, 44))	('higher', 'PosReg', (96, 102))	('IGFBP3', 'Gene', (23, 29))	('IGFBP3', 'Gene', '3486', (23, 29))
42362	25914189	With regard to pancreatic cancer, an increased TPX2 copy number has been reported in pancreatic cancer cell lines and surgically resected tumor samples analyzed by array comparative genomic hybridization.	('pancreatic cancer', 'Disease', (85, 102))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (15, 32))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('tumor', 'Disease', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('TPX2', 'Gene', (47, 51))	('pancreatic cancer', 'Disease', 'MESH:D010190', (15, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('pancreatic cancer', 'Disease', (15, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('increased', 'PosReg', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('copy number', 'Var', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
42378	25914189	There was a significant upregulation of IGFBP-3 in the TPX2 siRNA-treated tumors compared to the Control siRNA-treated tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', (119, 125))	('siRNA-treated', 'Var', (60, 73))	('IGFBP-3', 'Gene', '3486', (40, 47))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('TPX2', 'Gene', (55, 59))	('IGFBP-3', 'Gene', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('upregulation', 'PosReg', (24, 36))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
42381	25914189	Therefore, we speculate that antiproliferative effect of TPX2-siRNA may be at least partly associated with the upregulation of IGFBP-3.	('upregulation', 'PosReg', (111, 123))	('TPX2-siRNA', 'Var', (57, 67))	('antiproliferative effect', 'CPA', (29, 53))	('IGFBP-3', 'Gene', '3486', (127, 134))	('IGFBP-3', 'Gene', (127, 134))
42392	25914189	In summary, this study demonstrated that TPX2 silencing has a novel therapeutic potential in pancreatic cancer.	('pancreatic cancer', 'Disease', (93, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('silencing', 'Var', (46, 55))	('pancreatic cancer', 'Disease', 'MESH:D010190', (93, 110))	('TPX2', 'Gene', (41, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (93, 110))
42393	25914189	The upregulation of IGFBP-3 induced by TPX2 silencing may be at least partly responsible for the inhibitory effect on proliferation and angiogenesis in pancreatic cancer cells.	('IGFBP-3', 'Gene', (20, 27))	('TPX2', 'Gene', (39, 43))	('angiogenesis', 'biological_process', 'GO:0001525', ('136', '148'))	('angiogenesis', 'CPA', (136, 148))	('pancreatic cancer', 'Disease', (152, 169))	('proliferation', 'CPA', (118, 131))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('pancreatic cancer', 'Disease', 'MESH:D010190', (152, 169))	('silencing', 'Var', (44, 53))	('upregulation', 'PosReg', (4, 16))	('IGFBP-3', 'Gene', '3486', (20, 27))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (152, 169))
42445	26114017	The CT scan review by the radiologist revealed that of the 254 patients eligible for review, the TVI breakdown consisted of 62 patients (24.4%) with no TVI, 154 patients (60.6%) with TVI 180 , 28 patients (11%) with TVI > 180 , and 10 patients (3.9%) with venous occlusion associated with the pancreatic tumor.	('TVI', 'Chemical', '-', (216, 219))	('venous occlusion', 'Disease', 'None', (256, 272))	('patients', 'Species', '9606', (235, 243))	('TVI', 'Chemical', '-', (97, 100))	('pancreatic tumor', 'Disease', 'MESH:D010190', (293, 309))	('patients', 'Species', '9606', (196, 204))	('TVI', 'Chemical', '-', (152, 155))	('TVI 180', 'Var', (183, 190))	('TVI', 'Chemical', '-', (183, 186))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (293, 309))	('patients', 'Species', '9606', (63, 71))	('breakdown', 'biological_process', 'GO:0009056', ('101', '110'))	('venous occlusion', 'Disease', (256, 272))	('venous occlusion', 'Phenotype', 'HP:0025322', (256, 272))	('pancreatic tumor', 'Disease', (293, 309))
42446	26114017	SMV-PV resection was performed in 8 of the 62 patients (12.9%) who did not have TVI, 56 of the 154 (36.4%) with TVI 180 , 25 of the 28 (89%) with TVI > 180 , and 9 of the 10 (90%) with venous occlusion (p < .001).	('TVI 180', 'Var', (112, 119))	('TVI > 180', 'Var', (146, 155))	('patients', 'Species', '9606', (46, 54))	('venous occlusion', 'Phenotype', 'HP:0025322', (185, 201))	('venous occlusion', 'Disease', (185, 201))	('TVI', 'Chemical', '-', (146, 149))	('TVI', 'Chemical', '-', (80, 83))	('venous occlusion', 'Disease', 'None', (185, 201))	('TVI', 'Chemical', '-', (112, 115))
42556	25191517	SPN is a solid, secondarily cystic low-grade epithelial neoplasm with established clonal mutations in cancer-associated genes and an ability to metastasize.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('epithelial neoplasm', 'Disease', (45, 64))	('SPN', 'Disease', (0, 3))	('SPN', 'Chemical', '-', (0, 3))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('epithelial neoplasm', 'Phenotype', 'HP:0031492', (45, 64))	('neoplasm', 'Phenotype', 'HP:0002664', (56, 64))	('mutations', 'Var', (89, 98))	('epithelial neoplasm', 'Disease', 'MESH:D002277', (45, 64))
42598	25191517	Although, the combination of KRAS, LOH and quality and quantity of deoxyribonucleic acid correlates with malignancy, a KRAS mutation in and of itself is not specific for malignancy.	('KRAS', 'Gene', (29, 33))	('malignancy', 'Disease', 'MESH:D009369', (170, 180))	('KRAS', 'Gene', (119, 123))	('mutation', 'Var', (124, 132))	('KRAS', 'Gene', '3845', (29, 33))	('KRAS', 'Gene', '3845', (119, 123))	('malignancy', 'Disease', 'MESH:D009369', (105, 115))	('malignancy', 'Disease', (105, 115))	('malignancy', 'Disease', (170, 180))
42676	25191517	This uncommon variant accounts for 1-3% of PDAC and the vast majority arise in association with IPMN of intestinal type.	('association', 'Reg', (79, 90))	('PDAC', 'Disease', (43, 47))	('PDAC', 'Chemical', '-', (43, 47))	('IPMN', 'Chemical', '-', (96, 100))	('arise', 'Reg', (70, 75))	('variant', 'Var', (14, 21))	('IPMN', 'Disease', (96, 100))
42679	25191517	Medullary carcinoma is characterized by a special genetic profile with 69% of these tumors displaying wild-type KRAS genes and 22% of these tumors have microsatellite instability.	('KRAS', 'Gene', '3845', (112, 116))	('carcinoma', 'Disease', (10, 19))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('microsatellite instability', 'Var', (152, 178))	('KRAS', 'Gene', (112, 116))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('carcinoma', 'Disease', 'MESH:D002277', (10, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))
42754	21915976	A slight increase in the particle size was observed for PEG-1, and probably resulted from the extension of the PEG chains from the nanoparticle surface.	('PEG', 'Chemical', 'MESH:D011092', (56, 59))	('PEG', 'Chemical', 'MESH:D011092', (111, 114))	('increase', 'PosReg', (9, 17))	('particle size', 'MPA', (25, 38))	('PEG-1', 'Var', (56, 61))	('extension', 'PosReg', (94, 103))	('PEG chains', 'Protein', (111, 121))
42785	21915976	However, mice that received either PEG-1 or APEG-1 showed a statistically significant reduction in tumor growth (alpha = 0.06 for PEG-1 and alpha = 0.02 for APEG-1), thus limiting the average tumor volume to approximately 50%and 40%of the volume for untreated control mice, respectively.	('reduction', 'NegReg', (86, 95))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', (192, 197))	('APEG-1', 'Var', (44, 50))	('mice', 'Species', '10090', (268, 272))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('PEG-1', 'Var', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('mice', 'Species', '10090', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('limiting', 'NegReg', (171, 179))
42801	24348824	Cell proliferation assays were performed with MIA-Paca2 cells transfected with small interfering RNA (siRNA) or short hairpin RNA (shRNA) of Fz2.	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('RNA', 'cellular_component', 'GO:0005562', ('126', '129'))	('short hairpin RNA', 'Var', (112, 129))	('small interfering RNA', 'Var', (79, 100))	('Fz2', 'Gene', (141, 144))	('MIA-Paca2', 'CellLine', 'CVCL:0428', (46, 55))	('RNA', 'cellular_component', 'GO:0005562', ('97', '100'))	('Fz2', 'Gene', '2535', (141, 144))
42828	24348824	The primer pairs for quantitative PCR and the resultant product sizes were as follows: Fz2 (NM_001466) F, 5'-TCCTCAAGGTGCCAT CCTATCTC-3' and R, 5'-TGGTGACAGTGAAGAAGGTGG AAG-3' (183 bp); cyclin D1 (NM_053056) F, 5'-AGAGGCGGA GGAGAACAAACAG-3' and R, 5'-AGGCGGTAGTAGGAC AGGAAGTTG-3' (180 bp); and ribosomal protein L19 (RPL19; BC095445) F, 5'-CGAATGCCAGAGAAGGTCAC-3' and R, 5'-CCATGAGAATCCGCTTGTTT-3' (157 bp).	('cyclin D1', 'Gene', '595', (186, 195))	('ribosomal protein L19', 'Gene', '6143', (294, 315))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('294', '311'))	('cyclin', 'molecular_function', 'GO:0016538', ('186', '192'))	('RPL19', 'Gene', (317, 322))	('cyclin D1', 'Gene', (186, 195))	('protein', 'cellular_component', 'GO:0003675', ('304', '311'))	('NM_053056', 'Var', (197, 206))	('Fz2', 'Gene', '2535', (87, 90))	('Fz2', 'Gene', (87, 90))	('ribosomal protein L19', 'Gene', (294, 315))	('RPL19', 'Gene', '6143', (317, 322))
42876	24348824	Moreover, antisense oligonucleotides specific to cyclin D1 inhibit the growth of pancreatic cancer in vivo.	('antisense oligonucleotides', 'Var', (10, 36))	('cyclin D1', 'Gene', '595', (49, 58))	('cyclin D1', 'Gene', (49, 58))	('cyclin', 'molecular_function', 'GO:0016538', ('49', '55'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('growth', 'CPA', (71, 77))	('oligonucleotides', 'Chemical', 'MESH:D009841', (20, 36))	('inhibit', 'NegReg', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('pancreatic cancer', 'Disease', (81, 98))
42880	24348824	The main disadvantages of using antisense RNA in cancer treatment are that its half-life is short and its delivery is difficult.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('antisense RNA', 'molecular_function', 'GO:0009388', ('32', '45'))	('antisense RNA', 'Var', (32, 45))	('RNA', 'cellular_component', 'GO:0005562', ('42', '45'))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
42890	23633488	our findings strengthen the rationale for testing HIF inhibitors may therefore represent a novel therapeutic option for pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('inhibitors', 'Var', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('pancreatic cancer', 'Disease', (120, 137))
42899	23633488	The importance of HIF-1alpha to pancreatic cancer is directly demonstrated by the resistance to chemotherapy and radiation seen in pancreatic cancer cells constitutively expressing HIF-1alpha, and their increased in vivo tumorigenicity.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('HIF-1alpha to pancreatic cancer', 'Disease', 'MESH:D010190', (18, 49))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (32, 49))	('HIF-1alpha to pancreatic cancer', 'Disease', (18, 49))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('pancreatic cancer', 'Disease', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('pancreatic cancer', 'Disease', 'MESH:D010190', (32, 49))	('HIF-1alpha', 'Var', (181, 191))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('increased', 'PosReg', (203, 212))
42903	23633488	Altered HH signaling has been implicated in the development of approximately 20-25% of all cancers and has been classified into two major types.	('signaling', 'biological_process', 'GO:0023052', ('11', '20'))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Disease', (91, 98))	('Altered', 'Var', (0, 7))	('implicated', 'Reg', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
42904	23633488	The first type includes mutations in HH network genes resulting in HH ligand-independent tumors, they include PTCH inactivating mutations, SMO activating mutations, or loss of RENKCTD11, a GLI antagonist, in medulloblastoma.	('tumors', 'Disease', (89, 95))	('RENKCTD11', 'Gene', (176, 185))	('GLI', 'Gene', '2735', (189, 192))	('loss', 'Var', (168, 172))	('mutations', 'Var', (24, 33))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('SMO', 'Gene', '6608', (139, 142))	('PTCH', 'Gene', (110, 114))	('HH network genes', 'Gene', (37, 53))	('resulting in', 'Reg', (54, 66))	('ligand', 'molecular_function', 'GO:0005488', ('70', '76'))	('medulloblastoma', 'Disease', 'MESH:D008527', (208, 223))	('GLI', 'Gene', (189, 192))	('SMO', 'Gene', (139, 142))	('medulloblastoma', 'Phenotype', 'HP:0002885', (208, 223))	('medulloblastoma', 'Disease', (208, 223))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('RENKCTD11', 'Gene', '147040', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
42909	23633488	This concept is supported by the finding that mouse transgenic models with SHH expressed in pancreatic epithelium, together with mutant KRAS, show an enhanced incidence of pancreatic intraepithelial neoplasia and increased lethality.	('neoplasia', 'Phenotype', 'HP:0002664', (199, 208))	('pancreatic', 'Disease', (172, 182))	('mutant', 'Var', (129, 135))	('enhanced', 'PosReg', (150, 158))	('pancreatic intraepithelial neoplasia', 'Disease', (172, 208))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (183, 208))	('pancreatic', 'Disease', 'MESH:D010195', (92, 102))	('pancreatic intraepithelial neoplasia', 'Disease', 'MESH:D018290', (172, 208))	('mouse', 'Species', '10090', (46, 51))	('pancreatic', 'Disease', (92, 102))	('pancreatic', 'Disease', 'MESH:D010195', (172, 182))	('increased', 'PosReg', (213, 222))	('lethality', 'CPA', (223, 232))
42910	23633488	Furthermore, expression of SHH in transformed primary pancreatic ductal epithelial cells in an orthotopic model of pancreatic cancer leads to increased desmoplasia.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('SHH', 'Gene', (27, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('pancreatic', 'Disease', (115, 125))	('pancreatic', 'Disease', 'MESH:D010195', (54, 64))	('increased desmoplasia', 'Disease', 'MESH:D019586', (142, 163))	('pancreatic cancer', 'Disease', (115, 132))	('increased desmoplasia', 'Disease', (142, 163))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('expression', 'Var', (13, 23))	('pancreatic', 'Disease', (54, 64))	('pancreatic', 'Disease', 'MESH:D010195', (115, 125))
42911	23633488	Inhibition of HH signaling was shown to enhance vascular density and delivery of chemotherapy in a mouse model of pancreatic cancer and to inhibit tumor initiation and metastasis in orthotopic xenografts established from human pancreatic cancer cell lines.	('delivery of chemotherapy', 'MPA', (69, 93))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))	('tumor', 'Disease', (147, 152))	('pancreatic cancer', 'Disease', 'MESH:D010190', (227, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('human', 'Species', '9606', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('vascular density', 'CPA', (48, 64))	('pancreatic cancer', 'Disease', (227, 244))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (114, 131))	('Inhibition', 'Var', (0, 10))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('mouse', 'Species', '10090', (99, 104))	('inhibit', 'NegReg', (139, 146))	('pancreatic cancer', 'Disease', (114, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (227, 244))	('enhance', 'PosReg', (40, 47))
42912	23633488	While it has become clear that aberrant activation of HH signaling either by mutations or ligand overexpression can lead to cancer, the mechanisms responsible for regulating SHH expression in human cancer are poorly understood.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', (198, 204))	('human', 'Species', '9606', (192, 197))	('ligand', 'molecular_function', 'GO:0005488', ('90', '96'))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('lead to', 'Reg', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('activation', 'PosReg', (40, 50))	('mutations', 'Var', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
42952	23633488	Lipofectamine RNAiMAX (invitrogen, Carlsbad, CA) was used to transfect siRNA into Panc1 cells before plating the cells on NanoCultureR plates.	('siRNA', 'Gene', (71, 76))	('Panc1', 'CellLine', 'CVCL:0480', (82, 87))	('Lipofectamine', 'Chemical', 'MESH:C086724', (0, 13))	('transfect', 'Var', (61, 70))
42999	23633488	In addition, RT-PCR analysis showed that expression of HHIP and PTCH, two HH target genes, was reduced in NIH3T3 co-cultured with Panc cells transfected with siHIF-1alpha as compared to those transfected with siScr, suggesting that GLI activation in fibroblasts is dependent on expression of HIF-1alpha in the tumor cells (Figure S6).	('GLI', 'Gene', (232, 235))	('NIH3T3', 'Var', (106, 112))	('NIH3T3', 'CellLine', 'CVCL:0594', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('expression', 'MPA', (41, 51))	('PTCH', 'Gene', (64, 68))	('HHIP', 'Gene', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('GLI', 'Gene', '2735', (232, 235))	('tumor', 'Disease', (310, 315))	('reduced', 'NegReg', (95, 102))
43003	23633488	In addition, expression of HHIP and PTCH was reduced in fibroblasts co-cultured with Panc-1 cells overexpressing HHIP (Figure S5).	('Panc-1', 'Gene', (85, 91))	('HHIP', 'Gene', (27, 31))	('reduced', 'NegReg', (45, 52))	('PTCH', 'Gene', (36, 40))	('expression', 'MPA', (13, 23))	('overexpressing', 'PosReg', (98, 112))	('HHIP', 'Var', (113, 117))	('Panc-1', 'Gene', '104066', (85, 91))
43010	23633488	The requirement for HIF-1alpha and SHH expression by pancreatic cancer cells for the desmoplastic reaction was demonstrated by decreased fibronectin and collagen I staining in co-cultures of NIH-3T3 cells with MiaPaca2 cells stably transfected with shHIF-1alpha or siSHH, compared to MiaPaca2 cells expressing shVector or siSCR, respectively (Figure 5C and S7).	('MiaPaca2', 'CellLine', 'CVCL:0428', (210, 218))	('decreased', 'NegReg', (127, 136))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (53, 70))	('desmoplastic reaction', 'Disease', (85, 106))	('desmoplastic reaction', 'Disease', 'MESH:D004342', (85, 106))	('fibronectin', 'Gene', '2335', (137, 148))	('collagen', 'molecular_function', 'GO:0005202', ('153', '161'))	('shHIF-1alpha', 'Var', (249, 261))	('decreased fibronectin', 'Phenotype', 'HP:0032463', (127, 148))	('pancreatic cancer', 'Disease', (53, 70))	('MiaPaca2', 'CellLine', 'CVCL:0428', (284, 292))	('fibronectin', 'Gene', (137, 148))	('pancreatic cancer', 'Disease', 'MESH:D010190', (53, 70))	('NIH-3T3', 'CellLine', 'CVCL:0594', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
43019	23633488	We show that hypoxia, acting through elevated HIF-1alpha, increases the expression of SHH in pancreatic cancer cells and that patients with high expression of HIF-1alpha and SHH show decreased survival.	('increases', 'PosReg', (58, 67))	('HIF-1alpha', 'Gene', (159, 169))	('pancreatic cancer', 'Disease', (93, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('high expression', 'Var', (140, 155))	('hypoxia', 'Disease', (13, 20))	('SHH', 'Protein', (86, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (93, 110))	('hypoxia', 'Disease', 'MESH:D000860', (13, 20))	('HIF-1alpha', 'Gene', (46, 56))	('expression', 'MPA', (72, 82))	('decreased', 'NegReg', (183, 192))	('patients', 'Species', '9606', (126, 134))	('survival', 'CPA', (193, 201))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (93, 110))
43023	23633488	Both high HIF-1alpha and high SHH scores were associated with a significantly shorter patient survival, and the outcome of combining these two markers (high HIF-1alpha and high SHH vs low HIF-1alpha and low SHH) was a highly significant prediction for decreased patient survival.	('high HIF-1alpha', 'Var', (152, 167))	('high', 'Var', (5, 9))	('patient survival', 'CPA', (86, 102))	('high SHH', 'Var', (172, 180))	('patient', 'Species', '9606', (86, 93))	('patient', 'Species', '9606', (262, 269))	('decreased', 'NegReg', (252, 261))	('shorter', 'NegReg', (78, 85))
43035	23633488	Recent work suggests that pancreatic tumor cells are not competent to transduce HH signaling because they express oncogenic KRAS.	('pancreatic tumor', 'Phenotype', 'HP:0002894', (26, 42))	('pancreatic tumor', 'Disease', (26, 42))	('KRAS', 'Var', (124, 128))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('pancreatic tumor', 'Disease', 'MESH:D010190', (26, 42))
43036	23633488	Based on these studies KRAS suppresses ciliogenesis and therefore pancreatic tumor cells are devoid of primary cilia which are required for HH signaling.	('pancreatic tumor', 'Phenotype', 'HP:0002894', (66, 82))	('pancreatic tumor', 'Disease', 'MESH:D010190', (66, 82))	('ciliogenesis', 'biological_process', 'GO:0060271', ('39', '51'))	('suppresses', 'NegReg', (28, 38))	('KRAS', 'Var', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ciliogenesis', 'CPA', (39, 51))	('pancreatic tumor', 'Disease', (66, 82))	('signaling', 'biological_process', 'GO:0023052', ('143', '152'))
43041	23633488	Inhibiting HH signaling is an attractive approach for therapy of cancers where HH is aberrantly regulated and was shown to enhance delivery of chemotherapy in a mouse model of pancreatic cancer.	('signaling', 'biological_process', 'GO:0023052', ('14', '23'))	('enhance', 'PosReg', (123, 130))	('Inhibiting', 'Var', (0, 10))	('pancreatic cancer', 'Disease', (176, 193))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (176, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('delivery of chemotherapy', 'MPA', (131, 155))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (176, 193))	('cancers', 'Disease', (65, 72))	('mouse', 'Species', '10090', (161, 166))
43043	23633488	However, resistance to SMO inhibition has been shown to rapidly occur in medulloblastma patients due to mutations of SMO that do not affect HH signaling but disrupt the ability of the GDC-0449 inhibitor to bind SMO.	('disrupt', 'NegReg', (157, 164))	('occur', 'Reg', (64, 69))	('mutations', 'Var', (104, 113))	('SMO', 'Gene', '6608', (117, 120))	('patients', 'Species', '9606', (88, 96))	('SMO', 'Gene', (117, 120))	('signaling', 'biological_process', 'GO:0023052', ('143', '152'))	('medulloblastma', 'Disease', (73, 87))	('SMO', 'Gene', '6608', (211, 214))	('SMO', 'Gene', (211, 214))	('SMO', 'Gene', '6608', (23, 26))	('ability', 'MPA', (169, 176))	('SMO', 'Gene', (23, 26))	('bind', 'Interaction', (206, 210))	('GDC-0449', 'Chemical', 'MESH:C538724', (184, 192))
43046	23633488	We have shown that the HIF-1alpha inhibitor PX-478, can inhibit GLI activation in fibroblasts co-cultured with pancreatic cancer cells (Figure 6), strengthening the notion that HIF-1alpha inhibitors may be beneficial for hypoxic and HH ligand-dependent tumors such as pancreatic and prostate cancers.	('tumors', 'Disease', (253, 259))	('tumors', 'Disease', 'MESH:D009369', (253, 259))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('PX-478', 'Var', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('ligand', 'molecular_function', 'GO:0005488', ('236', '242'))	('prostate cancers', 'Phenotype', 'HP:0012125', (283, 299))	('GLI', 'Gene', (64, 67))	('pancreatic cancer', 'Disease', 'MESH:D010190', (111, 128))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('pancreatic cancer', 'Disease', (111, 128))	('PX-478', 'Chemical', 'MESH:C492908', (44, 50))	('cancers', 'Phenotype', 'HP:0002664', (292, 299))	('pancreatic and prostate cancers', 'Disease', 'MESH:D010190', (268, 299))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('GLI', 'Gene', '2735', (64, 67))	('inhibit', 'NegReg', (56, 63))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (111, 128))
43051	19064568	The aim of this study was to compare the prevalence of common genetic and epigenetic alterations in sporadic and familial pancreatic ductal adenocarcinomas.	('familial pancreatic ductal adenocarcinomas', 'Disease', (113, 155))	('epigenetic alterations', 'Var', (74, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (122, 154))	('familial pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (113, 155))
43053	19064568	KRAS2 mutations were detected by BstN1 digestion and/or cycle sequencing.	('digestion', 'biological_process', 'GO:0007586', ('39', '48'))	('mutations', 'Var', (6, 15))	('KRAS2', 'Gene', '3845', (0, 5))	('KRAS2', 'Gene', (0, 5))
43056	19064568	KRAS2 mutations were identified in 31 of 39 (80%) of the familial vs. 28 of 36 (78%) of the sporadic pancreatic cancers.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (101, 118))	('identified', 'Reg', (21, 31))	('KRAS2', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('sporadic pancreatic cancers', 'Disease', (92, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (101, 119))	('KRAS2', 'Gene', '3845', (0, 5))	('familial', 'Disease', (57, 65))	('sporadic pancreatic cancers', 'Disease', 'MESH:D010190', (92, 119))	('mutations', 'Var', (6, 15))
43058	19064568	The mean prevalence of aberrant methylation in the familial pancreatic cancers was 68.4%, not significantly different to that observed in sporadic pancreatic cancers.	('pancreatic cancers', 'Phenotype', 'HP:0002894', (147, 165))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('aberrant methylation', 'Var', (23, 43))	('sporadic pancreatic cancers', 'Disease', 'MESH:D010190', (138, 165))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('familial pancreatic cancers', 'Disease', (51, 78))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('sporadic pancreatic cancers', 'Disease', (138, 165))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (60, 78))	('familial pancreatic cancers', 'Disease', 'MESH:D010190', (51, 78))
43059	19064568	The prevalence of mutant KRAS2, inactivation of TP53 and SMAD4 and aberrant DNA methylation of a 7-gene panel is similar in familial pancreatic adenocarcinomas as in sporadic pancreatic adenocarcinomas.	('DNA methylation', 'biological_process', 'GO:0006306', ('76', '91'))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (175, 201))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (133, 158))	('sporadic pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (166, 201))	('SMAD4', 'Gene', '4089', (57, 62))	('KRAS2', 'Gene', '3845', (25, 30))	('TP53', 'Gene', '7157', (48, 52))	('mutant', 'Var', (18, 24))	('familial pancreatic adenocarcinomas', 'Disease', (124, 159))	('carcinomas', 'Phenotype', 'HP:0030731', (191, 201))	('familial pancreatic adenocarcinomas', 'Disease', 'MESH:C537262', (124, 159))	('sporadic pancreatic adenocarcinomas', 'Disease', (166, 201))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (133, 159))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('KRAS2', 'Gene', (25, 30))	('inactivation', 'Var', (32, 44))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('SMAD4', 'Gene', (57, 62))	('TP53', 'Gene', (48, 52))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (175, 200))	('aberrant', 'Var', (67, 75))
43069	19064568	In addition, having a germline mutation in the BRCA2, p16/CDKN2A, PRSS1, STK11, hMLH1 or FANCC genes predisposes to the development of pancreatic cancer.	('STK11', 'Gene', '6794', (73, 78))	('pancreatic cancer', 'Disease', (135, 152))	('FANCC', 'Gene', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('CDKN2A', 'Gene', (58, 64))	('BRCA2', 'Gene', (47, 52))	('PRSS1', 'Gene', (66, 71))	('CDKN2A', 'Gene', '1029', (58, 64))	('PRSS1', 'Gene', '5644', (66, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (135, 152))	('germline mutation', 'Var', (22, 39))	('predisposes to', 'Reg', (101, 115))	('STK11', 'Gene', (73, 78))	('BRCA2', 'Gene', '675', (47, 52))	('p16', 'Gene', (54, 57))	('FANCC', 'Gene', '2176', (89, 94))	('p16', 'Gene', '1029', (54, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (135, 152))	('hMLH1', 'Gene', (80, 85))	('STK11', 'molecular_function', 'GO:0033868', ('73', '78'))	('hMLH1', 'Gene', '4292', (80, 85))
43071	19064568	While risk prediction tools have been developed to help target screening to individuals at highest risk based on their family history, other risk factors such as cigarette smoking, obesity, diabetes mellitus and vitamin B12 deficiency may not increase pancreatic cancer risk sufficiently enough to justify early detection strategies targeting these risk groups.	('obesity', 'Phenotype', 'HP:0001513', (181, 188))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (190, 207))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (252, 269))	('increase pancreatic cancer', 'Phenotype', 'HP:0002894', (243, 269))	('vitamin B12', 'Gene', (212, 223))	('diabetes mellitus', 'Disease', (190, 207))	('obesity', 'Disease', 'MESH:D009765', (181, 188))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('deficiency', 'Var', (224, 234))	('pancreatic cancer', 'Disease', 'MESH:D010190', (252, 269))	('diabetes mellitus', 'Disease', 'MESH:D003920', (190, 207))	('obesity', 'Disease', (181, 188))	('pancreatic cancer', 'Disease', (252, 269))	('vitamin B12 deficiency', 'Phenotype', 'HP:0100502', (212, 234))
43072	19064568	Recognizing that individuals with an extensive family history of pancreatic cancer and those carrying a mutation in one of the pancreatic cancer susceptibility genes are at increased risk of developing pancreatic cancer has led to screening efforts to identify early pancreatic neoplasia in these high-risk individuals.	('pancreatic cancer', 'Disease', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('neoplasia', 'Phenotype', 'HP:0002664', (278, 287))	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('pancreatic cancer', 'Disease', (65, 82))	('pancreatic cancer', 'Disease', (202, 219))	('pancreatic cancer', 'Disease', 'MESH:D010190', (202, 219))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic neoplasia', 'Disease', (267, 287))	('mutation', 'Var', (104, 112))	('pancreatic neoplasia', 'Disease', 'MESH:D009369', (267, 287))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (202, 219))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('pancreatic neoplasia', 'Phenotype', 'HP:0002894', (267, 287))
43078	19064568	PanINs from patients with familial pancreatic cancer have been found to harbor KRAS2 mutations just as sporadic PanINs, and familial pancreatic cancers have broadly similar allelic loss patterns to sporadic pancreatic cancers; but molecular analysis of familial pancreatic cancers remains difficult because few familial pancreatic cancers are resected each year at any one institution.	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (26, 52))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (311, 337))	('cancers', 'Phenotype', 'HP:0002664', (273, 280))	('familial pancreatic cancers', 'Disease', (311, 338))	('KRAS2', 'Gene', '3845', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (35, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (320, 337))	('patients', 'Species', '9606', (12, 20))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (133, 151))	('sporadic pancreatic cancers', 'Disease', (198, 225))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (207, 224))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (253, 279))	('familial pancreatic cancers', 'Disease', 'MESH:D010190', (253, 280))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (262, 279))	('familial pancreatic cancers', 'Disease', 'MESH:D010190', (124, 151))	('familial pancreatic cancer', 'Disease', (26, 52))	('KRAS2', 'Gene', (79, 84))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (320, 338))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (133, 150))	('mutations', 'Var', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('sporadic pancreatic cancers', 'Disease', 'MESH:D010190', (198, 225))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (124, 150))	('familial pancreatic cancers', 'Disease', (253, 280))	('cancers', 'Phenotype', 'HP:0002664', (331, 338))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (262, 280))	('familial pancreatic cancers', 'Disease', 'MESH:D010190', (311, 338))	('familial pancreatic cancers', 'Disease', (124, 151))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (207, 225))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))
43082	19064568	We analyzed these cancers for evidence of mutations in the KRAS2, TP53, and SMAD4 genes, as well as for methylation of FoxE1, NPTX2, CLDN5, P16, TFPI-2, SPARC and ppENK.	('TP53', 'Gene', '7157', (66, 70))	('TFPI-2', 'Gene', (145, 151))	('KRAS2', 'Gene', (59, 64))	('FoxE1', 'Gene', (119, 124))	('SPARC', 'Gene', (153, 158))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('cancers', 'Disease', (18, 25))	('NPTX2', 'Gene', '4885', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('NPTX2', 'Gene', (126, 131))	('SPARC', 'Gene', '6678', (153, 158))	('CLDN5', 'Gene', '7122', (133, 138))	('TFPI-2', 'Gene', '7980', (145, 151))	('SMAD4', 'Gene', (76, 81))	('FoxE1', 'Gene', '2304', (119, 124))	('TP53', 'Gene', (66, 70))	('methylation', 'MPA', (104, 115))	('P16', 'Gene', '1029', (140, 143))	('KRAS2', 'Gene', '3845', (59, 64))	('cancers', 'Disease', 'MESH:D009369', (18, 25))	('P16', 'Gene', (140, 143))	('SMAD4', 'Gene', '4089', (76, 81))	('CLDN5', 'Gene', (133, 138))	('mutations', 'Var', (42, 51))	('methylation', 'biological_process', 'GO:0032259', ('104', '115'))
43091	19064568	12 of the familial patients had been tested for germline BRCA2 mutations.	('mutations', 'Var', (63, 72))	('BRCA2', 'Gene', (57, 62))	('patients', 'Species', '9606', (19, 27))	('BRCA2', 'Gene', '675', (57, 62))
43092	19064568	One patient with familial pancreatic cancer carried the Ashkenazi Jewish BRCA2 6174delT mutation.	('BRCA2', 'Gene', (73, 78))	('6174delT', 'Mutation', 'rs786204278', (79, 87))	('patient', 'Species', '9606', (4, 11))	('BRCA2', 'Gene', '675', (73, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (26, 43))	('familial pancreatic cancer', 'Disease', (17, 43))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (17, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('6174delT', 'Var', (79, 87))
43122	19064568	Mutations in KRAS2 were determined by one of two methods, BstN1 digestion and cycle sequencing.	('digestion', 'biological_process', 'GO:0007586', ('64', '73'))	('Mutations', 'Var', (0, 9))	('KRAS2', 'Gene', (13, 18))	('KRAS2', 'Gene', '3845', (13, 18))
43123	19064568	The BstN1 method is more sensitive than cycle sequencing for detecting low concentrations of KRAS2 gene mutations and so the former method was used for the formalin-fixed tissues with lower neoplastic cellularity.	('formalin', 'Chemical', 'MESH:D005557', (156, 164))	('mutations', 'Var', (104, 113))	('neoplastic cellularity', 'Phenotype', 'HP:0002664', (190, 212))	('KRAS2', 'Gene', (93, 98))	('KRAS2', 'Gene', '3845', (93, 98))
43125	19064568	We also confirmed the KRAS2 mutations of a subset of the frozen-tissue DNAs by the BstN1 method.	('KRAS2', 'Gene', (22, 27))	('mutations', 'Var', (28, 37))	('KRAS2', 'Gene', '3845', (22, 27))
43126	19064568	Polymerase chain reaction (PCR) amplification of the KRAS2 gene was done using an upstream KRAS2 primer (5' ACTGAATATAAACTTGTGGTAGTTGGACCT 3') that encoded a G to C substitution at the first position of codon 11.	('G to C substitution', 'Var', (158, 177))	('KRAS2', 'Gene', '3845', (53, 58))	('encoded', 'Reg', (148, 155))	('KRAS2', 'Gene', '3845', (91, 96))	('KRAS2', 'Gene', (53, 58))	('KRAS2', 'Gene', (91, 96))
43133	19064568	As a further control for assay performance, we also assayed 6 sporadic pancreatic cancers and found the prevalence of methylation in these 6 sporadic pancreatic cancers was similar to prevalence we reported previously for these 7 genes (average 76.2% vs. 74.5%).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('sporadic pancreatic cancers', 'Disease', 'MESH:D010190', (141, 168))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (150, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('sporadic pancreatic cancers', 'Disease', (141, 168))	('methylation', 'biological_process', 'GO:0032259', ('118', '129'))	('sporadic pancreatic cancers', 'Disease', (62, 89))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (71, 89))	('methylation', 'Var', (118, 129))	('sporadic pancreatic cancers', 'Disease', 'MESH:D010190', (62, 89))
43135	19064568	Thirty-one of the 39 familial pancreatic cancers (80%) tested for KRAS2 gene mutations harbored a mutation detected by BstN1 digestion and/or cycle sequencing.	('familial pancreatic cancers', 'Disease', (21, 48))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('digestion', 'biological_process', 'GO:0007586', ('125', '134'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (30, 47))	('KRAS2', 'Gene', (66, 71))	('mutations', 'Var', (77, 86))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('familial pancreatic cancers', 'Disease', 'MESH:D010190', (21, 48))	('KRAS2', 'Gene', '3845', (66, 71))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (30, 48))
43137	19064568	8/9 (89%) of the tissues obtained at autopsy harbored a KRAS2 gene mutation and 23 of the 30 (77%) samples obtained from surgical candidates contained a KRAS2 mutation and there was no significant difference in the detection of KRAS2 mutations using archival vs. frozen tissues.	('KRAS2', 'Gene', (228, 233))	('mutation', 'Var', (67, 75))	('KRAS2', 'Gene', '3845', (228, 233))	('KRAS2', 'Gene', '3845', (153, 158))	('harbored', 'Reg', (45, 53))	('KRAS2', 'Gene', (56, 61))	('KRAS2', 'Gene', (153, 158))	('KRAS2', 'Gene', '3845', (56, 61))
43139	19064568	The sporadic pancreatic cancers had almost an identical prevalence of KRAS2 gene mutations as the familial pancreatic cancers with 28 out of 36 cancers harboring a KRAS2 gene mutation (78%).	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('sporadic pancreatic cancers', 'Disease', 'MESH:D010190', (4, 31))	('KRAS2', 'Gene', (164, 169))	('mutations', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('familial pancreatic cancers', 'Disease', (98, 125))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (13, 31))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (107, 125))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('KRAS2', 'Gene', '3845', (70, 75))	('cancers', 'Disease', (24, 31))	('cancers', 'Disease', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('sporadic pancreatic cancers', 'Disease', (4, 31))	('KRAS2', 'Gene', '3845', (164, 169))	('KRAS2', 'Gene', (70, 75))	('familial pancreatic cancers', 'Disease', 'MESH:D010190', (98, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (13, 30))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))
43142	19064568	In the remaining four paired samples, both cancer and xenograft sample harbored a KRAS2 gene mutation.	('harbored', 'Reg', (71, 79))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('KRAS2', 'Gene', '3845', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutation', 'Var', (93, 101))	('KRAS2', 'Gene', (82, 87))
43143	19064568	Interestingly, in one of the primary cancer/xenograft pairs the primary cancer had a codon 13 mutation and the corresponding xenograft had a codon 12 mutation.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('codon 13 mutation', 'Var', (85, 102))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('mutation', 'Var', (94, 102))	('cancer', 'Disease', (72, 78))
43144	19064568	Previous studies have noted KRAS2 gene mutations at codon 12/13 in ~75-90% of primary pancreatic ductal adenocarcinomas and our findings in the sporadic and in the familial carcinomas are consistent with these results.	('pancreatic ductal adenocarcinomas', 'Disease', (86, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('KRAS2', 'Gene', (28, 33))	('mutations', 'Var', (39, 48))	('familial carcinomas', 'Disease', 'MESH:C536851', (164, 183))	('KRAS2', 'Gene', '3845', (28, 33))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (86, 119))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (86, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('familial carcinomas', 'Disease', (164, 183))
43146	19064568	Because mutations in the SMAD4 gene lead to ubiquination and degradation of Smad4 protein products, loss of Smad4 protein is a reliable indicator of mutational inactivation of SMAD4.	('loss', 'NegReg', (100, 104))	('lead to', 'Reg', (36, 43))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('ubiquination', 'MPA', (44, 56))	('Smad4', 'Gene', (76, 81))	('SMAD4', 'Gene', '4089', (176, 181))	('Smad4', 'Gene', '4089', (76, 81))	('Smad4', 'Gene', (108, 113))	('Smad4', 'Gene', '4089', (108, 113))	('mutations', 'Var', (8, 17))	('protein', 'Protein', (114, 121))	('SMAD4', 'Gene', '4089', (25, 30))	('degradation', 'biological_process', 'GO:0009056', ('61', '72'))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('degradation', 'MPA', (61, 72))	('SMAD4', 'Gene', (25, 30))	('SMAD4', 'Gene', (176, 181))	('protein', 'Protein', (82, 89))
43149	19064568	This finding is similar to our previous reports of loss of Smad4 observed in between 52-55% of surgically resectable pancreatic cancers.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('Smad4', 'Gene', (59, 64))	('Smad4', 'Gene', '4089', (59, 64))	('loss', 'Var', (51, 55))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (117, 135))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('pancreatic cancers', 'Disease', 'MESH:D010190', (117, 135))	('pancreatic cancers', 'Disease', (117, 135))
43151	19064568	TP53 gene mutations are found in approximately 70% of invasive pancreatic cancers.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (63, 81))	('invasive pancreatic cancers', 'Disease', 'MESH:D010190', (54, 81))	('mutations', 'Var', (10, 19))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (63, 80))	('invasive pancreatic cancers', 'Disease', (54, 81))	('found', 'Reg', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
43152	19064568	Most TP53 gene mutations are missense mutations and result in retention of the mutant p53 protein.	('p53', 'Gene', '7157', (86, 89))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('protein', 'Protein', (90, 97))	('mutations', 'Var', (15, 24))	('mutant', 'Var', (79, 85))	('retention', 'biological_process', 'GO:0051235', ('62', '71'))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))	('missense', 'Var', (29, 37))	('retention', 'MPA', (62, 71))	('p53', 'Gene', (86, 89))
43153	19064568	The resulting p53 protein overexpression is a reliable indicator of the presence of a TP53 gene missense mutation.	('TP53', 'Gene', '7157', (86, 90))	('missense mutation', 'Var', (96, 113))	('p53', 'Gene', (14, 17))	('overexpression', 'PosReg', (26, 40))	('p53', 'Gene', '7157', (14, 17))	('TP53', 'Gene', (86, 90))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))
43156	19064568	We also sequenced 8 familial pancreatic cancers and found TP53 gene mutations in 7 of the cancers (W53Ter, Y205D, R249M, H179R, R175H, R273H and a splice donor mutation in intron 6).	('H179R', 'Mutation', 'rs1057519991', (121, 126))	('cancers', 'Disease', (90, 97))	('H179R', 'Var', (121, 126))	('R273H', 'Var', (135, 140))	('TP53', 'Gene', '7157', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('donor', 'Species', '9606', (154, 159))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (29, 47))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('Y205D', 'Var', (107, 112))	('Ter', 'cellular_component', 'GO:0097047', ('102', '105'))	('cancers', 'Disease', (40, 47))	('familial pancreatic cancers', 'Disease', 'MESH:D010190', (20, 47))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('R249M', 'Mutation', 'rs587782329', (114, 119))	('TP53', 'Gene', (58, 62))	('W53Ter', 'Mutation', 'rs876658483', (99, 105))	('familial pancreatic cancers', 'Disease', (20, 47))	('Y205D', 'Mutation', 'rs1057520008', (107, 112))	('W53Ter', 'Var', (99, 105))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (29, 46))	('R249M', 'Var', (114, 119))	('R273H', 'Mutation', 'rs28934576', (135, 140))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('R175H', 'Mutation', 'rs28934578', (128, 133))	('R175H', 'Var', (128, 133))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))
43162	19064568	In this study we examined the prevalence of genetic and epigenetic alterations in familial pancreatic adenocarcinomas and find a similar prevalence of mutations of KRAS2 and inactivation of the TP53 and SMAD4 genes in familial as in sporadic pancreatic ductal adenocarcinomas We also find a similar prevalence of aberrant methylation of a gene panel in both familial and sporadic pancreatic adenocarcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (265, 275))	('KRAS2', 'Gene', (164, 169))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (380, 405))	('sporadic pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (371, 406))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (380, 406))	('SMAD4', 'Gene', (203, 208))	('TP53', 'Gene', (194, 198))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (242, 275))	('familial', 'Disease', (218, 226))	('mutations', 'Var', (151, 160))	('pancreatic ductal adenocarcinomas', 'Disease', (242, 275))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (91, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (396, 406))	('familial', 'Disease', (358, 366))	('KRAS2', 'Gene', '3845', (164, 169))	('sporadic pancreatic adenocarcinomas', 'Disease', (371, 406))	('methylation', 'biological_process', 'GO:0032259', ('322', '333'))	('familial pancreatic adenocarcinomas', 'Disease', (82, 117))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (91, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('inactivation', 'Var', (174, 186))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (242, 274))	('SMAD4', 'Gene', '4089', (203, 208))	('TP53', 'Gene', '7157', (194, 198))	('familial pancreatic adenocarcinomas', 'Disease', 'MESH:C537262', (82, 117))
43166	19064568	For example, activating KRAS2 gene mutations appear to be an early event in the development of pancreatic ductal adenocarcinoma and because the majority of mutations occur in one codon (codon 12), numerous studies have evaluated its potential use as a marker for pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (263, 280))	('activating', 'PosReg', (13, 23))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (95, 127))	('KRAS2', 'Gene', (24, 29))	('pancreatic ductal adenocarcinoma', 'Disease', (95, 127))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (95, 127))	('pancreatic cancer', 'Disease', (263, 280))	('pancreatic cancer', 'Disease', 'MESH:D010190', (263, 280))	('KRAS2', 'Gene', '3845', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('mutations', 'Var', (35, 44))
43167	19064568	Indeed studies have assessed its effectiveness in detecting pancreatic cancer by evaluating the KRAS2 gene mutation rate in the stool, cytological brushings, and plasma of patients with pancreatic cancer and comparing the mutation rate with that of healthy individuals and individuals with chronic pancreatitis.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (186, 203))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (290, 310))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (290, 310))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('pancreatitis', 'Phenotype', 'HP:0001733', (298, 310))	('pancreatic cancer', 'Disease', (186, 203))	('KRAS2', 'Gene', (96, 101))	('pancreatic cancer', 'Disease', 'MESH:D010190', (186, 203))	('pancreatic cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('chronic pancreatitis', 'Disease', (290, 310))	('patients', 'Species', '9606', (172, 180))	('mutation', 'Var', (107, 115))	('KRAS2', 'Gene', '3845', (96, 101))
43168	19064568	Because KRAS2 gene mutation detection has some predictive value for distinguishing pancreatic cancer from other non-cancerous conditions of the pancreas and because it is frequently mutated in both familial and sporadic pancreatic cancers, the quantification of KRAS2 gene mutations could potentially serve as one of a panel of molecular markers that could be used to help predict the presence of an underlying pancreatic neoplasm.	('pancreatic cancer', 'Disease', 'MESH:D010190', (220, 237))	('non-cancerous conditions of the pancreas', 'Disease', (112, 152))	('KRAS2', 'Gene', '3845', (262, 267))	('mutation', 'Var', (19, 27))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('KRAS2', 'Gene', '3845', (8, 13))	('pancreatic neoplasm', 'Disease', (411, 430))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (220, 238))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('non-cancerous conditions of the pancreas', 'Disease', 'MESH:D010190', (112, 152))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('neoplasm', 'Phenotype', 'HP:0002664', (422, 430))	('sporadic pancreatic cancers', 'Disease', (211, 238))	('pancreatic neoplasm', 'Disease', 'MESH:D010190', (411, 430))	('pancreatic cancer', 'Disease', (83, 100))	('KRAS2', 'Gene', (262, 267))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 237))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('KRAS2', 'Gene', (8, 13))	('mutations', 'Var', (273, 282))	('cancerous conditions of the pancreas', 'Phenotype', 'HP:0002894', (116, 152))	('sporadic pancreatic cancers', 'Disease', 'MESH:D010190', (211, 238))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))	('pancreatic neoplasm', 'Phenotype', 'HP:0002894', (411, 430))
43169	19064568	Similarly, since the TP53 gene is mutated in ~75% of sporadic pancreatic adenocarcinomas and in a significant fraction of familial pancreatic cancers, it too is a potential molecular marker of pancreatic neoplasia.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('TP53', 'Gene', (21, 25))	('familial pancreatic cancers', 'Disease', (122, 149))	('sporadic pancreatic adenocarcinomas', 'Disease', (53, 88))	('pancreatic neoplasia', 'Disease', (193, 213))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('neoplasia', 'Phenotype', 'HP:0002664', (204, 213))	('familial pancreatic cancers', 'Disease', 'MESH:D010190', (122, 149))	('pancreatic neoplasia', 'Phenotype', 'HP:0002894', (193, 213))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (62, 88))	('pancreatic neoplasia', 'Disease', 'MESH:D009369', (193, 213))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (131, 149))	('sporadic pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (53, 88))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (62, 87))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('mutated', 'Var', (34, 41))	('TP53', 'Gene', '7157', (21, 25))
43171	19064568	In conclusion, we demonstrate that the common genetic and epigenetic alterations that occur in sporadic pancreatic adenocarcinomas are also observed at a similar prevalence in familial pancreatic adenocarcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('sporadic pancreatic adenocarcinomas', 'Disease', (95, 130))	('familial pancreatic adenocarcinomas', 'Disease', (176, 211))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (185, 211))	('carcinomas', 'Phenotype', 'HP:0030731', (201, 211))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (104, 129))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (185, 210))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (104, 130))	('epigenetic alterations', 'Var', (58, 80))	('sporadic pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (95, 130))	('familial pancreatic adenocarcinomas', 'Disease', 'MESH:C537262', (176, 211))
43191	33912451	Published studies have revealed that loss of E-cadherin can promote tumor cell invasiveness and correlates with poor prognosis of cancers.	('tumor', 'Disease', (68, 73))	('promote', 'PosReg', (60, 67))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cadherin', 'molecular_function', 'GO:0008014', ('47', '55'))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('loss', 'Var', (37, 41))	('E-cadherin', 'Gene', (45, 55))	('E-cadherin', 'Gene', '999', (45, 55))
43192	33912451	Somatic mutations, silencing of the E-cadherin gene promoter, chromosomal deletions, or proteolytic cleavage of E-cadherin could lead to the suppression of E-cadherin expression, which is often detected in human tumors.	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('chromosomal deletions', 'Var', (62, 83))	('expression', 'MPA', (167, 177))	('suppression', 'NegReg', (141, 152))	('E-cadherin', 'Gene', (156, 166))	('E-cadherin', 'Gene', '999', (156, 166))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('mutations', 'Var', (8, 17))	('E-cadherin', 'Gene', (36, 46))	('E-cadherin', 'Gene', '999', (36, 46))	('human', 'Species', '9606', (206, 211))	('tumors', 'Disease', (212, 218))	('E-cadherin', 'Gene', (112, 122))	('E-cadherin', 'Gene', '999', (112, 122))	('silencing', 'Var', (19, 28))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('cadherin', 'molecular_function', 'GO:0008014', ('158', '166'))	('cadherin', 'molecular_function', 'GO:0008014', ('114', '122'))
43194	33912451	In contrast, E-cadherin inactivation may be involved in the differentiation of pancreatic tumor cells.	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('involved', 'Reg', (44, 52))	('pancreatic tumor', 'Disease', 'MESH:D010190', (79, 95))	('inactivation', 'Var', (24, 36))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (79, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('pancreatic tumor', 'Disease', (79, 95))
43210	33912451	To further assess the association between aberrant E-cadherin expression and OS in pancreatic cancer, subgroup analyses based on race, source of HRs, and cancer subtype were conducted.	('cadherin', 'molecular_function', 'GO:0008014', ('53', '61'))	('pancreatic cancer', 'Disease', (83, 100))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('cancer', 'Disease', (154, 160))	('aberrant', 'Var', (42, 50))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))	('E-cadherin', 'Gene', '999', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('E-cadherin', 'Gene', (51, 61))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
43227	33912451	Increasing evidence indicates that epigenetic changes regulate EMT, which is not dependent on DNA sequence alterations in normal and cancer cells.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('EMT', 'CPA', (63, 66))	('regulate', 'Reg', (54, 62))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('EMT', 'biological_process', 'GO:0001837', ('63', '66'))	('epigenetic changes', 'Var', (35, 53))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
43228	33912451	Furthermore, the identified somatic mutations and hypermethylation of the E-cadherin promoter did not result in its downregulation.	('cadherin', 'molecular_function', 'GO:0008014', ('76', '84'))	('E-cadherin', 'Gene', (74, 84))	('E-cadherin', 'Gene', '999', (74, 84))	('hypermethylation', 'Var', (50, 66))
43248	33912451	It has been reported that E-cadherin mutations and aberrant downregulation of E-cadherin can be observed in breast cancer, which might be associated with an abnormal TME.	('downregulation', 'NegReg', (60, 74))	('E-cadherin', 'Gene', (26, 36))	('E-cadherin', 'Gene', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))	('mutations', 'Var', (37, 46))	('E-cadherin', 'Gene', '999', (26, 36))	('E-cadherin', 'Gene', '999', (78, 88))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancer', 'Disease', (108, 121))	('cadherin', 'molecular_function', 'GO:0008014', ('28', '36'))
43320	33259017	According to the Union for International Cancer Control (UICC) TNM classification (8th edition), the tumor was T3 N0 M0, Stage IIA.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('Cancer', 'Disease', (41, 47))	('Cancer', 'Disease', 'MESH:D009369', (41, 47))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('T3 N0 M0', 'Var', (111, 119))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
43346	33259017	Recent reports indicated that DP-CAR contributed to improving PC prognosis.	('PC', 'Gene', '5091', (62, 64))	('CAR', 'cellular_component', 'GO:0005826', ('33', '36'))	('DP-CAR', 'Chemical', '-', (30, 36))	('PC', 'Phenotype', 'HP:0002894', (62, 64))	('DP-CAR', 'Var', (30, 36))	('improving', 'PosReg', (52, 61))
43359	33259017	Resection of the main veins around the stomach may have caused congestion and edema of the gastric mucosa, resulting in pyloric stenosis.	('edema of the gastric mucosa', 'Disease', (78, 105))	('congestion', 'MPA', (63, 73))	('pyloric stenosis', 'Phenotype', 'HP:0002021', (120, 136))	('Resection', 'Var', (0, 9))	('caused', 'Reg', (56, 62))	('resulting in', 'Reg', (107, 119))	('edema', 'Phenotype', 'HP:0000969', (78, 83))	('edema of the gastric mucosa', 'Disease', 'MESH:D004487', (78, 105))	('stenosis', 'Disease', 'MESH:D003251', (128, 136))	('stenosis', 'Disease', (128, 136))
43399	32409593	Inhibition of miR-21 reverted pro-tumorigenic functionalities to baseline levels.	('tumor', 'Disease', (34, 39))	('miR-21', 'Gene', (14, 20))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
43406	32409593	mKRAS is one of the earliest catalytic events and most highly expressed mutation in over 90% of human PanIN1 lesions and PDA.	('lesions', 'Var', (109, 116))	('mKRAS', 'Gene', '16653', (0, 5))	('human', 'Species', '9606', (96, 101))	('PanIN1', 'Gene', (102, 108))	('PDA', 'Phenotype', 'HP:0006725', (121, 124))	('mKRAS', 'Gene', (0, 5))	('PDA', 'Disease', (121, 124))
43412	32409593	However, the clinical benefit of these downstream therapeutics has been limited by compensatory mechanisms, narrow therapeutic windows with associated drug toxicities, the accumulation of additional genetic alterations in tumor cells, and the complexity of signaling by cancer-associated stromal cells.	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('genetic alterations', 'Var', (199, 218))	('drug toxicities', 'Disease', (151, 166))	('tumor', 'Disease', (222, 227))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('drug toxicities', 'Disease', 'MESH:D064420', (151, 166))	('signaling', 'biological_process', 'GO:0023052', ('257', '266'))
43424	32409593	Inhibition of miR-21 in tumor cells simultaneously downregulated multiple tumorigenic pathways downstream of activated mKRAS.	('mKRAS', 'Gene', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (24, 29))	('mKRAS', 'Gene', '16653', (119, 124))	('miR-21', 'Gene', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('Inhibition', 'Var', (0, 10))	('downregulated', 'NegReg', (51, 64))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
43472	32409593	Log fold changes for all gene transcripts were compared between (1) miR-21-inhibited and scramble-inhibited KPC tumor cells and (2) miR-224-inhibited and scramble-inhibited KPC CAFs.	('KPC tumor', 'Disease', (108, 117))	('KPC tumor', 'Disease', 'MESH:C565455', (108, 117))	('KPC CAFs', 'Disease', (173, 181))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('KPC CAFs', 'Disease', 'MESH:C565455', (173, 181))	('miR-21-inhibited', 'Var', (68, 84))
43473	32409593	GAGE pathway analyses on the differentially expressed gene sets produced by miR-21 and miR-224 inhibition revealed miR-21 inhibition significantly downregulated the MAPK, mTOR and actin cytoskeleton KEGG pathways in tumor cells (Supplementary Figure 4A), while miR-224 inhibition significantly downregulated the DNA replication, cell cycle and p53 signaling KEGG pathways in CAFs (Supplementary Figure 4B).	('miR-224', 'Gene', (87, 94))	('p53', 'Gene', (344, 347))	('DNA replication', 'biological_process', 'GO:0006260', ('312', '327'))	('cell cycle', 'Pathway', (329, 339))	('downregulated', 'NegReg', (294, 307))	('tumor', 'Disease', (216, 221))	('miR-21', 'Gene', (115, 121))	('MAPK', 'molecular_function', 'GO:0004707', ('165', '169'))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('MAPK', 'Pathway', (165, 169))	('CAF', 'Gene', (375, 378))	('CAF', 'Gene', '104272', (375, 378))	('mTOR', 'Gene', '56717', (171, 175))	('signaling', 'biological_process', 'GO:0023052', ('348', '357'))	('mTOR', 'Gene', (171, 175))	('inhibition', 'Var', (95, 105))	('p53', 'Gene', '22059', (344, 347))	('DNA', 'cellular_component', 'GO:0005574', ('312', '315'))	('inhibition', 'NegReg', (122, 132))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('180', '198'))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('downregulated', 'NegReg', (147, 160))	('cell cycle', 'biological_process', 'GO:0007049', ('329', '339'))	('miR-224', 'Gene', (261, 268))	('DNA replication', 'Pathway', (312, 327))
43488	32409593	Mice with tumors composed of miR-21-inhibited KPC tumor cells and normal KPC CAFs (T 21i/CAF) had the lowest tumor burden and longest survival compared to all other groups (Figure 4A, B).	('CAF', 'Gene', (77, 80))	('CAF', 'Gene', '104272', (77, 80))	('tumors', 'Disease', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (10, 15))	('lowest', 'NegReg', (102, 108))	('survival', 'CPA', (134, 142))	('KPC CAFs', 'Disease', (73, 81))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', (50, 55))	('CAF', 'Gene', (89, 92))	('KPC tumor', 'Disease', 'MESH:C565455', (46, 55))	('CAF', 'Gene', '104272', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('KPC tumor', 'Disease', (46, 55))	('KPC CAFs', 'Disease', 'MESH:C565455', (73, 81))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('miR-21-inhibited', 'Var', (29, 45))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (109, 114))
43490	32409593	Tumors composed of normal KPC tumor cells and miR-224-inhibited CAFs (T/CAF 224i) were comparable in size with scramble-inhibited tumors (T Scri/CAF Scri) and larger than normal non-transduced tumors (T/CAF).	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('CAF', 'Gene', '104272', (72, 75))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('Tumors', 'Disease', (0, 6))	('CAF', 'Gene', (203, 206))	('CAF', 'Gene', (145, 148))	('KPC tumor', 'Disease', 'MESH:C565455', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('CAF', 'Gene', '104272', (203, 206))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('miR-224-inhibited', 'Var', (46, 63))	('CAF', 'Gene', '104272', (145, 148))	('KPC tumor', 'Disease', (26, 35))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumors', 'Disease', (130, 136))	('CAF', 'Gene', (64, 67))	('CAF', 'Gene', '104272', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))	('CAF', 'Gene', (72, 75))
43491	32409593	Collectively, these data show that only miR-21 inhibition of tumor cells reduces tumor burden and confers survival benefit in established PDA.	('inhibition', 'Var', (47, 57))	('reduces', 'NegReg', (73, 80))	('PDA', 'Phenotype', 'HP:0006725', (138, 141))	('survival benefit', 'CPA', (106, 122))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('PDA', 'Disease', (138, 141))	('miR-21', 'Gene', (40, 46))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', (81, 86))
43492	32409593	Systemic administration of miR-21 and miR-224 inhibitors delayed progression of PanIN lesions to PDA in KPC mice.	('inhibitors', 'Var', (46, 56))	('delayed', 'NegReg', (57, 64))	('PanIN lesions', 'Disease', (80, 93))	('miR-21', 'Gene', (27, 33))	('mice', 'Species', '10090', (108, 112))	('PDA', 'Phenotype', 'HP:0006725', (97, 100))	('PanIN lesions', 'Disease', 'MESH:D001768', (80, 93))	('miR-224', 'Gene', (38, 45))
43500	32409593	qPCR quantification of miRNA levels in the whole pancreas of dosed KPC mice showed that LNA-miR-21 inhibitor-treated mice had a significant 112-fold decrease and 50-fold decrease of miR-21 levels in their pancreas compared to untreated mice and LNA-scramble inhibitor-treated mice, respectively (Figure 5B).	('mice', 'Species', '10090', (71, 75))	('mice', 'Species', '10090', (236, 240))	('miR', 'Gene', (23, 26))	('miR', 'Gene', (92, 95))	('miR', 'Gene', (182, 185))	('inhibitor-treated', 'Var', (99, 116))	('miR', 'Gene', '751557', (23, 26))	('mice', 'Species', '10090', (117, 121))	('miR', 'Gene', '751557', (92, 95))	('miR', 'Gene', '751557', (182, 185))	('mice', 'Species', '10090', (276, 280))	('decrease', 'NegReg', (170, 178))	('decrease', 'NegReg', (149, 157))
43506	32409593	Using the publicly available xCell quantification for TCGA, we compared epithelial and fibroblast content with miR-21 and miR-224 expression in 177 patients in the PDA cohort.	('PDA', 'Phenotype', 'HP:0006725', (164, 167))	('patients', 'Species', '9606', (148, 156))	('miR-224', 'Var', (122, 129))	('miR-21', 'Gene', (111, 117))
43519	32409593	However, here we show miR-21 inhibition is capable of simultaneously downregulating multiple mKRAS-activated biologic pathways responsible for tumor cell growth, metabolism, and EMT, indicating that miR-21 is a more potent regulator of mKRAS signaling than previously realized.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (143, 148))	('signaling', 'biological_process', 'GO:0023052', ('242', '251'))	('mKRAS', 'Gene', '16653', (236, 241))	('EMT', 'biological_process', 'GO:0001837', ('178', '181'))	('mKRAS', 'Gene', (93, 98))	('downregulating', 'NegReg', (69, 83))	('mKRAS', 'Gene', '16653', (93, 98))	('cell growth', 'biological_process', 'GO:0016049', ('149', '160'))	('miR-21', 'Gene', (22, 28))	('mKRAS', 'Gene', (236, 241))	('metabolism', 'biological_process', 'GO:0008152', ('162', '172'))	('inhibition', 'Var', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
43526	32409593	Moreover, endogenous overexpression of miR-224 in normal pancreatic fibroblasts significantly increased cell proliferation, migration, and invasion, indicating that overexpression of miR-224 may generate CAFs by conferring activated phenotypes to normal fibroblasts.	('CAF', 'Gene', (204, 207))	('invasion', 'CPA', (139, 147))	('miR-224', 'Var', (183, 190))	('CAF', 'Gene', '104272', (204, 207))	('migration', 'CPA', (124, 133))	('increased', 'PosReg', (94, 103))	('miR-224', 'Gene', (39, 46))	('cell proliferation', 'CPA', (104, 122))	('overexpression', 'PosReg', (21, 35))	('overexpression', 'PosReg', (165, 179))	('cell proliferation', 'biological_process', 'GO:0008283', ('104', '122'))
43530	32409593	Conversely, endogenous inhibition of miR-224 in KPC CAFs did not affect cell proliferation or invasion, but rather increased cell migration, an effect possibly mediated by significant downregulation of Shisa2 in miR-224-inhibited CAFs quantified by RNA-seq.	('CAF', 'Gene', '104272', (52, 55))	('increased', 'PosReg', (115, 124))	('cell migration', 'CPA', (125, 139))	('inhibition', 'Var', (23, 33))	('KPC CAFs', 'Disease', (48, 56))	('KPC CAFs', 'Disease', 'MESH:C565455', (48, 56))	('cell proliferation', 'biological_process', 'GO:0008283', ('72', '90'))	('cell migration', 'biological_process', 'GO:0016477', ('125', '139'))	('miR-224-inhibited', 'Var', (212, 229))	('CAF', 'Gene', (230, 233))	('miR-224', 'Gene', (37, 44))	('Shisa2', 'Gene', (202, 208))	('RNA', 'cellular_component', 'GO:0005562', ('249', '252'))	('CAF', 'Gene', '104272', (230, 233))	('CAF', 'Gene', (52, 55))	('downregulation', 'NegReg', (184, 198))	('Shisa2', 'Gene', '219134', (202, 208))
43532	32409593	Although miR-224 inhibition has been shown to reduce pro-tumorigenic functionalities of tumor cells in many cancer types, the effects of miR-224 inhibition in CAFs have not been reported.	('reduce', 'NegReg', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('miR-224', 'Gene', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('inhibition', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('CAF', 'Gene', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CAF', 'Gene', '104272', (159, 162))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', (88, 93))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
43535	32409593	Our study shows that inhibiting miR-21 may be a promising strategy to prevent or slow the development of other KRAS-driven cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('inhibiting', 'Var', (21, 31))	('slow', 'NegReg', (81, 85))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('miR-21', 'Gene', (32, 38))
43537	32409593	Utilizing a doxycycline-inducible mir-21LSL-Tetoff mouse model, induction of miR-21 produced pre-B-cell lymphoma, while miR-21 inactivation led to complete tumor regression.	('induction', 'Var', (64, 73))	('pre', 'molecular_function', 'GO:0003904', ('93', '96'))	('doxycycline', 'Chemical', 'MESH:D004318', (12, 23))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('mir', 'Gene', '751557', (34, 37))	('mouse', 'Species', '10090', (51, 56))	('B-cell lymphoma', 'Disease', (97, 112))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (97, 112))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (97, 112))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('mir', 'Gene', (34, 37))	('lymphoma', 'Phenotype', 'HP:0002665', (104, 112))	('miR-21', 'Gene', (77, 83))
43543	32409593	miR-21 expression is increased in CAFs compared to normal fibroblasts and miR-21 overexpression in normal fibroblasts enhances levels of CAF-specific markers, cell motility, and proliferation, indicating that miR-21, like miR-224, may induce CAF formation.	('enhances', 'PosReg', (118, 126))	('increased', 'PosReg', (21, 30))	('CAF', 'Gene', '104272', (242, 245))	('proliferation', 'CPA', (178, 191))	('miR-21', 'Var', (209, 215))	('induce', 'PosReg', (235, 241))	('miR-21', 'Gene', (0, 6))	('CAF', 'Gene', (34, 37))	('expression', 'MPA', (7, 17))	('CAF', 'Gene', (137, 140))	('overexpression', 'PosReg', (81, 95))	('cell motility', 'biological_process', 'GO:0048870', ('159', '172'))	('CAF', 'Gene', '104272', (34, 37))	('CAF', 'Gene', '104272', (137, 140))	('formation', 'biological_process', 'GO:0009058', ('246', '255'))	('cell motility', 'CPA', (159, 172))	('miR-21', 'Gene', (74, 80))	('CAF', 'Gene', (242, 245))
43544	32409593	Moreover, inhibition of miR-21 reduces CAF migration, invasion, and proliferation.	('miR-21', 'Gene', (24, 30))	('proliferation', 'CPA', (68, 81))	('invasion', 'CPA', (54, 62))	('CAF', 'Gene', (39, 42))	('reduces', 'NegReg', (31, 38))	('CAF', 'Gene', '104272', (39, 42))	('inhibition', 'Var', (10, 20))
43547	32409593	In fact, in vivo inhibition of miR-21 attenuated fibrosis in a mouse model of fibrotic lung disease, a finding that is highly applicable to PDA intervention because the fibrotic stroma is an integral component of the TME that propagates PDA.	('lung disease', 'Phenotype', 'HP:0002088', (87, 99))	('attenuated', 'NegReg', (38, 48))	('fibrotic lung disease', 'Disease', (78, 99))	('mouse', 'Species', '10090', (63, 68))	('PDA', 'Phenotype', 'HP:0006725', (140, 143))	('fibrotic lung disease', 'Disease', 'MESH:D008171', (78, 99))	('PDA', 'Phenotype', 'HP:0006725', (237, 240))	('fibrosis', 'Disease', 'MESH:D005355', (49, 57))	('miR-21', 'Gene', (31, 37))	('fibrosis', 'Disease', (49, 57))	('inhibition', 'Var', (17, 27))	('fibrotic stroma', 'Disease', 'None', (169, 184))	('fibrotic stroma', 'Disease', (169, 184))	('fibrotic lung', 'Phenotype', 'HP:0002206', (78, 91))
43549	32409593	In addition to CAFs in the stromal compartment, miR-21 has also been shown to promote pro-tumorigenic immune populations.	('CAF', 'Gene', (15, 18))	('promote', 'PosReg', (78, 85))	('miR-21', 'Var', (48, 54))	('CAF', 'Gene', '104272', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
43551	32409593	Inhibition of miR-21 in the premalignant microenvironment may act to simultaneously reduce fibrosis and suppress the generation of immunosuppressive cell populations, which may cumulatively delay premalignant progression and reduce tumor growth.	('premalignant progression', 'CPA', (196, 220))	('reduce', 'NegReg', (84, 90))	('suppress', 'NegReg', (104, 112))	('generation of immunosuppressive cell populations', 'MPA', (117, 165))	('reduce', 'NegReg', (225, 231))	('fibrosis', 'Disease', 'MESH:D005355', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('miR-21', 'Gene', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('Inhibition', 'Var', (0, 10))	('delay', 'NegReg', (190, 195))	('tumor', 'Disease', (232, 237))	('fibrosis', 'Disease', (91, 99))
43553	32409593	ANOVA analysis of variance CAF cancer associated fibroblast EMT epithelial to mesenchymal transition ER endoplasmic reticulum FGF fibroblast growth factor FGFR fibroblast growth factor receptor GAGE generally applicable gene-set enrichment GO gene ontology KEGG Kyoto encyclopedia of genes and genomes KPC KrasG12D/+;Trp53R172H/+;Pdx-1-Cre LNA locked nucleic acid MDSC myeloid-derived suppressor cell miRNA microRNA miR-FISH miRNA fluorescence in situ hybridization mKRAS mutated KRAS PanIN pancreatic intraepithelial neoplasias PDA pancreatic ductal adenocarcinoma PNAF normal pancreatic associated fibroblasts TCGA the cancer genome atlas TME tumor microenvironment Treg T regulatory cells	('Trp53', 'Gene', (317, 322))	('mKRAS', 'Gene', '16653', (466, 471))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('130', '154'))	('carcinoma', 'Phenotype', 'HP:0030731', (556, 565))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('104', '125'))	('cancer', 'Disease', (621, 627))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('160', '184'))	('tumor', 'Disease', (645, 650))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (533, 565))	('cancer', 'Phenotype', 'HP:0002664', (621, 627))	('Treg', 'Chemical', '-', (668, 672))	('miR', 'Gene', (401, 404))	('miR', 'Gene', (416, 419))	('mutated', 'Var', (472, 479))	('miR', 'Gene', (425, 428))	('PDA', 'Phenotype', 'HP:0006725', (529, 532))	('CAF', 'Gene', (27, 30))	('pancreatic intraepithelial neoplasias', 'Disease', (491, 528))	('tumor', 'Disease', 'MESH:D009369', (645, 650))	('mKRAS', 'Gene', (466, 471))	('CAF', 'Gene', '104272', (27, 30))	('cancer', 'Disease', (31, 37))	('Pdx-1', 'Gene', '18609', (330, 335))	('neoplasias', 'Phenotype', 'HP:0002664', (518, 528))	('pancreatic ductal adenocarcinoma', 'Disease', (533, 565))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('pancreatic intraepithelial neoplasias', 'Disease', 'MESH:D018290', (491, 528))	('Pdx-1', 'Gene', (330, 335))	('FGFR', 'molecular_function', 'GO:0005007', ('155', '159'))	('cancer', 'Disease', 'MESH:D009369', (621, 627))	('nucleic acid', 'cellular_component', 'GO:0005561', ('351', '363'))	('tumor', 'Phenotype', 'HP:0002664', (645, 650))	('miR', 'Gene', '751557', (401, 404))	('EMT', 'biological_process', 'GO:0001837', ('60', '63'))	('miR', 'Gene', '751557', (416, 419))	('miR', 'Gene', '751557', (425, 428))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (533, 565))	('gene ontology', 'biological_process', 'GO:0003673', ('243', '256'))	('intraepithelial neoplasias', 'Phenotype', 'HP:0032187', (502, 528))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('64', '100'))	('Trp53', 'Gene', '22059', (317, 322))	('cancer', 'Disease', 'MESH:D009369', (31, 37))
43566	32492856	Important risk factors for PDAC include genetic predisposition including germline mutations in BRCA2, CDKN2A, and CFTR as well as smoking, diabetes, obesity and chronic pancreatitis.	('pancreatitis', 'Disease', 'MESH:D010195', (169, 181))	('CDKN2A', 'Gene', '1029', (102, 108))	('pancreatitis', 'Disease', (169, 181))	('PDAC', 'Chemical', '-', (27, 31))	('chronic', 'Disease', (161, 168))	('obesity', 'Phenotype', 'HP:0001513', (149, 156))	('PDAC', 'Phenotype', 'HP:0006725', (27, 31))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (161, 181))	('BRCA2', 'Gene', (95, 100))	('diabetes', 'Disease', 'MESH:D003920', (139, 147))	('CFTR', 'Gene', '1080', (114, 118))	('CFTR', 'Gene', (114, 118))	('BRCA2', 'Gene', '675', (95, 100))	('obesity', 'Disease', (149, 156))	('pancreatitis', 'Phenotype', 'HP:0001733', (169, 181))	('CDKN2A', 'Gene', (102, 108))	('diabetes', 'Disease', (139, 147))	('PDAC', 'Disease', (27, 31))	('obesity', 'Disease', 'MESH:D009765', (149, 156))	('germline mutations', 'Var', (73, 91))
43571	32492856	The molecular pathology of PDAC is extremely challenging with a 92-95% prevalence in non-druggable activating KRAS mutation next to TP53 and/or CDKN2A alterations driving cancer survival, growth, resistance to therapeutic options and metastasis.	('PDAC', 'Chemical', '-', (27, 31))	('driving', 'Reg', (163, 170))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('KRAS', 'Gene', '3845', (110, 114))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('cancer', 'Disease', (171, 177))	('CDKN2A', 'Gene', (144, 150))	('PDAC', 'Phenotype', 'HP:0006725', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('CDKN2A', 'Gene', '1029', (144, 150))	('mutation', 'Var', (115, 123))	('alterations', 'Var', (151, 162))	('growth', 'CPA', (188, 194))	('KRAS', 'Gene', (110, 114))	('metastasis', 'CPA', (234, 244))
43617	32492856	Locked nucleic acid (LNA) probes and corresponding primer pairs for KRAS mutations were designed using Beacon Designer v.8.20 software (Premier Biosoft, Palo Alto, CA, USA).	('KRAS', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))	('KRAS', 'Gene', '3845', (68, 72))
43644	32492856	The table contains information about patient sex and year of birth, additional to clinical information about the tumor grading, the KRAS mutation, and the recurrence state of the tumor.	('tumor', 'Disease', (113, 118))	('KRAS', 'Gene', (132, 136))	('mutation', 'Var', (137, 145))	('patient', 'Species', '9606', (37, 44))	('KRAS', 'Gene', '3845', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (179, 184))
43716	32429174	Overexpression of Ctnnb1 may thus promote the metastatic capabilities of CTCs with stem-like properties via adherens junctions in murine PDAC.	('metastatic capabilities', 'CPA', (46, 69))	('adherens junctions', 'CPA', (108, 126))	('murine', 'Species', '10090', (130, 136))	('Ctnnb1', 'Gene', (18, 24))	('promote', 'PosReg', (34, 41))	('Overexpression', 'Var', (0, 14))
43745	32429174	This resulted in six pathways, including focal adhesion (KEGG: 04510), adherens junction (KEGG: 04520), ECM-receptor interaction (KEGG: 04512), AGE-RAGE signaling pathway in diabetic complications (KEGG: 04933), proteoglycans in cancer (KEGG: 05205) and fluid shear stress and atherosclerosis (KEGG: 05418) (Figure 5A).	('diabetic complications', 'Disease', 'MESH:D048909', (174, 196))	('KEGG', 'Var', (90, 94))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('focal adhesion', 'cellular_component', 'GO:0005925', ('41', '55'))	('RAGE', 'Gene', '177', (148, 152))	('atherosclerosis', 'Phenotype', 'HP:0002621', (277, 292))	('stress', 'Disease', 'MESH:D000079225', (266, 272))	('KEGG: 04512', 'Var', (130, 141))	('signaling pathway', 'biological_process', 'GO:0007165', ('153', '170'))	('resulted in', 'Reg', (5, 16))	('KEGG', 'Var', (198, 202))	('stress', 'Disease', (266, 272))	('adherens', 'Disease', (71, 79))	('cancer', 'Disease', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('atherosclerosis', 'Disease', 'MESH:D050197', (277, 292))	('atherosclerosis', 'Disease', (277, 292))	('RAGE', 'Gene', (148, 152))	('adherens junction', 'cellular_component', 'GO:0005912', ('71', '88'))	('diabetic complications', 'Disease', (174, 196))
43747	32429174	In addition, double enriched GO terms, such as the regulation of adherens junction organization (GO: 1903391), cell-cell junction (GO: 0005911), and cell-cell junction assembly (GO: 0007043) provide further evidence that adherens junctions are biologically relevant in the CTC-S group.	('CTC-S', 'Disease', (273, 278))	('regulation of adherens junction organization', 'biological_process', 'GO:1903391', ('51', '95'))	('GO: 0007043', 'Var', (178, 189))	('cell-cell junction', 'cellular_component', 'GO:0005911', ('111', '129'))	('cell-cell junction', 'cellular_component', 'GO:0005911', ('149', '167'))	('S', 'Chemical', 'MESH:D013455', (277, 278))	('adherens junction', 'cellular_component', 'GO:0005912', ('65', '82'))	('cell-cell junction assembly', 'biological_process', 'GO:0007043', ('149', '176'))
43780	32429174	Given that Klf4 is overexpressed in the CTC-S group, we believe that Klf4 inhibits Wnt signaling in this context.	('signaling', 'biological_process', 'GO:0023052', ('87', '96'))	('Wnt signaling', 'Pathway', (83, 96))	('S', 'Chemical', 'MESH:D013455', (44, 45))	('inhibits', 'NegReg', (74, 82))	('Klf4', 'Var', (69, 73))
43787	32429174	Even though there are studies claiming that Klf4 inhibits beta-catenin, there are other reports showing that the Klf4 / beta-catenin complex is necessary for the self-renewal capacity of stem/cancer cells.	('beta-catenin', 'Gene', (58, 70))	('beta-catenin', 'Gene', '1499', (120, 132))	('inhibits', 'NegReg', (49, 57))	('Klf4', 'Var', (44, 48))	('beta-catenin', 'Gene', '1499', (58, 70))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('catenin complex', 'cellular_component', 'GO:0016342', ('125', '140'))	('beta-catenin', 'Gene', (120, 132))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
43819	32429174	and S.S.; Writing:review and editing, L.Z., B.H., B.G., J.-C.J., C.Y., C.R.	('C.Y.', 'Var', (65, 69))	('J.-C.J.', 'Var', (56, 63))	('B.G.', 'Var', (50, 54))	('S', 'Chemical', 'MESH:D013455', (4, 5))	('S', 'Chemical', 'MESH:D013455', (6, 7))
43822	32358491	Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade.	('CD40', 'Gene', '21939', (69, 73))	('Cancer', 'Disease', (120, 126))	('tumor', 'Disease', (181, 186))	('CD40', 'Gene', (69, 73))	('inhibition', 'NegReg', (29, 39))	('MEK', 'Gene', (25, 28))	('Cancer', 'Disease', 'MESH:D009369', (120, 126))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mutational', 'Var', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('MEK', 'Gene', '17242', (25, 28))	('tumor', 'Disease', (106, 111))
43824	32358491	The combination of MEK inhibition with agonist anti-CD40 Ab is therefore a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma.	('CD40', 'Gene', '21939', (52, 56))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('CD40', 'Gene', (52, 56))	('Kras', 'Gene', '16653', (145, 149))	('tumors', 'Disease', (157, 163))	('mutant', 'Var', (138, 144))	('inhibition', 'NegReg', (23, 33))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('pancreatic ductal adenocarcinoma', 'Disease', (172, 204))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (172, 204))	('MEK', 'Protein', (19, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (172, 204))	('Kras', 'Gene', (145, 149))
43826	32358491	Here, the authors show that combining MEK inhibition with an agonist anti-CD40 immunostimulatory antibody improves antitumor treatment by inducing immunogenic changes in the tumor microenvironment.	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', (119, 124))	('antibody', 'cellular_component', 'GO:0019814', ('97', '105'))	('antibody', 'molecular_function', 'GO:0003823', ('97', '105'))	('MEK', 'Gene', (38, 41))	('inducing', 'Reg', (138, 146))	('inhibition', 'Var', (42, 52))	('improves', 'PosReg', (106, 114))	('CD40', 'Gene', '21939', (74, 78))	('CD40', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('immunogenic', 'MPA', (147, 158))	('antibody', 'cellular_component', 'GO:0042571', ('97', '105'))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('antibody', 'cellular_component', 'GO:0019815', ('97', '105'))
43834	32358491	Furthermore, anti-CD40 Abs were found to make tumors more permissive to immune responses by modifying the immune-suppressive myeloid infiltrate in tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('immune-suppressive myeloid infiltrate in', 'MPA', (106, 146))	('CD40', 'Gene', (18, 22))	('more', 'PosReg', (53, 57))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Abs', 'Var', (23, 26))	('modifying', 'Reg', (92, 101))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', (46, 52))	('CD40', 'Gene', '21939', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
43844	32358491	Analysis of the mechanism of action on the basis of immune-related parameters shows that this therapeutic efficacy is owing to the fact that MEK inhibitors exert strong antitumor cytotoxicity along with pro-immunogenic effects on tumor and TME that are complementary to the immunostimulatory action of anti-CD40 Ab.	('tumor', 'Disease', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('CD40', 'Gene', '21939', (307, 311))	('CD40', 'Gene', (307, 311))	('MEK', 'Gene', (141, 144))	('tumor cytotoxicity', 'Disease', 'MESH:D064420', (173, 191))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor cytotoxicity', 'Disease', (173, 191))	('inhibitors', 'Var', (145, 155))
43846	32358491	Benchmarking of the IC50 values against data available from literature led to the selection of MEK inhibitors (MEKi) GDC-0973 (cobimetinib), GDC-0623, as well as PI3K inhibitors (PI3Ki) GDC-0941 (pictilisib) and BAY 84-1236 (copanlisib) for further testing (Supplementary Fig.	('GDC-0941', 'Chemical', 'MESH:C532162', (186, 194))	('pictilisib', 'Chemical', 'MESH:C532162', (196, 206))	('BAY 84-1236', 'Chemical', '-', (212, 223))	('GDC-0623', 'Var', (141, 149))	('MEK', 'Pathway', (95, 98))	('copanlisib', 'Chemical', 'MESH:C000589253', (225, 235))	('PI3K', 'molecular_function', 'GO:0016303', ('162', '166'))	('cobimetinib', 'Chemical', 'MESH:C574276', (127, 138))	('GDC-0973', 'Chemical', 'MESH:C574276', (117, 125))	('GDC-0623', 'Chemical', 'MESH:C000622437', (141, 149))
43848	32358491	Given our specific interest in PDA, we also tested drug impact on a newly generated, C57BL/6-based tumor line PDA30364, which was established from a tumor that arose in a genetically engineered PDA model driven by KRAS-G12D and P53-R172H.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('P53-R172H', 'Var', (228, 237))	('PDA', 'Phenotype', 'HP:0006725', (31, 34))	('R172H', 'Mutation', 'p.R172H', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tested', 'Reg', (44, 50))	('PDA30364', 'Chemical', '-', (110, 118))	('KRAS-G12D', 'Var', (214, 223))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('PDA', 'Phenotype', 'HP:0006725', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('PDA', 'Phenotype', 'HP:0006725', (194, 197))	('G12D', 'Mutation', 'rs121913529', (219, 223))
43852	32358491	Mutational analysis of the three mouse tumor lines revealed that, as expected, mutated KRAS is a key driver mutation in PDA30364.	('KRAS', 'Gene', (87, 91))	('PDA', 'Phenotype', 'HP:0006725', (120, 123))	('mutated', 'Var', (79, 86))	('PDA30364', 'Chemical', '-', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('mouse', 'Species', '10090', (33, 38))	('PDA30364', 'Gene', (120, 128))
43853	32358491	B16-OVA and MC-38 do not harbor KRAS mutations, but instead carry a number of other potential driver mutations that could stimulate the MEK/ERK pathway, either directly or through cross-talk between signaling pathways (Supplementary Data 1).	('ERK', 'molecular_function', 'GO:0004707', ('140', '143'))	('mutations', 'Var', (101, 110))	('B16-OVA', 'Chemical', '-', (0, 7))	('stimulate', 'PosReg', (122, 131))	('MC-38', 'Chemical', '-', (12, 17))	('tween', 'Chemical', 'MESH:D011136', (193, 198))	('MEK/ERK pathway', 'Pathway', (136, 151))	('signaling', 'biological_process', 'GO:0023052', ('199', '208'))
43855	32358491	Nevertheless, the impact of MEK inhibition on cell viability is most prominent in PDA30364, in line with the pivotal role of mutated KRAS in this cell line (Fig.	('PDA30364', 'Chemical', '-', (82, 90))	('inhibition', 'NegReg', (32, 42))	('PDA30364', 'Var', (82, 90))	('MEK', 'Enzyme', (28, 31))	('PDA', 'Phenotype', 'HP:0006725', (82, 85))
43856	32358491	Detailed analysis of the balance between cell death and G0/G1 arrest, as induced in the three tumor cell lines by GDC-0623, confirmed that the degree of cell death was highest for PDA30364, whereas this drug induced a blend of cell death and stasis in B16-OVA and MC-38 (Fig.	('PDA30364', 'Var', (180, 188))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('arrest', 'Disease', 'MESH:D006323', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('arrest', 'Disease', (62, 68))	('tween', 'Chemical', 'MESH:D011136', (35, 40))	('cell death', 'biological_process', 'GO:0008219', ('41', '51'))	('stasis', 'MPA', (242, 248))	('tumor', 'Disease', (94, 99))	('PDA', 'Phenotype', 'HP:0006725', (180, 183))	('cell death', 'biological_process', 'GO:0008219', ('227', '237'))	('PDA30364', 'Chemical', '-', (180, 188))	('B16-OVA', 'Chemical', '-', (252, 259))	('GDC-0623', 'Chemical', 'MESH:C000622437', (114, 122))	('cell death', 'biological_process', 'GO:0008219', ('153', '163'))	('MC-38', 'Chemical', '-', (264, 269))	('GDC-0623', 'Gene', (114, 122))
43868	32358491	In line with our considerations, application of GDC-0623 with anti-CD40 Ab in the MC-38 and B16-OVA models showed striking synergy between these drugs, resulting in significant suppression of B16-OVA tumor growth and tumor stasis in the MC-38 model (Fig.	('B16-OVA', 'Chemical', '-', (192, 199))	('tween', 'Chemical', 'MESH:D011136', (133, 138))	('CD40', 'Gene', (67, 71))	('GDC-0623', 'Chemical', 'MESH:C000622437', (48, 56))	('MC-38', 'Chemical', '-', (82, 87))	('tumor stasis', 'Disease', 'MESH:D014647', (217, 229))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('B16-OVA', 'Chemical', '-', (92, 99))	('tumor stasis', 'Disease', (217, 229))	('MC-38', 'Chemical', '-', (237, 242))	('GDC-0623', 'Var', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('CD40', 'Gene', '21939', (67, 71))	('suppression', 'NegReg', (177, 188))	('OVA tumor', 'Phenotype', 'HP:0100615', (196, 205))
43870	32358491	For the MEKi this may be explained by the finding that also in the in vitro experiments GDC-0623 does not induce complete killing, but mostly stasis, in these tumor lines (Fig.	('GDC-0623', 'Chemical', 'MESH:C000622437', (88, 96))	('stasis', 'MPA', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('GDC-0623', 'Var', (88, 96))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
43871	32358491	As expected on basis of the in vitro data, mutant KRAS-driven PDA30364 tumors showed a much more profound in vivo response to MEKi alone (Fig.	('response', 'MPA', (114, 122))	('PDA30364', 'Gene', (62, 70))	('PDA', 'Phenotype', 'HP:0006725', (62, 65))	('PDA30364', 'Chemical', '-', (62, 70))	('mutant', 'Var', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
43875	32358491	Others recently reported that MEK inhibition promoted T cell and antitumor activity in combination with PD-L1/PD-1 checkpoint blockade in the AT3ova, MMTV-neu, and CT26 tumor models.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('inhibition', 'Var', (34, 44))	('tumor', 'Disease', (69, 74))	('CT26', 'CellLine', 'CVCL:7254', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('promoted', 'PosReg', (45, 53))	('PD-L1/PD-1 checkpoint blockade', 'Disease', 'MESH:D010300', (104, 134))	('MMTV', 'Species', '11757', (150, 154))	('tumor', 'Disease', (169, 174))	('MEK', 'Gene', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('PD-L1/PD-1 checkpoint blockade', 'Disease', (104, 134))
43884	32358491	These latter data vividly illustrate the anergic state of the T cells in the untreated tumors and, furthermore, that GDC-0623 synergizes with anti-CD40 Ab in unleashing T cell effector function.	('GDC-0623', 'Var', (117, 125))	('CD40', 'Gene', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('unleashing', 'MPA', (158, 168))	('T cell effector function', 'CPA', (169, 193))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('CD40', 'Gene', '21939', (147, 151))	('tumors', 'Disease', (87, 93))	('GDC-0623', 'Chemical', 'MESH:C000622437', (117, 125))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
43905	32358491	These signatures were most prominently observed in PDA30364 tumors, in line with the greatest degree of therapeutic impact of the treatment in this model.	('observed', 'Reg', (39, 47))	('PDA', 'Phenotype', 'HP:0006725', (51, 54))	('PDA30364', 'Chemical', '-', (51, 59))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('PDA30364', 'Var', (51, 59))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
43925	32358491	Further evaluation of the transcriptome data of the PDA30364 in vitro cell cultures treated with MEKi also revealed upregulation of pro-inflammatory pathways, in particular pathways related to interferon signaling (Fig.	('PDA30364', 'Var', (52, 60))	('pro-inflammatory pathways', 'Pathway', (132, 157))	('PDA30364', 'Chemical', '-', (52, 60))	('PDA', 'Phenotype', 'HP:0006725', (52, 55))	('upregulation', 'PosReg', (116, 128))	('signaling', 'biological_process', 'GO:0023052', ('204', '213'))
43927	32358491	In view of a report by others showing that MEK inhibition can increase antigen presentation on tumor cells cells, we also checked for the upregulation of MHC and antigen-processing genes, but found very little increase (Fig.	('inhibition', 'Var', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('MHC', 'Gene', (154, 157))	('antigen-processing', 'biological_process', 'GO:0019882', ('162', '180'))	('MEK', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('antigen presentation', 'MPA', (71, 91))	('antigen presentation', 'biological_process', 'GO:0019882', ('71', '91'))	('tumor', 'Disease', (95, 100))	('increase', 'PosReg', (62, 70))
43930	32358491	The use of OVA-transduced variants of PDA30364 enabled us to show that the increase in MHC class I surface expression was mirrored by increased presentation of the H-2Kb-restricted OVA-derived SIINFEKL epitope, as detected the Kb/OVA-specific antibody 25-D1.16 (Fig.	('OVA', 'Gene', (11, 14))	('antibody', 'molecular_function', 'GO:0003823', ('243', '251'))	('antibody', 'cellular_component', 'GO:0042571', ('243', '251'))	('H-2Kb', 'Gene', (164, 169))	('PDA30364', 'Gene', (38, 46))	('PDA', 'Phenotype', 'HP:0006725', (38, 41))	('variants', 'Var', (26, 34))	('antibody', 'cellular_component', 'GO:0019815', ('243', '251'))	('OVA', 'Gene', '396058', (230, 233))	('H-2Kb', 'Gene', '14972', (164, 169))	('MHC class I', 'Protein', (87, 98))	('OVA', 'Gene', (230, 233))	('increase', 'PosReg', (75, 83))	('OVA', 'Gene', '396058', (181, 184))	('antibody', 'cellular_component', 'GO:0019814', ('243', '251'))	('OVA', 'Gene', (181, 184))	('presentation', 'MPA', (144, 156))	('PDA30364', 'Chemical', '-', (38, 46))	('increased', 'PosReg', (134, 143))	('OVA', 'Gene', '396058', (11, 14))
43946	32358491	In spite of the documented role of MAPK in TCR-downstream signaling our data demonstrate that in vivo application of clinically relevant doses of MEK inhibitors, whereas effectively inducing regression of mutant KRAS-driven PDA30364 tumors, does not impair in vivo T cell priming, clonal expansion and effector function.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('TCR', 'cellular_component', 'GO:0042101', ('43', '46'))	('inducing', 'Reg', (182, 190))	('tumors', 'Disease', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('TCR', 'biological_process', 'GO:0006283', ('43', '46'))	('PDA30364', 'Chemical', '-', (224, 232))	('PDA', 'Phenotype', 'HP:0006725', (224, 227))	('KRAS-driven', 'Gene', (212, 223))	('MAPK', 'molecular_function', 'GO:0004707', ('35', '39'))	('MEK', 'Gene', (146, 149))	('mutant', 'Var', (205, 211))	('regression', 'CPA', (191, 201))	('signaling', 'biological_process', 'GO:0023052', ('58', '67'))	('PDA30364', 'Gene', (224, 232))
43969	32358491	In conclusion, the combination of MEK inhibitor GDC-0623 and agonist anti-CD40 Ab is a highly potent regimen for the treatment of tumors, especially for cancers such as PDA that are driven by mutated KRAS and heavily infiltrated by myeloid cells.	('tumors', 'Disease', (130, 136))	('PDA', 'Disease', (169, 172))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('KRAS', 'Gene', (200, 204))	('cancers', 'Disease', (153, 160))	('driven by', 'Reg', (182, 191))	('CD40', 'Gene', '21939', (74, 78))	('CD40', 'Gene', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('PDA', 'Phenotype', 'HP:0006725', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mutated', 'Var', (192, 199))	('GDC-0623', 'Chemical', 'MESH:C000622437', (48, 56))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
43993	32358491	The murine PDA cell line was generated from primary pancreatic tumors of PDA genetically engineered mouse model Elas-tTA/TetO-Cre Kras+/LSL-G12D Tp53+/LSL-R172H after cessation of doxycycline, which induces DNA recombination, and chronic pancreatitis induced by repetitive injections (three times per week, hourly injection for 6 hours) of 1 microg cholecystokinin analog cearulein (Sigma).	('pancreatic tumors', 'Disease', 'MESH:D010190', (52, 69))	('pancreatitis', 'Disease', 'MESH:D010195', (238, 250))	('Kras', 'Gene', (130, 134))	('doxycycline', 'Chemical', 'MESH:D004318', (180, 191))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('pancreatic tumors', 'Disease', (52, 69))	('DNA recombination', 'biological_process', 'GO:0006310', ('207', '224'))	('Tp53', 'Gene', (145, 149))	('pancreatitis', 'Disease', (238, 250))	('cholecystokinin', 'Chemical', 'MESH:D002766', (349, 364))	('cearulein', 'Chemical', '-', (372, 381))	('Tp53', 'Gene', '22059', (145, 149))	('R172H', 'Mutation', 'p.R172H', (155, 160))	('Kras', 'Gene', '16653', (130, 134))	('Elas-tTA/TetO-Cre', 'Var', (112, 129))	('PDA', 'Phenotype', 'HP:0006725', (11, 14))	('mouse', 'Species', '10090', (100, 105))	('DNA', 'cellular_component', 'GO:0005574', ('207', '210'))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (230, 250))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (52, 69))	('murine', 'Species', '10090', (4, 10))	('pancreatitis', 'Phenotype', 'HP:0001733', (238, 250))	('PDA', 'Phenotype', 'HP:0006725', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('G12D', 'Mutation', 'rs121913529', (140, 144))
43995	32358491	PDA30364-OVA variant was generated via lentiviral transduction of PDA30364 with ecotropic platinum-e retroviral packaging cell line (Cell Biolabs, Inc.) using the pLenti6.3_3xFLAG-Ovalbumin-F2A-EGFP construct (Bayer Pharma AG).	('Ovalbumin', 'Gene', '282665', (180, 189))	('PDA30364', 'Var', (66, 74))	('Ovalbumin', 'Gene', (180, 189))	('PDA', 'Phenotype', 'HP:0006725', (66, 69))	('PDA30364', 'Chemical', '-', (0, 8))	('PDA', 'Phenotype', 'HP:0006725', (0, 3))	('PDA30364', 'Chemical', '-', (66, 74))	('OVA', 'Gene', '396058', (9, 12))	('OVA', 'Gene', (9, 12))	('transduction', 'biological_process', 'GO:0009293', ('50', '62'))
44010	32358491	A-1180), GDC-0973-P2/R, GSK1120212 (trametinib; order no.	('GSK1120212', 'Var', (24, 34))	('GSK', 'molecular_function', 'GO:0050321', ('24', '27'))	('GDC-0973', 'Chemical', 'MESH:C574276', (9, 17))	('GDC-0973-P2/R', 'Var', (9, 22))
44053	32358491	On day two, treated mice were immunized by a single intravenously injection of a mixture of full OVA protein (50 mug) and anti-CD40 antibody (50 mug) diluted in PBS.	('antibody', 'cellular_component', 'GO:0042571', ('132', '140'))	('PBS', 'Chemical', 'MESH:D007854', (161, 164))	('OVA', 'Gene', '396058', (97, 100))	('OVA', 'Gene', (97, 100))	('mice', 'Species', '10090', (20, 24))	('antibody', 'cellular_component', 'GO:0019815', ('132', '140'))	('50 mug', 'Var', (110, 116))	('CD40', 'Gene', '21939', (127, 131))	('antibody', 'cellular_component', 'GO:0019814', ('132', '140'))	('antibody', 'molecular_function', 'GO:0003823', ('132', '140'))	('CD40', 'Gene', (127, 131))	('mug', 'molecular_function', 'GO:0043739', ('113', '116'))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('mug', 'molecular_function', 'GO:0043739', ('145', '148'))
44085	32358491	For MC-38, the annotated mutation table was kindly provided by John Castle (Agenus) and for B16-OVA data from supplementary table 2 of Castle JC et al., 'Exploiting the mutanome for tumor vaccines' was used for investigation of MAPK pathway-associated deriver mutations.	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('mutations', 'Var', (260, 269))	('MAPK', 'molecular_function', 'GO:0004707', ('228', '232'))	('MC-38', 'Chemical', '-', (4, 9))	('B16-OVA', 'Chemical', '-', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
44091	32358491	For the categorization of MAPK cascade-associated genes, we downloaded MAPK cascade gene lists (GO:0000165) for Homo sapiens and Mus musculus from the AmiGO 2 database and matched them with genes carrying somatic non-synonymous mutations including stop codon gains/losses.	('Mus musculus', 'Species', '10090', (129, 141))	('MAPK cascade', 'biological_process', 'GO:0000165', ('26', '38'))	('AmiGO 2', 'Gene', '105827', (151, 158))	('MAPK', 'molecular_function', 'GO:0004707', ('71', '75'))	('MAPK', 'molecular_function', 'GO:0004707', ('26', '30'))	('AmiGO 2', 'Gene', (151, 158))	('Homo sapiens', 'Species', '9606', (112, 124))	('stop codon gains/losses', 'Var', (248, 271))	('MAPK cascade', 'biological_process', 'GO:0000165', ('71', '83'))
44157	32358491	Following primary and secondary antibodies and dilutions were used: anti-mouse pERK1/2 (Cell signaling, clone 20G11, cat.	('anti-mouse', 'Var', (68, 78))	('pERK', 'Gene', '13666', (79, 83))	('pERK', 'Gene', (79, 83))	('signaling', 'biological_process', 'GO:0023052', ('93', '102'))	('mouse', 'Species', '10090', (73, 78))	('cat', 'molecular_function', 'GO:0004096', ('117', '120'))
44159	32358491	#4695, 1:1000), anti-mouse Gapdh (GeneTex, cat.	('mouse', 'Species', '10090', (21, 26))	('Gapdh', 'Gene', '14433', (27, 32))	('Gapdh', 'Gene', (27, 32))	('cat', 'molecular_function', 'GO:0004096', ('43', '46'))	('anti-mouse', 'Var', (16, 26))
44170	32358491	The mouse tumor and in vitro trancriptome data have been deposited in the GEO database under the accession codes GSE144128 (PDA30364: GEM/CD40 tumor), GSE144139 (MC-38: MEKi/CD40 tumor), GSE144145 (PDA30364: MEKi/CD40 tumor), GSE144146 (B16-OVA: MEKi in vitro), GSE144161 (MC-38: MEKi in vitro), GSE144166 (PDA30364: MEKi in vitro), GSE144570 (B16-OVA: MEKi/CD40 tumor) [https://www.ncbi.nlm.nih.gov/geo/].	('CD40', 'Gene', (138, 142))	('MC-38', 'Chemical', '-', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('MC-38', 'Chemical', '-', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('tumor', 'Disease', (218, 223))	('PDA', 'Phenotype', 'HP:0006725', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('B16-OVA', 'Chemical', '-', (237, 244))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('CD40', 'Gene', (358, 362))	('PDA', 'Phenotype', 'HP:0006725', (307, 310))	('PDA', 'Phenotype', 'HP:0006725', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('CD40', 'Gene', '21939', (213, 217))	('CD40', 'Gene', '21939', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('CD40', 'Gene', '21939', (358, 362))	('tumor', 'Disease', (179, 184))	('mouse', 'Species', '10090', (4, 9))	('GSE144570', 'Var', (333, 342))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (363, 368))	('PDA30364', 'Chemical', '-', (198, 206))	('CD40', 'Gene', (174, 178))	('CD40', 'Gene', '21939', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('CD40', 'Gene', (213, 217))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('PDA30364', 'Chemical', '-', (124, 132))	('B16-OVA', 'Chemical', '-', (344, 351))	('PDA30364', 'Chemical', '-', (307, 315))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('GEM', 'Chemical', 'MESH:C056507', (134, 137))
44194	32010427	In two-chamber invasion assays, KHSRP siRNA-transfected S2-013 cells were significantly less invasive than scrambled control siRNA-transfected S2-013 cells (Figure 2C).	('invasive', 'CPA', (93, 101))	('S2-013', 'CellLine', 'CVCL:B280', (56, 62))	('less', 'NegReg', (88, 92))	('KHSRP siRNA-transfected', 'Var', (32, 55))	('S2-013', 'CellLine', 'CVCL:B280', (143, 149))
44198	32010427	Moreover, KHSRP siRNA-transfected S2-013 cells did not form hepatic or lung metastases, whereas hepatic and lung metastases were seen in scrambled control siRNA-transfected S2-013 cells.	('KHSRP', 'Var', (10, 15))	('metastases', 'Disease', 'MESH:D009362', (76, 86))	('S2-013', 'CellLine', 'CVCL:B280', (173, 179))	('metastases', 'Disease', (113, 123))	('hepatic or lung metastases', 'Disease', (60, 86))	('hepatic or lung metastases', 'Disease', 'MESH:D009362', (60, 86))	('S2-013', 'CellLine', 'CVCL:B280', (34, 40))	('metastases', 'Disease', (76, 86))	('metastases', 'Disease', 'MESH:D009362', (113, 123))
44201	32010427	To investigate whether KHSRP-containing granules were stress granules (SGs) or P-bodies, S2-013 and PANC-1 cells cultured on fibronectin were double-labeled with anti-KHSRP, anti-G3BP (a marker for SG), and anti-Ge-1/HEDLS (a marker for P-bodies) antibodies.	('HEDLS', 'Gene', '23644', (217, 222))	('PANC-1', 'CellLine', 'CVCL:0480', (100, 106))	('Ge', 'Chemical', 'MESH:D005857', (212, 214))	('HEDLS', 'Gene', (217, 222))	('G3BP', 'Gene', '10146', (179, 183))	('fibronectin', 'Gene', (125, 136))	('S2-013', 'CellLine', 'CVCL:B280', (89, 95))	('anti-KHSRP', 'Var', (162, 172))	('G3BP', 'Gene', (179, 183))	('fibronectin', 'Gene', '2335', (125, 136))
44211	32010427	SNORA18 and SNORA22 immunoprecipitated with anti-KHSRP antibody, whereas neither transcript immunoprecipitated with isotype control antibody.	('SNORA18', 'Gene', '677805', (0, 7))	('anti-KHSRP', 'Var', (44, 54))	('antibody', 'cellular_component', 'GO:0042571', ('132', '140'))	('antibody', 'cellular_component', 'GO:0042571', ('55', '63'))	('anti-KHSRP', 'Protein', (44, 54))	('SNORA22', 'Gene', '677807', (12, 19))	('SNORA18', 'Gene', (0, 7))	('antibody', 'cellular_component', 'GO:0019815', ('55', '63'))	('SNORA22', 'Gene', (12, 19))	('antibody', 'cellular_component', 'GO:0019815', ('132', '140'))	('antibody', 'cellular_component', 'GO:0019814', ('55', '63'))	('antibody', 'cellular_component', 'GO:0019814', ('132', '140'))	('antibody', 'molecular_function', 'GO:0003823', ('55', '63'))	('antibody', 'molecular_function', 'GO:0003823', ('132', '140'))
44214	32010427	Confocal microscopy showed that peripheral actin structures were less abundant in KHSRP siRNA-transfected S2-013 cells than in scrambled control siRNA-transfected S2-013 cells grown on fibronectin (Figure 5A).	('KHSRP siRNA-transfected', 'Var', (82, 105))	('fibronectin', 'Gene', (185, 196))	('S2-013', 'CellLine', 'CVCL:B280', (163, 169))	('fibronectin', 'Gene', '2335', (185, 196))	('peripheral actin structures', 'Protein', (32, 59))	('less', 'NegReg', (65, 69))	('S2-013', 'CellLine', 'CVCL:B280', (106, 112))
44217	32010427	Cell protrusions were significantly more abundant in KHSRP siRNA-transfected S2-013 cells carrying a KHSRP-rescue construct than in KHSRP siRNA-transfected S2-013 cells not carrying a KHSRP-rescue construct (Figure 5C).	('S2-013', 'CellLine', 'CVCL:B280', (156, 162))	('Cell protrusions', 'CPA', (0, 16))	('KHSRP-rescue construct', 'Var', (101, 123))	('S2-013', 'CellLine', 'CVCL:B280', (77, 83))	('more', 'PosReg', (36, 40))
44237	32010427	First, KHSRP prompts invasiveness and metastasis of PDAC cells.	('KHSRP', 'Var', (7, 12))	('PDAC', 'Phenotype', 'HP:0006725', (52, 56))	('PDAC', 'Disease', 'MESH:D021441', (52, 56))	('invasiveness', 'CPA', (21, 33))	('PDAC', 'Disease', (52, 56))	('metastasis', 'CPA', (38, 48))
44248	32010427	Deregulation of Wnt/beta-catenin signaling is implicated in PDAC and promotes cell invasion and metastasis of PDAC.	('metastasis', 'CPA', (96, 106))	('PDAC', 'Disease', 'MESH:D021441', (60, 64))	('Deregulation', 'Var', (0, 12))	('PDAC', 'Disease', (60, 64))	('implicated', 'Reg', (46, 56))	('beta-catenin', 'Gene', '1499', (20, 32))	('PDAC', 'Phenotype', 'HP:0006725', (60, 64))	('promotes', 'PosReg', (69, 77))	('signaling', 'biological_process', 'GO:0023052', ('33', '42'))	('PDAC', 'Disease', (110, 114))	('PDAC', 'Phenotype', 'HP:0006725', (110, 114))	('PDAC', 'Disease', 'MESH:D021441', (110, 114))	('cell invasion', 'CPA', (78, 91))	('beta-catenin', 'Gene', (20, 32))
44249	32010427	Suppression of DVL3 enhances basal RAS-MEK-ERK activation and activates IGF signal transduction from the IGF1 receptor to RAS.	('activation', 'MPA', (47, 57))	('ERK', 'molecular_function', 'GO:0004707', ('43', '46'))	('IGF signal transduction', 'MPA', (72, 95))	('Suppression', 'Var', (0, 11))	('DVL3', 'Gene', '1857', (15, 19))	('signal transduction', 'biological_process', 'GO:0007165', ('76', '95'))	('ERK', 'Gene', (43, 46))	('enhances', 'PosReg', (20, 28))	('ERK', 'Gene', '5595;5594;5595', (43, 46))	('activates', 'PosReg', (62, 71))	('DVL3', 'Gene', (15, 19))
44255	32010427	It is interesting to consider the possibility that KHSRP-bound snoRNAs post-transcriptionally regulate levels of target mRNAs, and in turn they promote invasiveness and metastasis of PDAC cells.	('KHSRP-bound', 'Var', (51, 62))	('regulate', 'Reg', (94, 102))	('invasiveness', 'CPA', (152, 164))	('snoRNA', 'Gene', '84546', (63, 69))	('metastasis', 'CPA', (169, 179))	('promote', 'PosReg', (144, 151))	('levels of target mRNAs', 'MPA', (103, 125))	('PDAC', 'Disease', 'MESH:D021441', (183, 187))	('snoRNA', 'Gene', (63, 69))	('PDAC', 'Disease', (183, 187))	('PDAC', 'Phenotype', 'HP:0006725', (183, 187))
44257	32010427	p38-mediated phosphorylation of KHSRP post-transcriptionally downregulates utrophin A mRNA in skeletal muscle and may also enhance muscle regeneration.	('p38', 'Gene', (0, 3))	('enhance', 'PosReg', (123, 130))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('downregulates', 'NegReg', (61, 74))	('regeneration', 'biological_process', 'GO:0031099', ('138', '150'))	('p38', 'Gene', '5594', (0, 3))	('phosphorylation', 'Var', (13, 28))	('muscle regeneration', 'CPA', (131, 150))	('KHSRP', 'Protein', (32, 37))	('utrophin A mRNA in skeletal muscle', 'MPA', (75, 109))
44267	32010427	The functional importance of the association of KHSRP with snoRNAs mediated regulation of the invasiveness and metastasis in PDAC cells suggests that inhibition of KHSRP expression, binding of KHSRP with snoRNAs, or expression of KHSRP-bound snoRNAs such as SNORA18 and SNORA22 may be effective for PDAC targeted molecular therapy.	('snoRNA', 'Gene', '84546', (242, 248))	('PDAC', 'Phenotype', 'HP:0006725', (299, 303))	('snoRNA', 'Gene', (204, 210))	('PDAC', 'Phenotype', 'HP:0006725', (125, 129))	('KHSRP', 'Gene', (193, 198))	('snoRNA', 'Gene', '84546', (59, 65))	('SNORA18', 'Gene', '677805', (258, 265))	('binding', 'molecular_function', 'GO:0005488', ('182', '189'))	('SNORA18', 'Gene', (258, 265))	('snoRNA', 'Gene', (242, 248))	('inhibition', 'Var', (150, 160))	('SNORA22', 'Gene', '677807', (270, 277))	('snoRNA', 'Gene', (59, 65))	('PDAC', 'Disease', 'MESH:D021441', (299, 303))	('PDAC', 'Disease', 'MESH:D021441', (125, 129))	('PDAC', 'Disease', (299, 303))	('PDAC', 'Disease', (125, 129))	('binding', 'Interaction', (182, 189))	('KHSRP', 'Gene', (164, 169))	('snoRNA', 'Gene', '84546', (204, 210))	('regulation', 'biological_process', 'GO:0065007', ('76', '86'))	('invasiveness', 'CPA', (94, 106))	('SNORA22', 'Gene', (270, 277))	('association', 'Interaction', (33, 44))
44308	31480735	Additionally, we show that combining BET inhibitors with Quercetin or hnRNPA1 knockdown decreased the anti-apoptotic protein Survivin.	('Quercetin', 'Chemical', 'MESH:D011794', (57, 66))	('knockdown', 'Var', (78, 87))	('anti-apoptotic protein Survivin', 'MPA', (102, 133))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('hnRNPA1', 'Gene', (70, 77))	('decreased', 'NegReg', (88, 97))
44329	31480735	We identify hnRNPA1 as a target of Quercetin and show that hnRNPA1 knockdown mirrors the effects of Quercetin when combined with BET inhibitors.	('Quercetin', 'Chemical', 'MESH:D011794', (35, 44))	('Quercetin', 'Chemical', 'MESH:D011794', (100, 109))	('knockdown', 'Var', (67, 76))	('hnRNPA1', 'Gene', (59, 66))
44338	31480735	Since hnRNPA1 is a MNK effector, and is inhibited by Quercetin in prostate cancer cells, we evaluated whether hnRNPA1 knockdown also enhances the anti-tumor effects of BET inhibitors.	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('knockdown', 'Var', (118, 127))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('enhances', 'PosReg', (133, 141))	('Quercetin', 'Chemical', 'MESH:D011794', (53, 62))	('MNK', 'Gene', '538', (19, 22))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('prostate cancer', 'Disease', (66, 81))	('MNK', 'Gene', (19, 22))	('hnRNPA1', 'Gene', (110, 117))
44340	31480735	Moreover, hnRNPA1 knockdown enhanced the effects of JQ1 at suppressing sphere-forming ability of cancer cells (Figure 2B).	('knockdown', 'Var', (18, 27))	('cancer', 'Disease', (97, 103))	('enhanced', 'PosReg', (28, 36))	('suppressing', 'NegReg', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('hnRNPA1', 'Gene', (10, 17))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
44341	31480735	Similar to Quercetin treatment, knockdown of hnRNPA1 decreased proliferation and enhanced the anti-proliferative effects of JQ1 compared to control siRNA (Figure 2C and Table S1).	('proliferation', 'CPA', (63, 76))	('rat', 'Species', '10116', (70, 73))	('enhanced', 'PosReg', (81, 89))	('knockdown', 'Var', (32, 41))	('hnRNPA1', 'Gene', (45, 52))	('rat', 'Species', '10116', (106, 109))	('decreased', 'NegReg', (53, 62))	('Quercetin', 'Chemical', 'MESH:D011794', (11, 20))	('anti-proliferative effects', 'CPA', (94, 120))
44342	31480735	Importantly, hnRNPA1 knockdown also enhanced the effects of the BET inhibitor OTX-015 at inducing apoptosis and suppressing proliferation of cancer cells (Figure S1C,D and Table S1).	('rat', 'Species', '10116', (131, 134))	('inducing', 'NegReg', (89, 97))	('apoptosis', 'CPA', (98, 107))	('OTX-015', 'Chemical', 'MESH:C530377', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('suppressing', 'NegReg', (112, 123))	('proliferation', 'CPA', (124, 137))	('hnRNPA1', 'Gene', (13, 20))	('OTX-015', 'Gene', (78, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('enhanced', 'PosReg', (36, 44))	('knockdown', 'Var', (21, 30))	('cancer', 'Disease', (141, 147))
44346	31480735	To demonstrate that Quercetin enhanced the pro-apoptotic effects of BET inhibitors by decreasing hnRNPA1, we overexpressed hnRNPA1 and evaluated the effects of co-treatment with Quercetin and BET inhibitors on apoptosis.	('hnRNPA1', 'Protein', (97, 104))	('Quercetin', 'Chemical', 'MESH:D011794', (178, 187))	('rat', 'Species', '10116', (10, 13))	('Quercetin', 'Chemical', 'MESH:D011794', (20, 29))	('pro-apoptotic', 'MPA', (43, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('210', '219'))	('apoptosis', 'biological_process', 'GO:0006915', ('210', '219'))	('decreasing', 'NegReg', (86, 96))	('overexpressed', 'Var', (109, 122))
44349	31480735	There were minimal effects with single-agent treatment with JQ1 or Quercetin, or with the combination of JQ1 and Quercetin, on the expression of several apoptosis-regulating proteins such as Bad, Bax, and Bcl-2 in CD18 and K1 cells (Figure S3).	('Bax', 'Gene', '581', (196, 199))	('Quercetin', 'Chemical', 'MESH:D011794', (67, 76))	('Quercetin', 'Chemical', 'MESH:D011794', (113, 122))	('JQ1', 'Var', (105, 108))	('Bcl-2', 'Gene', (205, 210))	('expression', 'MPA', (131, 141))	('Bad', 'Gene', (191, 194))	('Bcl-2', 'Gene', '596', (205, 210))	('apoptosis', 'biological_process', 'GO:0097194', ('153', '162'))	('Bax', 'Gene', (196, 199))	('Bcl-2', 'molecular_function', 'GO:0015283', ('205', '210'))	('apoptosis', 'biological_process', 'GO:0006915', ('153', '162'))
44350	31480735	While single-agent treatment with Quercetin and JQ1 had minimal effects on Survivin protein levels in the array, co-treatment with Quercetin and JQ1 suppressed Survivin in these cell lines (Figure 4A and Figure S3).	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('Survivin protein levels', 'MPA', (75, 98))	('Quercetin', 'Chemical', 'MESH:D011794', (34, 43))	('Survivin', 'MPA', (160, 168))	('suppressed', 'NegReg', (149, 159))	('Quercetin', 'Chemical', 'MESH:D011794', (131, 140))	('JQ1', 'Var', (145, 148))
44353	31480735	hnRNPA1 knockdown and JQ1 treatment suppressed Survivin in cancer cells (Figure 5A), which was validated by western blot analysis (Figure 5B).	('suppressed', 'NegReg', (36, 46))	('knockdown', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Survivin', 'Protein', (47, 55))	('hnRNPA1', 'Gene', (0, 7))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
44354	31480735	Combination of hnRNPA1 knockdown and JQ1 also decreased Survivin levels in thyroid cancer cells (Figure 5B).	('hnRNPA1', 'Gene', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('knockdown', 'Var', (23, 32))	('thyroid cancer', 'Phenotype', 'HP:0002890', (75, 89))	('thyroid cancer', 'Disease', (75, 89))	('Survivin levels', 'MPA', (56, 71))	('decreased', 'NegReg', (46, 55))	('JQ1', 'Gene', (37, 40))	('thyroid cancer', 'Disease', 'MESH:D013964', (75, 89))
44356	31480735	Compared to JQ1 treatment alone, JQ1 in combination with either hnRNPA1 knockdown or Quercetin treatment further downregulated protein levels of cIAP-2 (cellular inhibitor of apoptosis protein 2), HSP70 (heat shock protein 70) and Survivin.	('hnRNPA1', 'Gene', (64, 71))	('cIAP-2', 'Gene', (145, 151))	('protein levels', 'MPA', (127, 141))	('heat shock protein 70', 'Gene', '3308', (204, 225))	('cellular inhibitor of apoptosis protein 2', 'Gene', (153, 194))	('HSP70', 'Gene', '3308', (197, 202))	('downregulated', 'NegReg', (113, 126))	('Survivin', 'Protein', (231, 239))	('cIAP-2', 'Gene', '330', (145, 151))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('heat shock protein 70', 'Gene', (204, 225))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('knockdown', 'Var', (72, 81))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))	('cellular inhibitor of apoptosis protein 2', 'Gene', '330', (153, 194))	('Quercetin', 'Chemical', 'MESH:D011794', (85, 94))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('HSP70', 'Gene', (197, 202))	('shock', 'Phenotype', 'HP:0031273', (209, 214))
44358	31480735	Established tumors were then treated with vehicle control (DMSO), JQ1, Quercetin, or a combination of JQ1 and Quercetin.	('Quercetin', 'Chemical', 'MESH:D011794', (71, 80))	('DMSO', 'Chemical', 'MESH:D004121', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('JQ1', 'Var', (102, 105))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('Quercetin', 'Chemical', 'MESH:D011794', (110, 119))
44363	31480735	While there were minimal effects on CC3 staining in the tumor specimens (Figure 6C and Figure S5), combination of Quercetin and JQ1 was significantly more effective than single-treatment at suppressing tumor proliferation (Figure 6D and Figure S5).	('Quercetin', 'Chemical', 'MESH:D011794', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (202, 207))	('JQ1', 'Gene', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('rat', 'Species', '10116', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('suppressing', 'NegReg', (190, 201))	('combination', 'Var', (99, 110))
44377	31480735	The following antibodies and dilutions were used: hnRNPA1 (1:2000, Cell Signaling, Danvers, MA, USA), cleaved PARP1 (1:1000, Cell Signaling), HSP90 (1:4000, Santa Cruz Biotechnology, Santa Cruz, CA, USA), GAPDH (1:3000, EMD Millipore, Billerica, MA, USA), Survivin (1:2000, Cell Signaling), and Flag-tag (1:2000, Sigma-Aldrich).	('EMD Millipore', 'Disease', 'None', (220, 233))	('1:3000', 'Var', (212, 218))	('Signaling', 'biological_process', 'GO:0023052', ('279', '288'))	('PARP1', 'Gene', '142', (110, 115))	('Signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('PARP1', 'Gene', (110, 115))	('EMD Millipore', 'Disease', (220, 233))	('Signaling', 'biological_process', 'GO:0023052', ('130', '139'))	('HSP90', 'Gene', (142, 147))	('1:4000', 'Var', (149, 155))	('GAPDH', 'Gene', '2597', (205, 210))	('GAPDH', 'Gene', (205, 210))	('HSP90', 'Gene', '3320', (142, 147))
44390	31480735	We recently published that in thyroid and pancreatic cancer, inhibitors targeting MNK kinases can enhance the efficacy of BET inhibitors by suppressing a pro-survival signaling pathway initiated by cancer cells following treatment with BET inhibitors.	('suppressing', 'NegReg', (140, 151))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('MNK', 'Gene', '538', (82, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (42, 59))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('thyroid', 'Disease', (30, 37))	('pro-survival signaling pathway', 'Pathway', (154, 184))	('cancer', 'Disease', (53, 59))	('inhibitors', 'Var', (61, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (42, 59))	('pro-survival', 'biological_process', 'GO:0043066', ('154', '166'))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('MNK', 'Gene', (82, 85))	('efficacy', 'MPA', (110, 118))	('signaling pathway', 'biological_process', 'GO:0007165', ('167', '184'))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('enhance', 'PosReg', (98, 105))	('pancreatic cancer', 'Disease', (42, 59))
44411	31480735	Here we show that hnRNPA1 knockdown, similar to Quercetin treatment, can enhance the effects of BET inhibitors on proliferation, apoptosis, and cell survival in both thyroid and pancreatic cancer cells.	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('pancreatic cancer', 'Disease', (178, 195))	('apoptosis', 'CPA', (129, 138))	('pancreatic cancer', 'Disease', 'MESH:D010190', (178, 195))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('rat', 'Species', '10116', (121, 124))	('thyroid', 'Disease', (166, 173))	('enhance', 'PosReg', (73, 80))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (178, 195))	('proliferation', 'CPA', (114, 127))	('knockdown', 'Var', (26, 35))	('Quercetin', 'Chemical', 'MESH:D011794', (48, 57))	('hnRNPA1', 'Gene', (18, 25))	('cell survival', 'CPA', (144, 157))
44413	31480735	Furthermore, similar to Quercetin, hnRNPA1 knockdown enhances the ability of BET inhibitors at suppressing Survivin expression.	('suppressing', 'NegReg', (95, 106))	('enhances', 'PosReg', (53, 61))	('knockdown', 'Var', (43, 52))	('Quercetin', 'Chemical', 'MESH:D011794', (24, 33))	('Survivin', 'Protein', (107, 115))	('hnRNPA1', 'Gene', (35, 42))
44416	31480735	Overall, we demonstrate that targeting of hnRNPA1 by Quercetin enhances the efficacy of BET inhibitors in thyroid and pancreatic tumors.	('thyroid', 'Disease', (106, 113))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (118, 135))	('efficacy', 'MPA', (76, 84))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('Quercetin', 'Chemical', 'MESH:D011794', (53, 62))	('pancreatic tumors', 'Disease', 'MESH:D010190', (118, 135))	('rat', 'Species', '10116', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('pancreatic tumors', 'Disease', (118, 135))	('enhances', 'PosReg', (63, 71))	('hnRNPA1', 'Protein', (42, 49))	('targeting', 'Var', (29, 38))
44418	31480735	The following are available online at , Figure S1: Both Quercetin and hnRNPA1 knockdown enhance the anti-tumor effects of BET inhibitors, Figure S2: Quercetin decreases hnRNPA1 protein, Figure S3: Co-treatment of Quercetin and JQ1 decreases Survivin while having no effects on other apoptosis regulating proteins, Figure S4: The combination treatment of Quercetin and BET inhibitor JQ1 was well-tolerated, Figure S5: Representative IHC images for cleaved caspase-3 and Ki67 for CD18 tumors, Table S1: Calculations for coefficients of drug interaction, Table S2: Effect of hnRNPA1 knockdown on JQ1-mediated changes in proteins in the ARY009 apoptosis array, Table S3: Effect of Quercetin on JQ1-mediated changes in proteins in the ARY009 apoptosis array.	('Quercetin', 'Chemical', 'MESH:D011794', (354, 363))	('tumor', 'Phenotype', 'HP:0002664', (483, 488))	('hnRNPA1', 'Gene', (572, 579))	('apoptosis', 'biological_process', 'GO:0097194', ('283', '292'))	('Quercetin', 'Chemical', 'MESH:D011794', (677, 686))	('apoptosis', 'biological_process', 'GO:0006915', ('283', '292'))	('tumors', 'Phenotype', 'HP:0002664', (483, 489))	('drug interaction', 'Phenotype', 'HP:0020172', (534, 550))	('apoptosis', 'biological_process', 'GO:0097194', ('640', '649'))	('apoptosis', 'biological_process', 'GO:0097194', ('737', '746'))	('apoptosis', 'biological_process', 'GO:0006915', ('640', '649'))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('apoptosis', 'biological_process', 'GO:0006915', ('737', '746'))	('Quercetin', 'Chemical', 'MESH:D011794', (56, 65))	('tumor', 'Disease', (105, 110))	('tumors', 'Disease', (483, 489))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('Quercetin', 'Chemical', 'MESH:D011794', (213, 222))	('knockdown', 'Var', (580, 589))	('tumor', 'Disease', (483, 488))	('Quercetin', 'Chemical', 'MESH:D011794', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (483, 488))	('rat', 'Species', '10116', (399, 402))	('tumors', 'Disease', 'MESH:D009369', (483, 489))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
44427	30365304	To analyze how the GOT1 inhibitor bound to GOT1, a series of GOT1 mutant enzymes that abolished PLP binding were generated.	('mutant', 'Var', (66, 72))	('PLP', 'Gene', (96, 99))	('GOT1', 'Gene', (19, 23))	('GOT1', 'Gene', '2805', (19, 23))	('GOT1', 'Gene', '2805', (43, 47))	('GOT1', 'Gene', '2805', (61, 65))	('PLP', 'Gene', '57026', (96, 99))	('binding', 'molecular_function', 'GO:0005488', ('100', '107'))	('GOT1', 'Gene', (43, 47))	('GOT1', 'Gene', (61, 65))
44429	30365304	Mutational studies revealed the relationship between PLP binding and the thermal stability of GOT1 while highlighting the essential nature of several residues for GOT1 catalytic activity.	('GOT1', 'Gene', '2805', (94, 98))	('relationship', 'Reg', (32, 44))	('revealed', 'Reg', (19, 27))	('binding', 'Interaction', (57, 64))	('GOT1', 'Gene', '2805', (163, 167))	('PLP', 'Gene', '57026', (53, 56))	('GOT1', 'Gene', (163, 167))	('GOT1', 'Gene', (94, 98))	('Mutational', 'Var', (0, 10))	('thermal stability', 'MPA', (73, 90))	('PLP', 'Gene', (53, 56))
44435	30365304	Inhibition of an essential enzyme in this pathway, cytosolic glutamate oxaloacetate transaminase 1 (GOT1, UniProtKB entry P17174), is profoundly growth inhibitory in PDA cells and tumors but well tolerated by normal pancreatic cells and fibroblasts.	('growth inhibitory', 'CPA', (145, 162))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('glutamate oxaloacetate transaminase 1', 'Gene', '2805', (61, 98))	('tumors', 'Disease', (180, 186))	('GOT1', 'Gene', '2805', (100, 104))	('Inhibition', 'Var', (0, 10))	('glutamate oxaloacetate transaminase 1', 'Gene', (61, 98))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('PDA', 'Phenotype', 'HP:0006725', (166, 169))	('P17174', 'Chemical', 'MESH:D010695', (122, 128))	('GOT1', 'Gene', (100, 104))
44442	30365304	In silico docking, X-ray crystallography, and thermal shift assays using wild type and mutant enzymes were then employed, which suggested, but were unable to formally conclude, that the GOT1 inhibitors act in a PLP-competitive manner.	('GOT1', 'Gene', '2805', (186, 190))	('GOT1', 'Gene', (186, 190))	('mutant', 'Var', (87, 93))	('PLP', 'Gene', (211, 214))	('PLP', 'Gene', '57026', (211, 214))
44461	30365304	The nal-concentrations of the components of the assay were as follows: 100 mM HEPES buffer, 100 mM KCl, 80 nM GLOX, 0.05 unit/mL HRP, 15 mg/mL Amplex Red, and ~1 nM GOT1 (adjusted from each purification to produce a 20 min linear reaction).	('GLOX', 'molecular_function', 'GO:0046569', ('110', '114'))	('HEPES', 'Chemical', 'MESH:D006531', (78, 83))	('GOT1', 'Gene', '2805', (165, 169))	('0.05', 'Var', (116, 120))	('GOT1', 'Gene', (165, 169))	('KCl', 'Chemical', 'MESH:D011189', (99, 102))
44477	30365304	GOT1 and GOT2 knockdowns were validated by Western blot analysis.	('GOT2', 'Gene', (9, 13))	('GOT1', 'Gene', '2805', (0, 4))	('GOT1', 'Gene', (0, 4))	('GOT2', 'Gene', '2806', (9, 13))	('knockdowns', 'Var', (14, 24))
44482	30365304	The following antibodies were used: anti-aspartate aminotransferase (anti-GOT1) at a 1:1000 dilution (Abcam, ab17193), anti-GOT2 at a 1:1000 dilution (Abcam, ab171739), and loading control vinculin at a 1:10000 dilution (Cell Signaling).	('GOT2', 'Gene', (124, 128))	('vinculin', 'Gene', '7414', (189, 197))	('GOT1', 'Gene', '2805', (74, 78))	('aspartate', 'Chemical', 'None', (41, 50))	('GOT1', 'Gene', (74, 78))	('vinculin', 'Gene', (189, 197))	('Signaling', 'biological_process', 'GO:0023052', ('226', '235'))	('GOT2', 'Gene', '2806', (124, 128))	('anti-aspartate', 'Var', (36, 50))
44486	30365304	GOT1 or mutant GOT1 protein (300 ng) was preincubated at 37  C in a buffer containing 200 mM HEPES (pH 7.4) and 200 mM KCl.	('GOT1', 'Gene', '2805', (15, 19))	('GOT1', 'Gene', (15, 19))	('mutant', 'Var', (8, 14))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('GOT1', 'Gene', '2805', (0, 4))	('HEPES', 'Chemical', 'MESH:D006531', (93, 98))	('GOT1', 'Gene', (0, 4))	('KCl', 'Chemical', 'MESH:D011189', (119, 122))
44487	30365304	A separate reaction mix containing 4 mM aspartate, 0.5 mM alphaKG, 80 nM GLOX, 0.5 unit of HRP (Sigma-Aldrich), and 1.285 mug of Amplex Red Reagent (Invitrogen) was also prepared and prewarmed at 37  C. WT-GOT1 or mutants were then added to the reaction mix to bring the final volume to 100 muL.	('GLOX', 'molecular_function', 'GO:0046569', ('73', '77'))	('mug', 'molecular_function', 'GO:0043739', ('122', '125'))	('alphaKG', 'Chemical', 'MESH:D020410', (58, 65))	('GOT1', 'Gene', (206, 210))	('GOT1', 'Gene', '2805', (206, 210))	('mutants', 'Var', (214, 221))	('aspartate', 'Chemical', 'None', (40, 49))
44491	30365304	Interpolation using the H2O2 standard curve was used to determine velocities (micromolar per minute per milligram) for WT-GOT1 or mutant GOT1 enzymes.	('GOT1', 'Gene', '2805', (122, 126))	('GOT1', 'Gene', '2805', (137, 141))	('H2O2', 'Chemical', 'MESH:D014867', (24, 28))	('GOT1', 'Gene', (137, 141))	('GOT1', 'Gene', (122, 126))	('mutant', 'Var', (130, 136))	('velocities', 'MPA', (66, 76))
44495	30365304	A glide grid of 8000 A3 was centered on residues previously identified as being near the PLP binding site, including F19, E142, and D223 as identified in the GOT1 crystal structure.	('E142', 'Var', (122, 126))	('PLP', 'Gene', '57026', (89, 92))	('binding', 'molecular_function', 'GO:0005488', ('93', '100'))	('GOT1', 'Gene', '2805', (158, 162))	('F19', 'Var', (117, 120))	('GOT1', 'Gene', (158, 162))	('D223', 'Var', (132, 136))	('PLP', 'Gene', (89, 92))
44509	30365304	In the T110A/S256A mutant structure, no density was observed for iGOT1-074-8.	('GOT1', 'Gene', (66, 70))	('S256A', 'Mutation', 'p.S256A', (13, 18))	('T110A', 'SUBSTITUTION', 'None', (7, 12))	('GOT1', 'Gene', '2805', (66, 70))	('T110A', 'Var', (7, 12))
44527	30365304	In addition, we demonstrated that shRNA-mediated GOT1 knockdown led to the accumulation of aspartate and predominantly the M + 4 isotopologue of aspartate.	('aspartate', 'Chemical', 'None', (91, 100))	('knockdown', 'Var', (54, 63))	('GOT1', 'Gene', (49, 53))	('aspartate', 'Chemical', 'None', (145, 154))	('GOT1', 'Gene', '2805', (49, 53))	('aspartate', 'MPA', (91, 100))	('M + 4 isotopologue of aspartate', 'MPA', (123, 154))	('accumulation', 'PosReg', (75, 87))
44531	30365304	In pancreatic cancer cells, inhibition of GOT1 preferentially leads to accumulation of the M + 4 aspartate isotopologue from [13C]glutamine.	('accumulation', 'PosReg', (71, 83))	('pancreatic cancer', 'Disease', (3, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('inhibition', 'Var', (28, 38))	('M + 4 aspartate isotopologue from [13C]glutamine', 'MPA', (91, 139))	('aspartate', 'Chemical', 'None', (97, 106))	('[13C]glutamine', 'Chemical', 'MESH:C513342', (125, 139))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('GOT1', 'Gene', '2805', (42, 46))	('GOT1', 'Gene', (42, 46))
44539	30365304	In contrast, here we found that the growth of DLD1 cells was not impacted by GOT1 or GOT2 knockdown (Figure 2H-K and Figure S5B-G).	('knockdown', 'Var', (90, 99))	('GOT2', 'Gene', '2806', (85, 89))	('GOT1', 'Gene', '2805', (77, 81))	('GOT1', 'Gene', (77, 81))	('GOT2', 'Gene', (85, 89))	('S5B-G', 'Chemical', 'MESH:D013455', (124, 129))	('H-K', 'Chemical', 'MESH:C024755', (109, 112))
44546	30365304	Several interactions were predicted between GOT1 and iGOT1-790-5, including hydrogen bonding among Tyr226, Trp141, Asp223, Asn195, and Gly39, three of which were also reported to bind PLP.	('GOT1', 'Gene', '2805', (44, 48))	('Asn195', 'Chemical', 'MESH:C499994', (123, 129))	('Asn195', 'Var', (123, 129))	('Gly39', 'Var', (135, 140))	('Tyr226', 'Var', (99, 105))	('interactions', 'Interaction', (8, 20))	('Asp223', 'Var', (115, 121))	('hydrogen', 'Chemical', 'MESH:D006859', (76, 84))	('predicted', 'Reg', (26, 35))	('hydrogen bonding', 'MPA', (76, 92))	('Trp141', 'Chemical', 'MESH:C068320', (107, 113))	('GOT1', 'Gene', (54, 58))	('PLP', 'Gene', (184, 187))	('Tyr', 'Chemical', 'MESH:C042696', (99, 102))	('Trp141', 'Gene', (107, 113))	('GOT1', 'Gene', '2805', (54, 58))	('GOT1', 'Gene', (44, 48))	('Asp223', 'Chemical', 'MESH:C076113', (115, 121))	('bind', 'Interaction', (179, 183))	('PLP', 'Gene', '57026', (184, 187))
44547	30365304	In this structure, PLP displayed polar contacts with Trp141, Asp223, Tyr226, Gly109, Thr110, Ser256, Phe257, and Lys259.	('Asp223', 'Var', (61, 67))	('Lys259', 'Var', (113, 119))	('polar contacts', 'MPA', (33, 47))	('Lys259', 'Chemical', 'MESH:C570647', (113, 119))	('Asp223', 'Chemical', 'MESH:C076113', (61, 67))	('Phe257', 'Chemical', 'MESH:C006076', (101, 107))	('Phe257', 'Var', (101, 107))	('Tyr', 'Chemical', 'MESH:C042696', (69, 72))	('Trp141', 'Chemical', 'MESH:C068320', (53, 59))	('Trp141', 'Var', (53, 59))	('Tyr226', 'Var', (69, 75))	('Ser', 'Chemical', 'MESH:C530429', (93, 96))	('PLP', 'Gene', '57026', (19, 22))	('Thr110', 'Var', (85, 91))	('Ser', 'cellular_component', 'GO:0005790', ('93', '96'))	('Ser256', 'Var', (93, 99))	('Gly109', 'Var', (77, 83))	('PLP', 'Gene', (19, 22))
44548	30365304	To eliminate the competition between iGOT1-790-5 and endogenous PLP, a series of mutants were designed (T110A, S256A, and T110A/S256A) to ablate PLP binding and open the active site for iGOT1-790-5.	('S256A', 'Mutation', 'p.S256A', (111, 116))	('GOT1', 'Gene', '2805', (187, 191))	('PLP', 'Gene', '57026', (64, 67))	('S256A', 'Mutation', 'p.S256A', (128, 133))	('S256A', 'Var', (111, 116))	('T110A', 'Mutation', 'rs1472691746', (104, 109))	('T110A', 'Var', (104, 109))	('PLP', 'Gene', (145, 148))	('T110A', 'SUBSTITUTION', 'None', (122, 127))	('binding', 'molecular_function', 'GO:0005488', ('149', '156'))	('active site', 'MPA', (170, 181))	('PLP', 'Gene', '57026', (145, 148))	('GOT1', 'Gene', (38, 42))	('T110A', 'SUBSTITUTION', 'None', (104, 109))	('PLP', 'Gene', (64, 67))	('ablate', 'NegReg', (138, 144))	('T110A', 'Var', (122, 127))	('GOT1', 'Gene', (187, 191))	('binding', 'Interaction', (149, 156))	('GOT1', 'Gene', '2805', (38, 42))	('T110A', 'Mutation', 'rs1472691746', (122, 127))	('open', 'PosReg', (161, 165))
44552	30365304	Next, we generated and analyzed the activity of the mutant GOT1 structures, relative to that of WT-GOT1.	('mutant', 'Var', (52, 58))	('activity', 'MPA', (36, 44))	('GOT1', 'Gene', '2805', (99, 103))	('GOT1', 'Gene', (99, 103))	('GOT1', 'Gene', '2805', (59, 63))	('GOT1', 'Gene', (59, 63))
44554	30365304	The relative activities of GOT1 mutants, compared to that of the wild type enzyme, were determined by comparison of the specific activity at the apparent KM of each substrate.	('GOT1', 'Gene', '2805', (27, 31))	('mutants', 'Var', (32, 39))	('GOT1', 'Gene', (27, 31))
44555	30365304	The T110A mutant trended toward being less active than the S256A mutant; however, the difference between the two was not significant (Figure 4).	('T110A', 'Mutation', 'rs1472691746', (4, 9))	('S256A', 'Mutation', 'p.S256A', (59, 64))	('active', 'MPA', (43, 49))	('less', 'NegReg', (38, 42))	('T110A', 'Var', (4, 9))
44557	30365304	Furthermore, introduction of the double mutant T110A/S256A completely ablated enzyme activity and allowed us to assume there was no PLP bound in the active site (Figure 4 and Figure S6C,D).	('S256A', 'Mutation', 'p.S256A', (53, 58))	('T110A', 'SUBSTITUTION', 'None', (47, 52))	('enzyme', 'Enzyme', (78, 84))	('ablated', 'NegReg', (70, 77))	('T110A', 'Var', (47, 52))	('PLP', 'Gene', (132, 135))	('PLP', 'Gene', '57026', (132, 135))	('activity', 'MPA', (85, 93))	('enzyme activity', 'molecular_function', 'GO:0003824', ('78', '93'))
44558	30365304	We performed X-ray protein co-crystallographic studies using wild type and mutant variants of GOT1 and a GOT1 inhibitor further optimized for solubility and into which bromine was substituted to facilitate phase determination [iGOT1-074-8 (Figure S6E)].	('variants', 'Var', (82, 90))	('GOT1', 'Gene', '2805', (94, 98))	('GOT1', 'Gene', '2805', (105, 109))	('GOT1', 'Gene', '2805', (228, 232))	('GOT1', 'Gene', (94, 98))	('bromine', 'Chemical', 'MESH:D001966', (168, 175))	('GOT1', 'Gene', (105, 109))	('GOT1', 'Gene', (228, 232))	('mutant variants', 'Var', (75, 90))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))
44560	30365304	On the basis of relative catalytic activities, we predicted that the T110A/S256A double mutant would not possess bound endogenous PLP and that this would facilitate the observation of iGOT1-074-8 bound within the GOT1 PLP binding site.	('PLP', 'Gene', (218, 221))	('T110A', 'Var', (69, 74))	('PLP', 'Gene', (130, 133))	('GOT1', 'Gene', (185, 189))	('PLP', 'Gene', '57026', (218, 221))	('bound', 'Interaction', (196, 201))	('PLP', 'Gene', '57026', (130, 133))	('GOT1', 'Gene', '2805', (213, 217))	('S256A', 'Mutation', 'p.S256A', (75, 80))	('GOT1', 'Gene', '2805', (185, 189))	('T110A', 'SUBSTITUTION', 'None', (69, 74))	('binding', 'molecular_function', 'GO:0005488', ('222', '229'))	('facilitate', 'PosReg', (154, 164))	('GOT1', 'Gene', (213, 217))
44561	30365304	Efforts to co-crystallize either the T110A or S256A single mutant with iGOT1-074-8 resulted in structures that contained electron density within the PLP binding site corresponding to bound PLP but not the iGOT1-074-8 ligand.	('S256A', 'Var', (46, 51))	('electron density', 'MPA', (121, 137))	('GOT1', 'Gene', '2805', (72, 76))	('GOT1', 'Gene', (72, 76))	('S256A', 'Mutation', 'p.S256A', (46, 51))	('ligand', 'molecular_function', 'GO:0005488', ('217', '223'))	('PLP', 'Gene', (189, 192))	('PLP', 'Gene', '57026', (189, 192))	('T110A', 'Mutation', 'rs1472691746', (37, 42))	('PLP', 'Gene', (149, 152))	('PLP', 'Gene', '57026', (149, 152))	('T110A', 'Var', (37, 42))	('binding', 'molecular_function', 'GO:0005488', ('153', '160'))	('contained', 'Reg', (111, 120))	('GOT1', 'Gene', '2805', (206, 210))	('bound', 'Interaction', (183, 188))	('GOT1', 'Gene', (206, 210))
44562	30365304	Consistent with the observed ablation of catalytic activity displayed by the T110A/S256A double mutant (Figure 4), efforts to co-crystallize this form of the protein resulted in a structure that lacked electron density within the PLP binding site that would correspond to either a bound molecule of PLP or the iGOT1-074-8 ligand.	('lacked', 'NegReg', (195, 201))	('T110A', 'SUBSTITUTION', 'None', (77, 82))	('binding', 'molecular_function', 'GO:0005488', ('234', '241'))	('PLP', 'Gene', (230, 233))	('PLP', 'Gene', '57026', (230, 233))	('PLP', 'Gene', (299, 302))	('PLP', 'Gene', '57026', (299, 302))	('electron density', 'MPA', (202, 218))	('T110A', 'Var', (77, 82))	('GOT1', 'Gene', '2805', (311, 315))	('GOT1', 'Gene', (311, 315))	('catalytic activity', 'molecular_function', 'GO:0003824', ('41', '59'))	('catalytic activity', 'MPA', (41, 59))	('S256A', 'Mutation', 'p.S256A', (83, 88))	('protein', 'cellular_component', 'GO:0003675', ('158', '165'))	('ligand', 'molecular_function', 'GO:0005488', ('322', '328'))
44567	30365304	In contrast to that of WT-GOT1, the structure of the T110A mutant has six monomers in the asymmetric unit with partial density for the PLP cofactor in the active site (Figure S7C).	('T110A', 'Mutation', 'rs1472691746', (53, 58))	('GOT1', 'Gene', '2805', (26, 30))	('T110A', 'Var', (53, 58))	('GOT1', 'Gene', (26, 30))	('PLP', 'Gene', (135, 138))	('PLP', 'Gene', '57026', (135, 138))
44570	30365304	We observed lower activity for the T110A mutant protein than for the WT protein, which correlated with a decrease in the electron density for PLP in the T110A mutant when compared to WT (Figure 5B,C).	('T110A', 'Mutation', 'rs1472691746', (35, 40))	('electron density', 'MPA', (121, 137))	('activity', 'MPA', (18, 26))	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('T110A', 'Var', (35, 40))	('T110A', 'Mutation', 'rs1472691746', (153, 158))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('T110A', 'Var', (153, 158))	('PLP', 'Gene', (142, 145))	('PLP', 'Gene', '57026', (142, 145))	('decrease', 'NegReg', (105, 113))	('lower', 'NegReg', (12, 17))
44571	30365304	In the double mutant structure, there was no density for PLP, confirming the abolishment of enzymatic activity (Figure 5D).	('PLP', 'Gene', '57026', (57, 60))	('PLP', 'Gene', (57, 60))	('enzymatic', 'MPA', (92, 101))	('double mutant', 'Var', (7, 20))
44572	30365304	Thermal shift assays (TSA) were utilized to biophysically characterize recombinant human WT-GOT1 and its mutants.	('GOT1', 'Gene', '2805', (92, 96))	('TSA', 'Chemical', 'MESH:C070842', (22, 25))	('human', 'Species', '9606', (83, 88))	('TSA', 'molecular_function', 'GO:0033984', ('22', '25'))	('GOT1', 'Gene', (92, 96))	('mutants', 'Var', (105, 112))
44574	30365304	In contrast to the WT protein, the T110A and S256A mutants were observed by SEC to be exclusively dimeric in solution (Figure S9A).	('T110A', 'Mutation', 'rs1472691746', (35, 40))	('T110A', 'Var', (35, 40))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('S256A', 'Mutation', 'p.S256A', (45, 50))	('S256A', 'Var', (45, 50))
44575	30365304	Via comparison of the TSA results of GOT1 variants (in the absence of iGOT1-074-8), both T110A and S256A GOT1 mutants displayed a minor melting peak near 40  C, likely corresponding to apoprotein, free of PLP (Figure 6A).	('GOT1', 'Gene', '2805', (105, 109))	('GOT1', 'Gene', '2805', (37, 41))	('GOT1', 'Gene', '2805', (71, 75))	('GOT1', 'Gene', (71, 75))	('TSA', 'Chemical', 'MESH:C070842', (22, 25))	('GOT1', 'Gene', (105, 109))	('TSA', 'molecular_function', 'GO:0033984', ('22', '25'))	('S256A', 'Mutation', 'p.S256A', (99, 104))	('GOT1', 'Gene', (37, 41))	('S256A', 'Var', (99, 104))	('PLP', 'Gene', (205, 208))	('T110A', 'Mutation', 'rs1472691746', (89, 94))	('T110A', 'Var', (89, 94))	('PLP', 'Gene', '57026', (205, 208))
44578	30365304	A titration of T110A/S256A with PLP at high concentrations shifted the melting profile from 40 to 70  C, supporting the assignment of these peaks as the PLP-unbound and -bound forms (Figure 6B).	('to 7', 'Species', '1214577', (95, 99))	('T110A', 'SUBSTITUTION', 'None', (15, 20))	('T110A', 'Var', (15, 20))	('PLP', 'Gene', (32, 35))	('S256A', 'Mutation', 'p.S256A', (21, 26))	('PLP', 'Gene', (153, 156))	('PLP', 'Gene', '57026', (32, 35))	('PLP', 'Gene', '57026', (153, 156))
44591	30365304	In addition, dependence on GOT activity is a feature of several types of cancer, and inhibition of mitochondrial metabolism sensitizes cancer cells to GOT inhibition.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (135, 141))	('metabolism', 'biological_process', 'GO:0008152', ('113', '123'))	('inhibition', 'Var', (85, 95))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mitochondrial metabolism sensitizes cancer', 'Disease', (99, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('mitochondrial metabolism sensitizes cancer', 'Disease', 'MESH:D009369', (99, 141))
44595	30365304	Residues Thr110 and Ser256 face the phosphate group.	('Thr110', 'Var', (9, 15))	('Ser', 'Chemical', 'MESH:C530429', (20, 23))	('Ser256', 'Var', (20, 26))	('Ser', 'cellular_component', 'GO:0005790', ('20', '23'))	('phosphate', 'Chemical', 'MESH:D010710', (36, 45))
44596	30365304	Lys259 faces the PLP aldehyde to form a Schiff base making an internal aldimine.	('PLP', 'Gene', (17, 20))	('PLP', 'Gene', '57026', (17, 20))	('Lys259', 'Var', (0, 6))	('aldimine', 'Chemical', 'MESH:C042448', (71, 79))	('Lys259', 'Chemical', 'MESH:C570647', (0, 6))	('aldehyde', 'Chemical', 'MESH:D000447', (21, 29))	('Schiff', 'Chemical', 'MESH:D012545', (40, 46))
44597	30365304	Residues Tyr226 and Asp195 make hydrogen bonds to the PLP hydroxyl group.	('PLP', 'Gene', '57026', (54, 57))	('hydrogen bonds', 'MPA', (32, 46))	('Asp', 'Chemical', 'MESH:C108952', (20, 23))	('Asp195', 'Var', (20, 26))	('Tyr', 'Chemical', 'MESH:C042696', (9, 12))	('Tyr226', 'Var', (9, 15))	('PLP', 'Gene', (54, 57))	('hydrogen', 'Chemical', 'MESH:D006859', (32, 40))
44598	30365304	Asp223 makes a hydrogen bond to the pyridinyl nitrogen of the PLP cofactor.	('hydrogen', 'Chemical', 'MESH:D006859', (15, 23))	('PLP', 'Gene', (62, 65))	('PLP', 'Gene', '57026', (62, 65))	('hydrogen bond', 'MPA', (15, 28))	('Asp223', 'Var', (0, 6))	('Asp223', 'Chemical', 'MESH:C076113', (0, 6))	('pyridinyl nitrogen', 'Chemical', 'MESH:D009584', (36, 54))
44600	30365304	As previously described, an extended hydrogen bond network involving residues Asp222, His143, and His189 and water molecules affects the protonation state of the PLP pyridine nitrogen and its activation.	('hydrogen', 'Chemical', 'MESH:D006859', (37, 45))	('Asp', 'Chemical', 'MESH:C108952', (78, 81))	('activation', 'MPA', (192, 202))	('His189', 'Var', (98, 104))	('nitrogen', 'Chemical', 'MESH:D009584', (175, 183))	('PLP', 'Gene', (162, 165))	('His143', 'Var', (86, 92))	('PLP', 'Gene', '57026', (162, 165))	('affects', 'Reg', (125, 132))
44602	30365304	It was interesting to note that single mutation of either Thr110A or Ser256A resulted in an altered oligomeric state of the protein, eliminating the tetrameric species compared to the WT protein.	('tetrameric species', 'MPA', (149, 167))	('oligomeric state of the', 'MPA', (100, 123))	('Ser', 'cellular_component', 'GO:0005790', ('69', '72'))	('protein', 'Protein', (124, 131))	('Ser256A', 'Mutation', 'p.S256A', (69, 76))	('eliminating', 'NegReg', (133, 144))	('Thr110A', 'Var', (58, 65))	('altered', 'Reg', (92, 99))	('Ser256A', 'Var', (69, 76))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))
44603	30365304	Comparing the structure of T110A or T110A/S256A to that of the WT does reveal a shift in the C-terminal helix (371-411) that sits at the dimer interface of tetrameric WT-GOT1 (Figure S8B).	('T110A', 'Var', (27, 32))	('GOT1', 'Gene', '2805', (170, 174))	('T110A', 'SUBSTITUTION', 'None', (36, 41))	('GOT1', 'Gene', (170, 174))	('T110A', 'Mutation', 'rs1472691746', (36, 41))	('T110A', 'SUBSTITUTION', 'None', (27, 32))	('T110A', 'Var', (36, 41))	('T110A', 'Mutation', 'rs1472691746', (27, 32))	('S256A', 'Mutation', 'p.S256A', (42, 47))
44605	30365304	Addition of iGOT1-074-8 to either the S256A or T110A mutant results in a melting profile that mimics the PLP-free state for the T110A/S256A mutant.	('T110A', 'SUBSTITUTION', 'None', (128, 133))	('T110A', 'SUBSTITUTION', 'None', (47, 52))	('S256A', 'Mutation', 'p.S256A', (38, 43))	('T110A', 'Mutation', 'rs1472691746', (128, 133))	('GOT1', 'Gene', '2805', (13, 17))	('S256A', 'Mutation', 'p.S256A', (134, 139))	('T110A', 'Var', (128, 133))	('T110A', 'Mutation', 'rs1472691746', (47, 52))	('GOT1', 'Gene', (13, 17))	('T110A', 'Var', (47, 52))	('melting profile', 'MPA', (73, 88))	('PLP', 'Gene', (105, 108))	('PLP', 'Gene', '57026', (105, 108))
44631	30338223	Recently, we reported that PRDM14 is overexpressed in PDAC tissues, compared to normal pancreatic tissues, and silencing the expression decreased cancer stem-like phenotypes including side population (SP) cells, tumor formation, and liver metastasis 12.	('cancer', 'Disease', (146, 152))	('pancreatic', 'Disease', 'MESH:D010195', (87, 97))	('pancreatic', 'Disease', (87, 97))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('silencing', 'Var', (111, 120))	('liver metastasis', 'Disease', (233, 249))	('liver metastasis', 'Disease', 'MESH:D009362', (233, 249))	('formation', 'biological_process', 'GO:0009058', ('218', '227'))	('PRDM14', 'Gene', (27, 33))	('expression', 'MPA', (125, 135))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('SP', 'Chemical', '-', (201, 203))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('PDAC', 'Chemical', '-', (54, 58))	('overexpressed', 'PosReg', (37, 50))	('decreased', 'NegReg', (136, 145))	('tumor', 'Disease', (212, 217))
44692	30338223	A cancer stem cell marker DclK1, which is also reported to be expressed in PanIN and facilitate tumor progression in KRAS-mutated mice and human pancreatic cancer, was upregulated by cerulein 28.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Disease', (2, 8))	('cancer', 'Phenotype', 'HP:0002664', (2, 8))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (145, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('mice', 'Species', '10090', (130, 134))	('cancer', 'Disease', 'MESH:D009369', (2, 8))	('upregulated', 'PosReg', (168, 179))	('tumor', 'Disease', (96, 101))	('pancreatic cancer', 'Disease', 'MESH:D010190', (145, 162))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('DclK1', 'Gene', (26, 31))	('cancer', 'Disease', (156, 162))	('pancreatic cancer', 'Disease', (145, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('DclK1', 'Gene', '13175', (26, 31))	('human', 'Species', '9606', (139, 144))	('cerulein 28', 'Var', (183, 194))	('facilitate', 'PosReg', (85, 95))
44706	30338223	We previously reported that inhibition of PRDM14 expression decreases cancer stem-like phenotypes, including SP cells, in pancreatic cancer cells 12.	('pancreatic cancer', 'Disease', 'MESH:D010190', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('decreases cancer', 'Disease', 'MESH:D009369', (60, 76))	('PRDM14', 'Gene', (42, 48))	('inhibition', 'Var', (28, 38))	('decreases cancer', 'Disease', (60, 76))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (122, 139))	('SP', 'Chemical', '-', (109, 111))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('pancreatic cancer', 'Disease', (122, 139))	('SP cells', 'CPA', (109, 117))
44717	30338223	To investigate the effects of PRDM14 expression induction by chronic pancreatitis on tumorigenesis, more experiments using transgenic mice, such as those harboring KRAS mutations and PRDM14 knockouts, should be performed in the future.	('pancreatitis', 'Phenotype', 'HP:0001733', (69, 81))	('tumor', 'Disease', (85, 90))	('PRDM14', 'Gene', (30, 36))	('mutations', 'Var', (169, 178))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (61, 81))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (61, 81))	('transgenic mice', 'Species', '10090', (123, 138))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('chronic pancreatitis', 'Disease', (61, 81))
44718	30338223	If PRDM14 knockout reduces either inflammatory responses or the formation of PanIN and PDAC, targeting PRDM14 expression may be useful treatment strategy against the early lesions prior to PDAC.	('formation', 'MPA', (64, 73))	('PDAC', 'Chemical', '-', (189, 193))	('PRDM14', 'Gene', (3, 9))	('PDAC', 'Chemical', '-', (87, 91))	('PRDM14', 'Gene', (103, 109))	('knockout', 'Var', (10, 18))	('formation', 'biological_process', 'GO:0009058', ('64', '73'))	('inflammatory responses', 'CPA', (34, 56))	('reduces', 'NegReg', (19, 26))	('PanIN', 'MPA', (77, 82))
44736	30038723	In conclusion, high circulating IL-6 was associated with short OS in most studies in GI cancer patients.	('high', 'Var', (15, 19))	('IL-6', 'molecular_function', 'GO:0005138', ('32', '36'))	('associated', 'Reg', (41, 51))	('GI cancer', 'Disease', (85, 94))	('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))
44737	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))	('IL-6', 'molecular_function', 'GO:0005138', ('22', '26'))	('inhibition', 'Var', (8, 18))
44775	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))	('secretion', 'biological_process', 'GO:0046903', ('185', '194'))	('men', 'Species', '9606', (67, 70))	('O2', 'Chemical', '-', (104, 106))	('IL-6', 'molecular_function', 'GO:0005138', ('198', '202'))	('increase', 'PosReg', (16, 24))	('lack', 'Var', (147, 151))	('secretion of IL-6', 'MPA', (185, 202))	('IL-1beta', 'Gene', '3553', (73, 81))	('IL-1', 'molecular_function', 'GO:0005149', ('73', '77'))	('PGE2', 'Chemical', 'MESH:D015232', (94, 98))	('PGE2', 'Gene', (94, 98))	('IL-1beta', 'Gene', (73, 81))
44783	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', (121, 127))	('high', 'Var', (2, 6))	('drug resistance', 'biological_process', 'GO:0009315', ('231', '246'))	('drug resistance', 'biological_process', 'GO:0042493', ('231', '246'))	('IL-6', 'Gene', (7, 11))	('cancer', 'Disease', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('ovarian and prostate cancer', 'Disease', 'MESH:D010051', (100, 127))	('cancer', 'Disease', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('drug resistance', 'Phenotype', 'HP:0020174', (231, 246))	('IL-6', 'molecular_function', 'GO:0005138', ('7', '11'))	('high IL-6 level', 'Phenotype', 'HP:0030783', (2, 17))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('men', 'Species', '9606', (211, 214))	('cancer', 'Disease', (121, 127))
44789	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))	('IL-6', 'molecular_function', 'GO:0005138', ('227', '231'))	('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))
44790	30038723	showed that CDX2 is suppressed by the activation of the IL-6/STAT3 signal pathway via miR181b in vitro.	('miR181b', 'Var', (86, 93))	('IL-6', 'molecular_function', 'GO:0005138', ('56', '60'))	('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))
44810	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))	('ligand', 'molecular_function', 'GO:0005488', ('70', '76'))	('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))	('death', 'Disease', 'MESH:D003643', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('decrease', 'NegReg', (110, 118))	('death', 'Disease', (62, 67))	('IL-6', 'molecular_function', 'GO:0005138', ('37', '41'))	('tumor', 'Disease', (122, 127))	('pancreatic cancer', 'Disease', (89, 106))
44813	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))	('IL-6', 'molecular_function', 'GO:0005138', ('130', '134'))	('regeneration', 'biological_process', 'GO:0031099', ('107', '119'))	('IL-6', 'molecular_function', 'GO:0005138', ('0', '4'))	('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))	('apoptosis', 'biological_process', 'GO:0097194', ('82', '91'))	('associated with', 'Reg', (152, 167))	('high IL-6 level', 'Phenotype', 'HP:0030783', (125, 140))	('GI', 'Phenotype', 'HP:0007378', (68, 70))	('apoptosis', 'biological_process', 'GO:0006915', ('82', '91'))	('high', 'Var', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
44814	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.	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('men', 'Species', '9606', (52, 55))	('increased', 'PosReg', (141, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('antibody', 'molecular_function', 'GO:0003823', ('118', '126'))	('anti-IL-6-antibody', 'Var', (108, 126))	('colorectal cancer', 'Disease', (81, 98))	('antibody', 'cellular_component', 'GO:0042571', ('118', '126'))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('chemo sensibility', 'CPA', (151, 168))	('IL-6', 'molecular_function', 'GO:0005138', ('113', '117'))	('cancer', 'Disease', (92, 98))	('antibody', 'cellular_component', 'GO:0019815', ('118', '126'))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('cancer', 'Disease', (60, 66))	('antibody', 'cellular_component', 'GO:0019814', ('118', '126'))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('IL-6', 'molecular_function', 'GO:0005138', ('12', '16'))
44848	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).	('IL-6', 'molecular_function', 'GO:0005138', ('116', '120'))	('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))
44860	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))	('IL-6', 'molecular_function', 'GO:0005138', ('137', '141'))	('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))
44862	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))	('IL-6', 'molecular_function', 'GO:0005138', ('50', '54'))	('low IL-6 level', 'Var', (46, 60))	('IL-6', 'molecular_function', 'GO:0005138', ('84', '88'))	('high IL-6 level', 'Phenotype', 'HP:0030783', (79, 94))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('patients', 'Species', '9606', (138, 146))
44863	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))	('IL-6', 'molecular_function', 'GO:0005138', ('59', '63'))	('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))	('IL-6', 'molecular_function', 'GO:0005138', ('144', '148'))	('patients', 'Species', '9606', (120, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (25, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (105, 119))	('gastric cancer', 'Disease', (25, 39))
44864	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))	('IL-6', 'molecular_function', 'GO:0005138', ('42', '46'))	('OS', 'Chemical', '-', (59, 61))	('high', 'Var', (37, 41))
44865	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))	('IL-6', 'molecular_function', 'GO:0005138', ('164', '168'))	('high IL-6 levels', 'Phenotype', 'HP:0030783', (50, 66))	('IL-6', 'molecular_function', 'GO:0005138', ('55', '59'))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('gastric cancer', 'Disease', (4, 18))	('gastric cancer', 'Disease', 'MESH:D013274', (4, 18))
44867	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.	('IL-6', 'molecular_function', 'GO:0005138', ('102', '106'))	('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))	('IL-6', 'molecular_function', 'GO:0005138', ('14', '18'))	('gastric cancer', 'Disease', 'MESH:D013274', (34, 48))	('patients', 'Species', '9606', (49, 57))	('high', 'Var', (97, 101))	('gastric cancer', 'Phenotype', 'HP:0012126', (34, 48))
44873	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))	('IL-6', 'molecular_function', 'GO:0005138', ('16', '20'))	('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))	('IL-6', 'molecular_function', 'GO:0005138', ('161', '165'))	('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))
44875	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))	('IL-6', 'molecular_function', 'GO:0005138', ('41', '45'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (57, 74))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('IL-6', 'molecular_function', 'GO:0005138', ('226', '230'))	('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))
44877	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))	('IL-1', 'molecular_function', 'GO:0005149', ('172', '176'))	('short PFS', 'Disease', (254, 263))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (54, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('IL-1', 'molecular_function', 'GO:0005149', ('42', '46'))	('gemcitabine', 'Chemical', 'MESH:C056507', (96, 107))	('high', 'Var', (157, 161))	('IL-6', 'molecular_function', 'GO:0005138', ('33', '37'))	('IL-1beta', 'Gene', (42, 50))	('OS', 'Chemical', '-', (235, 237))	('IL-6', 'molecular_function', 'GO:0005138', ('162', '166'))	('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))
44892	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))	('IL-6', 'molecular_function', 'GO:0005138', ('86', '90'))	('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))
44893	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))	('IL-6', 'molecular_function', 'GO:0005138', ('65', '69'))	('OS', 'Chemical', '-', (39, 41))	('serum IL-6', 'Gene', (59, 69))	('patients', 'Species', '9606', (45, 53))	('shorter', 'NegReg', (98, 105))
44914	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', 'molecular_function', 'GO:0005138', ('115', '119'))	('IL-6', 'Gene', (54, 58))	('high', 'Var', (49, 53))	('OS', 'Chemical', '-', (92, 94))	('patients', 'Species', '9606', (35, 43))	('IL-6', 'molecular_function', 'GO:0005138', ('54', '58'))	('shorter', 'NegReg', (77, 84))	('3-year', 'CPA', (85, 91))
44926	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))	('IL-6', 'molecular_function', 'GO:0005138', ('202', '206'))	('associated', 'Reg', (211, 221))	('high', 'Var', (187, 191))
44944	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))	('IL-6', 'molecular_function', 'GO:0005138', ('133', '137'))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
44949	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))	('IL-6', 'molecular_function', 'GO:0005138', ('11', '15'))	('patients', 'Species', '9606', (107, 115))	('pancreatic cancer', 'Disease', (89, 106))
44967	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.	('IL-6', 'molecular_function', 'GO:0005138', ('140', '144'))	('IL6R', 'Gene', (12, 16))	('antibody', 'molecular_function', 'GO:0003823', ('28', '36'))	('antibody', 'cellular_component', 'GO:0042571', ('28', '36'))	('down-regulate', 'NegReg', (62, 75))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('patients', 'Species', '9606', (180, 188))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('immune suppression', 'MPA', (80, 98))	('IL6R', 'Gene', '3570', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('antibody', 'cellular_component', 'GO:0019815', ('28', '36'))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))	('inhibition', 'Var', (126, 136))	('antibody', 'cellular_component', 'GO:0019814', ('28', '36'))	('cancer', 'Disease', (194, 200))	('Tocilizumab', 'Chemical', 'MESH:C502936', (37, 48))	('IL6R', 'molecular_function', 'GO:0004915', ('12', '16'))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('IL-6', 'molecular_function', 'GO:0005138', ('206', '210'))	('tumor', 'Disease', (109, 114))
44975	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))	('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', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('IL-6', 'molecular_function', 'GO:0005138', ('11', '15'))	('inhibition', 'Var', (173, 183))	('IL-6R', 'Gene', '3570', (192, 197))	('IL-6R', 'molecular_function', 'GO:0004915', ('192', '197'))
44995	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))	('IL-6', 'molecular_function', 'GO:0005138', ('21', '25'))	('general activity', 'CPA', (61, 77))
45016	29973215	Our findings are in contrast with previous research by finding an association between low HIF-1alpha and poor prognosis.	('poor prognosis', 'CPA', (105, 119))	('low', 'Var', (86, 89))	('HIF-1alpha', 'Gene', '3091', (90, 100))	('HIF-1alpha', 'Gene', (90, 100))
45081	29973215	Multivariate analysis identified weak nuclear HIF-1alpha intensity as an independent prognostic factor for PDAC-specific deaths (HR 2.176, 95% CI 1.216-3.893, p = 0.009; Additional file 2: Table S1).	('PDAC', 'Chemical', '-', (107, 111))	('PDAC-specific', 'Disease', (107, 120))	('weak nuclear', 'Var', (33, 45))	('HIF-1alpha', 'Gene', (46, 56))	('PDAC', 'Phenotype', 'HP:0006725', (107, 111))	('HIF-1alpha', 'Gene', '3091', (46, 56))
45099	29973215	We hypothesize that the loss of HIF-1alpha in tumors with adverse prognosis could just be a marker of the simultaneous presence of multiple severe genetic aberrations in PDAC cells.	('loss', 'Var', (24, 28))	('genetic aberrations', 'Disease', 'MESH:D030342', (147, 166))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PDAC', 'Chemical', '-', (170, 174))	('PDAC', 'Phenotype', 'HP:0006725', (170, 174))	('genetic aberrations', 'Disease', (147, 166))	('HIF-1alpha in tumors', 'Disease', 'MESH:D009369', (32, 52))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('HIF-1alpha in tumors', 'Disease', (32, 52))
45139	29853866	It has been suggested that increased neutrophil counts are associated with greater tumor sizes and poorer survival rates in patients with confined nasopharyngeal cancer and renal cell carcinoma.	('poorer', 'NegReg', (99, 105))	('renal cell carcinoma', 'Disease', (173, 193))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('increased', 'PosReg', (27, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (173, 193))	('increased neutrophil counts', 'Phenotype', 'HP:0011897', (27, 54))	('survival', 'CPA', (106, 114))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (147, 168))	('tumor sizes', 'CPA', (83, 94))	('confined nasopharyngeal cancer', 'Disease', (138, 168))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (173, 193))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('greater', 'PosReg', (75, 82))	('neutrophil counts', 'Var', (37, 54))
45158	29728096	In patients with unresectable pancreatic cancer, PERT in patients with PEI was associated with longer survival compared with those not receiving PERT, especially in those experiencing significant weight loss.	('pancreatic cancer', 'Disease', 'MESH:D010190', (30, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('PERT', 'Chemical', '-', (145, 149))	('longer', 'PosReg', (95, 101))	('weight loss', 'Disease', (196, 207))	('weight loss', 'Disease', 'MESH:D015431', (196, 207))	('patients', 'Species', '9606', (57, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (30, 47))	('weight loss', 'Phenotype', 'HP:0001824', (196, 207))	('PEI', 'Var', (71, 74))	('patients', 'Species', '9606', (3, 11))	('PEI', 'Phenotype', 'HP:0001738', (71, 74))	('survival', 'MPA', (102, 110))	('PERT', 'Chemical', '-', (49, 53))	('pancreatic cancer', 'Disease', (30, 47))
45173	29728096	PEI causes digestion to be impaired, which commonly manifests as diarrhea and steatorrhea.	('PEI', 'Phenotype', 'HP:0001738', (0, 3))	('diarrhea', 'Phenotype', 'HP:0002014', (65, 73))	('steatorrhea', 'Disease', 'MESH:D045602', (78, 89))	('diarrhea', 'Disease', 'MESH:D003967', (65, 73))	('digestion', 'MPA', (11, 20))	('steatorrhea', 'Disease', (78, 89))	('diarrhea', 'Disease', (65, 73))	('steatorrhea', 'Phenotype', 'HP:0002570', (78, 89))	('digestion', 'biological_process', 'GO:0007586', ('11', '20'))	('PEI', 'Var', (0, 3))
45227	29728096	In the univariate and multivariate analysis, chemotherapy and PERT were significantly and independently associated with longer survival in a model that included age and tumor stage (Table 2).	('longer', 'PosReg', (120, 126))	('PERT', 'Var', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('chemotherapy', 'Var', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('PERT', 'Chemical', '-', (62, 66))
45230	29728096	This retrospective analysis conducted in patients with unresectable pancreatic cancer (locally advanced or metastatic disease) showed that the evaluation and treatment of PEI, in addition to standard chemotherapy and best supportive care, was associated with significantly prolonged survival compared with standard chemotherapy alone (189 versus 95 days, respectively, P < 0.001).	('PEI', 'Phenotype', 'HP:0001738', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('survival', 'MPA', (283, 291))	('patients', 'Species', '9606', (41, 49))	('PEI', 'Var', (171, 174))	('pancreatic cancer', 'Disease', (68, 85))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))	('prolonged', 'PosReg', (273, 282))
45242	29728096	Furthermore, PEI has been shown to negatively impact the quality of life of patients with pancreatic cancer, mainly due to its associated difficulties in managing diet and gastrointestinal symptoms.	('patients', 'Species', '9606', (76, 84))	('impact', 'Reg', (46, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('quality of life', 'CPA', (57, 72))	('negatively', 'NegReg', (35, 45))	('gastrointestinal symptoms', 'Disease', (172, 197))	('pancreatic cancer', 'Disease', (90, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gastrointestinal symptoms', 'Disease', 'MESH:D012817', (172, 197))	('PEI', 'Var', (13, 16))	('PEI', 'Phenotype', 'HP:0001738', (13, 16))
45259	29728096	Interestingly, the proportion of patients in this study that were suitable for chemotherapy and the number of therapy cycles that these patients tolerated increased with PERT, thus suggesting that PERT may increase tolerance to chemotherapy.	('PERT', 'Chemical', '-', (170, 174))	('patients', 'Species', '9606', (33, 41))	('PERT', 'Chemical', '-', (197, 201))	('PERT', 'Var', (170, 174))	('patients', 'Species', '9606', (136, 144))	('increase', 'PosReg', (206, 214))	('tolerance to chemotherapy', 'MPA', (215, 240))
45279	28396463	The results of this unbiased proteomic mass spectrometry approach identified the target of P15 as the intermediate filament vimentin, biomarker of epithelial mesenchymal transition (EMT), which is an intracellular protein but is specifically expressed on the plasma membrane of cancer cells.	('EMT', 'biological_process', 'GO:0001837', ('182', '185'))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('vimentin', 'Gene', (124, 132))	('intracellular', 'cellular_component', 'GO:0005622', ('200', '213'))	('epithelial mesenchymal transition', 'biological_process', 'GO:0001837', ('147', '180'))	('vimentin', 'cellular_component', 'GO:0045099', ('124', '132'))	('intermediate filament', 'cellular_component', 'GO:0005882', ('102', '123'))	('vimentin', 'cellular_component', 'GO:0045098', ('124', '132'))	('P15', 'Var', (91, 94))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('259', '274'))	('cancer', 'Disease', (278, 284))	('epithelial mesenchymal transition', 'Disease', (147, 180))	('vimentin', 'Gene', '7431', (124, 132))
45283	28396463	These results, for the first time, demonstrate that P15 binding to cell surface vimentin inhibits the tumor cell invasion and is associated with reduced MMP3 expression.	('reduced', 'NegReg', (145, 152))	('vimentin', 'cellular_component', 'GO:0045099', ('80', '88'))	('inhibits', 'NegReg', (89, 97))	('cell surface', 'cellular_component', 'GO:0009986', ('67', '79'))	('expression', 'MPA', (158, 168))	('P15', 'Var', (52, 55))	('MMP3', 'Gene', '4314', (153, 157))	('vimentin', 'Gene', '7431', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('vimentin', 'cellular_component', 'GO:0045098', ('80', '88'))	('vimentin', 'Gene', (80, 88))	('binding', 'Interaction', (56, 63))	('binding', 'molecular_function', 'GO:0005488', ('56', '63'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('MMP3', 'molecular_function', 'GO:0004248', ('153', '157'))	('MMP3', 'Gene', (153, 157))
45284	28396463	Thus, suggesting that P15 has potential as an anti-metastatic therapy in pancreatic cancer.	('pancreatic cancer', 'Disease', (73, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('P15', 'Var', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))
45313	28396463	After preincubation with vimentin antibodies, Cy3-labeled aptamers at 200 nM of final concentration were added and incubated with 2 x 105 cells for 30 minutes on ice.	('vimentin', 'Gene', (25, 33))	('Cy3', 'Chemical', '-', (46, 49))	('vimentin', 'cellular_component', 'GO:0045098', ('25', '33'))	('aptamers', 'Protein', (58, 66))	('vimentin', 'Gene', '7431', (25, 33))	('vimentin', 'cellular_component', 'GO:0045099', ('25', '33'))	('Cy3-labeled', 'Var', (46, 57))
45315	28396463	Cells were incubated with Cy3-labeled P15 at 500 nM of final concentration, vimentin antibodies at 1:1000 dilution with anti-mouse Alexa Fluor 488 antibodies at 1:2000 dilution for 1 hour at 37 C. After washing with DPBS three times, the images were taken using a Zeiss LSM 880 confocal laser scanning microscope with Airyscan using a C-Apo 62x/1.2NA water immersion objective.	('vimentin', 'Gene', '7431', (76, 84))	('Cy3-labeled', 'Var', (26, 37))	('Alexa Fluor 488', 'Chemical', '-', (131, 146))	('DPBS', 'Chemical', 'MESH:C012939', (216, 220))	('mouse', 'Species', '10090', (125, 130))	('Cy3', 'Chemical', '-', (26, 29))	('vimentin', 'cellular_component', 'GO:0045099', ('76', '84'))	('vimentin', 'Gene', (76, 84))	('vimentin', 'cellular_component', 'GO:0045098', ('76', '84'))	('water', 'Chemical', 'MESH:D014867', (351, 356))
45334	28396463	PANC-1 cells treated with Cy3-labelled P15 aptamers demonstrated significantly higher levels of positively stained cells (Fig.	('Cy3-labelled P15', 'Var', (26, 42))	('Cy3', 'Chemical', '-', (26, 29))	('P15', 'Var', (39, 42))	('higher', 'PosReg', (79, 85))	('positively stained cells', 'MPA', (96, 120))	('PANC-1', 'CellLine', 'CVCL:0480', (0, 6))
45343	28396463	The antibodies to vimentin significantly reduced the binding of P15 to target cells, P<0.05 (Fig.	('reduced', 'NegReg', (41, 48))	('binding', 'Interaction', (53, 60))	('vimentin', 'Gene', (18, 26))	('antibodies', 'Var', (4, 14))	('P15', 'Protein', (64, 67))	('vimentin', 'Gene', '7431', (18, 26))
45344	28396463	Preincubation with anti-vimentin antibodies prevented the binding of P15 on PANC-1 by flow cytometry (Fig.	('vimentin', 'cellular_component', 'GO:0045098', ('24', '32'))	('P15', 'Var', (69, 72))	('binding', 'Interaction', (58, 65))	('prevented', 'NegReg', (44, 53))	('PANC-1', 'Gene', (76, 82))	('vimentin', 'Gene', (24, 32))	('binding', 'molecular_function', 'GO:0005488', ('58', '65'))	('vimentin', 'cellular_component', 'GO:0045099', ('24', '32'))	('vimentin', 'Gene', '7431', (24, 32))	('PANC-1', 'CellLine', 'CVCL:0480', (76, 82))
45345	28396463	These results strongly suggest the P15 bound to plasma membrane expressing vimentin on cancer cells.	('cancer', 'Disease', (87, 93))	('vimentin', 'cellular_component', 'GO:0045098', ('75', '83'))	('P15', 'Var', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('vimentin', 'Gene', '7431', (75, 83))	('vimentin', 'Gene', (75, 83))	('vimentin', 'cellular_component', 'GO:0045099', ('75', '83'))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('plasma membrane', 'cellular_component', 'GO:0005886', ('48', '63'))	('bound', 'Reg', (39, 44))
45347	28396463	In the colocalization assay, colocalization of Alexa 488-vimentin and Cy3-P15 were apparent in structures that appear yellow (Fig.	('Cy3', 'Chemical', '-', (70, 73))	('vimentin', 'cellular_component', 'GO:0045098', ('57', '65'))	('colocalization', 'Interaction', (29, 43))	('Cy3-P15', 'Var', (70, 77))	('vimentin', 'Gene', '7431', (57, 65))	('vimentin', 'Gene', (57, 65))	('vimentin', 'cellular_component', 'GO:0045099', ('57', '65'))
45353	28396463	These results strongly indicate the P15 inhibits the tumor cell invasion.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('P15', 'Var', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('inhibits', 'NegReg', (40, 48))	('tumor', 'Disease', (53, 58))
45361	28396463	The consistent down-regulation of MMP3 showed in 24 hrs and 48 hrs after treatment of P15 (Fig.	('down-regulation', 'NegReg', (15, 30))	('P15', 'Var', (86, 89))	('MMP3', 'molecular_function', 'GO:0004248', ('34', '38'))	('MMP3', 'Gene', (34, 38))	('regulation', 'biological_process', 'GO:0065007', ('20', '30'))	('MMP3', 'Gene', '4314', (34, 38))
45370	28396463	3F), suggesting that the cell surface vimentin binding P15 aptamer is internalized into the pancreatic cancer cells.	('vimentin', 'cellular_component', 'GO:0045098', ('38', '46'))	('vimentin', 'Gene', (38, 46))	('P15', 'Var', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('binding', 'molecular_function', 'GO:0005488', ('47', '54'))	('cell surface', 'cellular_component', 'GO:0009986', ('25', '37'))	('pancreatic cancer', 'Disease', (92, 109))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))	('vimentin', 'cellular_component', 'GO:0045099', ('38', '46'))	('vimentin', 'Gene', '7431', (38, 46))
45375	28396463	It is reported that the presence of vimentin-expressing in pancreatic cancer predicts a shorter postsurgical survival.	('shorter', 'NegReg', (88, 95))	('presence', 'Var', (24, 32))	('pancreatic cancer', 'Disease', 'MESH:D010190', (59, 76))	('pancreatic cancer', 'Disease', (59, 76))	('vimentin', 'Gene', '7431', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('vimentin', 'cellular_component', 'GO:0045098', ('36', '44'))	('postsurgical survival', 'CPA', (96, 117))	('vimentin', 'Gene', (36, 44))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (59, 76))	('vimentin', 'cellular_component', 'GO:0045099', ('36', '44'))
45378	28396463	For the therapeutic use of P15, we hypothesized that P15 might be associated with the loss of invasion capabilities in tumor cells.	('tumor', 'Disease', (119, 124))	('loss', 'NegReg', (86, 90))	('P15', 'Var', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
45381	28396463	As suggested by our hypothesis, P15 showed the significant inhibition of tumor cell metastasis (Fig.	('inhibition', 'NegReg', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('P15', 'Var', (32, 35))	('tumor', 'Disease', (73, 78))
45382	28396463	However, P15 showed the lack of nuclease resistance in human and mice serum (Fig.	('lack', 'NegReg', (24, 28))	('nuclease resistance', 'MPA', (32, 51))	('mice', 'Species', '10090', (65, 69))	('P15', 'Var', (9, 12))	('human', 'Species', '9606', (55, 60))	('nuclease', 'Chemical', '-', (32, 40))
45389	28396463	Our study suggest that P15 is associated with the downregulation of MMP3.	('MMP3', 'molecular_function', 'GO:0004248', ('68', '72'))	('downregulation', 'NegReg', (50, 64))	('MMP3', 'Gene', (68, 72))	('MMP3', 'Gene', '4314', (68, 72))	('P15', 'Var', (23, 26))
45390	28396463	In the MTT assay, P15 did not inhibit the tumor cell proliferation, which is consistent with the reported results that tumor-produced MMP3 does not affect in tumor growth.	('P15', 'Var', (18, 21))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', (158, 163))	('MTT', 'Chemical', 'MESH:C070243', (7, 10))	('MMP3', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('MMP3', 'molecular_function', 'GO:0004248', ('134', '138'))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('MMP3', 'Gene', '4314', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))
45398	27337224	In contrast to the DNA sequence, chromatin is highly dynamic, particularly brought about through modifications of both, the histones within nucleosomes and DNA cytosines, which together define the epigenome.	('chromatin', 'cellular_component', 'GO:0000785', ('33', '42'))	('brought about', 'Reg', (75, 88))	('histones', 'Protein', (124, 132))	('modifications', 'Var', (97, 110))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('cytosines', 'Chemical', 'MESH:D003596', (160, 169))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
45399	27337224	We now know that genes encoding components or regulators of the epigenetic machinery are frequently mutated in cancers and that these mutations, through their capacity to influence expression of many hundreds of genes, likely lead to heritable reconfigurations of gene expression (epimutations) many times priming healthy cells toward malignancy.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('gene expression', 'biological_process', 'GO:0010467', ('264', '279'))	('expression', 'MPA', (181, 191))	('cancers', 'Disease', (111, 118))	('malignancy', 'Disease', (335, 345))	('expression', 'Species', '29278', (269, 279))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('influence', 'Reg', (171, 180))	('reconfigurations', 'Disease', (244, 260))	('lead to', 'Reg', (226, 233))	('mutations', 'Var', (134, 143))	('malignancy', 'Disease', 'MESH:D009369', (335, 345))	('expression', 'Species', '29278', (181, 191))
45400	27337224	Recent publications in pancreatic cancer demonstrate that many of these tumors have one or more mutations or copy number aberrations in genes that regulate such chromatin marks.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('chromatin', 'cellular_component', 'GO:0000785', ('161', '170'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (23, 40))	('genes', 'Gene', (136, 141))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('copy number aberrations', 'Var', (109, 132))	('pancreatic cancer', 'Disease', (23, 40))	('pancreatic cancer', 'Disease', 'MESH:D010190', (23, 40))	('mutations', 'Var', (96, 105))
45402	27337224	An emerging set of critical studies indicates that epigenetic mechanisms, which can both silence or activate genes in a heritable manner independently of the coding capacity of DNA, could play an important role in PDAC.	('epigenetic', 'Var', (51, 61))	('PDAC', 'Disease', (214, 218))	('silence', 'NegReg', (89, 96))	('activate', 'PosReg', (100, 108))	('play', 'Reg', (188, 192))	('genes', 'Gene', (109, 114))	('DNA', 'cellular_component', 'GO:0005574', ('177', '180'))	('PDAC', 'Chemical', '-', (214, 218))	('role', 'Reg', (206, 210))
45410	27337224	Noteworthy, DNA methylation usually has significant physiological impact, such as genomic imprinting to guarantee monoallelic expression and hypermethylation of repetitive genomic sequences to prevent chromosomal instability, translocations, and gene disruption through the reactivation of transposable DNA sequences.	('expression', 'Species', '29278', (126, 136))	('chromosomal instability', 'MPA', (201, 224))	('translocations', 'CPA', (226, 240))	('hypermethylation', 'Var', (141, 157))	('DNA', 'cellular_component', 'GO:0005574', ('303', '306'))	('gene', 'CPA', (246, 250))	('DNA methylation', 'biological_process', 'GO:0006306', ('12', '27'))	('chromosomal instability', 'Phenotype', 'HP:0040012', (201, 224))	('DNA', 'cellular_component', 'GO:0005574', ('12', '15'))	('prevent', 'NegReg', (193, 200))
45411	27337224	However, during tumorigenesis, abnormal DNA methylation can assist the development of the cancer phenotype.	('assist', 'PosReg', (60, 66))	('abnormal', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('tumor', 'Disease', (16, 21))	('DNA', 'Protein', (40, 43))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('DNA methylation', 'biological_process', 'GO:0006306', ('40', '55'))
45417	27337224	Congruent with the concept that aberrant methylation occurs early during pancreatic carcinogenesis, Gazin et al.	('methylation', 'MPA', (41, 52))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('pancreatic carcinogenesis', 'Disease', (73, 98))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (73, 98))	('aberrant', 'Var', (32, 40))
45418	27337224	pioneered the notion that epigenetic changes are necessary for the transformation of NIH3T3 cells by mutant KRAS, including the regulation of DNMT1 expression in a 5-aza-dC-sensitive manner.	('KRAS', 'Gene', (108, 112))	('regulation', 'biological_process', 'GO:0065007', ('128', '138'))	('DNMT1', 'Gene', (142, 147))	('KRAS', 'Gene', '16653', (108, 112))	('DNMT1', 'Gene', '13433', (142, 147))	('mutant', 'Var', (101, 107))	('expression', 'Species', '29278', (148, 158))	('NIH3T3', 'CellLine', 'CVCL:0594', (85, 91))	('5-aza', 'Chemical', 'MESH:D001374', (164, 169))
45423	27337224	Thus, taking into consideration the importance of aberrant DNA methylation in PDAC, current or future members of this family of drugs are likely to find a place in the therapeutic arsenal against this disease.	('DNA methylation', 'biological_process', 'GO:0006306', ('59', '74'))	('PDAC', 'Disease', (78, 82))	('PDAC', 'Chemical', '-', (78, 82))	('aberrant', 'Var', (50, 58))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
45442	27337224	The methyl marks on histones have the potential to instigate long-term effects on cells through their strong signals for inheriting certain gene expression patterns.	('instigate', 'Reg', (51, 60))	('methyl marks', 'Var', (4, 16))	('expression', 'Species', '29278', (145, 155))	('histones', 'Protein', (20, 28))	('gene expression patterns', 'MPA', (140, 164))	('gene expression', 'biological_process', 'GO:0010467', ('140', '155'))
45444	27337224	Methylation in histones can occur on lysines, as mono-, di-, or tri-methylation or arginine residues, with up to two methyl groups in a symmetric or asymmetric position.	('di-', 'MPA', (56, 59))	('arginine', 'Var', (83, 91))	('histones', 'Protein', (15, 23))	('Methylation', 'Var', (0, 11))	('occur', 'Reg', (28, 33))	('mono-', 'MPA', (49, 54))	('arginine', 'Chemical', 'MESH:D001120', (83, 91))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('tri-methylation', 'Var', (64, 79))	('lysines', 'Chemical', 'MESH:D008239', (37, 44))
45450	27337224	So far, human EZH2 proteins and their related homolog, EZH1, are the only two types of enzymes found to catalyze H3-K27 methylation, resulting in the formation of heterochromatin for gene silencing.	('formation', 'MPA', (150, 159))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('formation', 'biological_process', 'GO:0009058', ('150', '159'))	('EZH1', 'Gene', (55, 59))	('heterochromatin', 'MPA', (163, 178))	('methylation', 'biological_process', 'GO:0032259', ('120', '131'))	('heterochromatin', 'cellular_component', 'GO:0000792', ('163', '178'))	('H3-K27', 'Var', (113, 119))	('EZH1', 'Gene', '2145', (55, 59))	('human', 'Species', '9606', (8, 13))	('gene', 'MPA', (183, 187))	('gene silencing', 'biological_process', 'GO:0016458', ('183', '197'))
45460	27337224	Both induce cell death upon decreasing the deposition of the trimethyl H3-K27 mark, which promotes the derepression of Polycomb-regulated genes.	('Polycomb-regulated genes', 'Gene', (119, 143))	('deposition', 'MPA', (43, 53))	('derepression', 'MPA', (103, 115))	('death', 'Disease', (17, 22))	('death', 'Disease', 'MESH:D003643', (17, 22))	('cell death', 'biological_process', 'GO:0008219', ('12', '22'))	('decreasing', 'NegReg', (28, 38))	('trimethyl H3-K27 mark', 'Var', (61, 82))
45461	27337224	In fact, DZNep has been shown to synergistically enhance the antiproliferative effect of gemcitabine in primary cultures of cells derived from human PDAC tumors and PDAC cell lines.	('gemcitabine', 'Chemical', 'MESH:C056507', (89, 100))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('PDAC', 'Chemical', '-', (165, 169))	('human', 'Species', '9606', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('enhance', 'PosReg', (49, 56))	('DZNep', 'Var', (9, 14))	('PDAC', 'Chemical', '-', (149, 153))	('DZNep', 'Chemical', 'MESH:C048460', (9, 14))	('antiproliferative effect', 'CPA', (61, 85))
45462	27337224	However, EZH2 activity is also inhibited as a result of downregulation of several proteins from the PRC2 complex after DZNep treatment.	('DZNep', 'Chemical', 'MESH:C048460', (119, 124))	('activity', 'MPA', (14, 22))	('EZH2', 'Gene', '2146', (9, 13))	('PRC2 complex', 'cellular_component', 'GO:0035098', ('100', '112'))	('downregulation', 'NegReg', (56, 70))	('EZH2', 'Gene', (9, 13))	('inhibited', 'NegReg', (31, 40))	('proteins', 'Protein', (82, 90))	('DZNep', 'Var', (119, 124))
45468	27337224	KDM1A/LSD1 and KDM1B/LSD2, which are members of the amine oxidase KDM1 subgroup and related to the well-characterized monoamine oxidases (MAOs), erase mono- and dimethyl lysine marks, but not the trimethyl lysine mark.	('KDM1A/LSD1', 'Var', (0, 10))	('KDM1B/LSD2', 'Var', (15, 25))	('dimethyl lysine marks', 'MPA', (161, 182))	('lysine', 'Chemical', 'MESH:D008239', (170, 176))	('mono-', 'MPA', (151, 156))	('erase', 'Reg', (145, 150))	('trimethyl lysine', 'Chemical', 'MESH:C003712', (196, 212))	('lysine', 'Chemical', 'MESH:D008239', (206, 212))
45476	27337224	For example, KDM6A has a significant frequency of somatic mutations in multiple myeloma as well as several other cancers, and the KDM6B gene is regularly lost along with the often deleted TP53 locus.	('mutations', 'Var', (58, 67))	('myeloma', 'Disease', (80, 87))	('KDM6A', 'Gene', (13, 18))	('KDM6B', 'Gene', (130, 135))	('lost', 'NegReg', (154, 158))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('myeloma', 'Disease', 'MESH:D009101', (80, 87))	('multiple myeloma', 'Phenotype', 'HP:0006775', (71, 87))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
45482	27337224	Remarkably, some of these including miR-155, miR-21, miR-221 and miR-222 had been previously reported as being differentially expressed in other human cancers, while others such as miR-376a and miR-301 were novel.	('miR-376a', 'Var', (181, 189))	('miR-21', 'Gene', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('miR-301', 'Gene', (194, 201))	('miR-221', 'Gene', '407006', (53, 60))	('miR-301', 'Gene', '407027', (194, 201))	('miR-221', 'Gene', (53, 60))	('miR-222', 'Gene', '407007', (65, 72))	('human', 'Species', '9606', (145, 150))	('miR-21', 'Gene', '406991', (45, 51))	('miR-155', 'Gene', '406947', (36, 43))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('miR-222', 'Gene', (65, 72))	('cancers', 'Disease', (151, 158))	('miR-155', 'Gene', (36, 43))
45483	27337224	In another study, some miRNAs, including miR-205, -18a, -31, -93, -221 and -224, were revealed to be overexpressed in primary neoplastic ductal cells and PDAC-derived cell lines, and thus found to represent encouraging biomarkers for PDAC.	('PDAC', 'Chemical', '-', (234, 238))	('PDAC', 'Chemical', '-', (154, 158))	('miR-205', 'Var', (41, 48))	('overexpressed', 'PosReg', (101, 114))	('PDAC', 'Disease', (234, 238))
45486	27337224	Current approaches to target small ncRNAs involve: small-molecule inhibitors, expression vectors (miRNA sponges) and antisense oligonucleotides (ASOs).	('oligonucleotides', 'Chemical', 'MESH:D009841', (127, 143))	('small-molecule', 'Var', (51, 65))	('antisense oligonucleotides', 'Var', (117, 143))	('expression vectors', 'Species', '29278', (78, 96))
45489	27337224	Sophisticated structural studies have shown the existence of not only a huge variety of reader-binding pocket architectures, but also common principles underlying the readout of marks carrying methyl-lysine, methyl-arginine, acetyl-lysine and phospho-serine.	('methyl-lysine', 'Var', (193, 206))	('methyl-arginine', 'Chemical', '-', (208, 223))	('acetyl-lysine', 'Chemical', '-', (225, 238))	('phospho-serine', 'Chemical', 'MESH:D010768', (243, 257))	('acetyl-lysine', 'MPA', (225, 238))	('methyl-lysine', 'Chemical', '-', (193, 206))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('methyl-arginine', 'MPA', (208, 223))
45495	27337224	This type of inhibitor, which includes compounds such as NP1, ischemin, MS7072, MS436 and BID1, inhibits the reader function of the BRD by steric exclusion of the acetyl lysine peptide.	('reader function', 'MPA', (109, 124))	('MS436', 'Var', (80, 85))	('inhibits', 'NegReg', (96, 104))	('acetyl lysine peptide', 'Chemical', '-', (163, 184))	('BID1', 'Var', (90, 94))	('MS7072', 'Var', (72, 78))	('steric exclusion', 'MPA', (139, 155))	('MS7072', 'Chemical', '-', (72, 78))	('MS436', 'Chemical', '-', (80, 85))
45499	27337224	Remarkably, in this way it was recently shown that treatment with JQ1, an inhibitor of the BRD and extraterminal family of proteins, suppresses PDAC development by inhibiting both MYC activity and inflammatory signals.	('PDAC', 'Chemical', '-', (144, 148))	('PDAC development', 'CPA', (144, 160))	('inhibiting', 'NegReg', (164, 174))	('suppresses', 'NegReg', (133, 143))	('inflammatory', 'CPA', (197, 209))	('MYC activity', 'MPA', (180, 192))	('JQ1', 'Var', (66, 69))
45501	27337224	These data support a strong proof-of-concept that epigenetic modulation can be used as an efficient tool for treating PDAC development.	('PDAC development', 'Disease', (118, 134))	('epigenetic modulation', 'Var', (50, 71))	('PDAC', 'Chemical', '-', (118, 122))
45504	27337224	According to this principle and to the Hruban model, the variations in expression of both oncogenes and tumor suppressors in PDAC were initially believed to occur via mutation or deletion and only later was promoter methylation integrated into the model.	('expression', 'MPA', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mutation', 'Var', (167, 175))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('PDAC', 'Chemical', '-', (125, 129))	('methylation', 'biological_process', 'GO:0032259', ('216', '227'))	('deletion', 'Var', (179, 187))	('expression', 'Species', '29278', (71, 81))	('occur', 'Reg', (157, 162))	('variations', 'Var', (57, 67))
45505	27337224	While we recognize the outstanding impact that this progression model of somatic genetics has had in progressing cancer research, we now recognize a model that also considers the theoretical context of epigenetics, and in particular, changes that occur at the protein level in the absence of DNA changes including deletion, mutation or even promoter methylation.	('mutation', 'Var', (324, 332))	('deletion', 'Var', (314, 322))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('methylation', 'biological_process', 'GO:0032259', ('350', '361'))	('promoter', 'MPA', (341, 349))	('DNA', 'cellular_component', 'GO:0005574', ('292', '295'))	('cancer', 'Disease', (113, 119))	('changes', 'Reg', (234, 241))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('protein', 'cellular_component', 'GO:0003675', ('260', '267'))
45506	27337224	For example, if we use the Hruban model to understand PDAC, in which the fundamental conceptual framework is genetic in nature, one could conclude that PDAC advances through multistep mechanisms with different lesions progressing via mutations in diverse genes.	('PDAC', 'Chemical', '-', (54, 58))	('mutations', 'Var', (234, 243))	('PDAC', 'Gene', (152, 156))	('PDAC', 'Chemical', '-', (152, 156))
45507	27337224	This model does not take into account what epigenetic changes, which can take place between the occurrences of landmark mutations, are responsible for cancer progression, nor can it prove that a later mutation is caused by an earlier one.	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))
45510	27337224	Genetic alterations crosstalk with epigenetic changes to not only give rise to neoplastic transformation but also are likely to determine many features of the cancer phenotype and its symptoms.	('cancer', 'Disease', (159, 165))	('Genetic alterations', 'Var', (0, 19))	('neoplastic transformation', 'CPA', (79, 104))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('give rise to', 'Reg', (66, 78))	('epigenetic changes', 'Var', (35, 53))	('determine', 'Reg', (128, 137))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
45513	27337224	Taking into consideration the importance the pathogenic role that aberrant DNA methylation plays in pancreatic ductal adenocarcinoma, current or future small molecule drugs targeting DNMTs hold promise as part of the therapeutic arsenal against this dismal disease.	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('DNA methylation', 'biological_process', 'GO:0006306', ('75', '90'))	('aberrant', 'Var', (66, 74))	('pancreatic ductal adenocarcinoma', 'Disease', (100, 132))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (100, 132))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (100, 132))
45517	27337224	Epigenomic-based pharmacology and its translation to therapies have the potential to serve as a robust tool to improve the future treatment of pancreatic cancer.	('Epigenomic-based', 'Var', (0, 16))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (143, 160))	('translation', 'biological_process', 'GO:0006412', ('38', '49'))	('pancreatic cancer', 'Disease', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('pancreatic cancer', 'Disease', 'MESH:D010190', (143, 160))
45521	26439801	The invasion of pancreatic cancer cells resulting from the activation of the H2O2/MAPK axis under high glucose conditions is effectively inhibited by PD 98059 (ERK inhibitor), SB 203580 (p38 MAPK inhibitor), polyethylene glycol-conjugated catalase (PEG-CAT), or the siRNA specific to SOD2.	('glucose', 'Chemical', 'MESH:D005947', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('p38', 'Gene', (187, 190))	('H2O2/MAPK axis', 'Pathway', (77, 91))	('invasion', 'CPA', (4, 12))	('H2O2', 'Chemical', 'MESH:D006861', (77, 81))	('polyethylene glycol', 'Chemical', 'MESH:D011092', (208, 227))	('pancreatic cancer', 'Disease', (16, 33))	('activation', 'PosReg', (59, 69))	('inhibited', 'NegReg', (137, 146))	('PD', 'Disease', 'MESH:D010300', (150, 152))	('ERK', 'Gene', '5594', (160, 163))	('SOD2', 'Gene', (284, 288))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('p38', 'Gene', '5594', (187, 190))	('SB 203580', 'Var', (176, 185))	('SB 203580', 'Chemical', 'MESH:C093642', (176, 185))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (16, 33))	('ERK', 'Gene', (160, 163))	('SOD2', 'Gene', '6648', (284, 288))	('catalase', 'Gene', (239, 247))	('catalase', 'Gene', '847', (239, 247))	('ERK', 'molecular_function', 'GO:0004707', ('160', '163'))	('MAPK', 'molecular_function', 'GO:0004707', ('191', '195'))	('CAT', 'molecular_function', 'GO:0004096', ('253', '256'))	('PEG', 'Chemical', 'MESH:D011092', (249, 252))	('SOD2', 'molecular_function', 'GO:0004784', ('284', '288'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (16, 33))	('high glucose', 'Phenotype', 'HP:0003074', (98, 110))
45548	26439801	We also tested the hypothesis that H2O2 mediates hyperglycemia-induced activation of the MAPK signaling pathways and regulates the invasive activity of PC cells.	('tested', 'Reg', (8, 14))	('hyperglycemia', 'Disease', (49, 62))	('MAPK signaling', 'biological_process', 'GO:0000165', ('89', '103'))	('H2O2', 'Var', (35, 39))	('activation', 'PosReg', (71, 81))	('H2O2', 'Chemical', 'MESH:D006861', (35, 39))	('hyperglycemia', 'Phenotype', 'HP:0003074', (49, 62))	('MAPK signaling pathways', 'Pathway', (89, 112))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('regulates', 'Reg', (117, 126))	('hyperglycemia', 'Disease', 'MESH:D006943', (49, 62))	('invasive activity', 'CPA', (131, 148))
45558	26439801	To further examine whether SOD2 could influence H2O2 production under HG conditions, we used SOD2 siRNA to knock down SOD2 expression in both BxPC-3 and Panc-1cancer cells and then examined the H2O2 levels (Figure 1F, 1G).	('H2O2', 'Chemical', 'MESH:D006861', (48, 52))	('SOD2', 'molecular_function', 'GO:0004784', ('118', '122'))	('SOD2', 'Gene', '6648', (93, 97))	('SOD2', 'molecular_function', 'GO:0004784', ('27', '31'))	('SOD2', 'Gene', (93, 97))	('BxPC-3', 'CellLine', 'CVCL:0186', (142, 148))	('examined', 'Reg', (181, 189))	('influence', 'Reg', (38, 47))	('SOD2', 'Gene', (118, 122))	('H2O2', 'Chemical', 'MESH:D006861', (194, 198))	('SOD2', 'Gene', '6648', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('SOD2', 'molecular_function', 'GO:0004784', ('93', '97'))	('knock', 'Var', (107, 112))	('SOD2', 'Gene', '6648', (27, 31))	('SOD2', 'Gene', (27, 31))
45559	26439801	Our results show that the increased H2O2 production of the PC cells in the presence of HG was diminished when SOD2 was knocked down, indicating that the HG-induced H2O2 level is dependent on SOD2 (Figure 1H).	('SOD2', 'Gene', '6648', (110, 114))	('SOD2', 'Gene', (110, 114))	('H2O2 production', 'MPA', (36, 51))	('SOD2', 'Gene', '6648', (191, 195))	('SOD2', 'molecular_function', 'GO:0004784', ('110', '114'))	('SOD2', 'Gene', (191, 195))	('H2O2', 'Chemical', 'MESH:D006861', (164, 168))	('knocked', 'Var', (119, 126))	('H2O2', 'Chemical', 'MESH:D006861', (36, 40))	('SOD2', 'molecular_function', 'GO:0004784', ('191', '195'))	('diminished', 'NegReg', (94, 104))
45566	26439801	A similar effect of H2O2 was also observed in the Panc-1 cancer cells (Supplementary Figures S2A).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Panc-1', 'CellLine', 'CVCL:0480', (50, 56))	('H2O2', 'Chemical', 'MESH:D006861', (20, 24))	('H2O2', 'Var', (20, 24))
45568	26439801	As shown in Figure 2B, H2O2 activated ERK and p38 MAPK in a time-dependent manner, with peak activation between 5 and 15 min.	('p38', 'Gene', (46, 49))	('ERK', 'molecular_function', 'GO:0004707', ('38', '41'))	('H2O2', 'Chemical', 'MESH:D006861', (23, 27))	('H2O2', 'Var', (23, 27))	('ERK', 'Gene', '5594', (38, 41))	('MAPK', 'molecular_function', 'GO:0004707', ('50', '54'))	('ERK', 'Gene', (38, 41))	('p38', 'Gene', '5594', (46, 49))
45569	26439801	Meanwhile, H2O2 treatment also led to an increase in the phosphorylation level of NF-kappaB and c-Jun, with a peak between 15 and 30 min.	('H2O2', 'Chemical', 'MESH:D006861', (11, 15))	('c-Jun', 'Gene', (96, 101))	('phosphorylation level', 'MPA', (57, 78))	('H2O2', 'Var', (11, 15))	('NF-kappaB', 'Gene', (82, 91))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('c-Jun', 'Gene', '3725', (96, 101))	('NF-kappaB', 'Gene', '4790', (82, 91))	('increase', 'PosReg', (41, 49))
45573	26439801	Interestingly, we found that PEG-CAT diminished the HG-induced ERK and p38 MAPK phosphorylation (Figure 2C).	('CAT', 'molecular_function', 'GO:0004096', ('33', '36'))	('ERK', 'molecular_function', 'GO:0004707', ('63', '66'))	('phosphorylation', 'biological_process', 'GO:0016310', ('80', '95'))	('MAPK', 'molecular_function', 'GO:0004707', ('75', '79'))	('PEG', 'Chemical', 'MESH:D011092', (29, 32))	('p38', 'Gene', (71, 74))	('PEG-CAT', 'Var', (29, 36))	('ERK', 'Gene', '5594', (63, 66))	('ERK', 'Gene', (63, 66))	('diminished', 'NegReg', (37, 47))	('p38', 'Gene', '5594', (71, 74))
45575	26439801	Furthermore, as shown in Figure 2E, the phosphorylation levels of ERK and p38 MAPK were significantly decreased following SOD2 knockdown, indicating that the SOD2-induced H2O2 level is intimately related to the MAPK pathway.	('ERK', 'molecular_function', 'GO:0004707', ('66', '69'))	('p38', 'Gene', '5594', (74, 77))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('decreased', 'NegReg', (102, 111))	('SOD2', 'Gene', (122, 126))	('phosphorylation levels', 'MPA', (40, 62))	('SOD2', 'molecular_function', 'GO:0004784', ('158', '162'))	('SOD2', 'Gene', '6648', (158, 162))	('MAPK', 'molecular_function', 'GO:0004707', ('211', '215'))	('MAPK', 'molecular_function', 'GO:0004707', ('78', '82'))	('p38', 'Gene', (74, 77))	('SOD2', 'Gene', '6648', (122, 126))	('ERK', 'Gene', '5594', (66, 69))	('H2O2', 'Chemical', 'MESH:D006861', (171, 175))	('SOD2', 'molecular_function', 'GO:0004784', ('122', '126'))	('knockdown', 'Var', (127, 136))	('SOD2', 'Gene', (158, 162))	('ERK', 'Gene', (66, 69))
45582	26439801	To explore whether the H2O2 level is involved in the HG-induced cell invasive ability, PC cells were treated with H2O2, PEG-CAT, and si-SOD2, and the invasive abilities of the cells were examined under different glucose conditions.	('CAT', 'molecular_function', 'GO:0004096', ('124', '127'))	('SOD2', 'molecular_function', 'GO:0004784', ('136', '140'))	('H2O2', 'Chemical', 'MESH:D006861', (114, 118))	('H2O2', 'Var', (114, 118))	('H2O2', 'Chemical', 'MESH:D006861', (23, 27))	('glucose', 'Chemical', 'MESH:D005947', (212, 219))	('SOD2', 'Gene', '6648', (136, 140))	('SOD2', 'Gene', (136, 140))	('PEG', 'Chemical', 'MESH:D011092', (120, 123))
45583	26439801	The results show that both HG and H2O2 increased the invasion rates of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('increased', 'PosReg', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('H2O2', 'Chemical', 'MESH:D006861', (34, 38))	('H2O2', 'Var', (34, 38))
45585	26439801	Furthermore, both PD 98059 and SB 203580 could decrease PC cells invasion under HG conditions, indicating that the activation of the ERK and p38 MAPK signaling pathways is involved in HG-induced PC cell invasion (Figure 5).	('activation', 'PosReg', (115, 125))	('p38', 'Gene', (141, 144))	('SB 203580', 'Var', (31, 40))	('SB 203580', 'Chemical', 'MESH:C093642', (31, 40))	('MAPK', 'molecular_function', 'GO:0004707', ('145', '149'))	('decrease', 'NegReg', (47, 55))	('ERK', 'Gene', '5594', (133, 136))	('ERK', 'molecular_function', 'GO:0004707', ('133', '136'))	('ERK', 'Gene', (133, 136))	('p38', 'Gene', '5594', (141, 144))	('PD', 'Disease', 'MESH:D010300', (18, 20))	('decrease PC', 'Phenotype', 'HP:0032198', (47, 58))	('p38 MAPK signaling', 'biological_process', 'GO:0051403', ('141', '159'))
45613	26439801	Our results indicate that high glucose resulted in an increase in the level of H2O2 to a non-toxic level in PC cells; treatment with H2O2 promoted cancer cell proliferation when its concentration was below 200 muM, but H2O2 concentrations above 200 muM were toxic to the cancer cells.	('muM', 'Gene', (249, 252))	('muM', 'Gene', '56925', (210, 213))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))	('muM', 'Gene', (210, 213))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('H2O2', 'Chemical', 'MESH:D006861', (133, 137))	('H2O2', 'Var', (133, 137))	('promoted', 'PosReg', (138, 146))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('muM', 'Gene', '56925', (249, 252))	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', (271, 277))	('high glucose', 'Phenotype', 'HP:0003074', (26, 38))	('H2O2', 'Chemical', 'MESH:D006861', (79, 83))	('glucose', 'Chemical', 'MESH:D005947', (31, 38))	('H2O2', 'Chemical', 'MESH:D006861', (219, 223))
45618	26439801	In our in vitro study, we observed that H2O2 could increase the invasive ability of the PC cells, whereas treatment with either PEG-CAT, which cleared the produced H2O2, or si-SOD2, which decreased the production of H2O2, could terminate this effect.	('increase', 'PosReg', (51, 59))	('SOD2', 'Gene', '6648', (176, 180))	('PEG', 'Chemical', 'MESH:D011092', (128, 131))	('CAT', 'molecular_function', 'GO:0004096', ('132', '135'))	('H2O2', 'Chemical', 'MESH:D006861', (40, 44))	('H2O2', 'Var', (40, 44))	('SOD2', 'molecular_function', 'GO:0004784', ('176', '180'))	('SOD2', 'Gene', (176, 180))	('H2O2', 'MPA', (164, 168))	('invasive ability of the PC cells', 'CPA', (64, 96))	('H2O2', 'Chemical', 'MESH:D006861', (216, 220))	('H2O2', 'Chemical', 'MESH:D006861', (164, 168))
45632	26439801	The A allele of the SOD2 - 1221G > A genotype was associated with a higher risk of pancreatic cancer among individuals with a low dietary vitamin E intake.	('SOD2', 'Gene', (20, 24))	('pancreatic cancer', 'Disease', (83, 100))	('1221G > A', 'Var', (27, 36))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('low dietary vitamin E', 'Phenotype', 'HP:0100513', (126, 147))	('vitamin E', 'Chemical', 'MESH:D014810', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('1221G > A', 'SUBSTITUTION', 'None', (27, 36))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))	('SOD2', 'molecular_function', 'GO:0004784', ('20', '24'))	('SOD2', 'Gene', '6648', (20, 24))
45642	26439801	Additionally, the down-regulation of H2O2 by either PEG-CAT or si-SOD2 inhibits the activation of the MAPK signaling pathways and tumor invasion, which indicates that H2O2 is the key factor that mediated HG-induced PC metastasis.	('SOD2', 'Gene', '6648', (66, 70))	('regulation', 'biological_process', 'GO:0065007', ('23', '33'))	('SOD2', 'Gene', (66, 70))	('PEG', 'Chemical', 'MESH:D011092', (52, 55))	('inhibits', 'NegReg', (71, 79))	('CAT', 'molecular_function', 'GO:0004096', ('56', '59'))	('MAPK', 'molecular_function', 'GO:0004707', ('102', '106'))	('PEG-CAT', 'Var', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('MAPK signaling pathways', 'Pathway', (102, 125))	('H2O2', 'Gene', (37, 41))	('H2O2', 'Chemical', 'MESH:D006861', (37, 41))	('MAPK signaling', 'biological_process', 'GO:0000165', ('102', '116'))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('H2O2', 'Chemical', 'MESH:D006861', (167, 171))	('SOD2', 'molecular_function', 'GO:0004784', ('66', '70'))	('tumor', 'Disease', (130, 135))	('down-regulation', 'NegReg', (18, 33))
45655	26439801	The anti-ERK, anti-phospho-ERK (Thr202/Tyr204), anti-p38 MAPK, anti-phospho-p38 MAPK (Thr180/Tyr182), anti-NF-kappaB, anti-phospho-NF-kappaB p65 (Ser468), anti-c-Jun and anti-phospho-c-Jun (Ser63) antibodies were obtained from Cell Signaling Technology (Beverly, MA, USA).	('Thr180/Tyr182', 'Var', (86, 99))	('Ser', 'cellular_component', 'GO:0005790', ('146', '149'))	('Signaling', 'biological_process', 'GO:0023052', ('232', '241'))	('p38', 'Gene', (53, 56))	('c-Jun', 'Gene', '3725', (183, 188))	('ERK', 'Gene', (27, 30))	('c-Jun', 'Gene', '3725', (160, 165))	('ERK', 'Gene', '5594', (9, 12))	('p38', 'Gene', (76, 79))	('c-Jun', 'Gene', (183, 188))	('Tyr182', 'Chemical', '-', (93, 99))	('c-Jun', 'Gene', (160, 165))	('Thr180', 'Chemical', '-', (86, 92))	('p38', 'Gene', '5594', (53, 56))	('ERK', 'molecular_function', 'GO:0004707', ('9', '12'))	('Ser468', 'Chemical', '-', (146, 152))	('ERK', 'molecular_function', 'GO:0004707', ('27', '30'))	('MAPK', 'molecular_function', 'GO:0004707', ('80', '84'))	('ERK', 'Gene', (9, 12))	('NF-kappaB', 'Gene', (107, 116))	('p38', 'Gene', '5594', (76, 79))	('NF-kappaB', 'Gene', (131, 140))	('MAPK', 'molecular_function', 'GO:0004707', ('57', '61'))	('Thr202/Tyr204', 'Var', (32, 45))	('NF-kappaB', 'Gene', '4790', (107, 116))	('NF-kappaB', 'Gene', '4790', (131, 140))	('Ser', 'cellular_component', 'GO:0005790', ('190', '193'))	('ERK', 'Gene', '5594', (27, 30))	('Tyr204', 'Chemical', '-', (39, 45))	('Thr202', 'Chemical', '-', (32, 38))	('Ser63', 'Chemical', '-', (190, 195))
45657	26439801	In this kit, the ferrous ions Fe2+ were oxidized to ferric ions Fe3+ by H2O2.	('Fe3+', 'Chemical', '-', (64, 68))	('H2O2', 'Chemical', 'MESH:D006861', (72, 76))	('H2O2', 'Var', (72, 76))	('ferrous ions Fe2+', 'MPA', (17, 34))	('oxidized to ferric ions Fe3+', 'MPA', (40, 68))	('Fe2+', 'Chemical', 'MESH:C038178', (30, 34))	('ferric', 'Chemical', '-', (52, 58))	('ferrous', 'Chemical', '-', (17, 24))
45693	26439801	The current study demonstrates that H2O2 contributes to the SOD2-induced invasion in PC cells in vitro by modulating the expression of the metastasis-related factor uPA through the activation of the ERK and p38 MAPK signaling pathways.	('ERK', 'molecular_function', 'GO:0004707', ('199', '202'))	('modulating', 'Reg', (106, 116))	('SOD2', 'molecular_function', 'GO:0004784', ('60', '64'))	('expression', 'MPA', (121, 131))	('H2O2', 'Chemical', 'MESH:D006861', (36, 40))	('H2O2', 'Var', (36, 40))	('p38', 'Gene', (207, 210))	('SOD2', 'Gene', '6648', (60, 64))	('MAPK', 'molecular_function', 'GO:0004707', ('211', '215'))	('ERK', 'Gene', '5594', (199, 202))	('activation', 'PosReg', (181, 191))	('p38 MAPK signaling', 'biological_process', 'GO:0051403', ('207', '225'))	('SOD2', 'Gene', (60, 64))	('uPA', 'Gene', '5328', (165, 168))	('uPA', 'Gene', (165, 168))	('uPA', 'molecular_function', 'GO:0008243', ('165', '168'))	('ERK', 'Gene', (199, 202))	('p38', 'Gene', '5594', (207, 210))
45701	25638159	Inhibition of PKC-theta activity impaired cell viability compared with EP2/EP4-antagonized IGF-1-stimulated cells.	('PKC-theta', 'Gene', '5588', (14, 23))	('EP4', 'Gene', '5734', (75, 78))	('cell viability', 'CPA', (42, 56))	('PKC-theta', 'Gene', (14, 23))	('impaired', 'NegReg', (33, 41))	('EP4', 'Gene', (75, 78))	('PKC', 'molecular_function', 'GO:0004697', ('14', '17'))	('Inhibition', 'Var', (0, 10))	('EP2', 'Gene', (71, 74))	('EP2', 'Gene', '5732', (71, 74))
45709	25638159	In patients with several cancers including pancreatic cancer, high expression of IGF-1R in tumors is associated with higher tumor grades and poor survival.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (43, 60))	('IGF-1R', 'Gene', '3480', (81, 87))	('tumor', 'Disease', (124, 129))	('IGF-1R', 'Gene', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('cancers', 'Disease', (25, 32))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('high', 'Var', (62, 66))	('pancreatic cancer', 'Disease', 'MESH:D010190', (43, 60))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('associated', 'Reg', (101, 111))	('pancreatic cancer', 'Disease', (43, 60))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (91, 97))	('poor', 'NegReg', (141, 145))
45710	25638159	In vitro studies have shown that exogenous IGF-1-stimulated growth of pancreatic cancer cell lines is abrogated following treatment with anti-IGF1R antibodies.	('IGF1R', 'Gene', '3480', (142, 147))	('pancreatic cancer', 'Disease', (70, 87))	('IGF-1-stimulated', 'Gene', (43, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (70, 87))	('abrogated', 'NegReg', (102, 111))	('growth', 'CPA', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (70, 87))	('IGF1R', 'Gene', (142, 147))	('antibodies', 'Var', (148, 158))
45730	25638159	To investigate the effects of the antagonism of EP2/EP4-mediated cellular signaling on growth factor receptor-mediated growth stimulation, we treated cells with EP2/EP4 antagonists, i.e., AH6809/GW627368X, and assessed HB-EGF-, IGF-1-, and IGF-2-mediated growth stimulation.	('IGF-2', 'Gene', (240, 245))	('EP4', 'Gene', (52, 55))	('EP2', 'Gene', (161, 164))	('GW627368X', 'Chemical', 'MESH:C515270', (195, 204))	('IGF-2', 'Gene', '3481', (240, 245))	('AH6809', 'Chemical', 'MESH:C053876', (188, 194))	('HB-EGF', 'Gene', (219, 225))	('EP2', 'Gene', '5732', (161, 164))	('EGF', 'molecular_function', 'GO:0005154', ('222', '225'))	('EP2', 'Gene', (48, 51))	('EP2', 'Gene', '5732', (48, 51))	('EP4', 'Gene', '5734', (165, 168))	('HB-EGF', 'Gene', '1839', (219, 225))	('AH6809/GW627368X', 'Var', (188, 204))	('EP4', 'Gene', (165, 168))	('EP4', 'Gene', '5734', (52, 55))	('signaling', 'biological_process', 'GO:0023052', ('74', '83'))
45731	25638159	Single treatments with AH6809/GW627368 did not significantly affect cell viability in any of the cell lines (Fig 1C).	('AH6809', 'Chemical', 'MESH:C053876', (23, 29))	('cell viability', 'CPA', (68, 82))	('GW627368', 'Chemical', '-', (30, 38))	('AH6809/GW627368', 'Var', (23, 38))
45733	25638159	In BxPC-3 cells, pretreatment with AH6809/GW627368X completely blocked the growth stimulated by HB-EGF and IGF-1 and partially inhibited stimulation following treatment with IGF-2.	('HB-EGF', 'Gene', '1839', (96, 102))	('AH6809/GW627368X', 'Var', (35, 51))	('IGF-2', 'Gene', '3481', (174, 179))	('EGF', 'molecular_function', 'GO:0005154', ('99', '102'))	('GW627368X', 'Chemical', 'MESH:C515270', (42, 51))	('HB-EGF', 'Gene', (96, 102))	('growth stimulated', 'MPA', (75, 92))	('inhibited', 'NegReg', (127, 136))	('BxPC-3', 'CellLine', 'CVCL:0186', (3, 9))	('IGF-1', 'Gene', (107, 112))	('blocked', 'NegReg', (63, 70))	('IGF-2', 'Gene', (174, 179))	('AH6809', 'Chemical', 'MESH:C053876', (35, 41))
45734	25638159	In PANC-1 cells, pretreatment with AH6809/GW627368X only blocked HB-EGF-mediated growth stimulation, whereas growth stimulation by these growth factors was not affected by pretreatment with AH6809/GW627368X in MiaPaCa-2 and Capan-1 cells (Fig 2A).	('EGF', 'molecular_function', 'GO:0005154', ('68', '71'))	('HB-EGF', 'Gene', '1839', (65, 71))	('AH6809', 'Chemical', 'MESH:C053876', (190, 196))	('AH6809/GW627368X', 'Var', (35, 51))	('GW627368X', 'Chemical', 'MESH:C515270', (42, 51))	('blocked', 'NegReg', (57, 64))	('AH6809/GW627368X', 'Var', (190, 206))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (210, 219))	('HB-EGF', 'Gene', (65, 71))	('AH6809', 'Chemical', 'MESH:C053876', (35, 41))	('PANC-1', 'CellLine', 'CVCL:0480', (3, 9))	('GW627368X', 'Chemical', 'MESH:C515270', (197, 206))	('Capan-1', 'CellLine', 'CVCL:0237', (224, 231))
45735	25638159	We also tested single treatments of AH6809 or GW627368X and assessed IGF-1-mediated growth stimulation in BxPC-3 cells.	('AH6809', 'Var', (36, 42))	('AH6809', 'Chemical', 'MESH:C053876', (36, 42))	('GW627368X', 'Var', (46, 55))	('GW627368X', 'Chemical', 'MESH:C515270', (46, 55))	('BxPC-3', 'CellLine', 'CVCL:0186', (106, 112))
45736	25638159	Pretreatment with GW627368X almost completely blocked growth stimulation by IGF-1 and pretreatment with AH6809 also suppressed it to a low but significant extent (Supplementary Fig 2A).	('AH6809', 'Var', (104, 110))	('blocked', 'NegReg', (46, 53))	('suppressed', 'NegReg', (116, 126))	('GW627368X', 'Var', (18, 27))	('GW627368X', 'Chemical', 'MESH:C515270', (18, 27))	('growth stimulation', 'MPA', (54, 72))	('AH6809', 'Chemical', 'MESH:C053876', (104, 110))	('IGF-1', 'Gene', (76, 81))
45737	25638159	Based on these results, we decided that it was appropriate to use AH6809/GW627368X in combination to achieve absolute inhibition of EP2/EP4-mediated cellular signaling.	('AH6809', 'Chemical', 'MESH:C053876', (66, 72))	('signaling', 'biological_process', 'GO:0023052', ('158', '167'))	('inhibition', 'NegReg', (118, 128))	('AH6809/GW627368X', 'Var', (66, 82))	('GW627368X', 'Chemical', 'MESH:C515270', (73, 82))	('EP4', 'Gene', '5734', (136, 139))	('EP2', 'Gene', (132, 135))	('EP2', 'Gene', '5732', (132, 135))	('EP4', 'Gene', (136, 139))
45740	25638159	In BxPC-3 cells, treatment with growth factors induced the phosphorylation of MEK and ERK, whereas pretreatment with AH6809/GW627368X attenuated their phosphorylation in IGF-1-treated cells (Fig 2B).	('MEK', 'Gene', (78, 81))	('MEK', 'Gene', '5609', (78, 81))	('ERK', 'molecular_function', 'GO:0004707', ('86', '89'))	('phosphorylation', 'MPA', (151, 166))	('phosphorylation', 'biological_process', 'GO:0016310', ('151', '166'))	('AH6809/GW627368X', 'Var', (117, 133))	('phosphorylation', 'biological_process', 'GO:0016310', ('59', '74'))	('phosphorylation', 'MPA', (59, 74))	('GW627368X', 'Chemical', 'MESH:C515270', (124, 133))	('ERK', 'Gene', '5594', (86, 89))	('BxPC-3', 'CellLine', 'CVCL:0186', (3, 9))	('attenuated', 'NegReg', (134, 144))	('AH6809', 'Chemical', 'MESH:C053876', (117, 123))	('ERK', 'Gene', (86, 89))
45741	25638159	Single treatments with AH6809/GW627368 did not affect the phosphorylation of MEK and ERK (Supplementary Fig 1).	('GW627368', 'Chemical', '-', (30, 38))	('phosphorylation', 'MPA', (58, 73))	('ERK', 'Gene', '5594', (85, 88))	('AH6809', 'Chemical', 'MESH:C053876', (23, 29))	('ERK', 'Gene', (85, 88))	('ERK', 'molecular_function', 'GO:0004707', ('85', '88'))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('MEK', 'Gene', (77, 80))	('MEK', 'Gene', '5609', (77, 80))	('AH6809/GW627368', 'Var', (23, 38))
45743	25638159	EP4 knockdown also abrogated IGF-1-induced cell growth and the phosphorylation of MEK and ERK with similar efficacy to that following pretreatment with AH6809/GW627368X (Supplementary Fig 3A).	('phosphorylation', 'biological_process', 'GO:0016310', ('63', '78'))	('ERK', 'Gene', (90, 93))	('IGF-1-induced', 'Gene', (29, 42))	('MEK', 'Gene', '5609', (82, 85))	('AH6809', 'Chemical', 'MESH:C053876', (152, 158))	('abrogated', 'NegReg', (19, 28))	('cell growth', 'CPA', (43, 54))	('EP4', 'Gene', '5734', (0, 3))	('GW627368X', 'Chemical', 'MESH:C515270', (159, 168))	('ERK', 'molecular_function', 'GO:0004707', ('90', '93'))	('phosphorylation', 'MPA', (63, 78))	('EP4', 'Gene', (0, 3))	('ERK', 'Gene', '5594', (90, 93))	('knockdown', 'Var', (4, 13))	('cell growth', 'biological_process', 'GO:0016049', ('43', '54'))	('MEK', 'Gene', (82, 85))
45744	25638159	Phospho-antibody arrays were used to assess changes in the protein phosphorylation status to identify molecules that are affected by antagonism of EP2/EP4 signaling in IGF-1-treated BxPC-3 cells.	('antibody', 'cellular_component', 'GO:0019815', ('8', '16'))	('EP2', 'Gene', (147, 150))	('EP2', 'Gene', '5732', (147, 150))	('antibody', 'cellular_component', 'GO:0019814', ('8', '16'))	('antibody', 'molecular_function', 'GO:0003823', ('8', '16'))	('antagonism', 'Var', (133, 143))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('protein phosphorylation', 'biological_process', 'GO:0006468', ('59', '82'))	('EP4', 'Gene', '5734', (151, 154))	('EP4', 'Gene', (151, 154))	('affected', 'Reg', (121, 129))	('antibody', 'cellular_component', 'GO:0042571', ('8', '16'))	('BxPC-3', 'CellLine', 'CVCL:0186', (182, 188))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
45747	25638159	Consistent with this observation, immunoblotting detected increased phospho-PKC-theta at Thr538 in AH6809/GW627368X-pretreated IGF-1-treated cells compared with IGF-1-treated cells and untreated cells (Fig 3A).	('GW627368X', 'Chemical', 'MESH:C515270', (106, 115))	('increased', 'PosReg', (58, 67))	('PKC-theta', 'Gene', '5588', (76, 85))	('PKC', 'molecular_function', 'GO:0004697', ('76', '79'))	('PKC-theta', 'Gene', (76, 85))	('Thr538', 'Var', (89, 95))	('AH6809', 'Chemical', 'MESH:C053876', (99, 105))	('AH6809/GW627368X-pretreated', 'Var', (99, 126))	('increased phospho-PKC', 'Phenotype', 'HP:0003236', (58, 79))	('Thr538', 'Chemical', '-', (89, 95))	('IGF-1-treated', 'Gene', (127, 140))
45748	25638159	Moreover, treatments with AH6809/GW627368X alone induced the phosphorylation of PKC-theta in a time-dependent manner (Fig 3B).	('PKC', 'molecular_function', 'GO:0004697', ('80', '83'))	('phosphorylation', 'MPA', (61, 76))	('induced', 'PosReg', (49, 56))	('AH6809', 'Chemical', 'MESH:C053876', (26, 32))	('PKC-theta', 'Gene', '5588', (80, 89))	('PKC-theta', 'Gene', (80, 89))	('GW627368X', 'Chemical', 'MESH:C515270', (33, 42))	('AH6809/GW627368X', 'Var', (26, 42))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))
45749	25638159	EP4 knockdown increased the phosphorylation of PKC-theta with similar efficacy to that following AH6809/GW627368X pretreatment (Supplementary Fig 2A).	('increased', 'PosReg', (14, 23))	('AH6809', 'Chemical', 'MESH:C053876', (97, 103))	('phosphorylation', 'MPA', (28, 43))	('EP4', 'Gene', '5734', (0, 3))	('PKC-theta', 'Gene', '5588', (47, 56))	('GW627368X', 'Chemical', 'MESH:C515270', (104, 113))	('PKC', 'molecular_function', 'GO:0004697', ('47', '50'))	('EP4', 'Gene', (0, 3))	('PKC-theta', 'Gene', (47, 56))	('knockdown', 'Var', (4, 13))	('phosphorylation', 'biological_process', 'GO:0016310', ('28', '43'))
45750	25638159	Because the phosphorylation of PKC-theta at Thr538 is associated directly with kinase activity, we examined the effect of PKC-theta inhibition using a pseudo-substrate as a specific inhibitor on growth stimulation following the antagonism of EP2/EP4 signaling.	('kinase activity', 'MPA', (79, 94))	('EP4', 'Gene', (246, 249))	('PKC-theta', 'Gene', '5588', (31, 40))	('EP4', 'Gene', '5734', (246, 249))	('signaling', 'biological_process', 'GO:0023052', ('250', '259'))	('PKC', 'molecular_function', 'GO:0004697', ('122', '125'))	('PKC-theta', 'Gene', (31, 40))	('Thr538', 'Var', (44, 50))	('Thr538', 'Chemical', '-', (44, 50))	('PKC-theta', 'Gene', '5588', (122, 131))	('PKC', 'molecular_function', 'GO:0004697', ('31', '34'))	('kinase activity', 'molecular_function', 'GO:0016301', ('79', '94'))	('phosphorylation', 'biological_process', 'GO:0016310', ('12', '27'))	('EP2', 'Gene', (242, 245))	('phosphorylation', 'MPA', (12, 27))	('EP2', 'Gene', '5732', (242, 245))	('associated', 'Reg', (54, 64))	('PKC-theta', 'Gene', (122, 131))
45752	25638159	Together with the AH6809/GW627368X pretreatments in the presence of the pseudo-substrate, the number of IGF-1-treated viable cells further decreased by approximately 43% and the MEK and ERK phosphorylation levels also reduced (Fig 3C).	('MEK', 'Gene', (178, 181))	('ERK', 'Gene', '5594', (186, 189))	('MEK', 'Gene', '5609', (178, 181))	('AH6809', 'Chemical', 'MESH:C053876', (18, 24))	('IGF-1-treated', 'Gene', (104, 117))	('ERK', 'Gene', (186, 189))	('AH6809/GW627368X', 'Var', (18, 34))	('GW627368X', 'Chemical', 'MESH:C515270', (25, 34))	('phosphorylation', 'biological_process', 'GO:0016310', ('190', '205'))	('ERK', 'molecular_function', 'GO:0004707', ('186', '189'))	('decreased', 'NegReg', (139, 148))	('reduced', 'NegReg', (218, 225))
45753	25638159	However, according to both growth stimulation assays and immunoblotting, the knockdown of PKC-theta using a specific siRNA impaired the effect of AH6809/GW627368X pretreatment (Fig 4A).	('PKC-theta', 'Gene', '5588', (90, 99))	('AH6809/GW627368X', 'Var', (146, 162))	('AH6809', 'Chemical', 'MESH:C053876', (146, 152))	('knockdown', 'Var', (77, 86))	('PKC-theta', 'Gene', (90, 99))	('effect', 'MPA', (136, 142))	('impaired', 'NegReg', (123, 131))	('GW627368X', 'Chemical', 'MESH:C515270', (153, 162))	('PKC', 'molecular_function', 'GO:0004697', ('90', '93'))
45756	25638159	The phospho-PDK1 levels were not altered in IGF-1-treated cells or in AH6809/GW627368X-pretreated IGF-1-treated cells (Fig 5A).	('PDK1', 'Gene', '5163', (12, 16))	('PDK1', 'Gene', (12, 16))	('AH6809', 'Chemical', 'MESH:C053876', (70, 76))	('PDK1', 'molecular_function', 'GO:0004740', ('12', '16'))	('GW627368X', 'Chemical', 'MESH:C515270', (77, 86))	('AH6809/GW627368X-pretreated', 'Var', (70, 97))
45757	25638159	However, AMPKalpha phosphorylation was not induced by any of the treatments described above and the total protein levels of PDK1, AMPKalpha, and MAP4K3 were similar in the non-treated cells, IGF-1-treated cells, and AH6809/GW627368X-pretreated IGF-1-treated cells.	('phosphorylation', 'biological_process', 'GO:0016310', ('19', '34'))	('AMPK', 'Gene', '5562', (9, 13))	('AMPK', 'Gene', (9, 13))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('GW627368X', 'Chemical', 'MESH:C515270', (223, 232))	('AMPK', 'Gene', '5562', (130, 134))	('AMPK', 'Gene', (130, 134))	('MAP', 'molecular_function', 'GO:0004239', ('145', '148'))	('MAP4K3', 'Gene', (145, 151))	('PDK1', 'Gene', '5163', (124, 128))	('PDK1', 'Gene', (124, 128))	('AH6809/GW627368X-pretreated', 'Var', (216, 243))	('MAP4K3', 'Gene', '8491', (145, 151))	('PDK1', 'molecular_function', 'GO:0004740', ('124', '128'))	('AH6809', 'Chemical', 'MESH:C053876', (216, 222))
45759	25638159	MAP4K3 knockdown abrogated the suppressive effect of AH6809/GW627368X on IGF-1-stimulated cell growth compared with negative control siRNA- and PDK1 siRNA-transfected cells (Fig 5C).	('GW627368X', 'Chemical', 'MESH:C515270', (60, 69))	('cell growth', 'biological_process', 'GO:0016049', ('90', '101'))	('AH6809', 'Chemical', 'MESH:C053876', (53, 59))	('PDK1', 'Gene', '5163', (144, 148))	('PDK1', 'molecular_function', 'GO:0004740', ('144', '148'))	('MAP4K3', 'Gene', (0, 6))	('abrogated', 'NegReg', (17, 26))	('AH6809/GW627368X', 'Var', (53, 69))	('PDK1', 'Gene', (144, 148))	('suppressive', 'MPA', (31, 42))	('MAP4K3', 'Gene', '8491', (0, 6))	('MAP', 'molecular_function', 'GO:0004239', ('0', '3'))	('cell growth', 'CPA', (90, 101))	('IGF-1-stimulated', 'Gene', (73, 89))
45760	25638159	To support this observation, immunoblotting showed that MAP4K3 knockdown cells failed to phosphorylate PKC-theta or to suppress the phosphorylation of MEK and ERK following AH6809/GW627368X pretreatment and IGF-1 treatment (Fig 5D).	('ERK', 'Gene', (159, 162))	('MEK', 'Gene', (151, 154))	('PKC-theta', 'Gene', (103, 112))	('PKC', 'molecular_function', 'GO:0004697', ('103', '106'))	('AH6809', 'Chemical', 'MESH:C053876', (173, 179))	('MAP4K3', 'Gene', (56, 62))	('MEK', 'Gene', '5609', (151, 154))	('ERK', 'molecular_function', 'GO:0004707', ('159', '162'))	('AH6809/GW627368X', 'Var', (173, 189))	('suppress', 'NegReg', (119, 127))	('MAP4K3', 'Gene', '8491', (56, 62))	('MAP', 'molecular_function', 'GO:0004239', ('56', '59'))	('GW627368X', 'Chemical', 'MESH:C515270', (180, 189))	('ERK', 'Gene', '5594', (159, 162))	('phosphorylation', 'MPA', (132, 147))	('phosphorylation', 'biological_process', 'GO:0016310', ('132', '147'))	('PKC-theta', 'Gene', '5588', (103, 112))
45761	25638159	Similar to that in AH6809/GW627368X-pretreated cells, the MAP4K3 knockdown abolished the suppression of IGF-1-stimulated cell growth, PKC-theta phosphorylation, and the inhibition of MEK and ERK phosphorylation in cells transfected with EP4 siRNA (Supplementary Fig 3B).	('PKC-theta', 'Gene', (134, 143))	('MAP4K3', 'Gene', '8491', (58, 64))	('PKC-theta', 'Gene', '5588', (134, 143))	('GW627368X', 'Chemical', 'MESH:C515270', (26, 35))	('ERK', 'Gene', '5594', (191, 194))	('EP4', 'Gene', '5734', (237, 240))	('EP4', 'Gene', (237, 240))	('ERK', 'molecular_function', 'GO:0004707', ('191', '194'))	('knockdown', 'Var', (65, 74))	('MAP4K3', 'Gene', (58, 64))	('ERK', 'Gene', (191, 194))	('AH6809', 'Chemical', 'MESH:C053876', (19, 25))	('abolished', 'NegReg', (75, 84))	('PKC', 'molecular_function', 'GO:0004697', ('134', '137'))	('MEK', 'Gene', '5609', (183, 186))	('cell growth', 'biological_process', 'GO:0016049', ('121', '132'))	('IGF-1-stimulated', 'Gene', (104, 120))	('MAP', 'molecular_function', 'GO:0004239', ('58', '61'))	('inhibition', 'NegReg', (169, 179))	('phosphorylation', 'biological_process', 'GO:0016310', ('144', '159'))	('MEK', 'Gene', (183, 186))	('suppression', 'NegReg', (89, 100))	('cell growth', 'CPA', (121, 132))	('phosphorylation', 'biological_process', 'GO:0016310', ('195', '210'))
45762	25638159	In the cells transfected with negative control siRNA or PDK1 siRNA, pretreatment with AH6809/GW627368X increased the phosphorylation of PKC-theta and suppressed the phosphorylation of MEK and ERK (Fig 5D).	('AH6809', 'Chemical', 'MESH:C053876', (86, 92))	('phosphorylation', 'biological_process', 'GO:0016310', ('117', '132'))	('ERK', 'Gene', '5594', (192, 195))	('phosphorylation', 'biological_process', 'GO:0016310', ('165', '180'))	('suppressed', 'NegReg', (150, 160))	('phosphorylation', 'MPA', (117, 132))	('ERK', 'molecular_function', 'GO:0004707', ('192', '195'))	('PDK1', 'molecular_function', 'GO:0004740', ('56', '60'))	('PDK1', 'Gene', '5163', (56, 60))	('ERK', 'Gene', (192, 195))	('GW627368X', 'Chemical', 'MESH:C515270', (93, 102))	('phosphorylation', 'MPA', (165, 180))	('PKC-theta', 'Gene', '5588', (136, 145))	('MEK', 'Gene', '5609', (184, 187))	('PKC-theta', 'Gene', (136, 145))	('increased', 'PosReg', (103, 112))	('AH6809/GW627368X', 'Var', (86, 102))	('PKC', 'molecular_function', 'GO:0004697', ('136', '139'))	('MEK', 'Gene', (184, 187))	('PDK1', 'Gene', (56, 60))
45763	25638159	In subsequent experiments, the specific PDK1 inhibitor BX912 had no effects on the AH6809/GW627368X-induced suppression of IGF-1-stimulated cell growth and PKC-theta, or MEK, and ERK phosphorylation (Supplementary Fig 4).	('BX912', 'Var', (55, 60))	('PKC-theta', 'Gene', '5588', (156, 165))	('PKC-theta', 'Gene', (156, 165))	('GW627368X', 'Chemical', 'MESH:C515270', (90, 99))	('PDK1', 'molecular_function', 'GO:0004740', ('40', '44'))	('PDK1', 'Gene', '5163', (40, 44))	('ERK', 'Gene', (179, 182))	('PKC', 'molecular_function', 'GO:0004697', ('156', '159'))	('ERK', 'molecular_function', 'GO:0004707', ('179', '182'))	('cell growth', 'biological_process', 'GO:0016049', ('140', '151'))	('IGF-1-stimulated', 'Gene', (123, 139))	('MEK', 'Gene', '5609', (170, 173))	('AH6809', 'Chemical', 'MESH:C053876', (83, 89))	('suppression', 'NegReg', (108, 119))	('cell growth', 'CPA', (140, 151))	('MEK', 'Gene', (170, 173))	('PDK1', 'Gene', (40, 44))	('phosphorylation', 'biological_process', 'GO:0016310', ('183', '198'))	('AH6809/GW627368X-induced', 'Var', (83, 107))	('ERK', 'Gene', '5594', (179, 182))
45764	25638159	We tested the effects of AH6809/GW627368X in an orthotopic nude mouse xenograft model to determine whether the aforementioned cellular events occured in vivo as well.	('AH6809/GW627368X', 'Var', (25, 41))	('tested', 'Reg', (3, 9))	('AH6809', 'Chemical', 'MESH:C053876', (25, 31))	('GW627368X', 'Chemical', 'MESH:C515270', (32, 41))	('mouse', 'Species', '10090', (64, 69))
45767	25638159	The growth rates of the BxPC-hmIGF1 transfectants were higher than those of the vector-control transfected cells (BxPC-mock), and treatments with AH6809/GW627368X decreased cell proliferation only in BxPC-hmIGF1 (Supplementary Fig 5A-C).	('growth rates', 'CPA', (4, 16))	('cell proliferation', 'biological_process', 'GO:0008283', ('173', '191'))	('AH6809/GW627368X', 'Var', (146, 162))	('AH6809', 'Chemical', 'MESH:C053876', (146, 152))	('decreased', 'NegReg', (163, 172))	('GW627368X', 'Chemical', 'MESH:C515270', (153, 162))	('cell proliferation', 'CPA', (173, 191))	('higher', 'PosReg', (55, 61))
45769	25638159	The average tumor weights and serum IGF-1 levels in BxPC-hmIGF1-injected mice were significantly higher than those in BxPC-mock-injected mice (Supplementary Fig 5D).	('higher', 'PosReg', (97, 103))	('mice', 'Species', '10090', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('BxPC-hmIGF1-injected', 'Var', (52, 72))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('mice', 'Species', '10090', (137, 141))
45772	25638159	Thus, the effects of AH6809/GW627368X on pancreatic tumor growth were examined in BxPC-hmIGF1-bearing mice.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mice', 'Species', '10090', (102, 106))	('pancreatic tumor', 'Disease', 'MESH:D010190', (41, 57))	('GW627368X', 'Chemical', 'MESH:C515270', (28, 37))	('pancreatic tumor', 'Disease', (41, 57))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (41, 57))	('AH6809', 'Chemical', 'MESH:C053876', (21, 27))	('AH6809/GW627368X', 'Var', (21, 37))
45774	25638159	The incidence of the visible tumors did not change (80% in control mice and 70% in AH6809/GW627368X-treated mice); however, the tumor weights significantly decreased in AH6809/GW627368X-treated mice (Fig 6A).	('AH6809', 'Chemical', 'MESH:C053876', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mice', 'Species', '10090', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('AH6809', 'Chemical', 'MESH:C053876', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('GW627368X', 'Chemical', 'MESH:C515270', (176, 185))	('mice', 'Species', '10090', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('decreased', 'NegReg', (156, 165))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('GW627368X', 'Chemical', 'MESH:C515270', (90, 99))	('tumor', 'Disease', (128, 133))	('tumors', 'Disease', (29, 35))	('mice', 'Species', '10090', (194, 198))	('AH6809/GW627368X-treated', 'Var', (169, 193))
45775	25638159	H&E and immunohistochemical staining for IGF-1 showed that treatment with AH6809/GW627368X did not alter the tumor types or IGF-1 expression (Fig 6B).	('with', 'Var', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('AH6809', 'Chemical', 'MESH:C053876', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('IGF-1', 'MPA', (124, 129))	('tumor', 'Disease', (109, 114))	('GW627368X', 'Chemical', 'MESH:C515270', (81, 90))
45776	25638159	Moreover, immunohistochemical staining for Ki-67 and the quantification of labeling indices indicated that the percentages of Ki-67-positive cells were significantly lower in AH6809/GW627368X-treated mice (Fig 6B).	('GW627368X', 'Chemical', 'MESH:C515270', (182, 191))	('Ki-67', 'Gene', '17345', (43, 48))	('AH6809/GW627368X-treated', 'Var', (175, 199))	('Ki-67', 'Gene', '17345', (126, 131))	('lower', 'NegReg', (166, 171))	('AH6809', 'Chemical', 'MESH:C053876', (175, 181))	('mice', 'Species', '10090', (200, 204))	('Ki-67', 'Gene', (43, 48))	('Ki-67', 'Gene', (126, 131))
45778	25638159	The relative expression levels of phospho-PKC-theta were significantly elevated in tumors treated with AH6809/GW627368X.	('PKC-theta', 'Gene', '5588', (42, 51))	('expression levels', 'MPA', (13, 30))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('PKC-theta', 'Gene', (42, 51))	('AH6809/GW627368X', 'Var', (103, 119))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('elevated', 'PosReg', (71, 79))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('GW627368X', 'Chemical', 'MESH:C515270', (110, 119))	('PKC', 'molecular_function', 'GO:0004697', ('42', '45'))	('AH6809', 'Chemical', 'MESH:C053876', (103, 109))
45791	25638159	Pretreatment with the EP2/EP4 antagonists AH6809/GW627368X completely blocked growth stimulation on treatment with IGF-1 and HB-EGF and partially blocked it following treatment with IGF-2.	('IGF-2', 'Gene', (182, 187))	('growth stimulation', 'MPA', (78, 96))	('EP4', 'Gene', '5734', (26, 29))	('AH6809/GW627368X', 'Var', (42, 58))	('EGF', 'molecular_function', 'GO:0005154', ('128', '131'))	('IGF-2', 'Gene', '3481', (182, 187))	('EP4', 'Gene', (26, 29))	('GW627368X', 'Chemical', 'MESH:C515270', (49, 58))	('HB-EGF', 'Gene', (125, 131))	('EP2', 'Gene', (22, 25))	('blocked', 'NegReg', (70, 77))	('EP2', 'Gene', '5732', (22, 25))	('HB-EGF', 'Gene', '1839', (125, 131))	('AH6809', 'Chemical', 'MESH:C053876', (42, 48))
45798	25638159	The AH6809/GW627368X pretreatments blocked the phosphorylation and activation of MEK and ERK, so we performed phospho-antibody arrays that demonstrated the dramatic phosphorylation of PKC-theta Thr538, which presumably leads to increased kinase activity.	('activation', 'PosReg', (67, 77))	('ERK', 'Gene', '5594', (89, 92))	('GW627368X', 'Chemical', 'MESH:C515270', (11, 20))	('increased', 'PosReg', (228, 237))	('kinase activity', 'molecular_function', 'GO:0016301', ('238', '253'))	('phosphorylation', 'biological_process', 'GO:0016310', ('165', '180'))	('antibody', 'molecular_function', 'GO:0003823', ('118', '126'))	('AH6809/GW627368X', 'Var', (4, 20))	('antibody', 'cellular_component', 'GO:0042571', ('118', '126'))	('ERK', 'molecular_function', 'GO:0004707', ('89', '92'))	('ERK', 'Gene', (89, 92))	('blocked', 'NegReg', (35, 42))	('MEK', 'Gene', '5609', (81, 84))	('AH6809', 'Chemical', 'MESH:C053876', (4, 10))	('Thr538', 'Chemical', '-', (194, 200))	('phosphorylation', 'MPA', (47, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('PKC-theta', 'Gene', '5588', (184, 193))	('phosphorylation', 'MPA', (165, 180))	('antibody', 'cellular_component', 'GO:0019815', ('118', '126'))	('PKC-theta', 'Gene', (184, 193))	('PKC', 'molecular_function', 'GO:0004697', ('184', '187'))	('MEK', 'Gene', (81, 84))	('Thr538', 'Var', (194, 200))	('kinase activity', 'MPA', (238, 253))	('antibody', 'cellular_component', 'GO:0019814', ('118', '126'))
45801	25638159	Treatments with AH6809/GW627368X alone induced PKC-theta phosphorylation, indicating that EP2/EP4 signaling may negatively regulate PKC-theta phosphorylation.	('PKC', 'molecular_function', 'GO:0004697', ('132', '135'))	('induced', 'Reg', (39, 46))	('EP2', 'Gene', (90, 93))	('AH6809', 'Chemical', 'MESH:C053876', (16, 22))	('EP2', 'Gene', '5732', (90, 93))	('PKC-theta', 'Gene', '5588', (132, 141))	('phosphorylation', 'biological_process', 'GO:0016310', ('142', '157'))	('PKC-theta', 'Gene', '5588', (47, 56))	('negatively', 'NegReg', (112, 122))	('AH6809/GW627368X', 'Var', (16, 32))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('PKC-theta', 'Gene', (132, 141))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('PKC', 'molecular_function', 'GO:0004697', ('47', '50'))	('PKC-theta', 'Gene', (47, 56))	('GW627368X', 'Chemical', 'MESH:C515270', (23, 32))	('EP4', 'Gene', '5734', (94, 97))	('EP4', 'Gene', (94, 97))
45803	25638159	Thus, phosphorylated PKC-theta may be associated with cell survival, maintenance of cell viability, and cell proliferation.	('PKC-theta', 'Gene', '5588', (21, 30))	('associated', 'Reg', (38, 48))	('PKC', 'molecular_function', 'GO:0004697', ('21', '24'))	('PKC-theta', 'Gene', (21, 30))	('cell proliferation', 'biological_process', 'GO:0008283', ('104', '122'))	('cell proliferation', 'CPA', (104, 122))	('phosphorylated', 'Var', (6, 20))	('cell survival', 'CPA', (54, 67))
45804	25638159	Inhibition of the basal activity of PKC-theta also suppressed IGF-1-mediated growth stimulation (data not shown).	('IGF-1-mediated', 'Gene', (62, 76))	('PKC', 'molecular_function', 'GO:0004697', ('36', '39'))	('basal', 'MPA', (18, 23))	('suppressed', 'NegReg', (51, 61))	('PKC-theta', 'Gene', '5588', (36, 45))	('Inhibition', 'Var', (0, 10))	('PKC-theta', 'Gene', (36, 45))
45808	25638159	Thus, a treatment with AH6809/GW627368X activates PKC-theta, and the effect of the PKC-theta pseudosubstrate may further decrease the cell viability.	('GW627368X', 'Chemical', 'MESH:C515270', (30, 39))	('PKC-theta', 'Gene', (83, 92))	('PKC-theta', 'Gene', '5588', (83, 92))	('PKC', 'molecular_function', 'GO:0004697', ('83', '86'))	('PKC-theta', 'Gene', '5588', (50, 59))	('activates', 'PosReg', (40, 49))	('AH6809', 'Chemical', 'MESH:C053876', (23, 29))	('PKC-theta', 'Gene', (50, 59))	('decrease', 'NegReg', (121, 129))	('AH6809/GW627368X', 'Var', (23, 39))	('PKC', 'molecular_function', 'GO:0004697', ('50', '53'))	('cell viability', 'CPA', (134, 148))
45809	25638159	PKC-theta knockdown impaired the effects of AH6809/GW627368X pretreatment and induced the expression of PKC-alpha mRNA, suggesting that the compensatory induction of PKC-alpha, following the knockdown of PKC-theta, protected against the effects of AH6809/GW627368X.	('GW627368X', 'Chemical', 'MESH:C515270', (51, 60))	('PKC-theta', 'Gene', '5588', (204, 213))	('PKC', 'molecular_function', 'GO:0004697', ('166', '169'))	('expression', 'MPA', (90, 100))	('PKC-alpha', 'Gene', (104, 113))	('PKC-theta', 'Gene', (204, 213))	('PKC-alpha', 'Gene', (166, 175))	('impaired', 'NegReg', (20, 28))	('AH6809/GW627368X', 'Var', (44, 60))	('GW627368X', 'Chemical', 'MESH:C515270', (255, 264))	('AH6809', 'Chemical', 'MESH:C053876', (44, 50))	('knockdown', 'Var', (10, 19))	('PKC', 'molecular_function', 'GO:0004697', ('204', '207'))	('induced', 'Reg', (78, 85))	('AH6809/GW627368X', 'Var', (248, 264))	('PKC-alpha', 'Gene', '5578', (104, 113))	('PKC-alpha', 'Gene', '5578', (166, 175))	('PKC-theta', 'Gene', '5588', (0, 9))	('PKC', 'molecular_function', 'GO:0004697', ('0', '3'))	('PKC-theta', 'Gene', (0, 9))	('effects', 'MPA', (33, 40))	('AH6809', 'Chemical', 'MESH:C053876', (248, 254))	('PKC', 'molecular_function', 'GO:0004697', ('104', '107'))
45811	25638159	The phospho-antibody arrays also indicated that the phosphorylation of IRS-1, which is closely related to the activation of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway, was induced by AH6809/GW627368X pretreatment in IGF-1 treated cells.	('AH6809/GW627368X', 'Var', (199, 215))	('signaling pathway', 'biological_process', 'GO:0007165', ('165', '182'))	('antibody', 'cellular_component', 'GO:0042571', ('12', '20'))	('PI3K', 'molecular_function', 'GO:0016303', ('155', '159'))	('IRS-1', 'Gene', '3667', (71, 76))	('Akt signaling', 'biological_process', 'GO:0043491', ('161', '174'))	('Akt', 'Gene', '207', (161, 164))	('antibody', 'molecular_function', 'GO:0003823', ('12', '20'))	('GW627368X', 'Chemical', 'MESH:C515270', (206, 215))	('antibody', 'cellular_component', 'GO:0019814', ('12', '20'))	('antibody', 'cellular_component', 'GO:0019815', ('12', '20'))	('IRS-1', 'Gene', (71, 76))	('AH6809', 'Chemical', 'MESH:C053876', (199, 205))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('Akt', 'Gene', (161, 164))	('phosphorylation', 'MPA', (52, 67))	('induced', 'PosReg', (188, 195))
45813	25638159	reported that the phosphorylation of IRS-1 Ser636/639 is associated with the reduced phosphorylation of IRS-1 on tyrosine and subsequent reduction in PI3K/Akt activation.	('activation', 'PosReg', (159, 169))	('Ser636', 'Chemical', '-', (43, 49))	('IRS-1', 'Gene', '3667', (37, 42))	('phosphorylation', 'MPA', (85, 100))	('Ser', 'cellular_component', 'GO:0005790', ('43', '46'))	('IRS-1', 'Gene', (104, 109))	('reduction', 'NegReg', (137, 146))	('Ser636/639', 'Var', (43, 53))	('phosphorylation', 'biological_process', 'GO:0016310', ('18', '33'))	('phosphorylation', 'biological_process', 'GO:0016310', ('85', '100'))	('phosphorylation', 'MPA', (18, 33))	('reduced', 'NegReg', (77, 84))	('IRS-1', 'Gene', (37, 42))	('tyrosine', 'Chemical', 'MESH:D014443', (113, 121))	('Akt', 'Gene', '207', (155, 158))	('IRS-1', 'Gene', '3667', (104, 109))	('PI3K', 'molecular_function', 'GO:0016303', ('150', '154'))	('Akt', 'Gene', (155, 158))
45816	25638159	Immunoblotting showed that there were no increases in PDK1 and AMPK phosphorylation or changes in MAP4K3 level with AH6809/GW627368X pretreatment.	('AH6809/GW627368X', 'Var', (116, 132))	('PDK1', 'Gene', '5163', (54, 58))	('PDK1', 'Gene', (54, 58))	('MAP', 'molecular_function', 'GO:0004239', ('98', '101'))	('MAP4K3', 'Gene', (98, 104))	('MAP4K3', 'Gene', '8491', (98, 104))	('GW627368X', 'Chemical', 'MESH:C515270', (123, 132))	('increases', 'PosReg', (41, 50))	('AH6809', 'Chemical', 'MESH:C053876', (116, 122))	('PDK1', 'molecular_function', 'GO:0004740', ('54', '58'))	('AMPK', 'Gene', '5562', (63, 67))	('AMPK', 'molecular_function', 'GO:0050405', ('63', '67'))	('phosphorylation', 'biological_process', 'GO:0016310', ('68', '83'))	('AMPK', 'molecular_function', 'GO:0004691', ('63', '67'))	('AMPK', 'Gene', (63, 67))	('AMPK', 'molecular_function', 'GO:0047322', ('63', '67'))
45817	25638159	However, MAP4K3 knockdown prevented the suppression of growth stimulation, phosphorylation of PKC-theta, and downregulation of phospho-MEK and -ERK by AH6809/GW627368X pretreatment, whereas the negative control siRNA and PDK-1 knockdown did not.	('PDK-1', 'molecular_function', 'GO:0004740', ('221', '226'))	('PKC-theta', 'Gene', '5588', (94, 103))	('PKC-theta', 'Gene', (94, 103))	('MEK', 'Gene', (135, 138))	('MAP4K3', 'Gene', '8491', (9, 15))	('PDK-1', 'Gene', (221, 226))	('downregulation', 'NegReg', (109, 123))	('growth stimulation', 'MPA', (55, 73))	('ERK', 'Gene', '5594', (144, 147))	('GW627368X', 'Chemical', 'MESH:C515270', (158, 167))	('ERK', 'molecular_function', 'GO:0004707', ('144', '147'))	('MAP4K3', 'Gene', (9, 15))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('phosphorylation', 'MPA', (75, 90))	('ERK', 'Gene', (144, 147))	('AH6809/GW627368X', 'Var', (151, 167))	('knockdown', 'Var', (16, 25))	('PDK-1', 'Gene', '5163', (221, 226))	('PKC', 'molecular_function', 'GO:0004697', ('94', '97'))	('MEK', 'Gene', '5609', (135, 138))	('AH6809', 'Chemical', 'MESH:C053876', (151, 157))	('MAP', 'molecular_function', 'GO:0004239', ('9', '12'))
45818	25638159	These data indicate that MAP4K3 is activated and that it phosphorylates PKC-theta in AH6809/GW627368X-pretreated IGF-1 treated cells.	('PKC-theta', 'Gene', '5588', (72, 81))	('phosphorylates', 'MPA', (57, 71))	('PKC-theta', 'Gene', (72, 81))	('MAP4K3', 'Gene', (25, 31))	('AH6809/GW627368X-pretreated', 'Var', (85, 112))	('MAP4K3', 'Gene', '8491', (25, 31))	('AH6809', 'Chemical', 'MESH:C053876', (85, 91))	('GW627368X', 'Chemical', 'MESH:C515270', (92, 101))
45821	25638159	However, further investigations using currently unavailable anti-phospho-MAP4K3 antibodies or specific inhibitors of MAP4K3 are required to determine whether AH6809/GW627368X pretreatment directly activates MAP4K3.	('AH6809/GW627368X', 'Var', (158, 174))	('MAP', 'molecular_function', 'GO:0004239', ('73', '76'))	('GW627368X', 'Chemical', 'MESH:C515270', (165, 174))	('MAP4K3', 'Gene', (117, 123))	('activates', 'PosReg', (197, 206))	('MAP4K3', 'Gene', '8491', (207, 213))	('MAP', 'molecular_function', 'GO:0004239', ('117', '120'))	('MAP4K3', 'Gene', (207, 213))	('MAP4K3', 'Gene', (73, 79))	('MAP4K3', 'Gene', '8491', (117, 123))	('AH6809', 'Chemical', 'MESH:C053876', (158, 164))	('MAP', 'molecular_function', 'GO:0004239', ('207', '210'))	('MAP4K3', 'Gene', '8491', (73, 79))
45822	25638159	AH6809/GW627368X pretreatment may also produce cellular stress, including alterations in the amino acid content, so further studies of the relationship between EP2/EP4 signaling and cellular stress-induced signal transduction are required to fully characterize the role of MAP4K3 in the present conditions.	('MAP4K3', 'Gene', '8491', (273, 279))	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('MAP', 'molecular_function', 'GO:0004239', ('273', '276'))	('AH6809/GW627368X pretreatment', 'Var', (0, 29))	('pretreatment', 'Var', (17, 29))	('GW627368X', 'Chemical', 'MESH:C515270', (7, 16))	('EP4', 'Gene', '5734', (164, 167))	('produce', 'Reg', (39, 46))	('EP4', 'Gene', (164, 167))	('alterations', 'Reg', (74, 85))	('cellular stress', 'MPA', (47, 62))	('AH6809', 'Chemical', 'MESH:C053876', (0, 6))	('signal transduction', 'biological_process', 'GO:0007165', ('206', '225'))	('MAP4K3', 'Gene', (273, 279))	('EP2', 'Gene', (160, 163))	('EP2', 'Gene', '5732', (160, 163))	('amino acid content', 'MPA', (93, 111))
45824	25638159	Initially, we established a stable transfectant cell line expressing hmIGF-1, which grew more rapidly than the vector-control cells and responded to AH6809/GW627368X treatment.	('AH6809', 'Chemical', 'MESH:C053876', (149, 155))	('grew', 'CPA', (84, 88))	('AH6809/GW627368X', 'Var', (149, 165))	('GW627368X', 'Chemical', 'MESH:C515270', (156, 165))	('hmIGF-1', 'Gene', (69, 76))	('responded', 'Reg', (136, 145))
45826	25638159	Using this transfectant, we examined the effects of AH6809/GW627368X treatment, which suppressed tumor growth and decreased the number of Ki-67-positive cells.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Ki-67', 'Gene', (138, 143))	('GW627368X', 'Chemical', 'MESH:C515270', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('AH6809/GW627368X', 'Var', (52, 68))	('tumor', 'Disease', (97, 102))	('decreased', 'NegReg', (114, 123))	('suppressed', 'NegReg', (86, 96))	('AH6809', 'Chemical', 'MESH:C053876', (52, 58))	('Ki-67', 'Gene', '17345', (138, 143))
45831	25638159	Thus, the mice in this model were athymic and treatment with AH6809/GW627368X could enhance the T cell-associated host tumor-immunity as well as obtaining additive and/or synergistic effects in general conditions, in addition to the effect of the EP antagonists itself.	('GW627368X', 'Chemical', 'MESH:C515270', (68, 77))	('mice', 'Species', '10090', (10, 14))	('AH6809', 'Chemical', 'MESH:C053876', (61, 67))	('cell-associated', 'cellular_component', 'GO:0009986', ('98', '113'))	('host tumor', 'Disease', (114, 124))	('host tumor', 'Disease', 'MESH:D006086', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('AH6809/GW627368X', 'Var', (61, 77))	('enhance', 'PosReg', (84, 91))
45833	25638159	According to these analyses, 17.4% of the cases were quadruple-positive for IGF-1R, EP2/EP4, MAP4K3, and PKC-theta, indicating that crosstalk may occur between these signaling pathways in human pancreatic cancers.	('PKC', 'molecular_function', 'GO:0004697', ('105', '108'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (194, 211))	('signaling', 'biological_process', 'GO:0023052', ('166', '175'))	('EP2', 'Gene', (84, 87))	('EP2', 'Gene', '5732', (84, 87))	('crosstalk', 'Reg', (132, 141))	('EP4', 'Gene', '5734', (88, 91))	('EP4', 'Gene', (88, 91))	('quadruple-positive', 'Var', (53, 71))	('MAP4K3', 'Gene', (93, 99))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (194, 212))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('pancreatic cancers', 'Disease', (194, 212))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('PKC-theta', 'Gene', '5588', (105, 114))	('IGF-1R', 'Gene', (76, 82))	('PKC-theta', 'Gene', (105, 114))	('IGF-1R', 'Gene', '3480', (76, 82))	('pancreatic cancers', 'Disease', 'MESH:D010190', (194, 212))	('human', 'Species', '9606', (188, 193))	('MAP', 'molecular_function', 'GO:0004239', ('93', '96'))	('MAP4K3', 'Gene', '8491', (93, 99))
45850	25638159	The EP2-selective antagonist AH6809 and EP4-selective antagonist GW627368X were purchased from Cayman Chemical (Ann Arbor, MI).	('AH6809', 'Chemical', 'MESH:C053876', (29, 35))	('EP4', 'Gene', '5734', (40, 43))	('EP4', 'Gene', (40, 43))	('EP2', 'Gene', (4, 7))	('GW627368X', 'Var', (65, 74))	('EP2', 'Gene', '5732', (4, 7))	('GW627368X', 'Chemical', 'MESH:C515270', (65, 74))
45855	25638159	Subsequently, equal volumes of serum-free medium containing HB-EGF, IGF-1, and IGF-2 (50, 20, and 50 ng/mL, respectively) were added, and the cells were incubated for 48 h or 20 min at 37 C. Pretreatments with 5 muM AH6809/GW627368X were performed for 3 h prior to the growth factor treatments.	('HB-EGF', 'Gene', (60, 66))	('IGF-2', 'Gene', (79, 84))	('IGF-2', 'Gene', '3481', (79, 84))	('GW627368X', 'Chemical', 'MESH:C515270', (223, 232))	('AH6809/GW627368X', 'Var', (216, 232))	('EGF', 'molecular_function', 'GO:0005154', ('63', '66'))	('HB-EGF', 'Gene', '1839', (60, 66))	('AH6809', 'Chemical', 'MESH:C053876', (216, 222))
45860	25638159	IGF-1R signaling was assessed in IGF-1-stimulated and AH6809/GW627368X-pretreated IGF-1-stimulated BxPC-3 cells (5 x 106) using a Phospho Antibody Array contract service (FullMoon BioSystems Inc; Filgen, Nagoya, Japan).	('AH6809/GW627368X-pretreated', 'Var', (54, 81))	('AH6809', 'Chemical', 'MESH:C053876', (54, 60))	('BxPC-3', 'CellLine', 'CVCL:0186', (99, 105))	('IGF-1R', 'Gene', '3480', (0, 6))	('signaling', 'biological_process', 'GO:0023052', ('7', '16'))	('IGF-1R', 'Gene', (0, 6))	('GW627368X', 'Chemical', 'MESH:C515270', (61, 70))
45862	25638159	The concentrations of IGF-1, AH6809, and GW627368X were the same as those used in the growth stimulation assays.	('AH6809', 'Var', (29, 35))	('AH6809', 'Chemical', 'MESH:C053876', (29, 35))	('IGF-1', 'Gene', (22, 27))	('GW627368X', 'Var', (41, 50))	('GW627368X', 'Chemical', 'MESH:C515270', (41, 50))
45863	25638159	BxPC-3 cells (3 x 105 cells/well) were seeded onto six-well plates and preincubated overnight at 37 C. The following day, the cells were transfected with negative universal control siRNA (Life Technologies, Carlsbad, CA), PKC-theta siRNA (ID SASI_Hs01_00239143; Sigma), MAP4K3 siRNA (ID SASI_Hs02_00335960 and SASI_Hs01_00040140; Sigma) and PDK1 siRNA (ID SASI_Hs01_00094378 and SASI_Hs01_00044485; Sigma) using lipofectamine RNAiMAX (Life Technologies), according to the manufacturer's protocol.	('MAP', 'molecular_function', 'GO:0004239', ('270', '273'))	('MAP4K3', 'Gene', '8491', (270, 276))	('PKC', 'molecular_function', 'GO:0004697', ('222', '225'))	('ID SASI_Hs01_00094378', 'Var', (353, 374))	('ID SASI_Hs02_00335960', 'Var', (284, 305))	('PDK1', 'Gene', '5163', (341, 345))	('PDK1', 'Gene', (341, 345))	('PKC-theta', 'Gene', '5588', (222, 231))	('PDK1', 'molecular_function', 'GO:0004740', ('341', '345'))	('BxPC-3', 'CellLine', 'CVCL:0186', (0, 6))	('MAP4K3', 'Gene', (270, 276))	('PKC-theta', 'Gene', (222, 231))
45864	25638159	After transfection, we analyzed the effects of AH6809/GW627368X on IGF-1-stimulated cell growth and the activations of PKC-theta, MEK, and ERK with a growth stimulation assay and immunoblotting using the conditions and procedures described above.	('cell growth', 'biological_process', 'GO:0016049', ('84', '95'))	('IGF-1-stimulated', 'Gene', (67, 83))	('PKC-theta', 'Gene', (119, 128))	('MEK', 'Gene', (130, 133))	('MEK', 'Gene', '5609', (130, 133))	('ERK', 'molecular_function', 'GO:0004707', ('139', '142'))	('ERK', 'Gene', '5594', (139, 142))	('ERK', 'Gene', (139, 142))	('AH6809', 'Chemical', 'MESH:C053876', (47, 53))	('GW627368X', 'Chemical', 'MESH:C515270', (54, 63))	('PKC', 'molecular_function', 'GO:0004697', ('119', '122'))	('AH6809/GW627368X', 'Var', (47, 63))	('PKC-theta', 'Gene', '5588', (119, 128))
45934	24637664	The cells were washed, re-suspended and stained with anti-human CD3 APC-eFluor780 (47-0036, eBioscience), CD4-FITC (11-0048-41, eBioscience), CD8 PerCP-Cy5.5 (45-0088, eBioscience) and CD25-PE antibodies (12-0259-41, eBioscience).	('human', 'Species', '9606', (58, 63))	('APC', 'cellular_component', 'GO:0005680', ('68', '71'))	('11-0048-41', 'Var', (116, 126))	('CD25', 'Gene', (185, 189))	('PerCP-Cy5', 'Chemical', '-', (146, 155))	('CD8', 'Gene', (142, 145))	('CD8', 'Gene', '925', (142, 145))	('CD25', 'Gene', '3559', (185, 189))	('CD4-FITC', 'Gene', '920', (106, 114))	('CD4-FITC', 'Gene', (106, 114))
46009	24637664	Other studies have shown that Treg depletion results in enhanced antitumor responses and inhibits tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('inhibits', 'NegReg', (89, 97))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('Treg', 'Chemical', '-', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('enhanced', 'PosReg', (56, 64))	('Treg', 'Protein', (30, 34))	('tumor', 'Disease', (98, 103))	('depletion', 'Var', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
46042	22050964	A large retrospective study of 466 consecutive patients with PDA who underwent R0 resection (all margins negative by histology) at Mayo Clinic showed a median OS of 25.2 in the patients who received neoadjuvant CRT compared to the median OS of 19.2 months in patients who did not receive neoadjuvant CRT (P= 0.001).	('PDA', 'Phenotype', 'HP:0006725', (61, 64))	('patients', 'Species', '9606', (259, 267))	('patients', 'Species', '9606', (177, 185))	('patients', 'Species', '9606', (47, 55))	('PDA', 'Disease', (61, 64))	('Mayo', 'Species', '162683', (131, 135))	('PDA', 'Chemical', '-', (61, 64))	('neoadjuvant', 'Var', (199, 210))
46044	22050964	pCR has been shown to be associated with lower frequencies of local recurrence and better survival in patients with adenocarcinoma of several anatomic sites who received neoadjuvant therapies.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('adenocarcinoma', 'Disease', (116, 130))	('adenocarcinoma', 'Disease', 'MESH:D000230', (116, 130))	('patients', 'Species', '9606', (102, 110))	('pCR', 'Var', (0, 3))	('lower', 'NegReg', (41, 46))	('better', 'PosReg', (83, 89))	('survival', 'CPA', (90, 98))
46085	22050964	The tumor in pancreatic FNA was positive for cytokeratin 7 and CA19.9, but negative for PSA and PAP (Figure 2C-2D).	('tumor', 'Disease', (4, 9))	('cytokeratin 7', 'Gene', (45, 58))	('cytokeratin 7', 'Gene', '3855', (45, 58))	('pancreatic', 'Disease', 'MESH:D010195', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('PSA', 'Gene', '354', (88, 91))	('PAP', 'molecular_function', 'GO:0043751', ('96', '99'))	('positive', 'Reg', (32, 40))	('PSA', 'Gene', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('pancreatic', 'Disease', (13, 23))	('CA19.9', 'Var', (63, 69))
46105	22050964	Patients with pCR in pancreatectomy specimen had significant better disease-specific OS than the patients who had post-treatment stage I or stage IIA disease in pancreaticoduodenectomy specimens after neoajuvant therapy (p < 0.001, Figure 4).	('better', 'PosReg', (61, 67))	('men', 'Species', '9606', (124, 127))	('disease-specific OS', 'MPA', (68, 87))	('Patients', 'Species', '9606', (0, 8))	('pancreatic', 'Disease', 'MESH:D010195', (161, 171))	('pCR', 'Var', (14, 17))	('men', 'Species', '9606', (190, 193))	('pancreatic', 'Disease', (161, 171))	('men', 'Species', '9606', (41, 44))	('patients', 'Species', '9606', (97, 105))
46157	23462329	Strikingly, T2DM patients who had taken metformin had a 62% lower adjusted incidence of PDAC compared with those who had not taken metformin, a result recently substantiated in a different patient population.	('PDAC', 'Disease', (88, 92))	('T2DM', 'Var', (12, 16))	('metformin', 'Chemical', 'MESH:D008687', (40, 49))	('patient', 'Species', '9606', (17, 24))	('lower', 'NegReg', (60, 65))	('PDAC', 'Phenotype', 'HP:0006725', (88, 92))	('patient', 'Species', '9606', (189, 196))	('patients', 'Species', '9606', (17, 25))	('PDAC', 'Chemical', '-', (88, 92))	('metformin', 'Chemical', 'MESH:D008687', (131, 140))	('metformin', 'Var', (40, 49))
46198	23462329	We also found a significant decrease in the phosphorylation of S6 ribosomal protein at Ser235/236, a site targeted by S6K, downstream of mTORC1, and in the phosphorylation of ERK (Fig.	('ERK', 'Protein', (175, 178))	('phosphorylation', 'MPA', (44, 59))	('phosphorylation', 'biological_process', 'GO:0016310', ('44', '59'))	('mTORC1', 'Gene', '382056', (137, 143))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('66', '83'))	('S6K', 'Var', (118, 121))	('S6 ribosomal protein', 'Protein', (63, 83))	('mTORC1', 'cellular_component', 'GO:0031931', ('137', '143'))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('phosphorylation', 'biological_process', 'GO:0016310', ('156', '171'))	('Ser', 'cellular_component', 'GO:0005790', ('87', '90'))	('ERK', 'molecular_function', 'GO:0004707', ('175', '178'))	('decrease', 'NegReg', (28, 36))	('mTORC1', 'Gene', (137, 143))	('Ser235', 'Chemical', '-', (87, 93))	('phosphorylation', 'MPA', (156, 171))
46200	23462329	These results demonstrate that metformin inhibits the growth of PANC-1 cells xenografted into nude mice in a dose-dependent manner and cause a marked decrease in mTORC1 and ERK signaling in the xenografts.	('nude mice', 'Species', '10090', (94, 103))	('signaling', 'biological_process', 'GO:0023052', ('177', '186'))	('inhibits', 'NegReg', (41, 49))	('mTORC1', 'Gene', (162, 168))	('mTORC1', 'cellular_component', 'GO:0031931', ('162', '168'))	('decrease', 'NegReg', (150, 158))	('ERK', 'molecular_function', 'GO:0004707', ('173', '176'))	('PANC-1', 'Gene', '104066', (64, 70))	('ERK signaling', 'MPA', (173, 186))	('metformin', 'Var', (31, 40))	('growth', 'CPA', (54, 60))	('mTORC1', 'Gene', '382056', (162, 168))	('PANC-1', 'Gene', (64, 70))	('metformin', 'Chemical', 'MESH:D008687', (31, 40))
46217	23462329	At the end of the 8-week long treatment, the weight and volume of the tumors were markedly reduced (by 73%) in the animals that received metformin, as shown in Fig.	('men', 'Species', '9606', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('metformin', 'Chemical', 'MESH:D008687', (137, 146))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('reduced', 'NegReg', (91, 98))	('metformin', 'Var', (137, 146))
46224	23462329	We previously demonstrated that metformin, the most widely prescribed drug for treatment of T2DM, inhibits mitogenic signaling, including mTORC1 activity, induced by crosstalk between insulin/IGF and GPCR signaling systems in pancreatic cancer cells in vitro.	('GPCR', 'Gene', '441931', (200, 204))	('T2DM', 'Var', (92, 96))	('crosstalk', 'MPA', (166, 175))	('pancreatic cancer', 'Disease', 'MESH:D010190', (226, 243))	('mTORC1', 'Gene', (138, 144))	('mitogenic signaling', 'MPA', (107, 126))	('signaling', 'biological_process', 'GO:0023052', ('205', '214'))	('mTORC1', 'cellular_component', 'GO:0031931', ('138', '144'))	('insulin/IGF', 'Gene', '3630', (184, 195))	('mTORC1', 'Gene', '382056', (138, 144))	('insulin', 'molecular_function', 'GO:0016088', ('184', '191'))	('pancreatic cancer', 'Disease', (226, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('inhibits', 'NegReg', (98, 106))	('insulin/IGF', 'Gene', (184, 195))	('GPCR', 'Gene', (200, 204))	('metformin', 'Chemical', 'MESH:D008687', (32, 41))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (226, 243))	('men', 'Species', '9606', (84, 87))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))
46232	23462329	The studies presented here provide further evidence indicating that metformin offers a potential novel approach for PDAC prevention and therapy and thus, warrant further experimental work to elucidate its precise mechanism of anticancer action.	('metformin', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('PDAC', 'Phenotype', 'HP:0006725', (116, 120))	('men', 'Species', '9606', (176, 179))	('PDAC', 'Disease', (116, 120))	('metformin', 'Chemical', 'MESH:D008687', (68, 77))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('PDAC', 'Chemical', '-', (116, 120))
46237	21948970	Furthermore, induction of AGR2 in tumor cells regulated the expression of several ER chaperones (PDI, CALU, RCN1), proteins of the ubiquitin-proteasome degradation pathway (HIP2, PSMB2, PSMA3, PSMC3, and PSMB4), and lysosomal proteases [cathepsin B (CTSB) and cathepsin D (CTSD)], in addition to promoting the secretion of the precursor form pro-CTSD.	('expression', 'MPA', (60, 70))	('proteasome', 'molecular_function', 'GO:0004299', ('141', '151'))	('tumor', 'Disease', (34, 39))	('PSMC3', 'Gene', '5702', (193, 198))	('PSMB4', 'Gene', '5692', (204, 209))	('proteasome', 'cellular_component', 'GO:0000502', ('141', '151'))	('PSMB2', 'Gene', '5690', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('ubiquitin', 'molecular_function', 'GO:0031386', ('131', '140'))	('PSMC3', 'Gene', (193, 198))	('CALU', 'Gene', (102, 106))	('PDI', 'Gene', '5034', (97, 100))	('HIP2', 'Gene', (173, 177))	('regulated', 'Reg', (46, 55))	('HIP2', 'Gene', '3093', (173, 177))	('proteasome degradation', 'biological_process', 'GO:1903009', ('141', '163'))	('induction', 'Var', (13, 22))	('promoting', 'PosReg', (296, 305))	('RCN1', 'Gene', (108, 112))	('cathepsin D', 'Gene', (260, 271))	('secretion', 'biological_process', 'GO:0046903', ('310', '319'))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PSMB2', 'Gene', (179, 184))	('PDI', 'Gene', (97, 100))	('cathepsin B', 'Gene', (237, 248))	('PSMA', 'molecular_function', 'GO:0043275', ('186', '190'))	('AGR2', 'Gene', (26, 30))	('cathepsin D', 'Gene', '1509', (260, 271))	('PSMA3', 'Gene', (186, 191))	('CALU', 'Gene', '813', (102, 106))	('RCN1', 'Gene', '5954', (108, 112))	('PSMA3', 'Gene', '5684', (186, 191))	('cathepsin B', 'Gene', '1508', (237, 248))	('secretion of the precursor form pro-CTSD', 'MPA', (310, 350))	('PSMB4', 'Gene', (204, 209))
46249	21948970	Recent data also suggested that silencing of AGR2 in the pancreatic cancer cell line MPanc-96 results in fewer metastases in an orthotopic pancreas tumor model.	('metastases', 'Disease', (111, 121))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('MPanc-96', 'CellLine', 'CVCL:7165', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('pancreas tumor', 'Disease', (139, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (57, 74))	('metastases', 'Disease', 'MESH:D009362', (111, 121))	('AGR2', 'Gene', (45, 49))	('silencing', 'Var', (32, 41))	('fewer', 'NegReg', (105, 110))	('pancreas tumor', 'Disease', 'MESH:D010190', (139, 153))	('pancreas tumor', 'Phenotype', 'HP:0002894', (139, 153))	('pancreatic cancer', 'Disease', (57, 74))	('pancreatic cancer', 'Disease', 'MESH:D010190', (57, 74))
46252	21948970	They showed that AGR2 mediates processing of the intestinal mucin MUC2 through formation of mixed disulfide bonds and that the absence of AGR2 resulted in a dramatic reduction of mucus production and secretion and an increased sensitivity to colitis in Agr2-/- mice.	('mucin', 'Gene', (60, 65))	('mixed disulfide bonds', 'MPA', (92, 113))	('mice', 'Species', '10090', (261, 265))	('colitis', 'Phenotype', 'HP:0002583', (242, 249))	('mucin', 'Gene', '100508689', (60, 65))	('Agr2', 'Gene', (253, 257))	('mucus', 'cellular_component', 'GO:0070701', ('179', '184'))	('absence', 'Var', (127, 134))	('AGR2', 'Gene', (138, 142))	('increased', 'PosReg', (217, 226))	('AGR2', 'Gene', (17, 21))	('secretion', 'biological_process', 'GO:0046903', ('200', '209'))	('colitis', 'Disease', (242, 249))	('Agr2', 'Gene', '23795', (253, 257))	('reduction', 'NegReg', (166, 175))	('mucus production', 'MPA', (179, 195))	('colitis', 'Disease', 'MESH:D003092', (242, 249))	('formation', 'biological_process', 'GO:0009058', ('79', '88'))	('disulfide', 'Chemical', 'MESH:D004220', (98, 107))	('mucus production', 'biological_process', 'GO:0070254', ('179', '195'))	('secretion', 'MPA', (200, 209))
46307	21948970	3B (i)], and a significant decrease (P < 0.05) in the number of invading cells was seen following siRNA-mediated knockdown of AGR2 in FA6 cells [Fig.	('decrease', 'NegReg', (27, 35))	('AGR2', 'Gene', (126, 130))	('knockdown', 'Var', (113, 122))	('FA6', 'CellLine', 'CVCL:4034', (134, 137))	('number of invading cells', 'CPA', (54, 78))
46318	21948970	As overexpression of CTSB and CTSD is often associated with an increase in their secretion, the culture supernatants of PDAC cells were analyzed: higher levels of pro-CTSD were detected in the supernatants of AGR2-expressing MiaPaCa2 than in vector-only transfected cells, and inversely, silencing of AGR2 in FA6 cells strongly inhibited pro-CTSD secretion (Fig.	('AGR2', 'Gene', (301, 305))	('secretion', 'biological_process', 'GO:0046903', ('81', '90'))	('secretion', 'biological_process', 'GO:0046903', ('347', '356'))	('MiaPaCa2', 'CellLine', 'CVCL:0428', (225, 233))	('inhibited', 'NegReg', (328, 337))	('PDAC', 'Phenotype', 'HP:0006725', (120, 124))	('silencing', 'Var', (288, 297))	('FA6', 'CellLine', 'CVCL:4034', (309, 312))	('PDAC', 'Chemical', '-', (120, 124))	('pro-CTSD secretion', 'MPA', (338, 356))
46321	21948970	The same dramatic effect was observed in FA6 cells after silencing of CTSB (P < 0.05) and CTSD [P < 0.001; Fig.	('silencing', 'Var', (57, 66))	('FA6', 'CellLine', 'CVCL:4034', (41, 44))	('CTSB', 'Gene', (70, 74))
46326	21948970	Silencing of AGR2 in PaTu 8988s cells significantly lowered the number of DTC than siRNA-control-transfected cells (P < 0.001; Fig.	('AGR2', 'Gene', (13, 17))	('number of DTC', 'MPA', (64, 77))	('DTC', 'Chemical', '-', (74, 77))	('PaTu 8988', 'CellLine', 'CVCL:1847', (21, 30))	('lowered', 'NegReg', (52, 59))	('Silencing', 'Var', (0, 9))
46327	21948970	A similar decrease of DTC was observed after silencing of CTSB (P < 0.001) or CTSD (P < 0.001; Fig.	('decrease', 'NegReg', (10, 18))	('silencing', 'Var', (45, 54))	('DTC', 'Chemical', '-', (22, 25))	('DTC', 'MPA', (22, 25))
46348	21948970	AGR2 expression induced an increase in the levels of CTSB and CTSD, 2 disulfide-containing thiol proteases that have previously been reported to be upregulated in pancreatic cancer and are known to play a role in the dissemination of cancer cells.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('expression', 'Var', (5, 15))	('cancer', 'Disease', (234, 240))	('CTSB', 'MPA', (53, 57))	('levels', 'MPA', (43, 49))	('cancer', 'Disease', (174, 180))	('AGR2', 'Gene', (0, 4))	('disulfide', 'Chemical', 'MESH:D004220', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('pancreatic cancer', 'Disease', (163, 180))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('pancreatic cancer', 'Disease', 'MESH:D010190', (163, 180))	('CTSD', 'MPA', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('increase', 'PosReg', (27, 35))	('upregulated', 'PosReg', (148, 159))
46382	21221179	Pancreatic cancer has a highly complex molecular pathology and is uniquely characterized by a high frequency of activating K-ras mutations and loss of function of the p53, p16, and Smad 4 tumor suppresser genes.	('tumor', 'Disease', (188, 193))	('loss of function', 'NegReg', (143, 159))	('K-ras', 'Gene', '3845', (123, 128))	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('mutations', 'Var', (129, 138))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('p16', 'Gene', '1029', (172, 175))	('p16', 'Gene', (172, 175))	('Smad 4', 'Gene', '4089', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('p53', 'Gene', '7157', (167, 170))	('K-ras', 'Gene', (123, 128))	('p53', 'Gene', (167, 170))	('Smad 4', 'Gene', (181, 187))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))	('activating', 'PosReg', (112, 122))
46384	21221179	The phosphoinositide 3-OH kinase (PI3K)/Akt pathway, which is frequently amplified or activated in pancreatic cancer, may also contribute to resistance in several ways including the inhibition of proapoptotic proteins BAD and caspase 9, dysregulation of the mammalian target of rapamycin (mTOR)-S6K1 signaling pathway, and activation of the nuclear factor kappa B (NFkappaB) transcription factor.	('activation', 'PosReg', (323, 333))	('NFkappaB', 'Gene', (365, 373))	('mTOR', 'Gene', (289, 293))	('Akt', 'Gene', '207', (40, 43))	('caspase 9', 'Gene', '842', (226, 235))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (99, 116))	('inhibition', 'NegReg', (182, 192))	('transcription factor', 'molecular_function', 'GO:0000981', ('375', '395'))	('mTOR', 'Gene', '2475', (289, 293))	('mammalian target of rapamycin', 'Gene', '2475', (258, 287))	('PI3K', 'molecular_function', 'GO:0016303', ('34', '38'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (99, 116))	('nuclear factor kappa B', 'Gene', '4790', (341, 363))	('amplified', 'PosReg', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mammalian target of rapamycin', 'Gene', (258, 287))	('NFkappaB', 'Gene', '4790', (365, 373))	('pancreatic cancer', 'Disease', (99, 116))	('transcription', 'biological_process', 'GO:0006351', ('375', '388'))	('caspase 9', 'Gene', (226, 235))	('Akt', 'Gene', (40, 43))	('dysregulation', 'Var', (237, 250))	('signaling pathway', 'biological_process', 'GO:0007165', ('300', '317'))	('nuclear factor kappa B', 'Gene', (341, 363))	('activated', 'PosReg', (86, 95))
46405	21221179	The overall survival was significantly better in the erlotinib arm compared with the placebo-controlled arm with a median survival of 6.4 versus 5.9 months [hazard ratio (HR) 0.81; 95% confidence intervals (CI) 0.67, 0.97; P=0.025] and a 1-year survival of 24% versus 17%, respectively.	('erlotinib', 'Chemical', 'MESH:D000069347', (53, 62))	('better', 'PosReg', (39, 45))	('erlotinib', 'Var', (53, 62))
46409	21221179	In December 2006, however, the CHMP recommended the granting of a variation to the marketing authorization for erlotinib for patients with metastatic cancer based on the evidence that there was a 25% improvement in overall survival in this group of patients (but not in patients with locally advanced disease).	('erlotinib', 'Chemical', 'MESH:D000069347', (111, 120))	('patients', 'Species', '9606', (270, 278))	('improvement', 'PosReg', (200, 211))	('patients', 'Species', '9606', (249, 257))	('overall survival', 'MPA', (215, 231))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('men', 'Species', '9606', (207, 210))	('variation', 'Var', (66, 75))	('erlotinib', 'Gene', (111, 120))	('cancer', 'Disease', (150, 156))	('men', 'Species', '9606', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('patients', 'Species', '9606', (125, 133))
46457	21221179	Cox multivariate analysis found that patients with KPS >=90 had an improved median survival when treated with the combination arm (10.1 months) compared with single-agent gemcitabine (7.5 months; P=0.033).	('KPS >=90', 'Var', (51, 59))	('gemcitabine', 'Chemical', 'MESH:C056507', (171, 182))	('patients', 'Species', '9606', (37, 45))	('median survival', 'MPA', (76, 91))	('improved', 'PosReg', (67, 75))
46502	21221179	Overall, when compared with fluorouracil, capecitabine results in 57% lower chemotherapy-related costs and is therefore a cost-effective option when used as a single agent in colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('capecitabine', 'Chemical', 'MESH:D000069287', (42, 54))	('colon cancer', 'Phenotype', 'HP:0003003', (175, 187))	('lower', 'NegReg', (70, 75))	('chemotherapy-related costs', 'MPA', (76, 102))	('colon cancer', 'Disease', 'MESH:D015179', (175, 187))	('fluorouracil', 'Chemical', 'MESH:D005472', (28, 40))	('colon cancer', 'Disease', (175, 187))	('capecitabine', 'Var', (42, 54))
46505	21221179	This was highlighted in the SAKK/CECOG study outlined above where a subgroup analysis showed a significantly improved median survival with capecitabine for patients with KPS >=90%.	('patients', 'Species', '9606', (156, 164))	('KPS >=90%', 'Var', (170, 179))	('CECOG', 'Chemical', '-', (33, 38))	('improved', 'PosReg', (109, 117))	('capecitabine', 'Chemical', 'MESH:D000069287', (139, 151))	('median survival', 'MPA', (118, 133))
46542	20236512	Blots were washed three times in TBS-T and then incubated for 1 h at room temperature with secondary antibody conjugated to horseradish peroxidase: goat anti-mouse IgG (NA931V, 1:3000, HRP-conjugated from sheep, GE Healthcare, Milan, Italy) and anti-rabbit IgG (NA934V 1:20000, HRP-conjugated from donkey, GE Healthcare) in TBS-T, 1% BSA at RT.	('mouse', 'Species', '10090', (158, 163))	('horseradish', 'Species', '3704', (124, 135))	('antibody', 'molecular_function', 'GO:0003823', ('101', '109'))	('antibody', 'cellular_component', 'GO:0019815', ('101', '109'))	('sheep', 'Species', '9940', (205, 210))	('rabbit', 'Species', '9986', (250, 256))	('antibody', 'cellular_component', 'GO:0042571', ('101', '109'))	('donkey', 'Species', '9793', (298, 304))	('goat', 'Species', '9925', (148, 152))	('NA934V', 'Var', (262, 268))	('antibody', 'cellular_component', 'GO:0019814', ('101', '109'))	('NA931V', 'Var', (169, 175))
46559	20236512	The number of adherent cells after 24 hours in the presence of DMSO or P1 peptide, used as controls, did not differ significantly between S2-m and S2-CP9.	('S2-m', 'Var', (138, 142))	('DMSO', 'Chemical', 'MESH:D004121', (63, 67))	('S2-CP9', 'Chemical', '-', (147, 153))	('S2-CP9', 'Var', (147, 153))
46564	20236512	Treatment with 50 muM PRKCZ or 50 muM P1-RHOA 23-40 inhibitory peptides either alone or in combination almost completely suppressed the ability of both S2-m and S2-CP9 to migrate to the bottom surface of the transwell (Figure 5).	('suppressed', 'NegReg', (121, 131))	('S2-CP9', 'Chemical', '-', (161, 167))	('S2-CP9', 'Var', (161, 167))
46583	20236512	When the capability of random movement was tested by the wound-healing assay, S2m was unable to migrate toward both ends of the wound even if its motility overlapped that of S2-CP9.	('wound-healing', 'biological_process', 'GO:0042060', ('57', '70'))	('S2m', 'Var', (78, 81))	('unable', 'NegReg', (86, 92))	('S2-CP9', 'Chemical', '-', (174, 180))
46584	20236512	These results validate those obtained in the wound healing assay as they demonstrate that the individual pathways are present and active in both S2-m and S2-CP9 clones This result also suggest that the pathways regulating this phenomenon are either distinct from the ones that regulate adhesion and polarized locomotion or are more sensitive to even a partial inhibition of the signaling originating by RHOA and PRKCZ.	('wound healing', 'biological_process', 'GO:0042060', ('45', '58'))	('S2-m', 'Var', (145, 149))	('signaling', 'biological_process', 'GO:0023052', ('378', '387'))	('S2-CP9', 'Chemical', '-', (154, 160))	('S2-CP9', 'Var', (154, 160))	('locomotion', 'biological_process', 'GO:0040011', ('309', '319'))
46585	20236512	Taken together, all these assays indicate that S2-CP9 clone appear to have acquired the capability to better regulate cytoskeleton dynamics compared to clones that are motile but with a lower metastatic capacity.	('regulate cytoskeleton dynamics', 'MPA', (109, 139))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('118', '130'))	('better', 'PosReg', (102, 108))	('S2-CP9', 'Chemical', '-', (47, 53))	('S2-CP9', 'Var', (47, 53))
46599	12213184	As experimental studies reveal a possible role for NSAIDs is reducing the risk of pancreatic cancer, epidemiological studies examining similar associations in human populations become more important.	('NSAIDs', 'Var', (51, 57))	('reducing', 'NegReg', (61, 69))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (82, 99))	('men', 'Species', '9606', (9, 12))	('human', 'Species', '9606', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('pancreatic cancer', 'Disease', (82, 99))	('pancreatic cancer', 'Disease', 'MESH:D010190', (82, 99))
46611	12213184	Since pancreatic tumors tend to exhibit a high frequency of K-ras mutations, the relationship between the K-ras oncogene and COX-2 should be explored further in vivo.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('pancreatic tumors', 'Disease', (6, 23))	('COX-2', 'Gene', (125, 130))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (6, 23))	('K-ras', 'Gene', (60, 65))	('K-ras', 'Gene', '3845', (60, 65))	('K-ras', 'Gene', (106, 111))	('pancreatic tumors', 'Disease', 'MESH:D010190', (6, 23))	('K-ras', 'Gene', '3845', (106, 111))	('COX-2', 'Gene', '4513', (125, 130))
46674	33537098	Overall survival of pancreatic ductal adenocarcinoma is doubled by Aldh7a1 deletion in the KPC mouse Rationale: The activity of aldehyde dehydrogenase 7A1 (ALDH7A1), an enzyme that catalyzes the lipid peroxidation of fatty aldehydes was found to be upregulated in pancreatic ductal adenocarcinoma (PDAC).	('Aldh7a1', 'Gene', '110695', (67, 74))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (264, 296))	('aldehyde dehydrogenase 7A1', 'Gene', '110695', (128, 154))	('upregulated', 'PosReg', (249, 260))	('Aldh7a1', 'Gene', (67, 74))	('lipid', 'Chemical', 'MESH:D008055', (195, 200))	('Aldh', 'molecular_function', 'GO:0004030', ('67', '71'))	('deletion', 'Var', (75, 83))	('aldehyde dehydrogenase 7A1', 'Gene', (128, 154))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (20, 52))	('activity', 'MPA', (116, 124))	('fatty aldehydes', 'Chemical', 'MESH:C001634', (217, 232))	('ALDH', 'molecular_function', 'GO:0004030', ('156', '160'))	('pancreatic ductal adenocarcinoma', 'Disease', (20, 52))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (20, 52))	('PDAC', 'Chemical', '-', (298, 302))	('pancreatic ductal adenocarcinoma', 'Disease', (264, 296))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (264, 296))
46675	33537098	ALDH7A1 knockdown significantly reduced tumor formation in PDAC.	('PDAC', 'Chemical', '-', (59, 63))	('ALDH', 'molecular_function', 'GO:0004030', ('0', '4'))	('knockdown', 'Var', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('reduced', 'NegReg', (32, 39))	('ALDH7A1', 'Gene', (0, 7))	('PDAC', 'Disease', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('formation', 'biological_process', 'GO:0009058', ('46', '55'))
46680	33537098	Results: ALDH7A1 knockdown significantly reduced tumor formation with reduction of OCR and ATP production, which was inversely correlated with increase of 4-hydroxynonenal.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('reduced', 'NegReg', (41, 48))	('reduction', 'NegReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('knockdown', 'Var', (17, 26))	('4-hydroxynonenal', 'Chemical', 'MESH:C027576', (155, 171))	('tumor', 'Disease', (49, 54))	('formation', 'biological_process', 'GO:0009058', ('55', '64'))	('ALDH', 'molecular_function', 'GO:0004030', ('9', '13'))	('ALDH7A1', 'Gene', (9, 16))	('4-hydroxynonenal', 'MPA', (155, 171))	('OCR', 'Chemical', '-', (83, 86))	('increase', 'PosReg', (143, 151))	('ATP', 'Chemical', 'MESH:D000255', (91, 94))
46693	33537098	The first anti-cancer drug targeting metabolic abnormality in glioblastoma related with mutation of isocitrate dehydrogenase 2 has been approved from FDA.	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('mutation', 'Var', (88, 96))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('glioblastoma', 'Disease', 'MESH:D005909', (62, 74))	('metabolic abnormality', 'Phenotype', 'HP:0001939', (37, 58))	('glioblastoma', 'Disease', (62, 74))	('metabolic abnormality', 'Disease', 'MESH:D008659', (37, 58))	('metabolic abnormality', 'Disease', (37, 58))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
46695	33537098	With a near 100% KRAS mutation frequency, PDAC is considered the most RAS-addicted of all cancers.	('cancers', 'Disease', (90, 97))	('mutation', 'Var', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('PDAC', 'Chemical', '-', (42, 46))	('KRAS', 'Gene', (17, 21))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('PDAC', 'Disease', (42, 46))	('KRAS', 'Gene', '3845', (17, 21))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
46706	33537098	Among them only three isoforms (3A1, 3B1, and 7A1) were associated with poor prognosis of pancreatic cancer patients by analysis of TCGA data (Figure S1B).	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('pancreatic cancer', 'Disease', (90, 107))	('3B1', 'Var', (37, 40))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('3A1', 'Var', (32, 35))	('patients', 'Species', '9606', (108, 116))	('7A1', 'Var', (46, 49))	('poor', 'NegReg', (72, 76))
46711	33537098	To test whether ALDH7A1 plays an important role of tumor growth, PDAC cell lines with ALDH7A1 knockdown were inoculated into the nude mouse and compared tumor growth with wild type cell lines (Figure 1D-I and Figure S1F and G).	('knockdown', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('PDAC', 'Chemical', '-', (65, 69))	('ALDH7A1', 'Gene', (86, 93))	('tumor', 'Disease', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('mouse', 'Species', '10090', (134, 139))
46712	33537098	MIA PaCa-2 cell line with ALDH7A1 knockdown showed over 30% reduction of tumor growth (Figure 1D-F and Figure S1F and H) as well as AsPC-1 cell line with ALDH7A1 knockdown showed complete loss of tumor growth (Figure 1G-I and Figure S1G).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (196, 201))	('AsPC-1', 'CellLine', 'CVCL:0152', (132, 138))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('loss of tumor', 'Disease', (188, 201))	('loss of tumor', 'Disease', 'MESH:D009369', (188, 201))	('reduction', 'NegReg', (60, 69))	('tumor', 'Disease', (73, 78))	('ALDH', 'molecular_function', 'GO:0004030', ('26', '30'))	('ALDH', 'molecular_function', 'GO:0004030', ('154', '158'))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('knockdown', 'Var', (34, 43))	('ALDH7A1', 'Gene', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
46718	33537098	We have tested whether ALDH7A1 knockdown increases the level of 4-HNE in PDAC cell lines (Figure 2A).	('ALDH', 'molecular_function', 'GO:0004030', ('23', '27'))	('ALDH7A1', 'Gene', (23, 30))	('level of 4-HNE', 'MPA', (55, 69))	('increases', 'PosReg', (41, 50))	('PDAC', 'Chemical', '-', (73, 77))	('4-HNE', 'Chemical', 'MESH:C027576', (64, 69))	('knockdown', 'Var', (31, 40))
46721	33537098	After transfection of ALDH7A1 siRNAs for 48 h, cells were cultured under substrate-limited medium with 0.5 mM glucose and 1% FBS for 24 h at 37 C. The next day, the medium was changed to assay medium and OCR analyzed with treatment of palmitate-BSA (palmitate conjugated with Bovine Serum Albumin).	('Serum Albumin', 'Gene', (283, 296))	('OCR', 'Chemical', '-', (204, 207))	('palmitate', 'Chemical', 'MESH:D010168', (250, 259))	('glucose', 'Chemical', 'MESH:D005947', (110, 117))	('ALDH7A1 siRNAs', 'Gene', (22, 36))	('transfection', 'Var', (6, 18))	('Serum Albumin', 'Gene', '11657', (283, 296))	('palmitate', 'Chemical', 'MESH:D010168', (235, 244))	('ALDH', 'molecular_function', 'GO:0004030', ('22', '26'))
46723	33537098	Furthermore, ALDH7A1 knockdown showed 36% and 56% decrease of ATP production in MIA PaCa-2 and AsPC-1 respectively (Figure 2B).	('ALDH', 'molecular_function', 'GO:0004030', ('13', '17'))	('ATP production', 'MPA', (62, 76))	('ALDH7A1', 'Gene', (13, 20))	('ATP', 'Chemical', 'MESH:D000255', (62, 65))	('AsPC-1', 'CellLine', 'CVCL:0152', (95, 101))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (80, 90))	('knockdown', 'Var', (21, 30))	('decrease', 'NegReg', (50, 58))
46729	33537098	To test whether ATP production depends on fatty acid oxidation through ALDH7A1, metabolite analysis was performed in cells subjected to ALDH7A1 knockdown for 24 h (Figure 2E).	('ATP', 'Chemical', 'MESH:D000255', (16, 19))	('ALDH', 'molecular_function', 'GO:0004030', ('71', '75'))	('ALDH', 'molecular_function', 'GO:0004030', ('136', '140'))	('knockdown', 'Var', (144, 153))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('42', '62'))	('fatty acid', 'Chemical', 'MESH:D005227', (42, 52))	('ALDH7A1', 'Gene', (136, 143))
46730	33537098	ALDH7A1 knockdown in AsPC-1 cells had no significant reduce on metabolites derived from the glycolysis and pentose phosphate pathways.	('reduce', 'NegReg', (53, 59))	('ALDH', 'molecular_function', 'GO:0004030', ('0', '4'))	('knockdown', 'Var', (8, 17))	('pentose phosphate', 'Chemical', 'MESH:D010428', (107, 124))	('ALDH7A1', 'Gene', (0, 7))	('metabolites derived from', 'MPA', (63, 87))	('AsPC-1', 'CellLine', 'CVCL:0152', (21, 27))	('glycolysis', 'biological_process', 'GO:0006096', ('92', '102'))
46731	33537098	ATP production fell by approximately 30% after knockdown of ALDH7A1 (Figure 2E), which was accompanied by a fall in levels of acetyl-CoA (Figure 2E).	('fall', 'NegReg', (108, 112))	('CoA', 'Gene', '12807', (133, 136))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))	('CoA', 'Gene', (133, 136))	('knockdown', 'Var', (47, 56))	('ALDH', 'molecular_function', 'GO:0004030', ('60', '64'))	('fall', 'Phenotype', 'HP:0002527', (108, 112))	('ALDH7A1', 'Gene', (60, 67))	('ATP production', 'MPA', (0, 14))	('fell', 'NegReg', (15, 19))
46740	33537098	To test whether ALDH7A1 knockdown may affect cancer cell growth, colony formation assays and OCR were performed (Figure 3A and B).	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cell growth', 'biological_process', 'GO:0016049', ('52', '63'))	('ALDH', 'molecular_function', 'GO:0004030', ('16', '20'))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('OCR', 'Chemical', '-', (93, 96))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))	('ALDH7A1', 'Gene', (16, 23))	('cancer', 'Disease', (45, 51))	('knockdown', 'Var', (24, 33))	('affect', 'Reg', (38, 44))
46741	33537098	Colony formation of pancreatic cancer cell lines were reduced average 64% and 85% by ALDH7A1 knockdown in MIA PaCa-2 and AsPC-1 respectively (Figure 3A).	('knockdown', 'Var', (93, 102))	('AsPC-1', 'CellLine', 'CVCL:0152', (121, 127))	('pancreatic cancer', 'Disease', 'MESH:D010190', (20, 37))	('ALDH7A1', 'Gene', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (106, 116))	('Colony formation of', 'CPA', (0, 19))	('reduced', 'NegReg', (54, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('formation', 'biological_process', 'GO:0009058', ('7', '16'))	('pancreatic cancer', 'Disease', (20, 37))	('ALDH', 'molecular_function', 'GO:0004030', ('85', '89'))
46742	33537098	OCR was reduced average 64% and 76% concomitantly with decrease of ATP production to 54% and 36% level of the control by ALDH7A1 knockdown in MIA PaCa-2 and AsPC-1 respectively (Figure 3B).	('ALDH', 'molecular_function', 'GO:0004030', ('121', '125'))	('knockdown', 'Var', (129, 138))	('OCR', 'Chemical', '-', (0, 3))	('OCR', 'MPA', (0, 3))	('reduced', 'NegReg', (8, 15))	('ATP production', 'MPA', (67, 81))	('decrease', 'NegReg', (55, 63))	('ALDH7A1', 'Gene', (121, 128))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (142, 152))	('ATP', 'Chemical', 'MESH:D000255', (67, 70))	('AsPC-1', 'CellLine', 'CVCL:0152', (157, 163))
46751	33537098	Previously delay in mitotic progression was shown by combined treatment of inhibitors against ALDH and mitochondria complex I accompanying synergistic decrease of ATP production.	('ALDH', 'Gene', (94, 98))	('mitochondria', 'cellular_component', 'GO:0005739', ('103', '115'))	('complex I', 'cellular_component', 'GO:0030964', ('116', '125'))	('inhibitors', 'Var', (75, 85))	('decrease', 'NegReg', (151, 159))	('delay', 'NegReg', (11, 16))	('ATP production', 'MPA', (163, 177))	('mitotic progression', 'CPA', (20, 39))	('ALDH', 'Gene', '11670', (94, 98))	('ATP', 'Chemical', 'MESH:D000255', (163, 166))	('ALDH', 'molecular_function', 'GO:0004030', ('94', '98'))	('mitochondria complex I', 'Enzyme', (103, 125))
46759	33537098	A transgenic mouse model has been created that expresses physiological levels of oncogenic Kras (KrasG12D) and mutant Trp53 (Trp53R172H) in the progenitor cells of mouse pancreas, which is KPC mouse model (KrasG12D; Trp53R172H; Pdx1-Cre).	('Kras', 'Gene', (91, 95))	('KrasG12D', 'Gene', (206, 214))	('Trp53', 'Gene', '22059', (125, 130))	('Trp53', 'Gene', '22059', (118, 123))	('Kras', 'Gene', (97, 101))	('mutant', 'Var', (111, 117))	('Kras', 'Gene', '16653', (91, 95))	('Trp53', 'Gene', (125, 130))	('Kras', 'Gene', (206, 210))	('Trp53', 'Gene', (118, 123))	('Kras', 'Gene', '16653', (97, 101))	('Trp53R172H', 'Chemical', '-', (216, 226))	('mouse', 'Species', '10090', (13, 18))	('mouse', 'Species', '10090', (164, 169))	('Trp53', 'Gene', '22059', (216, 221))	('KrasG12D', 'Gene', '16653', (97, 105))	('Kras', 'Gene', '16653', (206, 210))	('Pdx1', 'Gene', '18609', (228, 232))	('Trp53', 'Gene', (216, 221))	('Trp53R172H', 'Chemical', '-', (125, 135))	('KrasG12D', 'Gene', '16653', (206, 214))	('Pdx1', 'Gene', (228, 232))	('KrasG12D', 'Gene', (97, 105))	('mouse', 'Species', '10090', (193, 198))
46762	33537098	To generate knockout mouse having indel mutation in exon 5 of murine Aldh7a1 gene, target sequences of sgRNA were selected using CRISPR design tool (crispor.tefor.net) and indel mutations in F1 mice were identified using Sanger sequencing.	('mouse', 'Species', '10090', (21, 26))	('indel mutation in', 'Var', (34, 51))	('Aldh', 'molecular_function', 'GO:0004030', ('69', '73'))	('murine', 'Species', '10090', (62, 68))	('Aldh7a1', 'Gene', '110695', (69, 76))	('mice', 'Species', '10090', (194, 198))	('Aldh7a1', 'Gene', (69, 76))
46763	33537098	The mice having 38-nt deletion was used for further breeding because the mutation causes premature translation stop (Figure 5B, Figure S5A).	('translation', 'biological_process', 'GO:0006412', ('99', '110'))	('premature translation stop', 'MPA', (89, 115))	('mice', 'Species', '10090', (4, 8))	('causes', 'Reg', (82, 88))	('mutation', 'Var', (73, 81))
46764	33537098	Homozygote mutant of Aldh7a1 showed normal phenotype in mice, which is concord with the previous report (http://www.informatics.jax.org/marker/MGI:108186).	('mutant', 'Var', (11, 17))	('normal phenotype', 'MPA', (36, 52))	('Aldh7a1', 'Gene', '110695', (21, 28))	('mice', 'Species', '10090', (56, 60))	('Aldh', 'molecular_function', 'GO:0004030', ('21', '25'))	('Aldh7a1', 'Gene', (21, 28))
46767	33537098	Survival time of Aldh7a1-/-; KPC mice was also significantly increased than KPC mice (Figure 5E).	('KPC', 'Var', (29, 32))	('Aldh7a1', 'Gene', '110695', (17, 24))	('Survival time', 'CPA', (0, 13))	('increased', 'PosReg', (61, 70))	('Aldh7a1', 'Gene', (17, 24))	('mice', 'Species', '10090', (33, 37))	('mice', 'Species', '10090', (80, 84))	('Aldh', 'molecular_function', 'GO:0004030', ('17', '21'))
46768	33537098	And acinar-duct metaplasia (ADM), PanIN and pancreatic duct adenocarcinoma lesions of Aldh7a1-/-; KPC mice was reduced approximately 40% compared to the KPC mice (Figure 5F).	('mice', 'Species', '10090', (102, 106))	('metaplasia', 'biological_process', 'GO:0036074', ('16', '26'))	('PanIN', 'Disease', 'None', (34, 39))	('mice', 'Species', '10090', (157, 161))	('KPC', 'Var', (98, 101))	('PanIN', 'Disease', (34, 39))	('reduced', 'NegReg', (111, 118))	('pancreatic duct adenocarcinoma lesions', 'Disease', (44, 82))	('Aldh7a1', 'Gene', '110695', (86, 93))	('pancreatic duct adenocarcinoma', 'Phenotype', 'HP:0006725', (44, 74))	('acinar-duct metaplasia', 'CPA', (4, 26))	('pancreatic duct adenocarcinoma lesions', 'Disease', 'MESH:D010190', (44, 82))	('Aldh7a1', 'Gene', (86, 93))	('Aldh', 'molecular_function', 'GO:0004030', ('86', '90'))
46769	33537098	Cytokeratin-19 (CK-19) expression, a ductal epithelial marker, was also reduced 44% in Aldh7a1-/-; KPC mice than KPC mice (Figure 5G).	('Aldh7a1', 'Gene', (87, 94))	('reduced', 'NegReg', (72, 79))	('Aldh', 'molecular_function', 'GO:0004030', ('87', '91'))	('KPC', 'Var', (99, 102))	('Cytokeratin-19', 'Gene', (0, 14))	('mice', 'Species', '10090', (103, 107))	('mice', 'Species', '10090', (117, 121))	('CK-19', 'Gene', (16, 21))	('CK-19', 'Gene', '16669', (16, 21))	('Aldh7a1', 'Gene', '110695', (87, 94))	('Cytokeratin-19', 'Gene', '16669', (0, 14))	('expression', 'MPA', (23, 33))
46773	33537098	Ki-67 positive cell (proliferation marker) of pancreas in KPC mice showed that Aldh7a1 knockout decreased proliferation of cancer cell (Figure 5I).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Ki-67', 'Gene', (0, 5))	('decreased', 'NegReg', (96, 105))	('Aldh', 'molecular_function', 'GO:0004030', ('79', '83'))	('cell (proliferation', 'biological_process', 'GO:0008283', ('15', '34'))	('mice', 'Species', '10090', (62, 66))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('Ki-67', 'Gene', '17345', (0, 5))	('cancer', 'Disease', (123, 129))	('Aldh7a1', 'Gene', '110695', (79, 86))	('Aldh7a1', 'Gene', (79, 86))	('knockout', 'Var', (87, 95))
46775	33537098	Taken together, these results suggest that ALDH7A1 deficiency causes a significant reduction in pancreatic cancer progression of mice, implying the critical role of ALDH7A1 in PDAC.	('ALDH7A1', 'Gene', (43, 50))	('pancreatic cancer', 'Disease', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('ALDH', 'molecular_function', 'GO:0004030', ('165', '169'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('PDAC', 'Chemical', '-', (176, 180))	('ALDH', 'molecular_function', 'GO:0004030', ('43', '47'))	('deficiency', 'Var', (51, 61))	('mice', 'Species', '10090', (129, 133))	('reduction', 'NegReg', (83, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))
46785	33537098	After treatment, tumor volumes were reduced significantly with combination therapy compared to vehicle-treated control as well as single drug-treated groups while body weight remained constant, clearly demonstrating the enhanced efficacy of combined treatment in vivo.	('combination therapy', 'Var', (63, 82))	('tumor', 'Disease', (17, 22))	('enhanced', 'PosReg', (220, 228))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('reduced', 'NegReg', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
46795	33537098	CK-19 expression was also reduced 40% in combination treatment mice than vehicle treatment mice (Figure 6I).	('CK-19', 'Gene', (0, 5))	('mice', 'Species', '10090', (91, 95))	('CK-19', 'Gene', '16669', (0, 5))	('combination', 'Var', (41, 52))	('expression', 'MPA', (6, 16))	('mice', 'Species', '10090', (63, 67))	('reduced', 'NegReg', (26, 33))
46796	33537098	We observed that alpha-SMA-positive area of combination treatment mice pancreas compared with vehicle treatment mice pancreas were reduced 48% (Figure 6J).	('alpha-SMA', 'Gene', '11475', (17, 26))	('mice', 'Species', '10090', (66, 70))	('reduced', 'NegReg', (131, 138))	('combination', 'Var', (44, 55))	('alpha-SMA', 'Gene', (17, 26))	('mice', 'Species', '10090', (112, 116))
46798	33537098	After treatment, tumor progression were reduced significantly with combination therapy compared to vehicle-treated control as well as single drug-treated groups while body weight remained constant, clearly demonstrating the enhanced efficacy of combined treatment in vivo.	('tumor', 'Disease', (17, 22))	('enhanced', 'PosReg', (224, 232))	('combination therapy', 'Var', (67, 86))	('reduced', 'NegReg', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
46801	33537098	ALDH7A1 knockdown showed increase of fatty aldehyde HNE level which is inversely correlated with significant decrease of ATP production.	('decrease', 'NegReg', (109, 117))	('increase of fatty aldehyde HNE', 'Disease', (25, 55))	('ATP production', 'MPA', (121, 135))	('ALDH', 'molecular_function', 'GO:0004030', ('0', '4'))	('knockdown', 'Var', (8, 17))	('ALDH7A1', 'Gene', (0, 7))	('increase of fatty aldehyde HNE', 'Disease', 'MESH:D016111', (25, 55))	('ATP', 'Chemical', 'MESH:D000255', (121, 124))
46805	33537098	In this study, growth arrest by ATP depletion was induced by mTOR inactivation, which later lost control of survival.	('growth arrest', 'Disease', 'MESH:D006323', (15, 28))	('growth arrest', 'Disease', (15, 28))	('growth arrest', 'Phenotype', 'HP:0001510', (15, 28))	('inactivation', 'Var', (66, 78))	('mTOR', 'Gene', (61, 65))	('ATP', 'Chemical', 'MESH:D000255', (32, 35))	('mTOR', 'Gene', '56717', (61, 65))
46817	33537098	Results of this study imply that ALDH7A1 deficiency in pancreatic cells delays the progression of PDAC in KPC mice with following reasons.	('ALDH', 'molecular_function', 'GO:0004030', ('33', '37'))	('PDAC', 'Disease', (98, 102))	('PDAC', 'Chemical', '-', (98, 102))	('mice', 'Species', '10090', (110, 114))	('deficiency', 'Var', (41, 51))	('pancreatic cells delays', 'Disease', (55, 78))	('pancreatic cells delays', 'Disease', 'MESH:D010195', (55, 78))	('progression', 'CPA', (83, 94))	('ALDH7A1', 'Gene', (33, 40))
46819	33537098	Second, mice homozygous for disruptions in Aldh7a1 gene has been known to display a normal phenotype (http://www.informatics.jax.org/allele/MGI:3530146).	('Aldh7a1', 'Gene', '110695', (43, 50))	('Aldh7a1', 'Gene', (43, 50))	('mice', 'Species', '10090', (8, 12))	('Aldh', 'molecular_function', 'GO:0004030', ('43', '47'))	('disruptions', 'Var', (28, 39))
46820	33537098	Third, our results with cancer cell lines and xenograft models also suggest that knockout and knockdown in pancreas cells has an inhibitory effect on the progression of pancreatic cancer.	('knockdown', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (169, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (169, 186))	('pancreatic cancer', 'Disease', (169, 186))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))
46821	33537098	Taken together, ALDH7A1 deficiency in pancreatic cells appears to delay the progression of PDAC in KPC mice.	('PDAC', 'Chemical', '-', (91, 95))	('mice', 'Species', '10090', (103, 107))	('deficiency', 'Var', (24, 34))	('ALDH', 'molecular_function', 'GO:0004030', ('16', '20'))	('PDAC', 'Disease', (91, 95))	('delay', 'NegReg', (66, 71))	('progression', 'CPA', (76, 87))	('ALDH7A1', 'Gene', (16, 23))
46827	33537098	Therefore, it is reasonable to consider that anti-cancer effect of ALDH7A1 knockdown or inhibition resides on blocking fatty acid oxidation through inhibition of fatty aldehyde catalysis because level of fatty aldehyde (HNE) is inversely correlated with ATP production.	('fatty aldehyde', 'Chemical', 'MESH:C001634', (162, 176))	('cancer', 'Disease', (50, 56))	('inhibition', 'NegReg', (148, 158))	('HNE', 'Chemical', '-', (220, 223))	('blocking', 'NegReg', (110, 118))	('fatty aldehyde', 'Chemical', 'MESH:C001634', (204, 218))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('ALDH', 'molecular_function', 'GO:0004030', ('67', '71'))	('fatty acid oxidation', 'MPA', (119, 139))	('knockdown', 'Var', (75, 84))	('fatty aldehyde catalysis', 'MPA', (162, 186))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('119', '139'))	('ATP', 'Chemical', 'MESH:D000255', (254, 257))	('fatty acid', 'Chemical', 'MESH:D005227', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('ALDH7A1', 'Gene', (67, 74))	('ATP production', 'MPA', (254, 268))
46828	33537098	In PDAC, over 90% of pancreatic cancers showed about 100% frequency of KRAS mutation.	('PDAC', 'Chemical', '-', (3, 7))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (21, 39))	('KRAS', 'Gene', (71, 75))	('KRAS', 'Gene', '16653', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('pancreatic cancers', 'Disease', 'MESH:D010190', (21, 39))	('pancreatic cancers', 'Disease', (21, 39))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (21, 38))	('mutation', 'Var', (76, 84))
46843	33537098	AsPC-1, BxPC-3 and SNU-213 cells were grown in RPMI 1640 medium (SH30027.01, HyClone, Logan, UT, USA) containing 10% fetal bovine serum (SH30070.03HI, HyClone, Logan, UT, USA) and Cellmaxin (C3314-020, GenDEPOT, Texas, USA).	('SH30070.03HI', 'Var', (137, 149))	('Cellmaxin', 'Chemical', '-', (180, 189))	('BxPC-3', 'CellLine', 'CVCL:0186', (8, 14))	('SNU-213', 'CellLine', 'CVCL:5034', (19, 26))	('RPMI 1640 medium', 'Chemical', '-', (47, 63))	('C3314-020', 'Var', (191, 200))	('AsPC-1', 'CellLine', 'CVCL:0152', (0, 6))
46848	33537098	hTERT-HPNE cells were grown in 75% DMEM without glucose (D-5030, Sigma-Aldrich, St. Louis, MO, USA) with additional 2 mM L-glutamine and 1.5 g/L sodium bicarbonate, 25% Medium M3 Base (Incell Corp. Texas, USA) containing 5% fetal bovine serum, 5.5 mM D-glucose (G8270, Sigma-Aldrich, St. Louis, MO, USA), Cellmaxin, 10 ng/ml human recombinant EGF (E9644, Sigma-Aldrich, St. Louis, MO, USA).	('glucose', 'Chemical', 'MESH:D005947', (48, 55))	('EGF', 'Gene', (343, 346))	('G8270', 'Var', (262, 267))	('glucose', 'Chemical', 'MESH:D005947', (253, 260))	('E9644', 'Var', (348, 353))	('DMEM', 'Chemical', '-', (35, 39))	('EGF', 'Gene', '1950', (343, 346))	('hTERT-HPNE', 'CellLine', 'CVCL:C466', (0, 10))	('Cellmaxin', 'Chemical', '-', (305, 314))	('EGF', 'molecular_function', 'GO:0005154', ('343', '346'))	('glutamine', 'Chemical', 'MESH:D005973', (123, 132))	('carbon', 'Chemical', 'MESH:D002244', (154, 160))	('human', 'Species', '9606', (325, 330))
46895	33537098	The primary antibodies used in the experiments were ALDH1L1 (ab175198, Abcam, Cambridge, UK), ALDH1A3 (ab129815, Abcam), ALDH1L2 (ab113496, Abcam), ALDH2 (ab108306, Abcam), ALDH3A1 (ab76976, Abcam), ALDH3B1 (SAB4500866, Sigma-Aldrich), ALDH4A1 (ab185208, Abcam), ALDH7A1 (ab53278, Abcam), Flag (F1804, Sigma-Aldrich) and beta-actin (sc-47778, Santa Cruz Biotechnology).	('ALDH', 'molecular_function', 'GO:0004030', ('148', '152'))	('ALDH1L1', 'Gene', (52, 59))	('ALDH2', 'Gene', '11669', (148, 153))	('ALDH1A3', 'Gene', '56847', (94, 101))	('ALDH', 'molecular_function', 'GO:0004030', ('236', '240'))	('ALDH3A1', 'Gene', '11670', (173, 180))	('ALDH', 'molecular_function', 'GO:0004030', ('173', '177'))	('ALDH3B1', 'Gene', (199, 206))	('ALDH1A3', 'Gene', (94, 101))	('ALDH1L2', 'Gene', (121, 128))	('ab53278', 'Var', (272, 279))	('ALDH3A1', 'Gene', (173, 180))	('ALDH4A1', 'Gene', (236, 243))	('ALDH1L2', 'Gene', '216188', (121, 128))	('ALDH', 'molecular_function', 'GO:0004030', ('263', '267'))	('ALDH', 'molecular_function', 'GO:0004030', ('199', '203'))	('ALDH', 'molecular_function', 'GO:0004030', ('94', '98'))	('ALDH2', 'Gene', (148, 153))	('ALDH', 'molecular_function', 'GO:0004030', ('121', '125'))	('ALDH1L1', 'Gene', '107747', (52, 59))	('ALDH', 'molecular_function', 'GO:0004030', ('52', '56'))	('ALDH4A1', 'Gene', '212647', (236, 243))	('ALDH3B1', 'Gene', '67689', (199, 206))
46898	33537098	The antigens were retrieved with heat treatment in pH 6.0 Citrate buffer (Ribo CC, ventana) at 90  C for 30 min for anti-Ki-67 (ab15580; Abcam, Cambridge, United Kingdom), CK-19 (ab52625, Abcam, Cambridge, UK), alpha-SMA (ab5694, Abcam), 4-HNE (ab46545, Abcam) and ALDH7A1 (ab53278, Abcam).	('Ki-67', 'Gene', '17345', (121, 126))	('CK-19', 'Gene', (172, 177))	('4-HNE', 'Chemical', 'MESH:C027576', (238, 243))	('Ki-67', 'Gene', (121, 126))	('ab46545', 'Var', (245, 252))	('alpha-SMA', 'Gene', (211, 220))	('CK-19', 'Gene', '16669', (172, 177))	('alpha-SMA', 'Gene', '11475', (211, 220))	('Citrate', 'Chemical', 'MESH:D019343', (58, 65))	('ALDH', 'molecular_function', 'GO:0004030', ('265', '269'))	('ab15580;', 'Var', (128, 136))	('ab52625', 'Var', (179, 186))
46936	33445669	While the molecular pathways involved in the development, progression and metastasis of PDAC are not fully elucidated, mutations in genes such as KRAS, CDKN2A/p16, TP53 and SMAD4 and activation of their associated downstream signalling pathways appear to play a key role in the disease.	('p16', 'Gene', '1029', (159, 162))	('SMAD4', 'Gene', (173, 178))	('CDKN2A', 'Gene', (152, 158))	('TP53', 'Gene', (164, 168))	('KRAS', 'Gene', (146, 150))	('activation', 'PosReg', (183, 193))	('TP53', 'Gene', '7157', (164, 168))	('downstream signalling pathways', 'Pathway', (214, 244))	('PDAC', 'Disease', (88, 92))	('KRAS', 'Gene', '3845', (146, 150))	('CDKN2A', 'Gene', '1029', (152, 158))	('PDAC', 'Phenotype', 'HP:0006725', (88, 92))	('p16', 'Gene', (159, 162))	('PDAC', 'Chemical', '-', (88, 92))	('SMAD4', 'Gene', '4089', (173, 178))	('play', 'Reg', (255, 259))	('mutations', 'Var', (119, 128))	('signalling', 'biological_process', 'GO:0023052', ('225', '235'))
46937	33445669	KRAS mutations are the most frequent mutations in PDAC, present in 90-95% of tumours.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('PDAC', 'Phenotype', 'HP:0006725', (50, 54))	('tumours', 'Disease', (77, 84))	('mutations', 'Var', (5, 14))	('PDAC', 'Chemical', '-', (50, 54))	('PDAC', 'Gene', (50, 54))	('KRAS', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('KRAS', 'Gene', '3845', (0, 4))
46939	33445669	Small molecule inhibitors that directly target KRASG12C, as well as the development of inhibitors of Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2), a non-receptor protein tyrosine phosphatase that modulates RAS activity, have yielded promising pre-clinical results, although their clinical benefits remain to be determined.	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('phosphatase', 'molecular_function', 'GO:0016791', ('205', '216'))	('SHP2', 'Gene', (166, 170))	('pre', 'molecular_function', 'GO:0003904', ('269', '272'))	('SHP2', 'Gene', '5781', (166, 170))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('Src homology-2 domain-containing protein tyrosine phosphatase-2', 'Gene', '5781', (101, 164))	('KRAS', 'Gene', (47, 51))	('KRAS', 'Gene', '3845', (47, 51))	('inhibitors', 'Var', (87, 97))	('phosphatase', 'molecular_function', 'GO:0016791', ('151', '162'))
46966	33445669	Interestingly, this paracrine alteration of tumour metabolism is believed to occur in tandem with genetic mutations, such as mutations in KRAS which also acts to rewire PDAC metabolic pathways.	('mutations', 'Var', (125, 134))	('tumour metabolism', 'Disease', (44, 61))	('tumour metabolism', 'Disease', 'MESH:D009369', (44, 61))	('PDAC', 'Phenotype', 'HP:0006725', (169, 173))	('KRAS', 'Gene', (138, 142))	('KRAS', 'Gene', '3845', (138, 142))	('PDAC metabolic pathways', 'Pathway', (169, 192))	('metabolism', 'biological_process', 'GO:0008152', ('51', '61'))	('PDAC', 'Chemical', '-', (169, 173))	('rewire', 'PosReg', (162, 168))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
46993	33445669	Following dissociation of GRP78, IRE1 oligomerises and trans-autophoshorylates enabling its RNase activity.	('RNase activity', 'MPA', (92, 106))	('GRP78', 'Protein', (26, 31))	('dissociation', 'Var', (10, 22))	('enabling', 'PosReg', (79, 87))	('IRE1', 'Gene', '2081', (33, 37))	('RNase activity', 'molecular_function', 'GO:0004522', ('92', '106'))	('IRE1', 'Gene', (33, 37))
47001	33445669	Upon GRP78 dissociation, PERK dimerises, undergoes trans-autophosphorylation of its cytosolic domain and phosphorylates its primary substrate, eukaryotic translation initiation factor 2A (eIF2alpha).	('eIF2alpha', 'Gene', (188, 197))	('trans-autophosphorylation', 'biological_process', 'GO:0036290', ('51', '76'))	('translation initiation', 'biological_process', 'GO:0006413', ('154', '176'))	('eIF2alpha', 'Gene', '83939', (188, 197))	('dissociation', 'Var', (11, 23))	('dimerises', 'Interaction', (30, 39))	('undergoes', 'Reg', (41, 50))	('phosphorylates', 'MPA', (105, 119))	('eukaryotic translation initiation factor 2A', 'Gene', '83939', (143, 186))	('trans-autophosphorylation', 'MPA', (51, 76))	('eukaryotic translation initiation factor 2A', 'Gene', (143, 186))	('GRP78', 'Protein', (5, 10))	('eIF2', 'cellular_component', 'GO:0005850', ('188', '192'))
47005	33445669	Release of GRP78 causes a conformational change in ATF6 revealing two Golgi localisation signals.	('conformational change', 'MPA', (26, 47))	('Golgi localisation', 'biological_process', 'GO:0051645', ('70', '88'))	('ATF6', 'Gene', (51, 55))	('GRP78', 'Protein', (11, 16))	('Release', 'Var', (0, 7))	('ATF6', 'Gene', '22926', (51, 55))	('Golgi', 'cellular_component', 'GO:0005794', ('70', '75'))
47017	33445669	Transcriptomic analysis of the PDAC cell line S2-VP10, with or without shRNA-mediated knockdown of GRP78, suggests its influence may be broad-reaching with changes noted in key signalling pathways including cell-cycle, apoptosis and actin-cytoskeleton regulation.	('knockdown', 'Var', (86, 95))	('cell-cycle', 'CPA', (207, 217))	('changes', 'Reg', (156, 163))	('actin-cytoskeleton', 'MPA', (233, 251))	('regulation', 'biological_process', 'GO:0065007', ('252', '262'))	('cell-cycle', 'biological_process', 'GO:0007049', ('207', '217'))	('signalling', 'biological_process', 'GO:0023052', ('177', '187'))	('PDAC', 'Chemical', '-', (31, 35))	('apoptosis', 'biological_process', 'GO:0006915', ('219', '228'))	('apoptosis', 'CPA', (219, 228))	('apoptosis', 'biological_process', 'GO:0097194', ('219', '228'))	('actin-cytoskeleton', 'cellular_component', 'GO:0015629', ('233', '251'))	('GRP78', 'Gene', (99, 104))	('PDAC', 'Phenotype', 'HP:0006725', (31, 35))
47028	33445669	High levels of GRP78 are present in PDAC, and these studies indicate that reducing GRP78 has anti-tumour effects.	('reducing', 'Var', (74, 82))	('PDAC', 'Phenotype', 'HP:0006725', (36, 40))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('GRP78', 'Protein', (83, 88))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (98, 104))	('PDAC', 'Chemical', '-', (36, 40))
47039	33445669	In another study, STF-083010 reduced the viability of PDAC cells.	('PDAC', 'Phenotype', 'HP:0006725', (54, 58))	('STF-083010', 'Chemical', 'MESH:C556690', (18, 28))	('reduced', 'NegReg', (29, 36))	('STF-083010', 'Var', (18, 28))	('viability of PDAC cells', 'CPA', (41, 64))	('PDAC', 'Chemical', '-', (54, 58))
47059	33445669	Another study identified synergistic effects between gemcitabine and inhibitors of fatty acid synthesis that lead to decreases in stemness and increased ER-stress-associated apoptosis in PDAC cells.	('PDAC', 'Phenotype', 'HP:0006725', (187, 191))	('ER', 'Gene', '2069', (153, 155))	('increased', 'PosReg', (143, 152))	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('83', '103'))	('apoptosis', 'biological_process', 'GO:0097194', ('174', '183'))	('apoptosis', 'biological_process', 'GO:0006915', ('174', '183'))	('stemness', 'CPA', (130, 138))	('decreases', 'NegReg', (117, 126))	('fatty acid', 'Chemical', 'MESH:D005227', (83, 93))	('PDAC', 'Chemical', '-', (187, 191))	('gemcitabine', 'Chemical', 'MESH:C056507', (53, 64))	('inhibitors', 'Var', (69, 79))
47062	33445669	The role of UPR signalling in PSCs has not been extensively explored, although mitochondrial impairment and fatty acid exposure have both been reported to induce UPR activity in PSCs.	('UPR activity', 'MPA', (162, 174))	('fatty acid', 'Chemical', 'MESH:D005227', (108, 118))	('mitochondrial', 'CPA', (79, 92))	('impairment', 'Var', (93, 103))	('PSCs', 'Disease', (178, 182))	('mitochondrial impairment', 'Phenotype', 'HP:0003287', (79, 103))
47093	33445669	For example, STF-083010, MKC8866 and B-109 all act to inhibit the RNase activity of IRE1, while small molecules such as KIRA6 are kinase binders.	('MKC8866', 'Chemical', '-', (25, 32))	('STF-083010', 'Chemical', 'MESH:C556690', (13, 23))	('inhibit', 'NegReg', (54, 61))	('MKC8866', 'Var', (25, 32))	('RNase activity', 'molecular_function', 'GO:0004522', ('66', '80'))	('STF-083010', 'Var', (13, 23))	('RNase activity', 'MPA', (66, 80))	('B-109', 'Gene', (37, 42))	('IRE1', 'Gene', '2081', (84, 88))	('IRE1', 'Gene', (84, 88))
47107	29615456	Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer and increased the expression of ZO-1 and claudin-1.	('Genetic inactivation', 'Var', (0, 20))	('increased', 'PosReg', (87, 96))	('inhibited', 'NegReg', (29, 38))	('ZO-1', 'Gene', (115, 119))	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('pancreatic cancer', 'Disease', (65, 82))	('claudin-1', 'Gene', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('expression', 'MPA', (101, 111))	('ZIP4', 'Gene', (24, 28))
47119	29615456	Aberrant ZIP4 expression in pancreatic cancer at diagnosis correlates with the expression level of ZIP4 in the corresponding surgical samples, suggesting that ZIP4 may serve as a novel prognostic and predictive marker for pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('pancreatic cancer', 'Disease', (28, 45))	('Aberrant', 'Var', (0, 8))	('pancreatic cancer', 'Disease', 'MESH:D010190', (28, 45))	('ZIP4', 'Gene', (9, 13))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (222, 239))	('expression', 'MPA', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (28, 45))	('pancreatic cancer', 'Disease', (222, 239))	('pancreatic cancer', 'Disease', 'MESH:D010190', (222, 239))	('expression level', 'MPA', (79, 95))
47162	29615456	Furthermore, we investigated the effect of ZIP4 on the expression of those invasion markers in pancreatic cancer cell lines and found that knocking down ZIP4 in Panc-1 and AsPC-1 cells decreased the expression of mesenchymal markers ZEB1 and increased the expression of epithelial markers ZO-1 and claudin-1 (Figure 2A and 2B).	('decreased', 'NegReg', (185, 194))	('expression', 'MPA', (199, 209))	('Panc-1', 'Gene', (161, 167))	('Panc-1', 'CellLine', 'CVCL:0480', (161, 167))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (95, 112))	('ZIP4', 'Gene', (153, 157))	('knocking down', 'Var', (139, 152))	('increased', 'PosReg', (242, 251))	('claudin-1', 'Gene', (298, 307))	('pancreatic cancer', 'Disease', (95, 112))	('ZEB1', 'Gene', (233, 237))	('pancreatic cancer', 'Disease', 'MESH:D010190', (95, 112))	('AsPC-1', 'CellLine', 'CVCL:0152', (172, 178))	('expression', 'MPA', (256, 266))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
47166	29615456	ZIP4 overexpression downregulates ZO-1 and claudin-1 while knocking down ZEB1 enhances ZO-1 and claudin-1 expression in AsPC-1 and Panc-1 cells.	('enhances', 'PosReg', (78, 86))	('knocking down', 'Var', (59, 72))	('claudin-1', 'Gene', (43, 52))	('expression', 'MPA', (106, 116))	('ZO-1', 'Gene', (34, 38))	('downregulates', 'NegReg', (20, 33))	('Panc-1', 'CellLine', 'CVCL:0480', (131, 137))	('ZO-1', 'Gene', (87, 91))	('AsPC-1', 'CellLine', 'CVCL:0152', (120, 126))	('ZEB1', 'Gene', (73, 77))	('claudin-1', 'Gene', (96, 105))
47167	29615456	Moreover, we found knocking down ZEB1 attenuates the downregulation role of ZIP4 on ZO-1 and claudin-1 (Figure 2E, 2F).	('attenuates', 'NegReg', (38, 48))	('2F', 'Chemical', 'MESH:D005461', (115, 117))	('ZEB1', 'Gene', (33, 37))	('downregulation', 'MPA', (53, 67))	('ZO-1', 'MPA', (84, 88))	('knocking down', 'Var', (19, 32))	('claudin-1', 'Gene', (93, 102))
47171	29615456	We found that ZIP4 increased tumor migration and invasion was impaired by ZEB1 inactivation (Figure 3A-3C).	('impaired', 'NegReg', (62, 70))	('tumor migration', 'Disease', 'MESH:D014085', (29, 44))	('inactivation', 'Var', (79, 91))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('ZEB1', 'Gene', (74, 78))	('increased', 'PosReg', (19, 28))	('invasion', 'CPA', (49, 57))	('tumor migration', 'Disease', (29, 44))	('ZIP4', 'Gene', (14, 18))
47173	29615456	Previously we reported that ZIP4 induces changes in gene expression through the activation of this transcription factor; expression studies in multiple pancreatic cancer cells showed no effect on ZO-1 nor claudin-1 levels in cells with CREB knockdown (Figure.	('knockdown', 'Var', (241, 250))	('CREB', 'Gene', (236, 240))	('CREB', 'Gene', '1385', (236, 240))	('transcription factor', 'molecular_function', 'GO:0000981', ('99', '119'))	('transcription', 'biological_process', 'GO:0006351', ('99', '112'))	('pancreatic cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('pancreatic cancer', 'Disease', 'MESH:D010190', (152, 169))	('gene expression', 'MPA', (52, 67))	('gene expression', 'biological_process', 'GO:0010467', ('52', '67'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (152, 169))
47176	29615456	3D-3I, knocking down ZIP4 decreased pancreatic cancer migration and invasion in AsPC-1 and Panc-1 cells.	('AsPC-1', 'CellLine', 'CVCL:0152', (80, 86))	('knocking down', 'Var', (7, 20))	('invasion', 'CPA', (68, 76))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (36, 53))	('decreased pancreatic cancer migration', 'Disease', 'MESH:D010190', (26, 63))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('decreased pancreatic cancer migration', 'Disease', (26, 63))	('ZIP4', 'Gene', (21, 25))	('Panc-1', 'CellLine', 'CVCL:0480', (91, 97))
47178	29615456	Similarly, transwell migration and Matrigel invasion assays also showed that knockdown of ZO-1 and claudin-1 rescued the invasive and migratory capacities of AsPC-shZIP4 and Panc-1 siZIP4 cells, in which ZIP4 was silenced (Figure 3E-3I).	('Panc-1', 'CellLine', 'CVCL:0480', (174, 180))	('AsPC', 'Gene', '68938', (158, 162))	('knockdown', 'Var', (77, 86))	('hZIP4', 'Gene', (164, 169))	('claudin-1', 'Gene', (99, 108))	('hZIP4', 'Gene', '55630', (164, 169))	('AsPC', 'Gene', (158, 162))	('ZO-1', 'Gene', (90, 94))
47179	29615456	To further investigate whether ZO-1 and claudin-1 contribute to tumor metastasis in vivo, we constructed stable cells lines with ZO-1 and claudin-1 silenced by shRNA in AsPC-shZIP4 cells and implanted these cells in an orthotopic xenograft tumor model.	('claudin-1', 'Gene', (138, 147))	('tumor metastasis', 'Disease', 'MESH:D009362', (64, 80))	('ZO-1', 'Gene', (129, 133))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (240, 245))	('tumor metastasis', 'Disease', (64, 80))	('AsPC', 'Gene', (169, 173))	('hZIP4', 'Gene', '55630', (175, 180))	('hZIP4', 'Gene', (175, 180))	('silenced', 'Var', (148, 156))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('AsPC', 'Gene', '68938', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
47180	29615456	The knocking down efficiency of ZO-1 and claudin-1 in AsPC-shZIP4 cells was confirmed by RT-PCR and Western blot (Figure S5).	('claudin-1', 'Gene', (41, 50))	('knocking', 'Var', (4, 12))	('ZO-1', 'Gene', (32, 36))	('hZIP4', 'Gene', '55630', (60, 65))	('hZIP4', 'Gene', (60, 65))	('AsPC', 'Gene', (54, 58))	('AsPC', 'Gene', '68938', (54, 58))
47186	29615456	Next, we examined whether blocking ZO-1 and claudin-1 could activate FAK and Paxillin phosphorylation in AsPC-1 and Panc-1 cells.	('phosphorylation', 'biological_process', 'GO:0016310', ('86', '101'))	('FAK', 'molecular_function', 'GO:0004717', ('69', '72'))	('blocking', 'Var', (26, 34))	('AsPC-1', 'CellLine', 'CVCL:0152', (105, 111))	('claudin-1', 'Gene', (44, 53))	('ZO-1', 'Protein', (35, 39))	('activate', 'PosReg', (60, 68))	('Panc-1', 'CellLine', 'CVCL:0480', (116, 122))
47187	29615456	We also found knocking down ZO-1 and claudin-1 led to enhanced pFAK and pPaxillin in xenograft tumor tissue (Figure 4F) which was consistent with the in vitro data.	('pPaxillin', 'Protein', (72, 81))	('knocking down', 'Var', (14, 27))	('claudin-1', 'Gene', (37, 46))	('pFAK', 'Protein', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('ZO-1', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('enhanced', 'PosReg', (54, 62))	('tumor', 'Disease', (95, 100))
47188	29615456	We found that silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1 in both AsPC-1 and Panc-1 cells.	('silencing', 'Var', (14, 23))	('phosphorylation', 'MPA', (47, 62))	('Paxillin', 'Protein', (74, 82))	('AsPC-1', 'CellLine', 'CVCL:0152', (156, 162))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('FAK', 'molecular_function', 'GO:0004717', ('66', '69'))	('reduced', 'NegReg', (39, 46))	('Panc-1', 'CellLine', 'CVCL:0480', (167, 173))	('ZIP4', 'Gene', (27, 31))	('FAK', 'Protein', (66, 69))
47189	29615456	Together, our results showed that knocking down ZIP4 decreased FAK and Paxillin phosphorylation by activating ZO-1 and claudin-1 in pancreatic cancer cells.	('activating', 'PosReg', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('ZIP4', 'Gene', (48, 52))	('decreased FAK', 'Phenotype', 'HP:0032341', (53, 66))	('phosphorylation', 'biological_process', 'GO:0016310', ('80', '95'))	('pancreatic cancer', 'Disease', (132, 149))	('FAK', 'MPA', (63, 66))	('FAK', 'molecular_function', 'GO:0004717', ('63', '66'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (132, 149))	('claudin-1', 'Gene', (119, 128))	('ZO-1', 'Gene', (110, 114))	('decreased', 'NegReg', (53, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 149))	('knocking down', 'Var', (34, 47))
47191	29615456	Knocking down ZIP4 inhibited pancreatic cancer invasion and migration in pancreatic cancer cell lines and mouse models through repressing invasion markers.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (29, 46))	('inhibited', 'NegReg', (19, 28))	('pancreatic cancer', 'Disease', (73, 90))	('Knocking down', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('pancreatic cancer invasion', 'Disease', 'MESH:D010190', (29, 55))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))	('pancreatic cancer invasion', 'Disease', (29, 55))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('migration', 'CPA', (60, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (29, 46))	('invasion', 'CPA', (138, 146))	('repressing', 'NegReg', (127, 137))	('ZIP4', 'Gene', (14, 18))	('mouse', 'Species', '10090', (106, 111))
47192	29615456	Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1 in pancreatic cancer cells.	('phosphorylation', 'MPA', (33, 48))	('reduced', 'NegReg', (25, 32))	('FAK', 'Protein', (52, 55))	('Paxillin', 'Gene', (60, 68))	('FAK', 'molecular_function', 'GO:0004717', ('52', '55'))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (137, 154))	('ZIP4', 'Gene', (13, 17))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('pancreatic cancer', 'Disease', (137, 154))	('Silencing', 'Var', (0, 9))	('pancreatic cancer', 'Disease', 'MESH:D010190', (137, 154))
47202	29615456	ZIP4 has been shown to enhance migration, invasion, and suppress apoptosis in hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (78, 102))	('suppress', 'NegReg', (56, 64))	('migration', 'CPA', (31, 40))	('apoptosis', 'CPA', (65, 74))	('invasion', 'CPA', (42, 50))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (78, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('hepatocellular carcinoma', 'Disease', (78, 102))	('ZIP4', 'Var', (0, 4))	('enhance', 'PosReg', (23, 30))
47214	29615456	Our previous studies indicated that ZIP4 activates oncogenic miR-373 and IL-6-STAT3 pathways through a zinc-dependent transcriptional factor CREB.	('IL-6', 'molecular_function', 'GO:0005138', ('73', '77'))	('miR-373', 'Gene', (61, 68))	('miR-373', 'Gene', '442918', (61, 68))	('ZIP4', 'Var', (36, 40))	('CREB', 'Gene', (141, 145))	('IL-6', 'Gene', (73, 77))	('CREB', 'Gene', '1385', (141, 145))	('IL-6', 'Gene', '3569', (73, 77))	('activates', 'PosReg', (41, 50))
47215	29615456	To further investigate whether ZIP4 also regulates ZO-1 and claudin-1 through CREB, we knocked down CREB with siRNA in ZIP4 high pancreatic cancer cells MIA-ZIP4, Panc-ZIP4 and AsPC-1 cells, and did not find upregulated expression of ZO-1 and claudin-1, suggesting that ZIP4 repressed ZO-1 and claudin-1 is independent of CREB.	('CREB', 'Gene', (322, 326))	('CREB', 'Gene', '1385', (78, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('CREB', 'Gene', '1385', (322, 326))	('AsPC-1', 'CellLine', 'CVCL:0152', (177, 183))	('CREB', 'Gene', (100, 104))	('CREB', 'Gene', '1385', (100, 104))	('MIA-ZIP4', 'CellLine', 'CVCL:0428', (153, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('pancreatic cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('CREB', 'Gene', (78, 82))	('knocked', 'Var', (87, 94))
47217	29615456	Our results indicate that ZEB1 suppressed the expression of ZO-1 and claudin-1 in pancreatic cancer cells, and knocking down ZEB1 upregulated ZO-1 and claudin-1 in both AsPC-1 and Panc-1 cells, suggesting a novel zinc dependent regulatory pathway through which ZIP4 repressed ZO-1 and claudin-1 in human pancreatic cancer cells (Figure.	('upregulated', 'PosReg', (130, 141))	('ZEB1', 'Gene', (125, 129))	('human', 'Species', '9606', (298, 303))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (304, 321))	('AsPC-1', 'CellLine', 'CVCL:0152', (169, 175))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (82, 99))	('knocking down', 'Var', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Panc-1', 'CellLine', 'CVCL:0480', (180, 186))	('pancreatic cancer', 'Disease', (304, 321))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('pancreatic cancer', 'Disease', 'MESH:D010190', (304, 321))	('suppressed', 'NegReg', (31, 41))	('pancreatic cancer', 'Disease', (82, 99))	('expression', 'MPA', (46, 56))	('pancreatic cancer', 'Disease', 'MESH:D010190', (82, 99))
47232	29615456	Presently, we describe a novel signaling pathway in which ZIP4 inhibits ZEB1 and then suppresses ZO-1 and claudin-1, leading to phosphorylation of FAK and Paxillin, which further causes increased cell migration, invasion and tumor metastasis.	('cell migration', 'CPA', (196, 210))	('inhibits', 'NegReg', (63, 71))	('phosphorylation', 'MPA', (128, 143))	('tumor metastasis', 'Disease', 'MESH:D009362', (225, 241))	('FAK', 'molecular_function', 'GO:0004717', ('147', '150'))	('increased', 'PosReg', (186, 195))	('cell migration', 'biological_process', 'GO:0016477', ('196', '210'))	('tumor metastasis', 'Disease', (225, 241))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('signaling pathway', 'biological_process', 'GO:0007165', ('31', '48'))	('suppresses', 'NegReg', (86, 96))	('FAK', 'Protein', (147, 150))	('ZEB1', 'Protein', (72, 76))	('ZIP4', 'Var', (58, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('128', '143'))	('causes', 'Reg', (179, 185))	('invasion', 'CPA', (212, 220))	('ZO-1', 'Protein', (97, 101))	('Paxillin', 'Protein', (155, 163))
47233	29615456	In ZIP4-high cells such as AsPC-1 and Panc-1, knock down of ZIP4 upregulated ZO-1 and claudin-1 and reduced FAK and Paxillin phosphorylation.	('FAK', 'molecular_function', 'GO:0004717', ('108', '111'))	('ZO-1', 'Protein', (77, 81))	('reduced', 'NegReg', (100, 107))	('Panc-1', 'CellLine', 'CVCL:0480', (38, 44))	('knock down', 'Var', (46, 56))	('ZIP4', 'Gene', (60, 64))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('upregulated', 'PosReg', (65, 76))	('AsPC-1', 'CellLine', 'CVCL:0152', (27, 33))	('claudin-1', 'Protein', (86, 95))
47235	29615456	Furthermore, the reduced phosphorylation of FAK and Paxillin by silencing of ZIP4 can be rescued by simultaneous blocking of ZO-1 or claudin-1 in both AsPC-1 and Panc-1 cells, suggesting a direct link of ZIP4, ZO-1, claudin-1, FAK, and Paxillin in pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (248, 265))	('pancreatic cancer', 'Disease', (248, 265))	('Panc-1', 'CellLine', 'CVCL:0480', (162, 168))	('phosphorylation', 'biological_process', 'GO:0016310', ('25', '40'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (248, 265))	('phosphorylation', 'MPA', (25, 40))	('claudin-1', 'Gene', (133, 142))	('ZIP4', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('blocking', 'NegReg', (113, 121))	('FAK', 'molecular_function', 'GO:0004717', ('44', '47'))	('ZO-1', 'Gene', (125, 129))	('silencing', 'Var', (64, 73))	('reduced', 'NegReg', (17, 24))	('FAK', 'molecular_function', 'GO:0004717', ('227', '230'))	('AsPC-1', 'CellLine', 'CVCL:0152', (151, 157))
47241	29615456	Targeting ZIP4 might be a novel treatment strategy for pancreatic cancers with elevated expression of this transporter.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))	('pancreatic cancers', 'Disease', (55, 73))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('expression', 'MPA', (88, 98))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (55, 73))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('elevated', 'PosReg', (79, 87))	('Targeting', 'Var', (0, 9))	('pancreatic cancers', 'Disease', 'MESH:D010190', (55, 73))	('ZIP4', 'Gene', (10, 14))
47261	32014012	MiRNAs, which are approximately 20 to 24 nucleotides in length, are a well-known group of small ncRNAs that epigenetically or posttranscriptionally regulate the expression of target mRNAs by imperfectly base pairing with the mRNA 3'-untranslated region (3'-UTR) of target mRNAs.	('ncRNA', 'Gene', '220202', (96, 101))	('base pairing', 'molecular_function', 'GO:0003676', ('203', '215'))	('expression', 'MPA', (161, 171))	('imperfectly base pairing', 'Var', (191, 215))	('ncRNA', 'Gene', (96, 101))	('regulate', 'Reg', (148, 156))
47298	32014012	Moreover, miR-204 is inhibited by HIF-1alpha to upregulate VASP at the posttranscriptional level, providing a typical instance in which HIF-1alpha and suppressed miRNAs synergistically regulate the same gene in different ways.	('VASP', 'Gene', (59, 63))	('miR-204', 'Gene', '406987', (10, 17))	('VASP', 'Gene', '7408', (59, 63))	('miR-204', 'Gene', (10, 17))	('miR', 'Gene', '220972', (10, 13))	('regulate', 'Reg', (185, 193))	('miR', 'Gene', (10, 13))	('upregulate', 'PosReg', (48, 58))	('HIF-1alpha', 'Var', (136, 146))	('miR', 'Gene', '220972', (162, 165))	('miR', 'Gene', (162, 165))
47319	32014012	CircDENND2A was predicted to be an HRC in glioma via bioinformatic analysis.	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('CircDENND2A', 'Var', (0, 11))	('HRC', 'Gene', '3270', (35, 38))	('glioma', 'Disease', (42, 48))	('HRC', 'Gene', (35, 38))
47321	32014012	In addition, more HRCs, including circRNA_403658, circDENND4C, and circRNA_0000977, have been identified to participate in cancer progression by sponging corresponding miRNAs.	('participate', 'Reg', (108, 119))	('403658, circDENND4C', 'Chemical', 'MESH:C060809', (42, 61))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('HRC', 'Gene', (18, 21))	('circRNA_403658', 'Var', (34, 48))	('miR', 'Gene', '220972', (168, 171))	('miR', 'Gene', (168, 171))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('HRC', 'Gene', '3270', (18, 21))	('circRNA_0000977', 'Var', (67, 82))
47338	32014012	This mechanism mainly involves three kinds of RNAs, including mRNAs, pseudogene transcripts and lncRNAs, but circRNAs have followed lncRNAs in becoming a novel hotspot of research on the ceRNA family.	('ncRNA', 'Gene', '220202', (97, 102))	('ncRNA', 'Gene', (133, 138))	('pseudogene transcripts', 'Var', (69, 91))	('ncRNA', 'Gene', '220202', (133, 138))	('ncRNA', 'Gene', (97, 102))
47340	32014012	In addition, in hepatocellular carcinoma, circRNA_0046600 could upregulate HIF-1alpha by sponging miR-640 to promote cancer progression.	('miR-640', 'Gene', '693225', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('promote', 'PosReg', (109, 116))	('miR-640', 'Gene', (98, 105))	('HIF-1alpha', 'Protein', (75, 85))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (16, 40))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (16, 40))	('upregulate', 'PosReg', (64, 74))	('hepatocellular carcinoma', 'Disease', (16, 40))	('circRNA_0046600', 'Var', (42, 57))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
47352	32014012	MiR-128, which is regulated by snail family zinc finger 1 (SNAIL) transcriptionally, in turn modulates the expression of ribosomal protein S6 kinase, polypeptide 1 (RPS6KB1), also known as p70S6K, and afterwards disrupts downstream HIF-1alpha at the translational level and consequently suppresses pyruvate kinase 2 (PKM2) expression to inhibit the growth and metabolism of prostate cancer cells, which expands the interplay between HIF-1alpha and miRNA at the translational level.	('metabolism of prostate cancer', 'Disease', (360, 389))	('metabolism of prostate cancer', 'Disease', 'MESH:D011471', (360, 389))	('PKM2', 'Gene', (317, 321))	('snail family zinc finger 1', 'Gene', (31, 57))	('cancer', 'Phenotype', 'HP:0002664', (383, 389))	('modulates', 'Var', (93, 102))	('PKM2', 'Gene', '5315', (317, 321))	('metabolism', 'biological_process', 'GO:0008152', ('360', '370'))	('SNAIL', 'Gene', '6615', (59, 64))	('SNAIL', 'Gene', (59, 64))	('p70S6K', 'Gene', '6198', (189, 195))	('RPS6KB1', 'Gene', '6198', (165, 172))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('121', '138'))	('prostate cancer', 'Phenotype', 'HP:0012125', (374, 389))	('MiR-128', 'Gene', (0, 7))	('disrupts', 'NegReg', (212, 220))	('miR', 'Gene', '220972', (448, 451))	('suppresses', 'NegReg', (287, 297))	('pyruvate', 'Chemical', 'MESH:D011773', (298, 306))	('miR', 'Gene', (448, 451))	('snail family zinc finger 1', 'Gene', '6615', (31, 57))	('p70S6K', 'Gene', (189, 195))	('RPS6KB1', 'Gene', (165, 172))	('inhibit', 'NegReg', (337, 344))	('expression', 'MPA', (107, 117))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('expression', 'MPA', (323, 333))
47354	32014012	Enhanced phosphorylation at Ser235/236 of the 40S ribosomal protein S6 therefore boosts HIF-1alpha translation in the nickel-induced malignant transformation of human bronchial epithelial cells.	('human', 'Species', '9606', (161, 166))	('translation', 'biological_process', 'GO:0006412', ('99', '110'))	('phosphorylation', 'biological_process', 'GO:0016310', ('9', '24'))	('boosts', 'PosReg', (81, 87))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('Ser235/236', 'Var', (28, 38))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('50', '67'))	('Ser', 'Chemical', 'MESH:C530429', (28, 31))	('HIF-1alpha translation', 'MPA', (88, 110))	('nickel', 'Chemical', 'MESH:D009532', (118, 124))	('40S ribosomal protein S6', 'Gene', '6194', (46, 70))	('40S ribosomal protein S6', 'Gene', (46, 70))	('Ser', 'cellular_component', 'GO:0005790', ('28', '31'))	('phosphorylation', 'MPA', (9, 24))	('Enhanced', 'PosReg', (0, 8))
47399	32014012	In human umbilical vein endothelial cells, there is a negative regulatory loop containing miR-439 and HIF-1alpha in which HIF-1alpha induces miR-439 to bind to and destabilize HIF-1alpha mRNA, hence reducing the activity of HIF-1alpha in turn.	('HIF-1alpha', 'Protein', (176, 186))	('bind', 'Interaction', (152, 156))	('human', 'Species', '9606', (3, 8))	('miR', 'Gene', '220972', (90, 93))	('reducing', 'NegReg', (199, 207))	('miR', 'Gene', (90, 93))	('destabilize', 'NegReg', (164, 175))	('miR', 'Gene', '220972', (141, 144))	('miR', 'Gene', (141, 144))	('activity', 'MPA', (212, 220))	('HIF-1alpha', 'Var', (122, 132))
47410	32014012	Not surprisingly, scholars have revealed that aberrant expression of lncRNA H19 and miR-215 in glioblastoma confers a poor prognosis for patients.	('miR-215', 'Gene', (84, 91))	('glioblastoma', 'Disease', (95, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('miR-215', 'Gene', '406997', (84, 91))	('H19', 'Gene', '283120', (76, 79))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('patients', 'Species', '9606', (137, 145))	('H19', 'Gene', (76, 79))	('ncRNA', 'Gene', (70, 75))	('aberrant expression', 'Var', (46, 65))	('ncRNA', 'Gene', '220202', (70, 75))
47412	32014012	In addition, a strong correlation between high lncRNA EFNA3 expression and shorter metastasis-free survival was found in breast cancer patients, undoubtedly enriching the prognostic value of lncRNAs in this prevalent cancer.	('expression', 'MPA', (60, 70))	('patients', 'Species', '9606', (135, 143))	('EFNA3', 'Gene', '1944', (54, 59))	('shorter', 'NegReg', (75, 82))	('cancer', 'Disease', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('EFNA3', 'Gene', (54, 59))	('ncRNA', 'Gene', (192, 197))	('ncRNA', 'Gene', (48, 53))	('ncRNA', 'Gene', '220202', (192, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('ncRNA', 'Gene', '220202', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('metastasis-free survival', 'CPA', (83, 107))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Disease', (217, 223))	('breast cancer', 'Disease', (121, 134))	('high', 'Var', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
47419	32014012	found that the levels of specific biomarkers associated with drug resistance in clear cell renal cell carcinoma, such as HIFs, oncogenic miR-155 and miR-210, and VEGF, could be selectively downregulated by methylselenocysteine or seleno-L-methionine in a dose- and time-dependent manner, which conferred existing anticancer therapies with enhanced therapeutic efficacy and selectivity.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('VEGF', 'Gene', '7422', (162, 166))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (80, 111))	('methylselenocysteine', 'Chemical', 'MESH:C002979', (206, 226))	('VEGF', 'Gene', (162, 166))	('seleno-L-methionine', 'Var', (230, 249))	('clear cell renal cell carcinoma', 'Disease', (80, 111))	('levels', 'MPA', (15, 21))	('methylselenocysteine', 'Var', (206, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cancer', 'Disease', (317, 323))	('downregulated', 'NegReg', (189, 202))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (80, 111))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('drug resistance', 'biological_process', 'GO:0009315', ('61', '76'))	('miR-210', 'Gene', (149, 156))	('drug resistance', 'biological_process', 'GO:0042493', ('61', '76'))	('miR-155', 'Gene', (137, 144))	('miR-210', 'Gene', '406992', (149, 156))	('seleno-L-methionine', 'Chemical', 'MESH:C517785', (230, 249))	('drug resistance', 'Phenotype', 'HP:0020174', (61, 76))	('miR-155', 'Gene', '406947', (137, 144))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
47446	31921140	This process of DC tolerization involves the genetic reprogramming of DCs to ultimately disable immune recognition of developing malignancies.	('immune recognition', 'CPA', (96, 114))	('malignancies', 'Disease', (129, 141))	('genetic', 'Var', (45, 52))	('disable', 'NegReg', (88, 95))	('malignancies', 'Disease', 'MESH:D009369', (129, 141))
47453	31921140	Specifically, murine CD8a+CD103+BATF3+CLEC9A+XCR1+ cDC1s have been demonstrated to have a critical role in the cross-presentation of tumor antigens and are generally thought to be indispensable in the development of host anti-tumor immune responses.	('murine', 'Species', '10090', (14, 20))	('cross-presentation', 'biological_process', 'GO:0042590', ('111', '129'))	('CD8a+CD103+BATF3+CLEC9A+XCR1+', 'Var', (21, 50))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cross-presentation', 'biological_process', 'GO:0002479', ('111', '129'))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('cross-presentation', 'MPA', (111, 129))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (226, 231))	('cross-presentation', 'biological_process', 'GO:0002480', ('111', '129'))
47455	31921140	In human melanoma samples from the Cancer Genome Atlas (TCGA), the presence of BATF3+ DCs was correlated with enhanced CD8+ T cell infiltration and T cell homing chemokines CXCL9 and CXCL10.	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('CD8', 'Gene', (119, 122))	('human', 'Species', '9606', (3, 8))	('CD8', 'Gene', '925', (119, 122))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('enhanced', 'PosReg', (110, 118))	('presence', 'Var', (67, 75))	('T cell homing chemokines', 'CPA', (148, 172))	('BATF3+ DCs', 'Var', (79, 89))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CXCL9', 'MPA', (173, 178))
47456	31921140	Antigen cross-presentation defects, such as loss of Batf3, Clec9a, or Wdfy4 results in a restrained CD8+ T cell repertoire and an inability to reject tumors.	('Batf3', 'Gene', '55509', (52, 57))	('tumors', 'Disease', (150, 156))	('Batf3', 'Gene', (52, 57))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('cross-presentation', 'biological_process', 'GO:0002479', ('8', '26'))	('CD8', 'Gene', (100, 103))	('Wdfy4', 'Gene', (70, 75))	('Clec9a', 'Gene', '283420', (59, 65))	('CD8', 'Gene', '925', (100, 103))	('cross-presentation', 'biological_process', 'GO:0002480', ('8', '26'))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('loss', 'Var', (44, 48))	('Clec9a', 'Gene', (59, 65))	('restrained', 'NegReg', (89, 99))	('Wdfy4', 'Gene', '57705', (70, 75))	('cross-presentation', 'biological_process', 'GO:0042590', ('8', '26'))
47483	31921140	Blockade of IL-10 restored DC function and IL-12 production, and when combined with CSF-1 inhibition, reduced metastatic burden and improved the efficacy of paclitaxel chemotherapy in a manner dependent upon DC production of IL-12.	('efficacy', 'MPA', (145, 153))	('paclitaxel', 'Chemical', 'MESH:D017239', (157, 167))	('IL-10', 'Gene', (12, 17))	('metastatic burden', 'CPA', (110, 127))	('CSF-1', 'Gene', (84, 89))	('Blockade', 'Var', (0, 8))	('IL-12', 'molecular_function', 'GO:0005143', ('225', '230'))	('improved', 'PosReg', (132, 140))	('IL-12 production', 'MPA', (43, 59))	('CSF-1', 'Gene', '1435', (84, 89))	('DC function', 'MPA', (27, 38))	('IL-10', 'molecular_function', 'GO:0005141', ('12', '17'))	('reduced', 'NegReg', (102, 109))	('IL-12', 'molecular_function', 'GO:0005143', ('43', '48'))	('IL-12 production', 'biological_process', 'GO:0032615', ('43', '59'))	('CSF-1', 'molecular_function', 'GO:0005011', ('84', '89'))
47514	31921140	These alterations culminate in the development and accumulation of Tregs both in vitro and in vivo and are dominate over other TLR-dependent maturation stimuli.	('alterations', 'Var', (6, 17))	('accumulation', 'CPA', (51, 63))	('culminate in', 'Reg', (18, 30))	('TLR', 'Gene', '7097;7098;7099;51284;54106', (127, 130))	('TLR', 'Gene', (127, 130))	('Tregs', 'CPA', (67, 72))
47515	31921140	Illustrating the importance of this pathway, these studies also showed that the genetic silencing of Wnt5a in melanoma resulted in a significant influx of activated tumor antigen-specific CD8+ T cells.	('Wnt5a', 'Gene', '7474', (101, 106))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('genetic silencing', 'Var', (80, 97))	('CD8', 'Gene', (188, 191))	('CD8', 'Gene', '925', (188, 191))	('tumor antigen', 'molecular_function', 'GO:0008222', ('165', '178'))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('Wnt5a', 'Gene', (101, 106))	('influx', 'PosReg', (145, 151))	('tumor', 'Disease', (165, 170))
47518	31921140	The recent realization that tumor-derived exosomes are capable of genetically altering distant immune cell populations implies that these extracellular vesicles and their molecular cargo are likely to be very important players in DC tolerization and tumor-mediated immune evasion.	('tumor', 'Disease', (28, 33))	('cargo', 'molecular_function', 'GO:0140355', ('181', '186'))	('immune evasion', 'biological_process', 'GO:0051842', ('265', '279'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('genetically', 'Var', (66, 77))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('immune evasion', 'biological_process', 'GO:0042783', ('265', '279'))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('extracellular', 'cellular_component', 'GO:0005576', ('138', '151'))	('tumor', 'Disease', (250, 255))
47525	31921140	Due to the important role of DCs in activating adaptive immune responses, as well as the established capacity for tumor EVs to induce immune suppression, it is logical to anticipate that EVs can function in part by manipulating DC phenotype.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('manipulating', 'Var', (215, 227))	('immune', 'MPA', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('adaptive', 'CPA', (47, 55))	('activating', 'PosReg', (36, 46))
47530	31921140	demonstrated that pancreatic cancer exosomes deliver miR-212-3p to DCs resulting in silencing of the transcription factor regulatory factor-X associated protein (RFXAP), a critical transcription factor for the expression of the MHC II genes.	('pancreatic cancer', 'Disease', (18, 35))	('silencing', 'NegReg', (84, 93))	('pancreatic cancer', 'Disease', 'MESH:D010190', (18, 35))	('MHC II', 'Gene', (228, 234))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('transcription factor', 'molecular_function', 'GO:0000981', ('181', '201'))	('transcription', 'biological_process', 'GO:0006351', ('101', '114'))	('RFXAP', 'Gene', (162, 167))	('transcription factor', 'molecular_function', 'GO:0000981', ('101', '121'))	('RFXAP', 'Gene', '5994', (162, 167))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (18, 35))	('212-3p', 'Chemical', 'MESH:C014896', (57, 63))	('regulatory factor-X associated protein', 'Gene', '5994', (122, 160))	('transcription', 'biological_process', 'GO:0006351', ('181', '194'))	('regulatory factor-X associated protein', 'Gene', (122, 160))	('miR-212-3p', 'Var', (53, 63))
47532	31921140	Additionally, one study demonstrates that Tregs can transfer miRNAs (primarily miR-150-5p and miR-142-3p) to DCs resulting in the induction of a tolerogenic pathway including increased production of IL-10 and decreased IL-6.	('induction', 'Reg', (130, 139))	('IL-6', 'Gene', '3569', (219, 223))	('miR-142-3p', 'Var', (94, 104))	('production', 'MPA', (185, 195))	('tolerogenic pathway', 'Pathway', (145, 164))	('IL-10', 'molecular_function', 'GO:0005141', ('199', '204'))	('IL-6', 'Gene', (219, 223))	('increased', 'PosReg', (175, 184))	('IL-6', 'molecular_function', 'GO:0005138', ('219', '223'))	('miR-150-5p', 'Var', (79, 89))	('decreased IL-6', 'Phenotype', 'HP:0030783', (209, 223))	('decreased', 'NegReg', (209, 218))
47545	31921140	S100A proteins can also be produced by MDSCs themselves in a STAT3-dependent manner, representing a potential positive feedback loop to suppress the DC lineage in the setting of a malignancy.	('S100A', 'Var', (0, 5))	('DC lineage', 'CPA', (149, 159))	('S100A', 'SUBSTITUTION', 'None', (0, 5))	('malignancy', 'Disease', 'MESH:D009369', (180, 190))	('STAT3', 'Gene', '6774', (61, 66))	('malignancy', 'Disease', (180, 190))	('STAT3', 'Gene', (61, 66))	('suppress', 'NegReg', (136, 144))
47561	31921140	Snail-overexpressing melanomas were resistant to peptide-pulsed DC vaccines while both intra-tumoral Snail-specific siRNA and neutralization of TSP1 restored T cell infiltration.	('TSP1', 'Gene', (144, 148))	('intra-tumoral', 'Disease', (87, 100))	('Snail', 'Gene', (0, 5))	('T cell infiltration', 'CPA', (158, 177))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('Snail', 'Gene', '6615', (0, 5))	('neutralization', 'Var', (126, 140))	('melanomas', 'Disease', (21, 30))	('TSP1', 'molecular_function', 'GO:0004277', ('144', '148'))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('Snail', 'Gene', (101, 106))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('restored', 'PosReg', (149, 157))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('intra-tumoral', 'Disease', 'MESH:D009369', (87, 100))	('Snail', 'Gene', '6615', (101, 106))
47565	31921140	MDSCs also induce EMT via TGF-beta and HGF in a mouse model of melanoma, whereby depletion of MDSCs reversed the EMT process.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('HGF', 'Gene', (39, 42))	('EMT', 'CPA', (18, 21))	('TGF-beta', 'Protein', (26, 34))	('EMT', 'biological_process', 'GO:0001837', ('113', '116'))	('mouse', 'Species', '10090', (48, 53))	('depletion', 'Var', (81, 90))	('EMT', 'biological_process', 'GO:0001837', ('18', '21'))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('HGF', 'Gene', '15234', (39, 42))	('melanoma', 'Disease', (63, 71))
47575	31921140	Indeed, a subset of BATF3+ IRF8+ cDC1s are not only required for T cell trafficking, but are also necessary for the generation of effector T cell responses to anti-PD-1 therapy.	('PD-1', 'Gene', '5133', (164, 168))	('BATF3+ IRF8+', 'Var', (20, 32))	('PD-1', 'Gene', (164, 168))	('cDC1s', 'Gene', (33, 38))
47581	31921140	In a murine model of ovarian cancer, inhibition of Axl promotes tumor infiltration of CD8+ T cell and CD103+ DCs associated with an upregulation of the T cell recruiting chemokines CXCL9 and CXCL10.	('inhibition', 'Var', (37, 47))	('tumor', 'Disease', (64, 69))	('upregulation', 'PosReg', (132, 144))	('ovarian cancer', 'Phenotype', 'HP:0100615', (21, 35))	('murine', 'Species', '10090', (5, 11))	('CD8', 'Gene', (86, 89))	('CD103+ DCs', 'Var', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('CD8', 'Gene', '925', (86, 89))	('ovarian cancer', 'Disease', 'MESH:D010051', (21, 35))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('ovarian cancer', 'Disease', (21, 35))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('Axl', 'Protein', (51, 54))
47584	31921140	Pharmacologic modulation of the tumor's ability to recruit TAMs cia CSF1 has shown efficacy preclinically.	('CSF1', 'molecular_function', 'GO:0005011', ('68', '72'))	('CSF1', 'Gene', '1435', (68, 72))	('modulation', 'Var', (14, 24))	('TAM', 'Chemical', 'MESH:C419191', (59, 62))	('CSF1', 'Gene', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
47586	31921140	Other mechanisms for diminishing TAM recruitment by the tumor or re-polarizing TAMs to the M1 phenotype are also being investigated, including antagonism of CCL2 and/or CCL5 or their receptors.	('CCL', 'molecular_function', 'GO:0044101', ('157', '160'))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CCL2', 'Gene', (157, 161))	('TAM recruitment', 'MPA', (33, 48))	('tumor', 'Disease', (56, 61))	('TAM', 'Chemical', 'MESH:C419191', (79, 82))	('CCL', 'molecular_function', 'GO:0044101', ('169', '172'))	('antagonism', 'Var', (143, 153))	('CCL5', 'Gene', (169, 173))	('TAM', 'Chemical', 'MESH:C419191', (33, 36))	('CCL2', 'Gene', '6347', (157, 161))	('CCL5', 'Gene', '6352', (169, 173))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('diminishing', 'NegReg', (21, 32))
47587	31921140	demonstrated in a murine pancreatic cancer model that a partial agonist of CD11b+ repolarized TAMs and reduced MDSC infiltration while enhancing intratumoral CD103+ DC populations, rendering previously resistant murine pancreatic tumors responsive to checkpoint blockade.	('pancreatic cancer', 'Disease', (25, 42))	('pancreatic tumors', 'Disease', 'MESH:D010190', (219, 236))	('pancreatic tumors', 'Disease', (219, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('enhancing', 'PosReg', (135, 144))	('murine', 'Species', '10090', (212, 218))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (25, 42))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', (230, 235))	('CD11b+', 'Gene', (75, 81))	('CD103+ DC populations', 'MPA', (158, 179))	('reduced', 'NegReg', (103, 110))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (219, 236))	('TAM', 'Chemical', 'MESH:C419191', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Disease', (150, 155))	('pancreatic cancer', 'Disease', 'MESH:D010190', (25, 42))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('partial agonist', 'Var', (56, 71))	('murine', 'Species', '10090', (18, 24))	('MDSC infiltration', 'MPA', (111, 128))
47589	31921140	Manipulating the pro-tumorogenic cytokines and chemokines in the microenvironment also holds promise for sensitizing tumors to ICB.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (117, 122))	('Manipulating', 'Var', (0, 12))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
47591	31921140	We have further demonstrated that the inhibition of TGF-beta enhances anti-CTLA-4 antibody treatment in an autochthonous melanoma model, and that delayed inhibition of TGF-beta, but not initial combinatorial therapy, improves anti-PD-1 antibody responses by reversing adaptive resistance.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('antibody', 'cellular_component', 'GO:0019814', ('236', '244'))	('melanoma', 'Disease', (121, 129))	('CTLA-4', 'Gene', '1493', (75, 81))	('CTLA-4', 'Gene', (75, 81))	('reversing', 'NegReg', (258, 267))	('antibody', 'cellular_component', 'GO:0019814', ('82', '90'))	('antibody', 'molecular_function', 'GO:0003823', ('236', '244'))	('TGF-beta', 'Gene', (52, 60))	('antibody', 'cellular_component', 'GO:0042571', ('236', '244'))	('PD-1', 'Gene', (231, 235))	('adaptive resistance', 'CPA', (268, 287))	('PD-1', 'Gene', '5133', (231, 235))	('antibody', 'molecular_function', 'GO:0003823', ('82', '90'))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('antibody', 'cellular_component', 'GO:0042571', ('82', '90'))	('inhibition', 'Var', (38, 48))	('improves', 'PosReg', (217, 225))	('antibody', 'cellular_component', 'GO:0019815', ('236', '244'))	('TGF-beta', 'Gene', (168, 176))	('enhances', 'PosReg', (61, 69))	('antibody', 'cellular_component', 'GO:0019815', ('82', '90'))
47600	31921140	IDO1 has also been reported to be upregulated by both hypoxia and adenosine, which are typical components of the tumor microenvironment encountered by DCs.	('adenosine', 'Chemical', 'MESH:D000241', (66, 75))	('tumor', 'Disease', (113, 118))	('hypoxia', 'Disease', (54, 61))	('IDO1', 'Gene', (0, 4))	('hypoxia', 'Disease', 'MESH:D000860', (54, 61))	('upregulated', 'PosReg', (34, 45))	('IDO', 'molecular_function', 'GO:0047719', ('0', '3'))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('IDO1', 'Gene', '3620', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('adenosine', 'Var', (66, 75))	('IDO', 'molecular_function', 'GO:0033754', ('0', '3'))
47604	31921140	Agonism of CD40 has been shown in preclinical models to enhance both vaccines and anti-PD-1 antibody treatment, and has moved into several clinical trials.	('antibody', 'cellular_component', 'GO:0042571', ('92', '100'))	('CD40', 'Gene', '958', (11, 15))	('antibody', 'cellular_component', 'GO:0019815', ('92', '100'))	('CD40', 'Gene', (11, 15))	('antibody', 'cellular_component', 'GO:0019814', ('92', '100'))	('enhance', 'PosReg', (56, 63))	('Agonism', 'Var', (0, 7))	('PD-1', 'Gene', (87, 91))	('PD-1', 'Gene', '5133', (87, 91))	('antibody', 'molecular_function', 'GO:0003823', ('92', '100'))
47605	31921140	Myeloid development into DCs is impaired by STAT3 signaling, and inhibition of JAK2/STAT3 has been shown to enhance anti-tumor responses through the promotion of DC maturation in preclinical models.	('STAT3', 'Gene', '6774', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('JAK', 'molecular_function', 'GO:0004713', ('79', '82'))	('JAK2', 'Gene', '3717', (79, 83))	('promotion', 'PosReg', (149, 158))	('DC maturation', 'CPA', (162, 175))	('STAT3', 'Gene', (84, 89))	('tumor', 'Disease', (121, 126))	('enhance', 'PosReg', (108, 115))	('STAT3', 'Gene', '6774', (44, 49))	('inhibition', 'Var', (65, 75))	('STAT3', 'Gene', (44, 49))	('JAK2', 'Gene', (79, 83))	('Myeloid development', 'CPA', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
47606	31921140	Finally, we have shown that inhibition of the Wnt/beta-catenin pathway using an anti-Fzd receptor antibody or a Wnt ligand trap enhances anti-tumor immunity in autochthonous melanoma and Lewis lung carcinoma mouse models.	('Wnt/beta-catenin pathway', 'Pathway', (46, 70))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('antibody', 'cellular_component', 'GO:0019815', ('98', '106'))	('antibody', 'cellular_component', 'GO:0019814', ('98', '106'))	('tumor', 'Disease', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('ligand', 'molecular_function', 'GO:0005488', ('116', '122'))	('inhibition', 'Var', (28, 38))	('Lewis lung carcinoma', 'Disease', (187, 207))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (187, 207))	('antibody', 'molecular_function', 'GO:0003823', ('98', '106'))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))	('mouse', 'Species', '10090', (208, 213))	('antibody', 'cellular_component', 'GO:0042571', ('98', '106'))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('enhances', 'PosReg', (128, 136))
47608	31921140	We have further demonstrated that small molecule inhibitors of the PORCN acyltransferase enzyme, which effectively block Wnt ligand release, synergistically enhances the efficacy of anti-CTLA-4 antibody immunotherapy in pre-clinical models of melanoma.	('PORCN', 'Gene', (67, 72))	('CTLA-4', 'Gene', '1493', (187, 193))	('PORCN', 'Gene', '64840', (67, 72))	('Wnt ligand release', 'MPA', (121, 139))	('antibody', 'cellular_component', 'GO:0042571', ('194', '202'))	('CTLA-4', 'Gene', (187, 193))	('melanoma', 'Phenotype', 'HP:0002861', (243, 251))	('melanoma', 'Disease', (243, 251))	('antibody', 'cellular_component', 'GO:0019815', ('194', '202'))	('melanoma', 'Disease', 'MESH:D008545', (243, 251))	('enhances', 'PosReg', (157, 165))	('ligand', 'molecular_function', 'GO:0005488', ('125', '131'))	('antibody', 'cellular_component', 'GO:0019814', ('194', '202'))	('inhibitors', 'Var', (49, 59))	('pre', 'molecular_function', 'GO:0003904', ('220', '223'))	('antibody', 'molecular_function', 'GO:0003823', ('194', '202'))
47609	31921140	Others have also shown that deletion or pharmacologic inhibition of the Fzd co-receptors, LRP5/6, in DCs promoted their anti-tumor effects, further highlighting the therapeutic potential of targeting this pathway and a possible method of enhancing DC-based vaccines.	('promoted', 'PosReg', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('LRP5/6', 'Gene', (90, 96))	('LRP5/6', 'Gene', '4041;4040', (90, 96))	('tumor', 'Disease', (125, 130))	('deletion', 'Var', (28, 36))
47644	31440095	Results: The motility of human PDAC cells PANC-1 considerably decreased at ectopic expression of PDX1.	('motility', 'CPA', (13, 21))	('decreased', 'NegReg', (62, 71))	('PDAC', 'Chemical', '-', (31, 35))	('ectopic expression', 'Var', (75, 93))	('human', 'Species', '9606', (25, 30))	('PDX1', 'Gene', (97, 101))	('PANC-1', 'CellLine', 'CVCL:0480', (42, 48))	('PDAC', 'Phenotype', 'HP:0006725', (31, 35))
47658	31440095	In addition, it is currently evident that metastasizing is not an autonomous program of cancer cells, but a complex chain of events affected by intracellular mutations, multiple interactions between malignant and stromal cells, and signals of the extracellular matrix.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('interactions', 'Interaction', (178, 190))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('intracellular', 'cellular_component', 'GO:0005622', ('144', '157'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('247', '267'))	('mutations', 'Var', (158, 167))	('affected', 'Reg', (132, 140))
47678	31440095	In the present study, using Danio rerio (zebrafish) as a model organism , we report that the motility of human PDAC cells PANC-1 considerably decreased at ectopic expression of a key factor of pancreas embryogenesis PDX1.	('Danio rerio', 'Species', '7955', (28, 39))	('embryogenesis', 'biological_process', 'GO:0009790', ('202', '215'))	('PANC-1', 'Gene', (122, 128))	('motility', 'CPA', (93, 101))	('zebrafish', 'Species', '7955', (41, 50))	('decreased', 'NegReg', (142, 151))	('embryogenesis', 'biological_process', 'GO:0009793', ('202', '215'))	('PDAC', 'Chemical', '-', (111, 115))	('PANC-1', 'CellLine', 'CVCL:0480', (122, 128))	('ectopic', 'Var', (155, 162))	('human', 'Species', '9606', (105, 110))	('embryogenesis', 'biological_process', 'GO:0009792', ('202', '215'))	('PDAC', 'Phenotype', 'HP:0006725', (111, 115))
47687	31440095	RC222354) and inserted under the control of the PCNA promoter.	('PCNA', 'Gene', (48, 52))	('RC222354', 'Var', (0, 8))	('PCNA', 'Gene', '5111', (48, 52))	('PCNA', 'molecular_function', 'GO:0003892', ('48', '52'))
47733	31440095	According to Western blot data (Figure 1B), the expression of PDX1 protein in PANC-1PDX1 cells was conspicuously higher than in PANC-1Control cells.	('PANC-1', 'CellLine', 'CVCL:0480', (128, 134))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('expression', 'MPA', (48, 58))	('higher', 'PosReg', (113, 119))	('PANC-1', 'CellLine', 'CVCL:0480', (78, 84))	('PDX1', 'Gene', (62, 66))	('protein', 'Protein', (67, 74))	('PANC-1PDX1', 'CellLine', 'CVCL:0480', (78, 88))	('PANC-1PDX1', 'Var', (78, 88))
47734	31440095	The expression of PDX1 protein in PANC-1PDX1 cells treated with siPDX1 was lower than in those treated with siNeg.	('lower', 'NegReg', (75, 80))	('siPDX1', 'Var', (64, 70))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('expression', 'MPA', (4, 14))	('PDX1', 'Gene', (18, 22))	('protein', 'Protein', (23, 30))	('siNeg', 'Chemical', '-', (108, 113))	('PANC-1PDX1', 'CellLine', 'CVCL:0480', (34, 44))
47735	31440095	Real-time PCR data confirmed that the relative level of PDX1 transcript in PANC-1PDX1 cells 100-fold exceeded that in PANC-1Control cells (data not shown).	('PANC-1', 'CellLine', 'CVCL:0480', (118, 124))	('PANC-1', 'CellLine', 'CVCL:0480', (75, 81))	('PANC-1PDX1', 'CellLine', 'CVCL:0480', (75, 85))	('PANC-1PDX1', 'Var', (75, 85))	('PDX1', 'Gene', (56, 60))
47738	31440095	The results of the MTS assay showed that the growth of PANC-1Control optical density of cells in the control group was lower than that of PANC-1PDX1 cells (P<0.05, P<0.01) (Figure 2A).	('PANC-1', 'CellLine', 'CVCL:0480', (55, 61))	('lower', 'NegReg', (119, 124))	('growth', 'CPA', (45, 51))	('PANC-1Control', 'Var', (55, 68))	('PANC-1', 'CellLine', 'CVCL:0480', (138, 144))	('PANC-1PDX1', 'CellLine', 'CVCL:0480', (138, 148))
47740	31440095	The results revealed that the number of cells in the S stage of PANC-1PDX1 cells was smaller compared with that in the control group, whereas the number of cells in the G1 and G2 stages of PANC-1PDX1 cells was higher than that of PANC-1Control cells (Figure 2B).	('PANC-1', 'CellLine', 'CVCL:0480', (230, 236))	('smaller', 'NegReg', (85, 92))	('PANC-1PDX1', 'CellLine', 'CVCL:0480', (189, 199))	('PANC-1', 'CellLine', 'CVCL:0480', (64, 70))	('PANC-1', 'CellLine', 'CVCL:0480', (189, 195))	('higher', 'PosReg', (210, 216))	('PANC-1PDX1', 'CellLine', 'CVCL:0480', (64, 74))	('PANC-1PDX1', 'Var', (64, 74))
47742	31440095	As a whole, the expression of PDX1 significantly reduced both the migration and the invasion of human pancreatic cancer cells.	('migration', 'CPA', (66, 75))	('expression', 'Var', (16, 26))	('reduced', 'NegReg', (49, 56))	('PDX1', 'Gene', (30, 34))	('human', 'Species', '9606', (96, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
47745	31440095	It can be seen that the expression levels of epithelial genes, such as MUC1, KRT8, and CDH1, were slightly increased in PANC-1PDX1 cells, but the expression level of the mesenchymal transcription factor gene ZEB1 was decreased, although the expression of the mesenchymal genes VIM and SLUG was slightly increased.	('transcription factor', 'molecular_function', 'GO:0000981', ('182', '202'))	('decreased', 'NegReg', (217, 226))	('CDH1', 'Gene', (87, 91))	('expression levels', 'MPA', (24, 41))	('MUC1', 'Gene', (71, 75))	('expression', 'MPA', (241, 251))	('MUC1', 'Gene', '4582', (71, 75))	('SLUG', 'Gene', '6591', (285, 289))	('SLUG', 'Gene', (285, 289))	('PANC-1PDX1', 'CellLine', 'CVCL:0480', (120, 130))	('increased', 'PosReg', (107, 116))	('ZEB1', 'Gene', '6935', (208, 212))	('increased', 'PosReg', (303, 312))	('KRT8', 'Gene', '3856', (77, 81))	('transcription', 'biological_process', 'GO:0006351', ('182', '195'))	('PANC-1PDX1', 'Var', (120, 130))	('KRT8', 'Gene', (77, 81))	('VIM', 'Gene', '7431', (277, 280))	('expression level', 'MPA', (146, 162))	('ZEB1', 'Gene', (208, 212))	('CDH1', 'Gene', '999', (87, 91))	('VIM', 'Gene', (277, 280))
47750	31440095	The efficient knockdown of PDX1 in PANC-1PDX1 -siPDX1 was confirmed by Western blot analysis (Figure 1B).	('PDX1', 'Gene', (27, 31))	('PANC-1PDX1', 'CellLine', 'CVCL:0480', (35, 45))	('knockdown', 'Var', (14, 23))
47751	31440095	The effect of the PDX1 knockdown on PANC-1PDX1 cells was then evaluated morphologically in vivo.	('knockdown', 'Var', (23, 32))	('PDX1', 'Gene', (18, 22))	('PANC-1PDX1', 'CellLine', 'CVCL:0480', (36, 46))
47753	31440095	As shown in Table 2, PANC-1PDX1 -siPDX1 cells microinjected into zebrafish embryos at 2 dpt exhibited considerably higher levels of migration (average 40%) as compared with PANC-1PDX1 -siNeg cells (average 6%).	('zebrafish', 'Species', '7955', (65, 74))	('PANC-1PDX1', 'Var', (21, 31))	('siNeg', 'Chemical', '-', (185, 190))	('migration', 'CPA', (132, 141))	('PANC-1PDX1', 'CellLine', 'CVCL:0480', (173, 183))	('higher', 'PosReg', (115, 121))	('PANC-1PDX1', 'CellLine', 'CVCL:0480', (21, 31))
47754	31440095	These findings suggested that, first, zebrafish embryo models could be used to monitor the migration of pancreatic cancer cells in a living animal, and, second, expression of PDX1 caused a significant reduction in pancreatic cancer cell migration in vivo.	('reduction', 'NegReg', (201, 210))	('zebrafish', 'Species', '7955', (38, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (214, 231))	('PDX1', 'Gene', (175, 179))	('pancreatic cancer', 'Disease', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('expression', 'Var', (161, 171))	('pancreatic cancer', 'Disease', (214, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('pancreatic cancer', 'Disease', 'MESH:D010190', (214, 231))	('cell migration', 'biological_process', 'GO:0016477', ('232', '246'))
47760	31440095	Cell motility in a wound healing assay was slowed down in PANC-1PDX1 cells as compared to original PANC-1Control cells (Figure 3A).	('PANC-1PDX1', 'CellLine', 'CVCL:0480', (58, 68))	('PANC-1PDX1', 'Var', (58, 68))	('slowed down', 'NegReg', (43, 54))	('Cell motility', 'biological_process', 'GO:0048870', ('0', '13'))	('PANC-1', 'CellLine', 'CVCL:0480', (99, 105))	('Cell motility in a wound healing assay', 'CPA', (0, 38))	('wound healing', 'biological_process', 'GO:0042060', ('19', '32'))	('PANC-1', 'CellLine', 'CVCL:0480', (58, 64))
47761	31440095	The data of Table 2 demonstrate a significant decrease in the migration rate of PANC-1PDX1 cells as compared to original PANC-1 cells.	('PANC-1', 'CellLine', 'CVCL:0480', (121, 127))	('PANC-1', 'CellLine', 'CVCL:0480', (80, 86))	('PANC-1PDX1', 'CellLine', 'CVCL:0480', (80, 90))	('PANC-1PDX1', 'Var', (80, 90))	('decrease', 'NegReg', (46, 54))	('migration rate', 'CPA', (62, 76))
47766	31440095	Recently, it has been claimed that EMT is dispensable for metastasis because genetic depletion of the Snail or Twist1 EMT activators had no effect on tumor initiation, invasion, or metastasis in a mouse model of PDAC.	('Snail', 'Gene', (102, 107))	('Snail', 'Gene', '20613', (102, 107))	('EMT', 'biological_process', 'GO:0001837', ('118', '121'))	('Twist1', 'Gene', (111, 117))	('PDAC', 'Chemical', '-', (212, 216))	('PDAC', 'Phenotype', 'HP:0006725', (212, 216))	('depletion', 'Var', (85, 94))	('tumor initiation', 'Disease', 'MESH:D009369', (150, 166))	('Twist1', 'Gene', '7291', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('mouse', 'Species', '10090', (197, 202))	('EMT', 'biological_process', 'GO:0001837', ('35', '38'))	('invasion', 'CPA', (168, 176))	('metastasis', 'CPA', (181, 191))	('tumor initiation', 'Disease', (150, 166))	('genetic depletion', 'Var', (77, 94))
47797	31277663	For instance, circHIPK3 and TUG1 were upregulated, while LncRNA UCA1 was downregulated via RNA silencing, mitogen-activated protein kinase (MAPK) inhibition and in silico analyses.	('TUG1', 'Gene', '55000', (28, 32))	('TUG1', 'Gene', (28, 32))	('upregulated', 'PosReg', (38, 49))	('UCA1', 'Gene', '652995', (64, 68))	('MAPK', 'molecular_function', 'GO:0004707', ('140', '144'))	('UCA1', 'Gene', (64, 68))	('downregulated', 'NegReg', (73, 86))	('RNA silencing', 'Var', (91, 104))	('circHIPK3', 'Gene', (14, 23))	('RNA', 'cellular_component', 'GO:0005562', ('91', '94'))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))
47798	31277663	Studies have shown that circRNAs are distinctly downregulated in a KRAS mutant and can be transferred to the exosomes of colorectal cancer cell lines.	('mutant', 'Var', (72, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('downregulated', 'NegReg', (48, 61))	('KRAS', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('colorectal cancer', 'Disease', (121, 138))	('KRAS', 'Gene', '3845', (67, 71))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))
47799	31277663	Currently, exosomal circ-PDE8A was reported to be associated with tumor progression and lymphatic invasion by the miR-338/MACC1/MET pathway in pancreatic ductal adenocarcinoma.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('exosomal', 'Var', (11, 19))	('miR-338', 'Gene', (114, 121))	('MACC1', 'Gene', '346389', (122, 127))	('PDE', 'molecular_function', 'GO:0004114', ('25', '28'))	('tumor', 'Disease', (66, 71))	('MACC1', 'Gene', (122, 127))	('PDE8A', 'Gene', '5151', (25, 30))	('miR-338', 'Gene', '442906', (114, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('lymphatic invasion', 'CPA', (88, 106))	('pancreatic ductal adenocarcinoma', 'Disease', (143, 175))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (143, 175))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (143, 175))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('associated', 'Reg', (50, 60))	('PDE8A', 'Gene', (25, 30))
47815	31277663	Intriguingly, a recent study demonstrated that exosomal circRASSF2 promoted laryngeal squamous cell carcinoma (LSCC) progression.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('promoted', 'PosReg', (67, 75))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 109))	('RASSF2', 'Gene', '9770', (60, 66))	('progression', 'CPA', (117, 128))	('laryngeal squamous cell carcinoma', 'Disease', (76, 109))	('RASSF2', 'Gene', (60, 66))	('exosomal', 'Var', (47, 55))
47817	31277663	Moreover, they knockdown exosomal circ-RASSF2 remarkably inhibited cell proliferation and migration via miR-302b-3p/IGF-1R axis, indicating the significance of exosomal circRNAs in tumor cell proliferation.	('tumor', 'Disease', (181, 186))	('knockdown', 'Var', (15, 24))	('IGF-1R', 'Gene', '3480', (116, 122))	('inhibited', 'NegReg', (57, 66))	('miR', 'Gene', (104, 107))	('RASSF2', 'Gene', '9770', (39, 45))	('cell proliferation', 'biological_process', 'GO:0008283', ('187', '205'))	('IGF-1R', 'Gene', (116, 122))	('RASSF2', 'Gene', (39, 45))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('miR', 'Gene', '220972', (104, 107))	('cell proliferation', 'CPA', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
47828	31277663	For instance, Wang recently proved that exosomal circPTGR1 contributes to hepatocellular carcinoma metastasis.	('hepatocellular carcinoma metastasis', 'Disease', 'MESH:D009362', (74, 109))	('contributes', 'Reg', (59, 70))	('exosomal', 'Var', (40, 48))	('circPTGR1', 'Gene', (49, 58))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (74, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('hepatocellular carcinoma metastasis', 'Disease', (74, 109))
47829	31277663	In further, knockdown of exosomal circPTGR1 expression significantly suppressed tumor invasion and migration in non- and low-metastatic cell lines.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('knockdown', 'Var', (12, 21))	('tumor', 'Disease', (80, 85))	('suppressed', 'NegReg', (69, 79))	('exosomal circPTGR1', 'Gene', (25, 43))
47844	31277663	Epidermal growth factor receptor (EGFR), a member of the HER-ErbB family, plays a significant role in the proliferation, angiogenesis, gene mutation and drug resistance in CRC.	('gene mutation', 'Var', (135, 148))	('CRC', 'Phenotype', 'HP:0003003', (172, 175))	('drug resistance', 'biological_process', 'GO:0042493', ('153', '168'))	('EGFR', 'Gene', (34, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('0', '23'))	('drug resistance', 'CPA', (153, 168))	('drug resistance', 'Phenotype', 'HP:0020174', (153, 168))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('CRC', 'Disease', (172, 175))	('drug resistance', 'biological_process', 'GO:0009315', ('153', '168'))	('angiogenesis', 'biological_process', 'GO:0001525', ('121', '133'))	('EGFR', 'Gene', '1956', (34, 38))	('angiogenesis', 'CPA', (121, 133))
47845	31277663	KRAS is an intracellular signaling molecule, and its mutations are found in approximately 40% of colorectal tumors.	('signaling molecule', 'molecular_function', 'GO:0048018', ('25', '43'))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('colorectal tumors', 'Disease', 'MESH:D015179', (97, 114))	('found', 'Reg', (67, 72))	('mutations', 'Var', (53, 62))	('colorectal tumors', 'Disease', (97, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('intracellular', 'cellular_component', 'GO:0005622', ('11', '24'))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
47846	31277663	Therefore, the identification of the key signaling pathways impacted by the KRAS mutation is beneficial for our understanding of how to pharmacologically target therapies.	('KRAS', 'Gene', (76, 80))	('mutation', 'Var', (81, 89))	('KRAS', 'Gene', '3845', (76, 80))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('impacted', 'Reg', (60, 68))
47847	31277663	Interestingly, the abundance of circRTN4 was remarkably upregulated in the exosomes derived from DLD-1 CRC cells, which possess a KRAS mutation compared with DKs-8 cells (wild-type KRAS).	('KRAS', 'Gene', '3845', (130, 134))	('abundance', 'MPA', (19, 28))	('circRTN4', 'Gene', (32, 40))	('CRC', 'Phenotype', 'HP:0003003', (103, 106))	('KRAS', 'Gene', (130, 134))	('KRAS', 'Gene', '3845', (181, 185))	('mutation', 'Var', (135, 143))	('upregulated', 'PosReg', (56, 67))	('KRAS', 'Gene', (181, 185))
47863	30154469	In this study, we show that BAG3 knockdown significantly decreases migration and invasion of PDACs via reduction of interleukine-8 (IL-8) production.	('BAG3', 'Gene', '9531', (28, 32))	('BAG3', 'Gene', (28, 32))	('knockdown', 'Var', (33, 42))	('invasion', 'CPA', (81, 89))	('PDAC', 'Chemical', '-', (93, 97))	('migration', 'CPA', (67, 76))	('IL-8', 'molecular_function', 'GO:0005153', ('132', '136'))	('IL-8) production', 'biological_process', 'GO:0032637', ('132', '148'))	('decreases', 'NegReg', (57, 66))	('reduction', 'NegReg', (103, 112))	('PDAC', 'Phenotype', 'HP:0006725', (93, 97))
47864	30154469	BAG3 knockdown regulates IL-8 expression at the posttranscriptional levels via interplay between recruitment of RNA-binding protein HuR and miR-4312.	('BAG3', 'Gene', (0, 4))	('IL-8', 'molecular_function', 'GO:0005153', ('25', '29'))	('RNA-binding', 'molecular_function', 'GO:0003723', ('112', '123'))	('expression', 'MPA', (30, 40))	('miR-4312', 'Gene', '100422971', (140, 148))	('knockdown', 'Var', (5, 14))	('HuR', 'Gene', (132, 135))	('RNA', 'cellular_component', 'GO:0005562', ('112', '115'))	('HuR', 'Gene', '1994', (132, 135))	('interplay', 'Interaction', (79, 88))	('IL-8', 'Gene', (25, 29))	('miR-4312', 'Gene', (140, 148))	('BAG3', 'Gene', '9531', (0, 4))	('regulates', 'Reg', (15, 24))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))
47867	30154469	BAG3 knockdown decreases cytoplasmic distribution of HuR via increasing its phosphorylation at Ser202, therefore compromising its recruitment while promoting recruitment of miR-4312 containing miRISC to IL-8 transcript.	('promoting', 'PosReg', (148, 157))	('knockdown', 'Var', (5, 14))	('miR-4312', 'Gene', '100422971', (173, 181))	('HuR', 'Gene', '1994', (53, 56))	('miR', 'Gene', '220972', (193, 196))	('cytoplasmic distribution', 'MPA', (25, 49))	('BAG3', 'Gene', (0, 4))	('increasing', 'PosReg', (61, 71))	('Ser', 'cellular_component', 'GO:0005790', ('95', '98'))	('miR-4312', 'Gene', (173, 181))	('recruitment', 'MPA', (130, 141))	('miR', 'Gene', (193, 196))	('phosphorylation', 'biological_process', 'GO:0016310', ('76', '91'))	('miR', 'Gene', '220972', (173, 176))	('compromising', 'NegReg', (113, 125))	('Ser202', 'Chemical', '-', (95, 101))	('IL-8', 'molecular_function', 'GO:0005153', ('203', '207'))	('decreases', 'NegReg', (15, 24))	('recruitment', 'MPA', (158, 169))	('phosphorylation at Ser202', 'MPA', (76, 101))	('HuR', 'Gene', (53, 56))	('BAG3', 'Gene', '9531', (0, 4))	('miR', 'Gene', (173, 176))
47869	30154469	BAG3 knockdown increases phosphorylation of Ago2 at Ser387, thereby further promoting loading of miR-4312 containing miRISC to IL-8 transcript.	('Ser', 'cellular_component', 'GO:0005790', ('52', '55'))	('loading', 'MPA', (86, 93))	('knockdown', 'Var', (5, 14))	('phosphorylation', 'MPA', (25, 40))	('miR', 'Gene', (117, 120))	('BAG3', 'Gene', (0, 4))	('Ser387', 'Chemical', '-', (52, 58))	('promoting', 'PosReg', (76, 85))	('IL-8', 'molecular_function', 'GO:0005153', ('127', '131'))	('Ago2', 'Gene', (44, 48))	('miR', 'Gene', '220972', (97, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('25', '40'))	('Ago2', 'Gene', '27161', (44, 48))	('miR-4312', 'Gene', '100422971', (97, 105))	('increases', 'PosReg', (15, 24))	('miR', 'Gene', (97, 100))	('miR-4312', 'Gene', (97, 105))	('miR', 'Gene', '220972', (117, 120))	('BAG3', 'Gene', '9531', (0, 4))
47871	30154469	Our results reveal a novel pathway linking BAG3 expression to enhanced PDAC metastasis, thus making BAG3 a potential target for intervention in pancreatic cancer.	('PDAC metastasis', 'CPA', (71, 86))	('pancreatic cancer', 'Disease', (144, 161))	('BAG3', 'Gene', (100, 104))	('pancreatic cancer', 'Disease', 'MESH:D010190', (144, 161))	('PDAC', 'Phenotype', 'HP:0006725', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('enhanced', 'PosReg', (62, 70))	('BAG3', 'Gene', '9531', (43, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (144, 161))	('expression', 'Var', (48, 58))	('BAG3', 'Gene', (43, 47))	('PDAC', 'Chemical', '-', (71, 75))	('BAG3', 'Gene', '9531', (100, 104))
47886	30154469	This study demonstrated that BAG3 knockdown destabilizes IL-8 transcript by hindering cytoplasmic translocation of HuR, promoting loading of miR-4312 containing miRNA-induced silencing complex (miRISC) to destabilize IL-8 transcript.	('HuR', 'Gene', (115, 118))	('IL-8', 'Gene', (217, 221))	('miR-4312', 'Gene', '100422971', (141, 149))	('IL-8', 'molecular_function', 'GO:0005153', ('217', '221'))	('miR', 'Gene', '220972', (194, 197))	('miR-4312', 'Gene', (141, 149))	('BAG3', 'Gene', '9531', (29, 33))	('IL-8', 'Gene', (57, 61))	('destabilizes', 'NegReg', (44, 56))	('miR', 'Gene', '220972', (161, 164))	('HuR', 'Gene', '1994', (115, 118))	('transcript', 'MPA', (62, 72))	('loading', 'MPA', (130, 137))	('knockdown', 'Var', (34, 43))	('miR', 'Gene', (194, 197))	('miR', 'Gene', (161, 164))	('miR', 'Gene', '220972', (141, 144))	('BAG3', 'Gene', (29, 33))	('promoting', 'PosReg', (120, 129))	('hindering', 'NegReg', (76, 85))	('IL-8', 'molecular_function', 'GO:0005153', ('57', '61'))	('miR', 'Gene', (141, 144))	('destabilize', 'NegReg', (205, 216))
47889	30154469	A dual single guide RNA approach was used to knockdown BAG3 by CRISPR/Cas9 system as previously reported.	('BAG3', 'Gene', '9531', (55, 59))	('BAG3', 'Gene', (55, 59))	('RNA', 'cellular_component', 'GO:0005562', ('20', '23'))	('knockdown', 'Var', (45, 54))	('Cas', 'cellular_component', 'GO:0005650', ('70', '73'))
47907	30154469	Immunoblots showed that BAG3 expression was downregulated by 80-90% in BAG3 knockdown cells (Fig.	('downregulated', 'NegReg', (44, 57))	('BAG3', 'Gene', (24, 28))	('knockdown', 'Var', (76, 85))	('BAG3', 'Gene', '9531', (71, 75))	('BAG3', 'Gene', (71, 75))	('BAG3', 'Gene', '9531', (24, 28))	('expression', 'MPA', (29, 39))
47908	30154469	Downregulation of BAG3 significantly deceased migration (Fig.	('migration', 'CPA', (46, 55))	('BAG3', 'Gene', (18, 22))	('Downregulation', 'Var', (0, 14))	('deceased', 'NegReg', (37, 45))	('BAG3', 'Gene', '9531', (18, 22))
47910	30154469	Both cell migratory and invasive (Supplementary Figure 1A-B) capacity of PDACs with BAG3 knockdown were rescued by addition of conditional medium (CM) derived from control Cytokines antibody microarrays demonstrated that IL-6, IL-8, PDGF-BB release was decreased, whereas ICAM-1 release was increased in BxPC3 and SW1990 cells with BAG3 knockdown, and BAG3 knockdown also decreased secretion of TNFgamma and TNFbeta, whereas increased release of TNFalpha and TNF RII in SW1990 cells (Fig.	('IL-6', 'Gene', (221, 225))	('TNFalpha', 'Gene', (446, 454))	('release', 'MPA', (435, 442))	('ICAM-1', 'Gene', (272, 278))	('antibody', 'cellular_component', 'GO:0019814', ('182', '190'))	('BAG3', 'Gene', (352, 356))	('BAG3', 'Gene', '9531', (332, 336))	('increased', 'PosReg', (425, 434))	('knockdown', 'Var', (337, 346))	('decreased', 'NegReg', (372, 381))	('BAG3', 'Gene', '9531', (84, 88))	('antibody', 'molecular_function', 'GO:0003823', ('182', '190'))	('IL-8', 'molecular_function', 'GO:0005153', ('227', '231'))	('secretion', 'biological_process', 'GO:0046903', ('382', '391'))	('TNFbeta', 'Gene', '4049', (408, 415))	('TNF RII', 'Gene', '7133', (459, 466))	('decreased', 'NegReg', (253, 262))	('BAG3', 'Gene', (332, 336))	('SW1990', 'CellLine', 'CVCL:1723', (314, 320))	('antibody', 'cellular_component', 'GO:0042571', ('182', '190'))	('ICAM-1', 'Gene', '3383', (272, 278))	('secretion of TNFgamma', 'MPA', (382, 403))	('PDAC', 'Chemical', '-', (73, 77))	('TNFalpha', 'Gene', '7124', (446, 454))	('BAG3', 'Gene', (84, 88))	('BxPC3', 'CellLine', 'CVCL:0186', (304, 309))	('PDAC', 'Phenotype', 'HP:0006725', (73, 77))	('TNFbeta', 'Gene', (408, 415))	('knockdown', 'Var', (357, 366))	('IL-6', 'Gene', '3569', (221, 225))	('PDGF', 'molecular_function', 'GO:0005161', ('233', '237'))	('antibody', 'cellular_component', 'GO:0019815', ('182', '190'))	('BAG3', 'Gene', '9531', (352, 356))	('SW1990', 'CellLine', 'CVCL:1723', (470, 476))	('TNF RII', 'Gene', (459, 466))	('IL-6', 'molecular_function', 'GO:0005138', ('221', '225'))
47911	30154469	As IL-8 is reported to promote invasion of PDACs, neutral antibody was used to neutralizing IL-8 in culture supernatant.	('antibody', 'molecular_function', 'GO:0003823', ('58', '66'))	('promote', 'PosReg', (23, 30))	('PDAC', 'Phenotype', 'HP:0006725', (43, 47))	('IL-8', 'molecular_function', 'GO:0005153', ('3', '7'))	('neutralizing', 'Var', (79, 91))	('invasion', 'CPA', (31, 39))	('antibody', 'cellular_component', 'GO:0042571', ('58', '66'))	('IL-8', 'molecular_function', 'GO:0005153', ('92', '96'))	('IL-8', 'Gene', (3, 7))	('antibody', 'cellular_component', 'GO:0019815', ('58', '66'))	('PDAC', 'Chemical', '-', (43, 47))	('antibody', 'cellular_component', 'GO:0019814', ('58', '66'))
47913	30154469	The suppressive extent was more prominent in control BxPC3 cells than BAG3 knockdown (Fig.	('knockdown', 'Var', (75, 84))	('BAG3', 'Gene', '9531', (70, 74))	('BxPC3', 'CellLine', 'CVCL:0186', (53, 58))	('BAG3', 'Gene', (70, 74))
47916	30154469	On the contrast, migration and invasion of SW1990 cells with BAG3 knockdown was unaltered by IL-8 antibody (Fig.	('BAG3', 'Gene', (61, 65))	('antibody', 'cellular_component', 'GO:0019815', ('98', '106'))	('IL-8', 'molecular_function', 'GO:0005153', ('93', '97'))	('antibody', 'cellular_component', 'GO:0019814', ('98', '106'))	('invasion', 'CPA', (31, 39))	('antibody', 'molecular_function', 'GO:0003823', ('98', '106'))	('BAG3', 'Gene', '9531', (61, 65))	('knockdown', 'Var', (66, 75))	('antibody', 'cellular_component', 'GO:0042571', ('98', '106'))	('SW1990', 'CellLine', 'CVCL:1723', (43, 49))
47917	30154469	In addition, CM derived from parental control cells mediated promotion of migration and invasion of PDACs with BAG3 knockdown was significantly suppressed by addition of IL-8 antibody (Supplementary Figure 1C-D).	('IL-8', 'molecular_function', 'GO:0005153', ('170', '174'))	('invasion', 'CPA', (88, 96))	('BAG3', 'Gene', '9531', (111, 115))	('antibody', 'molecular_function', 'GO:0003823', ('175', '183'))	('PDAC', 'Chemical', '-', (100, 104))	('antibody', 'cellular_component', 'GO:0019814', ('175', '183'))	('BAG3', 'Gene', (111, 115))	('suppressed', 'NegReg', (144, 154))	('knockdown', 'Var', (116, 125))	('migration', 'CPA', (74, 83))	('antibody', 'cellular_component', 'GO:0042571', ('175', '183'))	('promotion', 'PosReg', (61, 70))	('PDAC', 'Phenotype', 'HP:0006725', (100, 104))	('antibody', 'cellular_component', 'GO:0019815', ('175', '183'))
47918	30154469	To investigate the possible mechanisms underlying suppression of IL-8 release by BAG3 knockdown, Using real-time PCR demonstrated that IL-8 mRNA was significantly decreased in PDACs with BAG3 knockdown (Fig.	('PDAC', 'Phenotype', 'HP:0006725', (176, 180))	('BAG3', 'Gene', (81, 85))	('BAG3', 'Gene', '9531', (187, 191))	('IL-8', 'molecular_function', 'GO:0005153', ('65', '69'))	('IL-8', 'Gene', (135, 139))	('BAG3', 'Gene', (187, 191))	('PDAC', 'Chemical', '-', (176, 180))	('IL-8', 'molecular_function', 'GO:0005153', ('135', '139'))	('mRNA', 'MPA', (140, 144))	('BAG3', 'Gene', '9531', (81, 85))	('decreased', 'NegReg', (163, 172))	('knockdown', 'Var', (192, 201))
47919	30154469	However, de novo IL-8 mRNA synthesis was unaltered by BAG3 knockdown (Fig.	('BAG3', 'Gene', '9531', (54, 58))	('IL-8', 'molecular_function', 'GO:0005153', ('17', '21'))	('BAG3', 'Gene', (54, 58))	('knockdown', 'Var', (59, 68))	('mRNA synthesis', 'biological_process', 'GO:0009299', ('22', '36'))
47920	30154469	2b), indicating that BAG3 knockdown suppressed IL-8 expression at the posttranscriptional level.	('suppressed', 'NegReg', (36, 46))	('BAG3', 'Gene', (21, 25))	('IL-8', 'Gene', (47, 51))	('expression', 'MPA', (52, 62))	('knockdown', 'Var', (26, 35))	('IL-8', 'molecular_function', 'GO:0005153', ('47', '51'))	('BAG3', 'Gene', '9531', (21, 25))
47922	30154469	Unexpectedly, short time exposure of PDACs to Actinomycin D resulted in significant increase in IL-8 mRNA levels (Fig.	('Actinomycin D', 'Chemical', 'MESH:D003609', (46, 59))	('PDAC', 'Phenotype', 'HP:0006725', (37, 41))	('Actinomycin D', 'Var', (46, 59))	('increase', 'PosReg', (84, 92))	('PDAC', 'Chemical', '-', (37, 41))	('IL-8', 'molecular_function', 'GO:0005153', ('96', '100'))	('IL-8 mRNA levels', 'MPA', (96, 112))
47924	30154469	2c-f), the remained IL-8 mRNA at 4 h relative to those at 2 h was significantly decreased in PDACs with BAG3 knockdown (Fig.	('BAG3', 'Gene', (104, 108))	('IL-8 mRNA', 'MPA', (20, 29))	('PDAC', 'Chemical', '-', (93, 97))	('knockdown', 'Var', (109, 118))	('decreased', 'NegReg', (80, 89))	('IL-8', 'molecular_function', 'GO:0005153', ('20', '24'))	('PDAC', 'Phenotype', 'HP:0006725', (93, 97))	('BAG3', 'Gene', '9531', (104, 108))
47925	30154469	BAG3 knockdown significantly decreased luciferase activity of the reporter construct containing 3'-UTR of IL-8 (Fig.	('BAG3', 'Gene', (0, 4))	('luciferase', 'Enzyme', (39, 49))	('knockdown', 'Var', (5, 14))	('luciferase activity', 'molecular_function', 'GO:0047077', ('39', '58'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('39', '58'))	('activity', 'MPA', (50, 58))	('luciferase activity', 'molecular_function', 'GO:0047712', ('39', '58'))	('IL-8', 'molecular_function', 'GO:0005153', ('106', '110'))	('decreased', 'NegReg', (29, 38))	('luciferase activity', 'molecular_function', 'GO:0050397', ('39', '58'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('39', '58'))	('BAG3', 'Gene', '9531', (0, 4))
47926	30154469	2i) mediated by BAG3 knockdown was more apparent than IL-8 mRNA (Fig.	('BAG3', 'Gene', (16, 20))	('knockdown', 'Var', (21, 30))	('BAG3', 'Gene', '9531', (16, 20))	('IL-8', 'molecular_function', 'GO:0005153', ('54', '58'))
47927	30154469	2a), indicating that BAG3 knockdown might also reduce the translational efficiency of IL-8 mRNA functioning as template.	('translational efficiency', 'MPA', (58, 82))	('BAG3', 'Gene', (21, 25))	('reduce', 'NegReg', (47, 53))	('knockdown', 'Var', (26, 35))	('IL-8', 'molecular_function', 'GO:0005153', ('86', '90'))	('BAG3', 'Gene', '9531', (21, 25))	('IL-8', 'Protein', (86, 90))
47928	30154469	RIP demonstrated that enrichment of IL-8 transcript by TTP or AUF1 was unaltered by BAG3 knockdown in PDACs (Fig.	('IL-8', 'Gene', (36, 40))	('PDAC', 'Chemical', '-', (102, 106))	('AUF1', 'Gene', '3184', (62, 66))	('BAG3', 'Gene', '9531', (84, 88))	('PDAC', 'Phenotype', 'HP:0006725', (102, 106))	('IL-8', 'molecular_function', 'GO:0005153', ('36', '40'))	('BAG3', 'Gene', (84, 88))	('AUF1', 'Gene', (62, 66))	('knockdown', 'Var', (89, 98))
47929	30154469	On the contrast, interaction of HuR with IL-8 mRNA was significantly suppressed by BAG3 knockdown (Fig.	('BAG3', 'Gene', '9531', (83, 87))	('interaction', 'Interaction', (17, 28))	('BAG3', 'Gene', (83, 87))	('HuR', 'Gene', (32, 35))	('knockdown', 'Var', (88, 97))	('HuR', 'Gene', '1994', (32, 35))	('suppressed', 'NegReg', (69, 79))	('IL-8', 'molecular_function', 'GO:0005153', ('41', '45'))
47930	30154469	Western blot demonstrated that HuR expression was unaltered by BAG3 knockdown in PDACs (Fig.	('BAG3', 'Gene', (63, 67))	('HuR', 'Gene', (31, 34))	('HuR', 'Gene', '1994', (31, 34))	('PDAC', 'Phenotype', 'HP:0006725', (81, 85))	('knockdown', 'Var', (68, 77))	('PDAC', 'Chemical', '-', (81, 85))	('BAG3', 'Gene', '9531', (63, 67))
47932	30154469	Quantitative phosphoproteomics identified that phosphorylation of HuR at Ser202 was increased by BAG3 knockdown in BxPC3 cells (supplementary Figure 2A).	('Ser202', 'Chemical', '-', (73, 79))	('HuR', 'Gene', (66, 69))	('HuR', 'Gene', '1994', (66, 69))	('BAG3', 'Gene', '9531', (97, 101))	('phosphorylation', 'MPA', (47, 62))	('BAG3', 'Gene', (97, 101))	('BxPC3', 'CellLine', 'CVCL:0186', (115, 120))	('knockdown', 'Var', (102, 111))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('Ser', 'cellular_component', 'GO:0005790', ('73', '76'))	('Ser202', 'Gene', (73, 79))	('increased', 'PosReg', (84, 93))
47933	30154469	Immunoprecipitation using antibody against pan-Ser/Thr phosphorylation confirmed that BAG3 knockdown increased HuR phosphorylation in PDACs (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('Ser', 'Chemical', 'MESH:D012694', (47, 50))	('antibody', 'cellular_component', 'GO:0019815', ('26', '34'))	('PDAC', 'Chemical', '-', (134, 138))	('BAG3', 'Gene', '9531', (86, 90))	('increased', 'PosReg', (101, 110))	('antibody', 'cellular_component', 'GO:0019814', ('26', '34'))	('antibody', 'molecular_function', 'GO:0003823', ('26', '34'))	('BAG3', 'Gene', (86, 90))	('HuR', 'Gene', '1994', (111, 114))	('knockdown', 'Var', (91, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('115', '130'))	('HuR', 'Gene', (111, 114))	('PDAC', 'Phenotype', 'HP:0006725', (134, 138))	('antibody', 'cellular_component', 'GO:0042571', ('26', '34'))	('Thr', 'Chemical', 'MESH:D013912', (51, 54))	('Ser', 'cellular_component', 'GO:0005790', ('47', '50'))
47934	30154469	It has been reported that phosphorylation of HuR at Ser202 entraps it in the nucleus.	('entraps', 'Reg', (59, 66))	('Ser', 'cellular_component', 'GO:0005790', ('52', '55'))	('HuR', 'Gene', (45, 48))	('HuR', 'Gene', '1994', (45, 48))	('nucleus', 'cellular_component', 'GO:0005634', ('77', '84'))	('phosphorylation', 'biological_process', 'GO:0016310', ('26', '41'))	('Ser202', 'Chemical', '-', (52, 58))	('Ser202', 'Var', (52, 58))	('phosphorylation', 'MPA', (26, 41))
47935	30154469	Nuclear fractionation was demonstrated that nuclear HuR was unaltered, whereas cytoplasmic HuR was significantly decreased in PDACs with BAG3 knockdown (Fig.	('PDAC', 'Chemical', '-', (126, 130))	('HuR', 'Gene', '1994', (52, 55))	('BAG3', 'Gene', '9531', (137, 141))	('HuR', 'Gene', (52, 55))	('HuR', 'Gene', '1994', (91, 94))	('PDAC', 'Phenotype', 'HP:0006725', (126, 130))	('HuR', 'Gene', (91, 94))	('BAG3', 'Gene', (137, 141))	('decreased', 'NegReg', (113, 122))	('knockdown', 'Var', (142, 151))
47936	30154469	Cytoimmunofluorescence confirmed that cytoplasmic distribution of HuR was significantly decreased in BAG3 knockdown BxPC3 and SW1990 cells (Supplementary Figure 2B-C).	('HuR', 'Gene', (66, 69))	('BAG3', 'Gene', '9531', (101, 105))	('HuR', 'Gene', '1994', (66, 69))	('SW1990', 'CellLine', 'CVCL:1723', (126, 132))	('BAG3', 'Gene', (101, 105))	('knockdown', 'Var', (106, 115))	('decreased', 'NegReg', (88, 97))	('BxPC3', 'CellLine', 'CVCL:0186', (116, 121))	('cytoplasmic distribution', 'MPA', (38, 62))
47937	30154469	To investigate the potential involvement of HuR in BAG3 knockdown-mediated destabilization of IL-8 mRNA, HuR was knockdown using lentivirus containing shRNAs (shHuR) (Fig.	('BAG3', 'Gene', (51, 55))	('IL-8', 'molecular_function', 'GO:0005153', ('94', '98'))	('HuR', 'Gene', '1994', (105, 108))	('knockdown', 'Var', (113, 122))	('HuR', 'Gene', (105, 108))	('HuR', 'Gene', (44, 47))	('HuR', 'Gene', '1994', (44, 47))	('BAG3', 'Gene', '9531', (51, 55))	('HuR', 'Gene', (161, 164))	('HuR', 'Gene', '1994', (161, 164))
47938	30154469	Real-time PCR demonstrated that downregulation of HuR reduced IL-8 mRNA expression in control, whereas had no obvious effect in BAG3 knockdown cells (Fig.	('BAG3', 'Gene', '9531', (128, 132))	('BAG3', 'Gene', (128, 132))	('reduced', 'NegReg', (54, 61))	('HuR', 'Gene', '1994', (50, 53))	('downregulation', 'Var', (32, 46))	('HuR', 'Gene', (50, 53))	('IL-8', 'molecular_function', 'GO:0005153', ('62', '66'))	('IL-8', 'Gene', (62, 66))
47939	30154469	ShHuR significantly decreased luciferase activity of construct with insertion of IL-8 3'-UTR in control, whereas no obvious effect in BAG3 knockdown cells (Fig.	('BAG3', 'Gene', (134, 138))	('decreased', 'NegReg', (20, 29))	('luciferase activity', 'molecular_function', 'GO:0050397', ('30', '49'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('30', '49'))	('luciferase', 'Enzyme', (30, 40))	('luciferase activity', 'molecular_function', 'GO:0050248', ('30', '49'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('30', '49'))	('insertion', 'Var', (68, 77))	('IL-8', 'Gene', (81, 85))	('HuR', 'Gene', (2, 5))	('HuR', 'Gene', '1994', (2, 5))	('BAG3', 'Gene', '9531', (134, 138))	('IL-8', 'molecular_function', 'GO:0005153', ('81', '85'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('30', '49'))	('activity', 'MPA', (41, 49))
47941	30154469	3i) of BxPC3 cells with BAG3 knockdown was significantly lower than control even when HuR was knockdown.	('HuR', 'Gene', (86, 89))	('BAG3', 'Gene', (24, 28))	('HuR', 'Gene', '1994', (86, 89))	('knockdown', 'Var', (29, 38))	('BxPC3', 'CellLine', 'CVCL:0186', (7, 12))	('BAG3', 'Gene', '9531', (24, 28))	('lower', 'NegReg', (57, 62))
47942	30154469	HuR was also knockdown in SW1990 cells (Supplementary Figure 3A).	('HuR', 'Gene', '1994', (0, 3))	('knockdown', 'Var', (13, 22))	('SW1990', 'CellLine', 'CVCL:1723', (26, 32))	('HuR', 'Gene', (0, 3))
47943	30154469	IL-8 mRNA was decreased by HuR knockdown in control, whereas unaltered in BAG3 knockdown SW1990 cells (Supplementary Figure 3B).	('HuR', 'Gene', (27, 30))	('HuR', 'Gene', '1994', (27, 30))	('decreased', 'NegReg', (14, 23))	('SW1990', 'CellLine', 'CVCL:1723', (89, 95))	('mRNA', 'MPA', (5, 9))	('BAG3', 'Gene', '9531', (74, 78))	('IL-8', 'Gene', (0, 4))	('BAG3', 'Gene', (74, 78))	('IL-8', 'molecular_function', 'GO:0005153', ('0', '4'))	('knockdown', 'Var', (31, 40))
47944	30154469	To further explore the potential implication of HuR phosphorylation at Ser202, BxPC3 cells were transfected with constructs containing WT, nonphosphorylatable mutant (S202A) or phosphorylation mimetic mutant (S202D) HuR (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('177', '192'))	('HuR', 'Gene', (216, 219))	('HuR', 'Gene', '1994', (216, 219))	('HuR', 'Gene', (48, 51))	('S202A', 'Var', (167, 172))	('Ser202', 'Chemical', '-', (71, 77))	('HuR', 'Gene', '1994', (48, 51))	('S202D', 'Mutation', 'p.S202D', (209, 214))	('Ser', 'cellular_component', 'GO:0005790', ('71', '74'))	('S202A', 'Mutation', 'p.S202A', (167, 172))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('S202D', 'Var', (209, 214))	('BxPC3', 'CellLine', 'CVCL:0186', (79, 84))
47945	30154469	IL-8 mRNA was increased by ectopic expression of S202A HuR, whereas unaltered by WT or S202D HuR in both control and BAG3 knockdown cells (Fig.	('increased', 'PosReg', (14, 23))	('BAG3', 'Gene', '9531', (117, 121))	('HuR', 'Gene', '1994', (55, 58))	('S202A', 'Mutation', 'p.S202A', (49, 54))	('HuR', 'Gene', '1994', (93, 96))	('HuR', 'Gene', (55, 58))	('mRNA', 'MPA', (5, 9))	('BAG3', 'Gene', (117, 121))	('HuR', 'Gene', (93, 96))	('ectopic expression', 'MPA', (27, 45))	('S202D', 'Mutation', 'p.S202D', (87, 92))	('IL-8', 'Gene', (0, 4))	('S202A', 'Var', (49, 54))	('IL-8', 'molecular_function', 'GO:0005153', ('0', '4'))
47948	30154469	S202A HuR significantly increased the luciferase activity of construct with insertion of IL-8 3'-UTR, whereas WT or S202D HuR demonstrated no effect in both control and BAG3 knockdown BxPC3 cells (Fig.	('HuR', 'Gene', '1994', (6, 9))	('S202D', 'Mutation', 'p.S202D', (116, 121))	('activity', 'MPA', (49, 57))	('luciferase activity', 'molecular_function', 'GO:0045289', ('38', '57'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('38', '57'))	('BAG3', 'Gene', (169, 173))	('luciferase', 'Enzyme', (38, 48))	('HuR', 'Gene', (122, 125))	('luciferase activity', 'molecular_function', 'GO:0050397', ('38', '57'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('38', '57'))	('IL-8', 'Gene', (89, 93))	('HuR', 'Gene', '1994', (122, 125))	('insertion', 'Var', (76, 85))	('increased', 'PosReg', (24, 33))	('HuR', 'Gene', (6, 9))	('BAG3', 'Gene', '9531', (169, 173))	('BxPC3', 'CellLine', 'CVCL:0186', (184, 189))	('IL-8', 'molecular_function', 'GO:0005153', ('89', '93'))	('S202A', 'Mutation', 'p.S202A', (0, 5))	('luciferase activity', 'molecular_function', 'GO:0047077', ('38', '57'))
47949	30154469	Consistent with IL-8 mRNA expression, BAG3 knockdown cells and control demonstrated similar luciferase activity of construct with insertion of IL-8 3'-UTR when S202A HuR was forced expressed (Fig.	('luciferase activity', 'molecular_function', 'GO:0047077', ('92', '111'))	('BAG3', 'Gene', (38, 42))	('luciferase', 'Enzyme', (92, 102))	('activity', 'MPA', (103, 111))	('IL-8', 'molecular_function', 'GO:0005153', ('143', '147'))	('insertion', 'Var', (130, 139))	('luciferase activity', 'molecular_function', 'GO:0045289', ('92', '111'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('92', '111'))	('HuR', 'Gene', (166, 169))	('IL-8', 'Gene', (143, 147))	('HuR', 'Gene', '1994', (166, 169))	('luciferase activity', 'molecular_function', 'GO:0050397', ('92', '111'))	('S202A', 'Mutation', 'p.S202A', (160, 165))	('luciferase activity', 'molecular_function', 'GO:0050248', ('92', '111'))	('BAG3', 'Gene', '9531', (38, 42))	('IL-8', 'molecular_function', 'GO:0005153', ('16', '20'))
47950	30154469	Overexpression of intact or mutant HuR unaltered the luciferase activity of control reporter construct (data not shown).	('mutant', 'Var', (28, 34))	('HuR', 'Gene', '1994', (35, 38))	('luciferase', 'Enzyme', (53, 63))	('luciferase activity', 'molecular_function', 'GO:0045289', ('53', '72'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('53', '72'))	('HuR', 'Gene', (35, 38))	('luciferase activity', 'molecular_function', 'GO:0050248', ('53', '72'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('53', '72'))	('activity', 'MPA', (64, 72))	('luciferase activity', 'molecular_function', 'GO:0047077', ('53', '72'))
47952	30154469	3i), compared with control, whereas in the presence of S202A HuR, BAG3 knockdown cells and control expressed comparable IL-8 mRNA (Fig.	('IL-8', 'molecular_function', 'GO:0005153', ('120', '124'))	('S202A', 'Mutation', 'p.S202A', (55, 60))	('BAG3', 'Gene', (66, 70))	('HuR', 'Gene', '1994', (61, 64))	('S202A', 'Var', (55, 60))	('IL-8 mRNA', 'MPA', (120, 129))	('HuR', 'Gene', (61, 64))	('BAG3', 'Gene', '9531', (66, 70))
47953	30154469	These data indicated that additional factor(s) might be responsible for suppression of IL-8 by BAG3 knockdown.	('knockdown', 'Var', (100, 109))	('suppression', 'NegReg', (72, 83))	('IL-8', 'molecular_function', 'GO:0005153', ('87', '91'))	('BAG3', 'Gene', '9531', (95, 99))	('IL-8', 'Gene', (87, 91))	('BAG3', 'Gene', (95, 99))
47957	30154469	Importantly, recruitment of Ago2 to IL-8 transcript was significantly enhanced by BAG3 knockdown (Fig.	('IL-8', 'Gene', (36, 40))	('Ago2', 'Gene', (28, 32))	('BAG3', 'Gene', '9531', (82, 86))	('IL-8', 'molecular_function', 'GO:0005153', ('36', '40'))	('enhanced', 'PosReg', (70, 78))	('recruitment', 'MPA', (13, 24))	('Ago2', 'Gene', '27161', (28, 32))	('BAG3', 'Gene', (82, 86))	('knockdown', 'Var', (87, 96))
47958	30154469	Western blot demonstrated that BAG3 knockdown unaltered Ago2 expression (Fig.	('Ago2', 'Gene', '27161', (56, 60))	('BAG3', 'Gene', '9531', (31, 35))	('BAG3', 'Gene', (31, 35))	('knockdown', 'Var', (36, 45))	('Ago2', 'Gene', (56, 60))
47960	30154469	Real-time PCR demonstrated that knockdown of Ago2 increased IL-8 mRNA in both control and BAG3 knockdown cells (Fig.	('BAG3', 'Gene', '9531', (90, 94))	('IL-8', 'molecular_function', 'GO:0005153', ('60', '64'))	('Ago2', 'Gene', (45, 49))	('IL-8', 'Gene', (60, 64))	('knockdown', 'Var', (32, 41))	('increased', 'PosReg', (50, 59))	('BAG3', 'Gene', (90, 94))	('Ago2', 'Gene', '27161', (45, 49))
47961	30154469	The degree of IL-8 mRNA upregulation was more apparent in BAG3 knockdown cells (Fig.	('BAG3', 'Gene', '9531', (58, 62))	('BAG3', 'Gene', (58, 62))	('mRNA', 'MPA', (19, 23))	('IL-8', 'Gene', (14, 18))	('knockdown', 'Var', (63, 72))	('IL-8', 'molecular_function', 'GO:0005153', ('14', '18'))	('upregulation', 'PosReg', (24, 36))
47964	30154469	BAG3 knockdown decreased IL-8 mRNA (Fig.	('BAG3', 'Gene', (0, 4))	('IL-8', 'molecular_function', 'GO:0005153', ('25', '29'))	('knockdown', 'Var', (5, 14))	('decreased', 'NegReg', (15, 24))	('BAG3', 'Gene', '9531', (0, 4))
47969	30154469	When Ago2 was forced expressed, BAG3 knockdown still decreased IL-8 mRNA (Fig.	('IL-8 mRNA', 'MPA', (63, 72))	('BAG3', 'Gene', '9531', (32, 36))	('knockdown', 'Var', (37, 46))	('Ago2', 'Gene', '27161', (5, 9))	('BAG3', 'Gene', (32, 36))	('Ago2', 'Gene', (5, 9))	('decreased', 'NegReg', (53, 62))	('IL-8', 'molecular_function', 'GO:0005153', ('63', '67'))
47972	30154469	RIP demonstrated that knockdown of Ago2 had no obvious effect on loading of HuR on IL-8 mRNA in control, whereas significantly increased recruitment of HuR to the IL-8 mRNA in BAG3 knockdown BxPC3 cells (Fig.	('IL-8', 'molecular_function', 'GO:0005153', ('83', '87'))	('BAG3', 'Gene', '9531', (176, 180))	('Ago2', 'Gene', '27161', (35, 39))	('loading', 'MPA', (65, 72))	('HuR', 'Gene', (76, 79))	('BAG3', 'Gene', (176, 180))	('HuR', 'Gene', (152, 155))	('knockdown', 'Var', (22, 31))	('Ago2', 'Gene', (35, 39))	('HuR', 'Gene', '1994', (76, 79))	('HuR', 'Gene', '1994', (152, 155))	('BxPC3', 'CellLine', 'CVCL:0186', (191, 196))	('recruitment', 'MPA', (137, 148))	('increased', 'PosReg', (127, 136))	('IL-8', 'molecular_function', 'GO:0005153', ('163', '167'))
47973	30154469	It should be noted that even when Ago2 was downregulated, less HuR was recruited to the IL-8 mRNA in cells with BAG3 knockdown (Fig.	('HuR', 'Gene', '1994', (63, 66))	('Ago2', 'Gene', (34, 38))	('HuR', 'Gene', (63, 66))	('IL-8', 'molecular_function', 'GO:0005153', ('88', '92'))	('BAG3', 'Gene', '9531', (112, 116))	('BAG3', 'Gene', (112, 116))	('Ago2', 'Gene', '27161', (34, 38))	('knockdown', 'Var', (117, 126))
47977	30154469	RIP demonstrated that knockdown of HuR significantly promoted recruitment of Ago2 to the IL-8 transcript in control, whereas unaltered in BAG3 knockdown BxPC3 cells (Fig.	('promoted', 'PosReg', (53, 61))	('HuR', 'Gene', '1994', (35, 38))	('HuR', 'Gene', (35, 38))	('BAG3', 'Gene', (138, 142))	('IL-8', 'molecular_function', 'GO:0005153', ('89', '93'))	('knockdown', 'Var', (22, 31))	('BxPC3', 'CellLine', 'CVCL:0186', (153, 158))	('Ago2', 'Gene', '27161', (77, 81))	('recruitment', 'MPA', (62, 73))	('Ago2', 'Gene', (77, 81))	('BAG3', 'Gene', '9531', (138, 142))
47979	30154469	Downregulation of HuR unaltered Ago2 expression (Supplementary Figure 4D), whereas significantly increased its recruitment to IL-8 mRNA in control, and knockdown HuR unaltered recruitment of Ago2 in BAG3 knockdown SW1990 cells (Supplementary Figure 4E).	('knockdown', 'Var', (152, 161))	('BAG3', 'Gene', (199, 203))	('increased', 'PosReg', (97, 106))	('Ago2', 'Gene', '27161', (191, 195))	('HuR', 'Gene', (18, 21))	('Downregulation', 'NegReg', (0, 14))	('HuR', 'Gene', '1994', (18, 21))	('Ago2', 'Gene', '27161', (32, 36))	('HuR', 'Gene', (162, 165))	('HuR', 'Gene', '1994', (162, 165))	('Ago2', 'Gene', (191, 195))	('IL-8', 'molecular_function', 'GO:0005153', ('126', '130'))	('recruitment to IL-8 mRNA', 'MPA', (111, 135))	('Ago2', 'Gene', (32, 36))	('expression', 'MPA', (37, 47))	('SW1990', 'CellLine', 'CVCL:1723', (214, 220))	('BAG3', 'Gene', '9531', (199, 203))
47980	30154469	To further confirm the interplay between miRISC complex and HuR, HuR was overexpressed in control and BxPC3 with BAG3 knockdown cells and western blot demonstrated that neither intact nor mutant HuR altered Ago2 expression (Fig.	('HuR', 'Gene', '1994', (195, 198))	('altered', 'Reg', (199, 206))	('Ago2', 'Gene', '27161', (207, 211))	('HuR', 'Gene', (195, 198))	('HuR', 'Gene', (65, 68))	('HuR', 'Gene', '1994', (65, 68))	('BAG3', 'Gene', '9531', (113, 117))	('miR', 'Gene', '220972', (41, 44))	('miR', 'Gene', (41, 44))	('HuR', 'Gene', (60, 63))	('Ago2', 'Gene', (207, 211))	('BAG3', 'Gene', (113, 117))	('BxPC3', 'CellLine', 'CVCL:0186', (102, 107))	('HuR', 'Gene', '1994', (60, 63))	('mutant', 'Var', (188, 194))
47981	30154469	RIP demonstrated that ectopic expression of either intact or mutant HuR unaltered the recruitment of Ago2 to the IL-8 mRNA in control BxPC3 cells (Fig.	('Ago2', 'Gene', '27161', (101, 105))	('Ago2', 'Gene', (101, 105))	('unaltered', 'NegReg', (72, 81))	('mutant', 'Var', (61, 67))	('BxPC3', 'CellLine', 'CVCL:0186', (134, 139))	('IL-8', 'molecular_function', 'GO:0005153', ('113', '117'))	('HuR', 'Gene', (68, 71))	('HuR', 'Gene', '1994', (68, 71))
47982	30154469	S202A mutant HuR significantly suppressed Ago2 loading on the IL-8 mRNA, whereas Ago2 recruitment was unaltered by WT or S202D mutant HuR in BAG3 knockdown BxPC3 cells (Fig.	('Ago2', 'Gene', (81, 85))	('HuR', 'Gene', '1994', (134, 137))	('BAG3', 'Gene', '9531', (141, 145))	('S202D', 'Var', (121, 126))	('S202A', 'Var', (0, 5))	('BAG3', 'Gene', (141, 145))	('Ago2', 'Gene', (42, 46))	('HuR', 'Gene', '1994', (13, 16))	('S202D', 'Mutation', 'p.S202D', (121, 126))	('BxPC3', 'CellLine', 'CVCL:0186', (156, 161))	('Ago2', 'Gene', '27161', (81, 85))	('suppressed', 'NegReg', (31, 41))	('IL-8', 'molecular_function', 'GO:0005153', ('62', '66'))	('Ago2', 'Gene', '27161', (42, 46))	('HuR', 'Gene', (13, 16))	('S202A', 'Mutation', 'p.S202A', (0, 5))	('HuR', 'Gene', (134, 137))
47984	30154469	Quantitative phosphoproteomics identified that phosphorylation of Ago2 at Ser387 was also increased by BAG3 knockdown in BxPC3 cells (Supplementary Figure 4F).	('BAG3', 'Gene', '9531', (103, 107))	('knockdown', 'Var', (108, 117))	('BAG3', 'Gene', (103, 107))	('increased', 'PosReg', (90, 99))	('phosphorylation', 'MPA', (47, 62))	('Ago2', 'Gene', (66, 70))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('BxPC3', 'CellLine', 'CVCL:0186', (121, 126))	('Ser', 'cellular_component', 'GO:0005790', ('74', '77'))	('Ser387', 'Var', (74, 80))	('Ser387', 'Chemical', '-', (74, 80))	('Ago2', 'Gene', '27161', (66, 70))
47985	30154469	Immunoprecipitation using an antibody against pan-Ser/Thr phosphorylation confirmed that BAG3 knockdown increased Ago2 phosphorylation in PDACs (Fig.	('BAG3', 'Gene', (89, 93))	('knockdown', 'Var', (94, 103))	('antibody', 'cellular_component', 'GO:0042571', ('29', '37'))	('Thr', 'Chemical', 'MESH:D013912', (54, 57))	('Ago2', 'Gene', '27161', (114, 118))	('increased', 'PosReg', (104, 113))	('antibody', 'cellular_component', 'GO:0019815', ('29', '37'))	('PDAC', 'Chemical', '-', (138, 142))	('antibody', 'cellular_component', 'GO:0019814', ('29', '37'))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('Ser', 'Chemical', 'MESH:D012694', (50, 53))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('antibody', 'molecular_function', 'GO:0003823', ('29', '37'))	('Ago2', 'Gene', (114, 118))	('Ser', 'cellular_component', 'GO:0005790', ('50', '53'))	('BAG3', 'Gene', '9531', (89, 93))	('PDAC', 'Phenotype', 'HP:0006725', (138, 142))
47986	30154469	BxPC3 cells were transfected with constructs containing WT, nonphosphorylatable mutant (S387A) or phosphorylation mimetic mutant (S387D) Ago2 (Fig.	('S387D', 'Var', (130, 135))	('Ago2', 'Gene', (137, 141))	('phosphorylation', 'biological_process', 'GO:0016310', ('98', '113'))	('S387A', 'Var', (88, 93))	('S387D', 'Mutation', 'p.S387D', (130, 135))	('Ago2', 'Gene', '27161', (137, 141))	('S387A', 'Mutation', 'p.S387A', (88, 93))	('BxPC3', 'CellLine', 'CVCL:0186', (0, 5))
47987	30154469	Total HuR expression or cytoplasmic distribution was unaltered by intact or mutant Ago2 in both control and BAG3 knockdown cells (Fig.	('Ago2', 'Gene', '27161', (83, 87))	('HuR', 'Gene', '1994', (6, 9))	('BAG3', 'Gene', '9531', (108, 112))	('HuR', 'Gene', (6, 9))	('Ago2', 'Gene', (83, 87))	('mutant', 'Var', (76, 82))	('BAG3', 'Gene', (108, 112))
47988	30154469	RIP demonstrated that WT and S387D Ago2 expression significantly decreased recruitment of HuR to the IL-8 mRNA, whereas S387A Ago2 had no effect in control BxPC3 cells (Fig.	('S387D', 'Mutation', 'p.S387D', (29, 34))	('Ago2', 'Gene', '27161', (35, 39))	('HuR', 'Gene', (90, 93))	('decreased', 'NegReg', (65, 74))	('Ago2', 'Gene', (126, 130))	('HuR', 'Gene', '1994', (90, 93))	('S387A', 'Var', (120, 125))	('Ago2', 'Gene', (35, 39))	('S387A', 'Mutation', 'p.S387A', (120, 125))	('IL-8', 'molecular_function', 'GO:0005153', ('101', '105'))	('Ago2', 'Gene', '27161', (126, 130))	('BxPC3', 'CellLine', 'CVCL:0186', (156, 161))	('S387D', 'Var', (29, 34))
47989	30154469	WT or mutant Ago2 unaltered the recruitment of HuR to the IL-8 mRNA obviously in cells with BAG3 knockdown (Fig.	('mutant', 'Var', (6, 12))	('recruitment', 'MPA', (32, 43))	('IL-8', 'molecular_function', 'GO:0005153', ('58', '62'))	('BAG3', 'Gene', '9531', (92, 96))	('Ago2', 'Gene', '27161', (13, 17))	('HuR', 'Gene', '1994', (47, 50))	('BAG3', 'Gene', (92, 96))	('Ago2', 'Gene', (13, 17))	('HuR', 'Gene', (47, 50))
47990	30154469	S387D Ago2 demonstrated more potent suppressive effect on HuR recruitment compared with WT (Fig.	('Ago2', 'Gene', (6, 10))	('S387D', 'Var', (0, 5))	('suppressive', 'NegReg', (36, 47))	('S387D', 'Mutation', 'p.S387D', (0, 5))	('Ago2', 'Gene', '27161', (6, 10))	('HuR', 'Gene', (58, 61))	('HuR', 'Gene', '1994', (58, 61))
47991	30154469	RIP using Flag antibody demonstrated more S387D Ago2 was recruited to the IL-8 transcript than WT Ago2, whereas no S387A Ago2 (Fig.	('Ago2', 'Gene', (98, 102))	('Ago2', 'Gene', '27161', (121, 125))	('IL-8', 'Gene', (74, 78))	('antibody', 'cellular_component', 'GO:0042571', ('15', '23'))	('S387D', 'Var', (42, 47))	('S387A', 'Mutation', 'p.S387A', (115, 120))	('Ago2', 'Gene', (48, 52))	('Ago2', 'Gene', (121, 125))	('Ago2', 'Gene', '27161', (98, 102))	('IL-8', 'molecular_function', 'GO:0005153', ('74', '78'))	('S387D', 'Mutation', 'p.S387D', (42, 47))	('antibody', 'cellular_component', 'GO:0019815', ('15', '23'))	('antibody', 'cellular_component', 'GO:0019814', ('15', '23'))	('antibody', 'molecular_function', 'GO:0003823', ('15', '23'))	('Ago2', 'Gene', '27161', (48, 52))	('recruited', 'MPA', (57, 66))
47993	30154469	BAG3 knockdown cells demonstrated more WT Ago2 recruitment, whereas similar extent of S387D Ago2 recruitment was observed to control, when HuR was downregulated (Fig.	('BAG3', 'Gene', (0, 4))	('downregulated', 'NegReg', (147, 160))	('Ago2', 'Gene', (42, 46))	('S387D', 'Var', (86, 91))	('Ago2', 'Gene', '27161', (92, 96))	('HuR', 'Gene', '1994', (139, 142))	('S387D', 'Mutation', 'p.S387D', (86, 91))	('HuR', 'Gene', (139, 142))	('Ago2', 'Gene', (92, 96))	('BAG3', 'Gene', '9531', (0, 4))	('Ago2', 'Gene', '27161', (42, 46))
47994	30154469	To further investigate the involvement of phosphorylation of HuR and Ago2 in downregulation of IL-8 mediated by BAG3 knockdown, luciferase activity assays were performed in BxPC3 cells infected with shAgo2 and S202A HuR alone or in combination.	('HuR', 'Gene', '1994', (61, 64))	('BAG3', 'Gene', (112, 116))	('downregulation', 'NegReg', (77, 91))	('HuR', 'Gene', (216, 219))	('Ago2', 'Gene', (69, 73))	('BxPC3', 'CellLine', 'CVCL:0186', (173, 178))	('luciferase activity', 'molecular_function', 'GO:0047077', ('128', '147'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('128', '147'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('128', '147'))	('Ago2', 'Gene', '27161', (69, 73))	('HuR', 'Gene', '1994', (216, 219))	('IL-8', 'Gene', (95, 99))	('Ago2', 'Gene', (201, 205))	('S202A', 'Var', (210, 215))	('luciferase activity', 'molecular_function', 'GO:0050397', ('128', '147'))	('IL-8', 'molecular_function', 'GO:0005153', ('95', '99'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('128', '147'))	('Ago2', 'Gene', '27161', (201, 205))	('S202A', 'Mutation', 'p.S202A', (210, 215))	('BAG3', 'Gene', '9531', (112, 116))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('HuR', 'Gene', (61, 64))
47997	30154469	In addition, combination of HuR knockdown and S387D Ago2 significantly decreased the luciferase activity in control BxPC3 cells, when compared with Ago2 knockdown or S387D Ago2 alone (Fig.	('activity', 'MPA', (96, 104))	('luciferase activity', 'molecular_function', 'GO:0045289', ('85', '104'))	('HuR', 'Gene', (28, 31))	('luciferase activity', 'molecular_function', 'GO:0047712', ('85', '104'))	('HuR', 'Gene', '1994', (28, 31))	('luciferase activity', 'molecular_function', 'GO:0050248', ('85', '104'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('85', '104'))	('Ago2', 'Gene', (148, 152))	('luciferase', 'Enzyme', (85, 95))	('S387D', 'Var', (46, 51))	('BxPC3', 'CellLine', 'CVCL:0186', (116, 121))	('decreased', 'NegReg', (71, 80))	('Ago2', 'Gene', '27161', (148, 152))	('Ago2', 'Gene', (52, 56))	('Ago2', 'Gene', (172, 176))	('Ago2', 'Gene', '27161', (52, 56))	('Ago2', 'Gene', '27161', (172, 176))	('luciferase activity', 'molecular_function', 'GO:0047077', ('85', '104'))	('S387D', 'Mutation', 'p.S387D', (46, 51))	('S387D', 'Mutation', 'p.S387D', (166, 171))
47998	30154469	It should be noted that combination of HuR knockdown and S387D Ago2 resulted in similar extent of reduction to BAG3 knockdown (Fig.	('BAG3', 'Gene', '9531', (111, 115))	('S387D', 'Mutation', 'p.S387D', (57, 62))	('Ago2', 'Gene', (63, 67))	('BAG3', 'Gene', (111, 115))	('knockdown', 'Var', (43, 52))	('Ago2', 'Gene', '27161', (63, 67))	('HuR', 'Gene', (39, 42))	('HuR', 'Gene', '1994', (39, 42))	('S387D', 'Var', (57, 62))
48001	30154469	To evaluate the potential contribution of the miR-4312 or miR-4436b-5p-binding site in the 3'-UTR of IL-8 mRNA, intact or mutant IL-8 3'-UTR was inserted into a luciferase reporter vector just after the stop codon of Luciferase gene.	('miR', 'Gene', (46, 49))	('miR-4312', 'Gene', (46, 54))	('IL-8', 'Gene', (129, 133))	('IL-8', 'molecular_function', 'GO:0005153', ('129', '133'))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('miR-4312', 'Gene', '100422971', (46, 54))	('5p', 'Chemical', '-', (68, 70))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))	('IL-8', 'molecular_function', 'GO:0005153', ('101', '105'))	('mutant', 'Var', (122, 128))	('IL-8', 'Gene', (101, 105))	('miR', 'Gene', '220972', (46, 49))
48002	30154469	Mutation of miR-4436b-5p potential binding site increased, whereas mutation of miR-4312 potential binding site unaltered in BxPC3 cells (Fig.	('increased', 'PosReg', (48, 57))	('miR-4312', 'Gene', (79, 87))	('miR-4312', 'Gene', '100422971', (79, 87))	('5p', 'Chemical', '-', (22, 24))	('Mutation', 'Var', (0, 8))	('BxPC3', 'CellLine', 'CVCL:0186', (124, 129))	('miR', 'Gene', '220972', (79, 82))	('binding', 'molecular_function', 'GO:0005488', ('98', '105'))	('miR', 'Gene', (79, 82))	('binding', 'molecular_function', 'GO:0005488', ('35', '42'))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', (12, 15))
48004	30154469	On the contrast, miR-4436b-5p antagomir significantly increased the reporter activity fused to intact or miR-4312-binding site mutant IL-8 3'-UTR, whereas no obvious effect on the reporter activity fused to its potential binding site mutant IL-8 3'-UTR in BxPC3 cells (Fig.	('mutant', 'Var', (127, 133))	('miR', 'Gene', (105, 108))	('binding', 'molecular_function', 'GO:0005488', ('221', '228'))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('binding', 'molecular_function', 'GO:0005488', ('114', '121'))	('IL-8', 'Gene', (134, 138))	('miR-4312', 'Gene', (105, 113))	('increased', 'PosReg', (54, 63))	('reporter activity', 'MPA', (68, 85))	('IL-8', 'molecular_function', 'GO:0005153', ('241', '245'))	('IL-8', 'molecular_function', 'GO:0005153', ('134', '138'))	('miR-4312', 'Gene', '100422971', (105, 113))	('BxPC3', 'CellLine', 'CVCL:0186', (256, 261))	('5p', 'Chemical', '-', (27, 29))	('miR', 'Gene', '220972', (105, 108))
48007	30154469	BAG3 knockdown significantly decreased luciferase activity of reporter construct containing intact IL-8 3'-UTR, which was partly compromised by mutation of miR-4312 or miR-4436b-5p potential binding sites (Fig.	('luciferase', 'Enzyme', (39, 49))	('miR-4312', 'Gene', '100422971', (156, 164))	('miR', 'Gene', (156, 159))	('BAG3', 'Gene', (0, 4))	('IL-8', 'molecular_function', 'GO:0005153', ('99', '103'))	('miR-4312', 'Gene', (156, 164))	('binding', 'molecular_function', 'GO:0005488', ('191', '198'))	('miR', 'Gene', '220972', (168, 171))	('5p', 'Chemical', '-', (178, 180))	('luciferase activity', 'molecular_function', 'GO:0047077', ('39', '58'))	('miR', 'Gene', (168, 171))	('mutation', 'Var', (144, 152))	('luciferase activity', 'molecular_function', 'GO:0045289', ('39', '58'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('39', '58'))	('decreased', 'NegReg', (29, 38))	('binding', 'Interaction', (191, 198))	('miR', 'Gene', '220972', (156, 159))	('activity', 'MPA', (50, 58))	('luciferase activity', 'molecular_function', 'GO:0050397', ('39', '58'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('39', '58'))	('BAG3', 'Gene', '9531', (0, 4))
48008	30154469	Compared with reporter construct containing intact IL-8 3'-UTR, mutation of miR-4312-binding site unaltered the luciferase activity in control, whereas it demonstrated stronger promotive effect than that of miR-4436b-5p-binding site in BAG3 knockdown BXPC3 cells (Fig.	('binding', 'molecular_function', 'GO:0005488', ('220', '227'))	('miR', 'Gene', '220972', (76, 79))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('stronger', 'PosReg', (168, 176))	('BAG3', 'Gene', '9531', (236, 240))	('miR-4312', 'Gene', '100422971', (76, 84))	('BXPC3', 'CellLine', 'CVCL:0186', (251, 256))	('5p', 'Chemical', '-', (217, 219))	('miR', 'Gene', (76, 79))	('miR', 'Gene', '220972', (207, 210))	('mutation', 'Var', (64, 72))	('miR-4312', 'Gene', (76, 84))	('luciferase activity', 'molecular_function', 'GO:0047077', ('112', '131'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('112', '131'))	('BAG3', 'Gene', (236, 240))	('activity', 'MPA', (123, 131))	('luciferase activity', 'molecular_function', 'GO:0047712', ('112', '131'))	('miR', 'Gene', (207, 210))	('luciferase', 'Enzyme', (112, 122))	('luciferase activity', 'molecular_function', 'GO:0050397', ('112', '131'))	('promotive effect', 'MPA', (177, 193))	('luciferase activity', 'molecular_function', 'GO:0050248', ('112', '131'))	('IL-8', 'molecular_function', 'GO:0005153', ('51', '55'))
48012	30154469	6g) expression was altered by BAG3 knockdown in PDACs.	('knockdown', 'Var', (35, 44))	('PDAC', 'Chemical', '-', (48, 52))	('expression', 'MPA', (4, 14))	('BAG3', 'Gene', '9531', (30, 34))	('altered', 'Reg', (19, 26))	('PDAC', 'Phenotype', 'HP:0006725', (48, 52))	('BAG3', 'Gene', (30, 34))
48013	30154469	RIP demonstrated that BAG3 knockdown unaltered miR-4312 (Fig.	('knockdown', 'Var', (27, 36))	('miR-4312', 'Gene', '100422971', (47, 55))	('BAG3', 'Gene', '9531', (22, 26))	('miR-4312', 'Gene', (47, 55))	('BAG3', 'Gene', (22, 26))
48027	30154469	Clinical studies have shown a high IL-8 expression correlates with an enhanced metastatic potential and overall poor prognosis in pancreatic cancers.	('expression', 'MPA', (40, 50))	('metastatic potential', 'CPA', (79, 99))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('pancreatic cancers', 'Disease', 'MESH:D010190', (130, 148))	('pancreatic cancers', 'Disease', (130, 148))	('high', 'Var', (30, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (130, 147))	('enhanced', 'PosReg', (70, 78))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('IL-8', 'molecular_function', 'GO:0005153', ('35', '39'))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (130, 148))	('IL-8', 'Gene', (35, 39))
48038	30154469	The current study demonstrated that BAG3 knockdown trapped HuR in the nucleus via increasing its phosphorylation at Ser202, thereby prohibiting its enrichment to IL-8 transcript.	('HuR', 'Gene', '1994', (59, 62))	('HuR', 'Gene', (59, 62))	('BAG3', 'Gene', '9531', (36, 40))	('Ser202', 'Chemical', '-', (116, 122))	('phosphorylation at Ser202', 'MPA', (97, 122))	('increasing', 'PosReg', (82, 92))	('nucleus', 'cellular_component', 'GO:0005634', ('70', '77'))	('BAG3', 'Gene', (36, 40))	('IL-8', 'molecular_function', 'GO:0005153', ('162', '166'))	('prohibiting', 'NegReg', (132, 143))	('enrichment', 'MPA', (148, 158))	('knockdown', 'Var', (41, 50))	('Ser', 'cellular_component', 'GO:0005790', ('116', '119'))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))
48122	29856804	The results clearly showed a marked increase in AG and AGG concentration after GBS-01 intake, but no increase in lactate concentration was observed (S2 Fig).	('GBS-01', 'Gene', (79, 85))	('increase', 'PosReg', (36, 44))	('GBS-01', 'Chemical', '-', (79, 85))	('lactate', 'Chemical', 'MESH:D019344', (113, 120))	('AGG', 'Protein', (55, 58))	('intake', 'Var', (86, 92))
48231	27034160	Furthermore, knockdown of UNC5b expression in both MiaPaCa II and AsPC-1 cells by RNAi abrogated the observed down-regulation of integrin beta4 following treatment with the recombinant netrin-1 protein (Figure 5E-5F; Supplementary Figure S4B-S4C).	('RNAi', 'biological_process', 'GO:0016246', ('82', '86'))	('AsPC-1', 'CellLine', 'CVCL:0152', (66, 72))	('down-regulation', 'NegReg', (110, 125))	('regulation', 'biological_process', 'GO:0065007', ('115', '125'))	('UNC5b', 'Gene', (26, 31))	('integrin beta4', 'Protein', (129, 143))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('knockdown', 'Var', (13, 22))	('abrogated', 'NegReg', (87, 96))	('MiaPaCa II', 'CellLine', 'CVCL:0428', (51, 61))
48251	27034160	NO is a signaling molecule that is downstream of netrin-1 and was reported to augment PP2A phosphatase activity via nitrification of the enzyme at Tyr284.	('augment', 'PosReg', (78, 85))	('PP2A', 'Gene', (86, 90))	('Tyr284', 'Var', (147, 153))	('PP2A', 'Gene', '19052', (86, 90))	('activity', 'MPA', (103, 111))	('nitrification', 'MPA', (116, 129))	('Tyr284', 'Chemical', '-', (147, 153))	('signaling', 'biological_process', 'GO:0023052', ('8', '17'))	('signaling molecule', 'molecular_function', 'GO:0048018', ('8', '26'))	('phosphatase activity', 'molecular_function', 'GO:0016791', ('91', '111'))
48253	27034160	The FAK inhibitor PF-562271 abrogated the netrin-1-induced NO production (Figure 6F).	('PF-562271', 'Chemical', '-', (18, 27))	('FAK', 'Gene', '14083', (4, 7))	('PF-562271', 'Var', (18, 27))	('FAK', 'Gene', (4, 7))	('FAK', 'molecular_function', 'GO:0004717', ('4', '7'))	('NO production', 'MPA', (59, 72))	('abrogated', 'NegReg', (28, 37))
48271	27034160	Previous studies reported that netrin-1 promotes the adhesion, survival and invasion of PDAC cells and that netrin-1 is associated with a worse prognosis of PDAC patients.	('netrin-1', 'Gene', (31, 39))	('associated', 'Reg', (120, 130))	('patients', 'Species', '9606', (162, 170))	('PDAC', 'Phenotype', 'HP:0006725', (88, 92))	('survival', 'CPA', (63, 71))	('PDAC', 'Disease', (157, 161))	('PDAC', 'Phenotype', 'HP:0006725', (157, 161))	('adhesion', 'CPA', (53, 61))	('netrin-1', 'Var', (108, 116))	('PDAC', 'Chemical', '-', (88, 92))	('PDAC', 'Chemical', '-', (157, 161))	('invasion', 'CPA', (76, 84))	('promotes', 'PosReg', (40, 48))
48282	27034160	In the present study, we detected significant FAK phosphorylation that was abolished by UNC5b knockdown in netrin-1-stimulated PDAC cells, suggesting that UNC5b also regulates FAK activity.	('FAK', 'Gene', (46, 49))	('knockdown', 'Var', (94, 103))	('UNC5b', 'Gene', (88, 93))	('PDAC', 'Phenotype', 'HP:0006725', (127, 131))	('FAK', 'Gene', '14083', (46, 49))	('phosphorylation', 'biological_process', 'GO:0016310', ('50', '65'))	('FAK', 'molecular_function', 'GO:0004717', ('46', '49'))	('FAK', 'molecular_function', 'GO:0004717', ('176', '179'))	('regulates', 'Reg', (166, 175))	('PDAC', 'Chemical', '-', (127, 131))	('FAK', 'Gene', '14083', (176, 179))	('abolished', 'NegReg', (75, 84))	('FAK', 'Gene', (176, 179))
48310	27034160	The RNAi retroviral vector for integrin beta4 and UNC5b was constructed by inserting ITGB4 (NM_001005731.1) and UNC5B (NM_001244889.1) interfering sequence (Supplementary Table S1) into the pSIREN-Retro Q vector (631526, Clontech Inc.).	('NM_001244889.1', 'Var', (119, 133))	('NM_001005731.1', 'Var', (92, 106))	('UNC5B', 'Gene', (112, 117))	('RNAi', 'biological_process', 'GO:0016246', ('4', '8'))	('ITGB4', 'Gene', (85, 90))	('UNC5B', 'Gene', '107449', (112, 117))	('ITGB4', 'Gene', '192897', (85, 90))
48343	27034160	The anti-integrin beta4 (#4707), anti-GAPDH (#5174), anti-FAK (#3285), anti-phospho-FAK (#3283), anti-MEK1/2 (#9122), anti-phospho-MEK1/2 (S217/221, #9121), anti-ERK1/2 (#4695), anti-phospho-ERK1/2 (T202/Y204, #4370), anti-c-Jun (#9165), anti-phospho-c-Jun (S73, #3270), anti-phospho-P55 (Y199, #4228), anti-P55 (#11889), anti-phospho-Akt (T308, #13038), anti-Akt (#9272) and anti-Nitro-Tyrosine (#9691) antibodies used in the other western blot assays were purchased from Cell Signaling Technology.	('#9272', 'Var', (365, 370))	('FAK', 'Gene', (84, 87))	('MEK1/2', 'Gene', '26395;26396', (131, 137))	('ERK1/2', 'Gene', (162, 168))	('S73', 'Var', (258, 261))	('FAK', 'Gene', (58, 61))	('c-Jun', 'Gene', '16476', (251, 256))	('T308', 'Var', (340, 344))	('ERK1', 'molecular_function', 'GO:0004707', ('162', '166'))	('MEK1/2', 'Gene', (102, 108))	('c-Jun', 'Gene', (223, 228))	('FAK', 'Gene', '14083', (84, 87))	('ERK1/2', 'Gene', '26417;26413', (162, 168))	('FAK', 'molecular_function', 'GO:0004717', ('58', '61'))	('ERK1', 'molecular_function', 'GO:0004707', ('191', '195'))	('FAK', 'Gene', '14083', (58, 61))	('Signaling', 'biological_process', 'GO:0023052', ('478', '487'))	('MEK1/2', 'Gene', (131, 137))	('ERK1/2', 'Gene', (191, 197))	('P55', 'Gene', '21937', (284, 287))	('P55', 'Gene', '21937', (308, 311))	('ERK1/2', 'Gene', '26417;26413', (191, 197))	('#9165', 'Var', (230, 235))	('FAK', 'molecular_function', 'GO:0004717', ('84', '87'))	('c-Jun', 'Gene', '16476', (223, 228))	('MEK1', 'molecular_function', 'GO:0004708', ('131', '135'))	('P55', 'Gene', (284, 287))	('c-Jun', 'Gene', (251, 256))	('GAPDH', 'Gene', (38, 43))	('P55', 'Gene', (308, 311))	('#11889', 'Var', (313, 319))	('MEK1', 'molecular_function', 'GO:0004708', ('102', '106'))	('MEK1/2', 'Gene', '26395;26396', (102, 108))	('GAPDH', 'Gene', '14433', (38, 43))
48344	27034160	The anti-MEK2 (ab32517), anti-phospho-MEK2 (T394, ab131095), anti-PP2A alpha+beta (ab32141) and anti-phospho-PP2A-alpha (Y307, ab32104) antibodies were purchased from Abcam.	('PP2A', 'Gene', '19052', (66, 70))	('Y307', 'Var', (121, 125))	('A alpha', 'Species', '355258', (69, 76))	('PP2A', 'Gene', (109, 113))	('PP2A', 'Gene', '19052', (109, 113))	('MEK2', 'Gene', (38, 42))	('MEK2', 'Gene', '26396', (38, 42))	('MEK2', 'molecular_function', 'GO:0004708', ('38', '42'))	('MEK2', 'molecular_function', 'GO:0004708', ('9', '13'))	('PP2A', 'Gene', (66, 70))	('MEK2', 'Gene', '26396', (9, 13))	('A-alpha', 'Species', '355258', (112, 119))	('MEK2', 'Gene', (9, 13))
48345	27034160	The primary antibodies used for immuno-histochemical staining were Netrin-1 (ab122903, Abcam), CD31 (ab28364, Abcam), integrin beta4 (ab110167, Abcam), and ZO-1 (ab59720, Abcam).	('ZO-1', 'Gene', (156, 160))	('Netrin-1', 'Gene', (67, 75))	('ab110167', 'Var', (134, 142))	('Netrin-1', 'Gene', '18208', (67, 75))	('CD31', 'Gene', '18613', (95, 99))	('CD31', 'Gene', (95, 99))	('ZO-1', 'Gene', '21872', (156, 160))
48383	25588761	Since then, many series of patients have documented a 2-10% incidence of concomitant pancreatic cancer in patients with IPMN.21, 22, 23, 24, 25, 26, 27, 28, 29, 30 Uehara et al.24 reported that even <=1-cm BD-IPMN were associated with an 8% risk of distinct pancreatic cancer during surveillance.	('pancreatic cancer', 'Disease', (85, 102))	('pancreatic cancer', 'Disease', (258, 275))	('BD-IPMN', 'Chemical', '-', (206, 213))	('pancreatic cancer', 'Disease', 'MESH:D010190', (258, 275))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('IPMN', 'Chemical', '-', (209, 213))	('IPMN', 'Chemical', '-', (120, 124))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (106, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (258, 275))	('<=1-cm', 'Var', (199, 205))
48420	26516699	At 25 weeks, the miRNA microarray analysis revealed significant downregulation of miR-150, miR-494, miR-138, miR-148a, miR-216a, and miR-217 and upregulation of miR-146b, miR-205, miR-31, miR-192, and miR-21 in KC mice compared to controls.	('miR-192', 'Gene', (188, 195))	('upregulation', 'PosReg', (145, 157))	('miR-31', 'Gene', (180, 186))	('miR-205', 'Gene', (171, 178))	('miR-150', 'Gene', (82, 89))	('downregulation', 'NegReg', (64, 78))	('miR-494', 'Var', (91, 98))	('miR-148a', 'Var', (109, 117))	('miR-138', 'Var', (100, 107))	('miR-216a', 'Var', (119, 127))	('mice', 'Species', '10090', (214, 218))	('miR-217', 'Var', (133, 140))	('miR-146b', 'Gene', (161, 169))
48422	26516699	In addition, from 10 to 50 weeks of age, stage-specific expression profiling of miRNA in KC mice revealed downregulation of miR-216, miR-217, miR-100, miR-345, miR-141, miR-483-3p, miR-26b, miR-150, miR-195, Let-7b and Let-96 and upregulation of miR-21, miR-205, miR-146b, miR-34c, miR-1273, miR-223 and miR-195 compared to control mice.	('miR-150', 'Gene', (190, 197))	('miR-483', 'Gene', (169, 176))	('upregulation', 'PosReg', (230, 242))	('mice', 'Species', '10090', (92, 96))	('miR-1273', 'Var', (282, 290))	('miR-216', 'Gene', (124, 131))	('miR-483', 'Gene', '619552', (169, 176))	('miR-216', 'Gene', '406998', (124, 131))	('miR-205', 'Gene', (254, 261))	('miR-223', 'Var', (292, 299))	('Let-96', 'Gene', (219, 225))	('downregulation', 'NegReg', (106, 120))	('miR-141', 'Gene', (160, 167))	('miR-100', 'Var', (142, 149))	('miR-195', 'Var', (304, 311))	('miR-34c', 'Gene', (273, 280))	('miR-26b', 'Var', (181, 188))	('miR-195', 'Gene', (199, 206))	('miR-146b', 'Var', (263, 271))	('miR-345', 'Var', (151, 158))	('Let-7b', 'Gene', (208, 214))	('miR-21', 'Gene', (246, 252))	('miR-217', 'Gene', (133, 140))	('mice', 'Species', '10090', (332, 336))
48439	26516699	The panel of differentially expressed miRNAs were validated by real-time PCR using TaqMan assays, and the results were consistent with the miRNA microarray data that showed up-regulation of miR-21, miR-221, miR-100 and miR-26a and down-regulation of miR-26b, miR-141, miR-96, miR483-3p, miR-216, and miR-217 in the KC compared to control mice (Figure 1A).	('miR-216', 'Gene', '406998', (287, 294))	('PC', 'Phenotype', 'HP:0002894', (73, 75))	('miR-217', 'Var', (300, 307))	('miR483-3p', 'Var', (276, 285))	('miR-221', 'Var', (198, 205))	('miR-96', 'Var', (268, 274))	('miR-26b', 'Gene', (250, 257))	('regulation', 'biological_process', 'GO:0065007', ('176', '186'))	('down-regulation', 'NegReg', (231, 246))	('mice', 'Species', '10090', (338, 342))	('up-regulation', 'PosReg', (173, 186))	('miR-100', 'Var', (207, 214))	('miR-21', 'Var', (190, 196))	('miR-216', 'Gene', (287, 294))	('miR-26a', 'Var', (219, 226))	('miR-141', 'Var', (259, 266))	('regulation', 'biological_process', 'GO:0065007', ('236', '246'))
48442	26516699	On the other hand, miR-146b, miR-34c, miR-223, miR-195 (p-value = 0.031) and miR-216 (p-value = 0.063) were downregulated in KC mice compared to control littermates.	('miR-223', 'Var', (38, 45))	('miR-34c', 'Var', (29, 36))	('miR-146b', 'Var', (19, 27))	('miR-216', 'Gene', (77, 84))	('miR-195', 'Var', (47, 54))	('mice', 'Species', '10090', (128, 132))	('downregulated', 'NegReg', (108, 121))	('miR-216', 'Gene', '406998', (77, 84))
48443	26516699	At 30 weeks of age, the expression of miR-216 (p-value = 0.016), miR-217 (p-value = 0.0078), miR-150 (p-value =0.023), Let-7b (p-value = 0.031,) and miR-96 were significantly downregulated, whereas the expression of miR-146b (p-value = 0.0078), miR-205, (p-value - 0.0078), miR-21, miR-195 (p-value = 0.031), and miR-34c (p-value = 0.063) were significantly upregulated in KC animals compared to control animals (Figure 2B).	('miR-216', 'Gene', (38, 45))	('miR-146b', 'Gene', (216, 224))	('downregulated', 'NegReg', (175, 188))	('Let-7b', 'Gene', (119, 125))	('miR-96', 'Gene', (149, 155))	('expression', 'MPA', (24, 34))	('miR-216', 'Gene', '406998', (38, 45))	('miR-205', 'Var', (245, 252))	('miR-195', 'Gene', (282, 289))	('expression', 'MPA', (202, 212))	('miR-34c', 'Var', (313, 320))	('miR-150', 'Gene', (93, 100))	('upregulated', 'PosReg', (358, 369))	('miR-21', 'Var', (274, 280))	('miR-217', 'Gene', (65, 72))
48444	26516699	At 40 weeks of age, the expression of miR-216, miR-217, miR-223, miR-141, miR-483-3p (p-value = 0.031), miR-195, Let-7b (p-value = 0.063) and miR-96 were significantly downregulated; on the other hand, the expression of miR-21, miR-205, miR-146b (p-value = 0.031), and miR-34c (p-value = 0.063) were upregulated in KC mice compared to the control animals (Figure 2C).	('miR-195', 'Var', (104, 111))	('miR-216', 'Gene', (38, 45))	('miR-146b', 'Var', (237, 245))	('miR-96', 'Gene', (142, 148))	('expression', 'MPA', (24, 34))	('expression', 'MPA', (206, 216))	('miR-216', 'Gene', '406998', (38, 45))	('miR-21', 'Gene', (220, 226))	('miR-141', 'Var', (65, 72))	('downregulated', 'NegReg', (168, 181))	('miR-483', 'Gene', '619552', (74, 81))	('miR-223', 'Gene', (56, 63))	('upregulated', 'PosReg', (300, 311))	('miR-483', 'Gene', (74, 81))	('miR-217', 'Gene', (47, 54))	('miR-205', 'Var', (228, 235))	('miR-34c', 'Var', (269, 276))	('mice', 'Species', '10090', (318, 322))
48445	26516699	Further, at 50 weeks of age, the expression of miR-216, miR-217, miR-345, miR-141, miR-483-3p, miR-26b, miR-96, Let-7b (p-value = 0.01), miR-100, miR-26a and miR-150 (p-value = 0.094) were further downregulated in KC animals compared to control mice (Figure 2D).	('miR-100', 'Var', (137, 144))	('miR-96', 'Var', (104, 110))	('miR-141', 'Var', (74, 81))	('miR-483', 'Gene', (83, 90))	('downregulated', 'NegReg', (197, 210))	('miR-26b', 'Var', (95, 102))	('miR-217', 'Var', (56, 63))	('miR-26a', 'Var', (146, 153))	('miR-150', 'Var', (158, 165))	('Let-7b', 'Var', (112, 118))	('expression', 'MPA', (33, 43))	('miR-216', 'Gene', (47, 54))	('mice', 'Species', '10090', (245, 249))	('miR-483', 'Gene', '619552', (83, 90))	('miR-345', 'Var', (65, 72))	('miR-216', 'Gene', '406998', (47, 54))
48446	26516699	The expressions of miR-216 and miR-217 were also progressively reduced in KC mice, but the expressions of miR-21, miR-205, miR-146b, miR-34c, and miR-223 progressively increased (Figure 1A, 2A-2D).	('mice', 'Species', '10090', (77, 81))	('increased', 'PosReg', (168, 177))	('expressions', 'MPA', (91, 102))	('miR-34c', 'Var', (133, 140))	('miR-217', 'Var', (31, 38))	('reduced', 'NegReg', (63, 70))	('miR-21', 'Var', (106, 112))	('miR-223', 'Var', (146, 153))	('miR-146b', 'Var', (123, 131))	('expressions', 'MPA', (4, 15))	('miR-216', 'Gene', (19, 26))	('miR-205', 'Var', (114, 121))	('miR-216', 'Gene', '406998', (19, 26))
48453	26516699	The expression of miR-223, miR-483-3p (p-value = 0.01), 146b, 205 (p-value = 0.001), 221, 21 (p-value = 0.023), 195, 34c and miR-26a (p-value = 0.0078) were significantly upregulated, whereas the expression of miR-216, miR-141, miR-217, Let-7b (p-value = 0.001), and Let-150 (p-value = 0.01) were significantly downregulated in human PC tissues as compared to the cancer-adjacent normal tissues (Figure 3E).	('miR-483', 'Gene', (27, 34))	('miR-141', 'Var', (219, 226))	('miR-483', 'Gene', '619552', (27, 34))	('PC', 'Phenotype', 'HP:0002894', (334, 336))	('221', 'Var', (85, 88))	('downregulated', 'NegReg', (311, 324))	('miR-223', 'Var', (18, 25))	('upregulated', 'PosReg', (171, 182))	('Let-7b', 'Gene', (237, 243))	('cancer', 'Disease', (364, 370))	('miR-216', 'Gene', (210, 217))	('146b', 'Var', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('Let-150', 'Gene', (267, 274))	('miR-216', 'Gene', '406998', (210, 217))	('miR-26a', 'Var', (125, 132))	('195', 'Var', (112, 115))	('expression', 'MPA', (196, 206))	('miR-217', 'Var', (228, 235))	('cancer', 'Disease', 'MESH:D009369', (364, 370))	('human', 'Species', '9606', (328, 333))
48456	26516699	Previous studies have shown that restoration of Let-7 results in downregulation of oncogenic Kras, leading to inhibition of cell proliferation and activation of the mitogen-activated protein kinase.	('Let-7', 'Gene', (48, 53))	('inhibition', 'NegReg', (110, 120))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('downregulation', 'NegReg', (65, 79))	('restoration', 'Var', (33, 44))	('cell proliferation', 'CPA', (124, 142))	('mitogen-activated protein kinase', 'Pathway', (165, 197))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('110', '142'))	('activation', 'PosReg', (147, 157))	('Let-7', 'Gene', '266952', (48, 53))	('Kras', 'Gene', (93, 97))
48465	26516699	Using this PC model, we and others have observed PanIN lesions at as early as 10 weeks of age, as well as PDAC with metastasis (in 60-70% of KC animals) to distant organs by 50 weeks of age.	('PanIN', 'Gene', (49, 54))	('PDAC', 'Phenotype', 'HP:0006725', (106, 110))	('lesions', 'Var', (55, 62))	('metastasis', 'CPA', (116, 126))	('PC', 'Phenotype', 'HP:0002894', (11, 13))	('PDAC', 'Chemical', '-', (106, 110))
48480	26516699	In addition to affecting proliferation, the increased expression of cleaved caspase-9 in both HPAF/CD18 and Capan1 cells suggests it has a pro-apoptotic role that remains to be determined.	('affecting', 'Reg', (15, 24))	('expression', 'MPA', (54, 64))	('caspase-9', 'Gene', (76, 85))	('CD18', 'Gene', (99, 103))	('proliferation', 'CPA', (25, 38))	('Capan1', 'CellLine', 'CVCL:0237', (108, 114))	('CD18', 'Gene', '3689', (99, 103))	('caspase-9', 'Gene', '842', (76, 85))	('increased', 'PosReg', (44, 53))	('cleaved', 'Var', (68, 75))
48488	26516699	However, a recent report in colorectal cancer patient tissues has shown significantly methylated mir-345 promoter region compared to the non-cancerous, adenoma, and normal colon tissues; further, ectopic over-expression of mir-345 in colorectal cancer cells significantly reduced cell proliferation by inhibiting the translation of anti-apoptotic BAG3 gene.	('cancerous', 'Disease', (141, 150))	('cell proliferation', 'CPA', (280, 298))	('adenoma', 'Disease', (152, 159))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('colorectal cancer', 'Phenotype', 'HP:0003003', (234, 251))	('BAG3', 'Gene', '9531', (347, 351))	('reduced', 'NegReg', (272, 279))	('cell proliferation', 'biological_process', 'GO:0008283', ('280', '298'))	('adenoma', 'Disease', 'MESH:D000236', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('patient', 'Species', '9606', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('BAG3', 'Gene', (347, 351))	('cancerous', 'Disease', 'MESH:D009369', (141, 150))	('ectopic', 'Var', (196, 203))	('inhibiting', 'NegReg', (302, 312))	('colorectal cancer', 'Disease', 'MESH:D015179', (234, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('translation', 'MPA', (317, 328))	('mir-345', 'Gene', '442910', (97, 104))	('mir-345', 'Gene', (97, 104))	('colorectal cancer', 'Disease', (28, 45))	('colorectal cancer', 'Disease', (234, 251))	('over-expression', 'PosReg', (204, 219))	('mir-345', 'Gene', '442910', (223, 230))	('translation', 'biological_process', 'GO:0006412', ('317', '328'))	('mir-345', 'Gene', (223, 230))
48489	26516699	The miR-26a miRNA inhibits the expression of c-myc, Cyclin D3 and E2, and cyclin-dependent kinases such as CDK4 and CDK6.	('miR-26a', 'Var', (4, 11))	('cyclin', 'molecular_function', 'GO:0016538', ('74', '80'))	('CDK4', 'Gene', '1019', (107, 111))	('Cyclin', 'molecular_function', 'GO:0016538', ('52', '58'))	('c-myc', 'Gene', '4609', (45, 50))	('inhibits', 'NegReg', (18, 26))	('CDK', 'molecular_function', 'GO:0004693', ('116', '119'))	('CDK6', 'Gene', (116, 120))	('cyclin-dependent', 'Enzyme', (74, 90))	('CDK6', 'Gene', '1021', (116, 120))	('Cyclin D3', 'Gene', '896', (52, 61))	('expression', 'MPA', (31, 41))	('c-myc', 'Gene', (45, 50))	('Cyclin D3', 'Gene', (52, 61))	('CDK', 'molecular_function', 'GO:0004693', ('107', '110'))	('CDK4', 'Gene', (107, 111))
48492	26516699	Recently, significant downregulation of miR-26a was also reported in nasopharyngeal carcinoma tissues and cell lines (53); its ectopic expression has been shown to downregulate EZH2 expression, thereby inducing G1-phase cell-cycle arrest to decrease cell proliferation and colony formation (53).	('EZH2', 'Gene', (177, 181))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (69, 93))	('expression', 'MPA', (182, 192))	('formation', 'biological_process', 'GO:0009058', ('280', '289'))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('220', '237'))	('colony formation', 'CPA', (273, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (69, 93))	('cell proliferation', 'biological_process', 'GO:0008283', ('250', '268'))	('nasopharyngeal carcinoma', 'Disease', (69, 93))	('G1-phase cell-cycle arrest', 'CPA', (211, 237))	('downregulate', 'NegReg', (164, 176))	('decrease', 'NegReg', (241, 249))	('ectopic expression', 'Var', (127, 145))	('EZH2', 'Gene', '2146', (177, 181))	('inducing', 'PosReg', (202, 210))	('cell proliferation', 'CPA', (250, 268))	('G1-phase', 'biological_process', 'GO:0051318', ('211', '219'))
48501	26516699	In addition, miR-21 has been shown to suppress the activity of the tumor suppressor gene tropomyosin 1 (TPM1), thereby promoting tumorigenesis.	('activity', 'MPA', (51, 59))	('miR-21', 'Var', (13, 19))	('tumor suppressor', 'biological_process', 'GO:0051726', ('67', '83'))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tropomyosin 1', 'Gene', (89, 102))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('67', '83'))	('TPM1', 'Gene', (104, 108))	('promoting', 'PosReg', (119, 128))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (129, 134))	('tropomyosin 1', 'Gene', '7168', (89, 102))	('suppress', 'NegReg', (38, 46))
48506	26516699	Similarly, the expression of miR-10, miR-21, miR-100 and miR-155 was shown to increase in p48-Cre/KrasG12D mice when compared to control animals.	('p48', 'Gene', (90, 93))	('miR-155', 'Gene', '387173', (57, 64))	('miR-100', 'Var', (45, 52))	('miR-155', 'Gene', (57, 64))	('increase', 'PosReg', (78, 86))	('expression', 'MPA', (15, 25))	('mice', 'Species', '10090', (107, 111))	('p48', 'Gene', '16391', (90, 93))	('miR-10', 'Gene', (29, 35))	('miR-21', 'Var', (37, 43))
48509	26516699	Abnormal expression of this machinery is associated with hematological malignancies, ovarian cancer, and neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (105, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (85, 99))	('Abnormal expression', 'Var', (0, 19))	('associated', 'Reg', (41, 51))	('ovarian cancer', 'Disease', 'MESH:D010051', (85, 99))	('hematological malignancies', 'Disease', 'MESH:D019337', (57, 83))	('neuroblastoma', 'Disease', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('hematological malignancies', 'Phenotype', 'HP:0004377', (57, 83))	('ovarian cancer', 'Disease', (85, 99))	('neuroblastoma', 'Phenotype', 'HP:0003006', (105, 118))	('hematological malignancies', 'Disease', (57, 83))
48513	26516699	Both miR-216 and miR-217 act as potential tumor suppressors for PC by targeting the Kras oncogene.	('tumor', 'Disease', (42, 47))	('Kras oncogene', 'Gene', (84, 97))	('PC', 'Phenotype', 'HP:0002894', (64, 66))	('miR-216', 'Gene', (5, 12))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('targeting', 'Reg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('miR-216', 'Gene', '406998', (5, 12))	('miR-217', 'Var', (17, 24))
48514	26516699	We have shown that in tumor samples compared to normal samples, the majority of miRNAs (miR-216, miR-217, miR-100, miR-345, miR-141, miR-483-3p, miR-26b, miR-150, Let-7b, Let-195 and miR-96) were downregulated, and few were upregulated (miR-146b, miR-205, miR-31, miR-192, miR-194 21, miR-379, miR-431, miR-541, and miR-199b).	('miR-199b', 'Gene', (316, 324))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('miR-31', 'Var', (256, 262))	('miR-431', 'Gene', (294, 301))	('miR-141', 'Var', (124, 131))	('miR-541', 'Gene', (303, 310))	('Let-195', 'Var', (171, 178))	('miR-100', 'Var', (106, 113))	('miR-379', 'Gene', '494328', (285, 292))	('miR-431', 'Gene', '574038', (294, 301))	('miR-205', 'Var', (247, 254))	('miR-96', 'Var', (183, 189))	('miR-199b', 'Gene', '406978', (316, 324))	('miR-150', 'Var', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('miR-541', 'Gene', '100126308', (303, 310))	('miR-379', 'Gene', (285, 292))	('miR-345', 'Var', (115, 122))	('miR-192', 'Var', (264, 271))	('miR-217', 'Var', (97, 104))	('upregulated', 'PosReg', (224, 235))	('miR-483', 'Gene', (133, 140))	('miR-194 21', 'Var', (273, 283))	('Let-7b', 'Var', (163, 169))	('downregulated', 'NegReg', (196, 209))	('miR-483', 'Gene', '619552', (133, 140))	('miR-216', 'Gene', (88, 95))	('tumor', 'Disease', (22, 27))	('miR-216', 'Gene', '406998', (88, 95))	('miR-26b', 'Var', (145, 152))
48565	25613377	We also identified Sck as the molecular link between CD95 and activation of the PI3K and MAPK pathways.	('MAPK pathways', 'Pathway', (89, 102))	('PI3', 'Gene', (80, 83))	('Sck', 'Gene', '25759', (19, 22))	('CD95', 'Var', (53, 57))	('PI3K', 'molecular_function', 'GO:0016303', ('80', '84'))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('Sck', 'Gene', (19, 22))	('PI3', 'Gene', '5266', (80, 83))
48566	25613377	Neutralization of the CD95L reduces PDAC growth and metastasis.	('CD95L', 'Var', (22, 27))	('PDAC', 'Phenotype', 'HP:0006725', (36, 40))	('reduces', 'NegReg', (28, 35))	('PDAC growth', 'CPA', (36, 47))	('Neutralization', 'Var', (0, 14))	('PDAC', 'Chemical', '-', (36, 40))
48587	25613377	Animals injected with PanD3 cells (containing 9.3% of CD95+, 17.8% CD24+ and 23.6% CD44+ cells; Figures 3b and c) developed tumours that were manually detectable 3 months after the injection.	('PanD3', 'Gene', (22, 27))	('CD24', 'Gene', '100133941', (67, 71))	('CD95+', 'Var', (54, 59))	('PanD3', 'Gene', '677663', (22, 27))	('CD24', 'Gene', (67, 71))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('CD44', 'Gene', '960', (83, 87))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('CD44', 'Gene', (83, 87))	('tumours', 'Disease', 'MESH:D009369', (124, 131))	('tumours', 'Disease', (124, 131))
48589	25613377	Immunohistochemically, both human and mouse tumours displayed a membrane-bound and cytoplasmic expression of CD95 and CD95L in ductal cells.	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('mouse', 'Species', '10090', (38, 43))	('CD95', 'Gene', (109, 113))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('human', 'Species', '9606', (28, 33))	('membrane', 'cellular_component', 'GO:0016020', ('64', '72'))	('tumours', 'Disease', (44, 51))	('CD95L', 'Var', (118, 123))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
48602	25613377	Interestingly, knockdown (KD) of SCK in Panc1 cells decreased CD95-mediated upregulation of vimentin and E-cadherin protein levels, yet a mild induction of vimentin is still detectable (Supplementary Figure 4).	('SCK', 'Gene', (33, 36))	('CD95-mediated upregulation', 'MPA', (62, 88))	('vimentin', 'cellular_component', 'GO:0045098', ('92', '100'))	('knockdown', 'Var', (15, 24))	('SCK', 'Gene', '25759', (33, 36))	('vimentin', 'Gene', '7431', (156, 164))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('decreased', 'NegReg', (52, 61))	('cadherin', 'molecular_function', 'GO:0008014', ('107', '115'))	('E-cadherin', 'Gene', (105, 115))	('vimentin', 'Gene', (156, 164))	('E-cadherin', 'Gene', '999', (105, 115))	('vimentin', 'cellular_component', 'GO:0045099', ('156', '164'))	('Panc1', 'CellLine', 'CVCL:0480', (40, 45))	('vimentin', 'Gene', '7431', (92, 100))	('vimentin', 'cellular_component', 'GO:0045098', ('156', '164'))	('vimentin', 'Gene', (92, 100))	('vimentin', 'cellular_component', 'GO:0045099', ('92', '100'))
48607	25613377	Three and seven days after the orthotopic injection, mice were intravenously treated with either CD95-Fc or NaCl and monitored until the establishment of palpable tumours 105 days later.	('tumours', 'Disease', (163, 170))	('tumours', 'Disease', 'MESH:D009369', (163, 170))	('CD95-Fc', 'Var', (97, 104))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('NaCl', 'Chemical', 'MESH:D012965', (108, 112))	('tumours', 'Phenotype', 'HP:0002664', (163, 170))	('mice', 'Species', '10090', (53, 57))
48612	25613377	Animals treated with CD95-Fc showed reduced tumour volumes compared with the saline-treated ones (Figures 4d and g).	('saline', 'Chemical', 'MESH:D012965', (77, 83))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Disease', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('reduced', 'NegReg', (36, 43))	('CD95-Fc', 'Var', (21, 28))
48613	25613377	Furthermore, treatment with CD95-Fc reduced the incidence of liver metastasis and the size of metastatic tumours as compared with untreated animals (Figures 4e and f).	('CD95-Fc', 'Var', (28, 35))	('liver metastasis', 'Disease', 'MESH:D009362', (61, 77))	('liver metastasis', 'Disease', (61, 77))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumours', 'Disease', (105, 112))	('reduced', 'NegReg', (36, 43))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
48615	25613377	PanD3 and PanD24 clones are resistant to CD95-induced apoptosis, even at high doses of CD95L-T4, a recombinant trimerized CD95L (Supplementary Figure 1).	('CD95L-T4', 'Var', (87, 95))	('PanD3', 'Gene', (0, 5))	('PanD3', 'Gene', '677663', (0, 5))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))
48616	25613377	Stimulation of PanD24 cells with CD95L-T4 induced both AKT and ERK phosphorylation and led to inhibition of GSK3beta as evidenced by Ser9 phosphorylation (Figure 5a and Supplementary Figures 2 and 3).	('inhibition', 'NegReg', (94, 104))	('AKT', 'Gene', (55, 58))	('GSK', 'molecular_function', 'GO:0050321', ('108', '111'))	('inhibition of GSK', 'biological_process', 'GO:1902948', ('94', '111'))	('ERK', 'molecular_function', 'GO:0004707', ('63', '66'))	('CD95L-T4', 'Var', (33, 41))	('GSK3beta', 'Gene', '2932', (108, 116))	('Ser9', 'Chemical', '-', (133, 137))	('phosphorylation', 'biological_process', 'GO:0016310', ('67', '82'))	('Ser', 'cellular_component', 'GO:0005790', ('133', '136'))	('Ser9 phosphorylation', 'MPA', (133, 153))	('phosphorylation', 'biological_process', 'GO:0016310', ('138', '153'))	('AKT', 'Gene', '207', (55, 58))	('ERK', 'Gene', '5594', (63, 66))	('ERK', 'Gene', (63, 66))	('GSK3beta', 'Gene', (108, 116))
48627	25613377	The ITAM/ITIM-like motif surrounding Tyr291 of CD95 offers an alternative-docking site for the allocation of SH2-containing proteins.	('Tyr291', 'Chemical', '-', (37, 43))	('CD95', 'Gene', (47, 51))	('Tyr291', 'Var', (37, 43))
48628	25613377	After incubation of CD95L-stimulated cell lysates of PANC-1 and PanD3 cells with SH2 domain protein arrays, showed the spots corresponding to the SH2 domain of Shc2/Sck demonstrated the strongest CD95 binding (Figure 5c and Supplementary Figure 2).	('binding', 'molecular_function', 'GO:0005488', ('201', '208'))	('CD95', 'Protein', (196, 200))	('PanD3', 'Gene', (64, 69))	('Shc2', 'Gene', (160, 164))	('PANC-1', 'CellLine', 'CVCL:0480', (53, 59))	('Shc2', 'Gene', '25759', (160, 164))	('Sck', 'Gene', '25759', (165, 168))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('PanD3', 'Gene', '677663', (64, 69))	('SH2 domain', 'Var', (146, 156))	('strongest', 'PosReg', (186, 195))	('Sck', 'Gene', (165, 168))
48637	25613377	Cells treated with 20 ng/ml of CD95L-T4 contained a higher fraction of EdU-positive cells as compared with the untreated sample (Figure 6a), thus confirming accelerated entry into the S phase.	('S phase', 'biological_process', 'GO:0051320', ('184', '191'))	('CD95L-T4', 'Var', (31, 39))	('EdU', 'Chemical', '-', (71, 74))	('accelerated', 'PosReg', (157, 168))
48642	25613377	In this study, we show that CD95 expression strongly correlates with stemness and EMT and demonstrates that CD95 drives migration and proliferation in PDACs.	('drives', 'PosReg', (113, 119))	('PDAC', 'Chemical', '-', (151, 155))	('EMT', 'biological_process', 'GO:0001837', ('82', '85'))	('CD95', 'Var', (108, 112))	('migration', 'CPA', (120, 129))	('stemness', 'Disease', (69, 77))	('CD95', 'Gene', (28, 32))	('EMT', 'CPA', (82, 85))	('stemness', 'Disease', 'MESH:D020295', (69, 77))	('correlates', 'Reg', (53, 63))	('PDAC', 'Phenotype', 'HP:0006725', (151, 155))	('proliferation', 'CPA', (134, 147))
48643	25613377	Moreover, blocking the receptor in vivo decreases tumour growth and metastasis.	('blocking', 'Var', (10, 18))	('decreases tumour growth', 'Disease', (40, 63))	('decreases tumour growth', 'Disease', 'MESH:D006130', (40, 63))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))
48654	25613377	The relevance of CD95 expression for detection of EMT is further supported by the fact that CD95-positive cells within a tumour exhibit a higher concomitant expression of epithelial and mesenchymal transcripts as compared with CD95-negative tumour cells.	('tumour', 'Disease', (241, 247))	('expression', 'MPA', (157, 167))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('EMT', 'biological_process', 'GO:0001837', ('50', '53'))	('epithelial', 'Protein', (171, 181))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumour', 'Disease', 'MESH:D009369', (241, 247))	('tumour', 'Disease', (121, 127))	('CD95-positive', 'Var', (92, 105))	('higher', 'PosReg', (138, 144))
48664	25613377	Tyr291 present in CD95 death domain has been shown to undergo phosphorylation upon receptor activation via number of the SKFs.	('undergo', 'Reg', (54, 61))	('phosphorylation', 'MPA', (62, 77))	('Tyr291', 'Var', (0, 6))	('Tyr291', 'Chemical', '-', (0, 6))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))
48668	25613377	Those results stand in accordance with the observations made for lprcg mice, carrying spontaneous CD95 mutation (I225N) that prevents both FADD binding and induction of apoptosis.	('mice', 'Species', '10090', (71, 75))	('apoptosis', 'CPA', (169, 178))	('binding', 'molecular_function', 'GO:0005488', ('144', '151'))	('CD95', 'Gene', (98, 102))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('156', '178'))	('I225N', 'Mutation', 'p.I225N', (113, 118))	('FADD', 'Protein', (139, 143))	('mutation', 'Var', (103, 111))	('prevents', 'NegReg', (125, 133))
48669	25613377	This mutation should not affect the ITAM-like motif of CD95, thus still allowing PAC formation.	('allowing', 'Reg', (72, 80))	('PAC', 'Disease', (81, 84))	('PAC', 'Chemical', '-', (81, 84))	('formation', 'biological_process', 'GO:0009058', ('85', '94'))	('PAC', 'Phenotype', 'HP:0006699', (81, 84))	('mutation', 'Var', (5, 13))
48671	25613377	Moreover, lprcg mice develop liver tumours when transplanted with wild-type bone marrow.	('liver tumours', 'Disease', 'MESH:D008113', (29, 42))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('lprcg', 'Var', (10, 15))	('liver tumours', 'Disease', (29, 42))	('mice', 'Species', '10090', (16, 20))
48674	25613377	Interestingly, it was reported that blocking Shc/Grb2 interaction suppressed the growth of B104-1-1 tumours xenografted in nude mice, showing that cancer treatment might also target the adapter proteins.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Grb2', 'Gene', (49, 53))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('nude mice', 'Species', '10090', (123, 132))	('B104-1-1 tumours', 'Disease', 'MESH:D010051', (91, 107))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('B104-1-1 tumours', 'Disease', (91, 107))	('suppressed', 'NegReg', (66, 76))	('Shc', 'Gene', (45, 48))	('blocking', 'Var', (36, 44))	('interaction', 'Interaction', (54, 65))	('cancer', 'Disease', (147, 153))	('Shc', 'Gene', '20416', (45, 48))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('growth', 'CPA', (81, 87))	('Grb2', 'Gene', '14784', (49, 53))
48675	25613377	The treatment of PanD24-transplanted animals with CD95-Fc resulted in decreased tumour growth strengthening the conclusions derived from murine tumour treatment.	('tumour', 'Disease', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('CD95-Fc', 'Var', (50, 57))	('decreased tumour', 'Disease', 'MESH:D009369', (70, 86))	('murine', 'Species', '10090', (137, 143))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', (144, 150))	('tumour growth', 'Disease', (80, 93))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('tumour growth', 'Disease', 'MESH:D006130', (80, 93))	('decreased tumour', 'Disease', (70, 86))
48676	25613377	Strikingly, the study objective of increasing the percentage of patients reaching the 6-month rate of progression-free survival by 100% in the CD95-Fc group was substantially exceeded.	('patients', 'Species', '9606', (64, 72))	('CD95-Fc', 'Var', (143, 150))	('increasing', 'PosReg', (35, 45))
48683	25613377	Probe sets were preranked according to the differential expression between CD95 High (33% of samples with highest CD95 expression) and CD95 Low (33% of samples with lowest CD95 expression) tumour samples using empirical Bayes moderated t-statistics computed with the limma package from Bioconductor ('R package' UCR, Institute for integrative genome biology, Riverside, CA, USA).	('tumour', 'Disease', (189, 195))	('CD95', 'Var', (135, 139))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))
48699	25613377	Immunohistochemistry staining of paraffin-embedded pancreatic tumour sections was performed as described previously using the following antibodies: CD95 (alpha-APG101; Apogenix GmbH), CD95L (CD95L; ab15285; Abcam, Cambridge, UK).	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('pancreatic tumour', 'Phenotype', 'HP:0002894', (51, 68))	('CD95L', 'Var', (184, 189))	('paraffin', 'Chemical', 'MESH:D010232', (33, 41))	('pancreatic tumour', 'Disease', 'MESH:D010190', (51, 68))	('pancreatic tumour', 'Disease', (51, 68))
48704	25714017	A review of the COSMIC database reveals that most pancreatic cancers contain somatic mutations, with the five most frequent being KRAS, TP53, CDKN2A, SMAD4, and ARID1A, and multiple other abnormalities seen including, but not limited to, mutations in STK11/LKB1, FBXW7, PIK3CA, and BRAF.	('FBXW7', 'Gene', (263, 268))	('CDKN2A', 'Gene', '1029', (142, 148))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 67))	('STK11', 'Gene', (251, 256))	('SMAD4', 'Gene', (150, 155))	('pancreatic cancers', 'Disease', 'MESH:D010190', (50, 68))	('TP53', 'Gene', '7157', (136, 140))	('KRAS', 'Gene', '3845', (130, 134))	('LKB1', 'Gene', (257, 261))	('ARID1A', 'Gene', (161, 167))	('mutations', 'Var', (238, 247))	('PIK3CA', 'Gene', '5290', (270, 276))	('KRAS', 'Gene', (130, 134))	('STK11', 'Gene', '6794', (251, 256))	('FBXW7', 'Gene', '55294', (263, 268))	('STK11', 'molecular_function', 'GO:0033868', ('251', '256'))	('SMAD4', 'Gene', '4089', (150, 155))	('ARID1A', 'Gene', '8289', (161, 167))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (50, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('al', 'Chemical', 'MESH:D000535', (36, 38))	('BRAF', 'Gene', (282, 286))	('BRAF', 'Gene', '673', (282, 286))	('TP53', 'Gene', (136, 140))	('CDKN2A', 'Gene', (142, 148))	('PIK3CA', 'Gene', (270, 276))	('pancreatic cancers', 'Disease', (50, 68))	('LKB1', 'Gene', '6794', (257, 261))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('al', 'Chemical', 'MESH:D000535', (194, 196))
48720	25714017	For the approximately 40% of patients that harbor a V600E BRAF mutation, vemurafenib produces a response rate of 48%.	('patients', 'Species', '9606', (29, 37))	('V600E', 'Var', (52, 57))	('vemurafenib', 'Chemical', 'MESH:D000077484', (73, 84))	('BRAF', 'Gene', '673', (58, 62))	('BRAF', 'Gene', (58, 62))	('V600E', 'Mutation', 'rs113488022', (52, 57))
48727	25714017	If specific "actionable" mutations can drive marked improvements in survival in melanoma and NSCLC, similar opportunities might reasonably be expected in pancreatic cancer.	('mutations', 'Var', (25, 34))	('improvements', 'PosReg', (52, 64))	('pancreatic cancer', 'Disease', 'MESH:D010190', (154, 171))	('NSCLC', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('nab', 'Chemical', '-', (133, 136))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (154, 171))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('survival', 'MPA', (68, 76))	('nab', 'Chemical', '-', (18, 21))	('al', 'Chemical', 'MESH:D000535', (74, 76))	('pancreatic cancer', 'Disease', (154, 171))
48732	25714017	Common KRAS mutations hinder its ability to hydrolyze GTP, leaving it constitutively active.	('KRAS', 'Gene', '3845', (7, 11))	('ability', 'MPA', (33, 40))	('mutations', 'Var', (12, 21))	('hydrolyze GTP', 'MPA', (44, 57))	('GTP', 'Chemical', 'MESH:D006160', (54, 57))	('hinder', 'NegReg', (22, 28))	('KRAS', 'Gene', (7, 11))
48733	25714017	KRAS mutations are common in pancreatic duct lesions and are thought to play an early role in oncogenesis.	('oncogenesis', 'biological_process', 'GO:0007048', ('94', '105'))	('pancreatic duct lesions', 'Disease', (29, 52))	('mutations', 'Var', (5, 14))	('pancreatic duct lesions', 'Disease', 'MESH:D010182', (29, 52))	('common', 'Reg', (19, 25))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
48744	25714017	Forty-nine percent of pancreatic cancers in the COSMIC database demonstrate TP53 mutations.	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('TP53', 'Gene', '7157', (76, 80))	('pancreatic cancers', 'Disease', 'MESH:D010190', (22, 40))	('pancreatic cancers', 'Disease', (22, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (22, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('TP53', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (22, 40))
48746	25714017	Wee-1 inhibitors such as MK1775 target aberrant p53 by blocking cell cycle checkpoint regulation and increasing susceptibility to cytotoxic chemotherapy.	('cell', 'MPA', (64, 68))	('p53', 'Gene', (48, 51))	('blocking', 'NegReg', (55, 63))	('increasing', 'PosReg', (101, 111))	('Wee-1', 'Gene', (0, 5))	('p53', 'Gene', '7157', (48, 51))	('Wee-1', 'Gene', '7465', (0, 5))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('64', '85'))	('susceptibility', 'MPA', (112, 126))	('aberrant', 'Var', (39, 47))	('MK1775', 'Chemical', 'MESH:C549567', (25, 31))
48747	25714017	In addition, retrospective analysis by Said et al suggested that tumors with aberrant p53 may be more sensitive to bevacizumab.	('aberrant', 'Var', (77, 85))	('bevacizumab', 'Chemical', 'MESH:D000068258', (115, 126))	('p53', 'Gene', '7157', (86, 89))	('sensitive', 'MPA', (102, 111))	('al', 'Chemical', 'MESH:D000535', (29, 31))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('al', 'Chemical', 'MESH:D000535', (47, 49))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('p53', 'Gene', (86, 89))
48748	25714017	Patients with aberrant p53 had a median PFS of 11 months while the median PFS in those with wild-type p53 was 5.0 months.	('aberrant', 'Var', (14, 22))	('Patients', 'Species', '9606', (0, 8))	('p53', 'Gene', '7157', (23, 26))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (102, 105))
48749	25714017	On multivariate analysis, the interaction between p53 mutation status and bevacizumab therapy was statistically significant [HR 0.15, 95% CI 0.05-0.44, p < 0.001].	('al', 'Chemical', 'MESH:D000535', (107, 109))	('bevacizumab', 'Chemical', 'MESH:D000068258', (74, 85))	('al', 'Chemical', 'MESH:D000535', (18, 20))	('mutation status', 'Var', (54, 69))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))
48754	25714017	A search of clinicaltrials.gov lists multiple MDM2 antagonists currently under early-phase investigation, including RO5045337, RO5503781, and DS-3032b.	('DS-3032b', 'Var', (142, 150))	('al', 'Chemical', 'MESH:D000535', (18, 20))	('RO5503781', 'Var', (127, 136))	('RO5045337', 'Var', (116, 125))	('MDM2', 'Gene', '4193', (46, 50))	('al', 'Chemical', 'MESH:D000535', (23, 25))	('MDM2', 'Gene', (46, 50))
48755	25714017	CDKN2A is aberrant in twenty-two percent of patients with pancreatic cancer.	('pancreatic cancer', 'Disease', (58, 75))	('patients', 'Species', '9606', (44, 52))	('pancreatic cancer', 'Disease', 'MESH:D010190', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('aberrant', 'Var', (10, 18))	('CDKN2A', 'Gene', (0, 6))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (58, 75))	('CDKN2A', 'Gene', '1029', (0, 6))
48759	25714017	Loss of p16 results in activation of CDK4/6 and is associated with high-grade pre-malignant pancreatic lesions.	('CDK', 'molecular_function', 'GO:0004693', ('37', '40'))	('pre', 'molecular_function', 'GO:0003904', ('78', '81'))	('p16', 'Gene', '1029', (8, 11))	('CDK4/6', 'Gene', (37, 43))	('al', 'Chemical', 'MESH:D000535', (83, 85))	('activation', 'PosReg', (23, 33))	('associated', 'Reg', (51, 61))	('pancreatic lesions', 'Disease', (92, 110))	('p16', 'Gene', (8, 11))	('pancreatic lesions', 'Disease', 'MESH:D010182', (92, 110))	('Loss', 'Var', (0, 4))	('CDK4/6', 'Gene', '1019;1021', (37, 43))
48764	25714017	SMAD4 mutations are present in twenty percent of pancreatic cancers and have been associated a poorer prognosis and increased metastases.	('SMAD4', 'Gene', '4089', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('SMAD4', 'Gene', (0, 5))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (49, 67))	('metastases', 'Disease', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (49, 66))	('metastases', 'Disease', 'MESH:D009362', (126, 136))	('pancreatic cancers', 'Disease', 'MESH:D010190', (49, 67))	('pancreatic cancers', 'Disease', (49, 67))	('mutations', 'Var', (6, 15))
48765	25714017	Inactivation of SMAD4 may enable TGF-beta signaling, which is usually suppressive, to promote cancer growth.	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('SMAD4', 'Gene', (16, 21))	('al', 'Chemical', 'MESH:D000535', (65, 67))	('enable', 'PosReg', (26, 32))	('TGF-beta', 'Gene', '7040', (33, 41))	('promote', 'PosReg', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('nab', 'Chemical', '-', (27, 30))	('SMAD4', 'Gene', '4089', (16, 21))	('al', 'Chemical', 'MESH:D000535', (46, 48))	('TGF-beta', 'Gene', (33, 41))	('Inactivation', 'Var', (0, 12))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
48766	25714017	To our knowledge, the role of TGF-beta inhibitors in patients with SMAD4 mutations has not been investigated.	('patients', 'Species', '9606', (53, 61))	('SMAD4', 'Gene', (67, 72))	('TGF-beta', 'Gene', '7040', (30, 38))	('SMAD4', 'Gene', '4089', (67, 72))	('mutations', 'Var', (73, 82))	('TGF-beta', 'Gene', (30, 38))
48767	25714017	ARID1a mutations are present in six percent of pancreatic cancers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('pancreatic cancers', 'Disease', (47, 65))	('ARID1a', 'Gene', '8289', (0, 6))	('pancreatic cancers', 'Disease', 'MESH:D010190', (47, 65))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (47, 64))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (47, 65))	('ARID1a', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
48770	25714017	Whether or not mutations in ARID1a can be targeted by using PIK3CA, AKT or mTOR inhibitors is currently unknown.	('PIK3CA', 'Gene', (60, 66))	('ARID1a', 'Gene', '8289', (28, 34))	('PIK3CA', 'Gene', '5290', (60, 66))	('mutations', 'Var', (15, 24))	('AKT', 'Gene', '207', (68, 71))	('ARID1a', 'Gene', (28, 34))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))	('AKT', 'Gene', (68, 71))
48772	25714017	Murphy et al demonstrated that 5/29 patients (17%) with a strong family history of pancreatic cancer harbored BRCA2 mutations.	('BRCA2', 'Gene', (110, 115))	('patients', 'Species', '9606', (36, 44))	('pancreatic cancer', 'Disease', (83, 100))	('al', 'Chemical', 'MESH:D000535', (10, 12))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('BRCA2', 'Gene', '675', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutations', 'Var', (116, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))	('harbored', 'Reg', (101, 109))
48774	25714017	PALB2 mutations were reported in 3/96 patients (3.1%) with familial pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('PALB2', 'Gene', '79728', (0, 5))	('familial pancreatic cancer', 'Disease', (59, 85))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (59, 85))	('PALB2', 'Gene', (0, 5))	('patients', 'Species', '9606', (38, 46))	('mutations', 'Var', (6, 15))
48775	25714017	In theory, patients with BRCA2 or PALB2 mutations should be more sensitive to DNA-damaging agents.	('BRCA2', 'Gene', (25, 30))	('BRCA2', 'Gene', '675', (25, 30))	('mutations', 'Var', (40, 49))	('PALB2', 'Gene', (34, 39))	('PALB2', 'Gene', '79728', (34, 39))	('sensitive', 'MPA', (65, 74))	('patients', 'Species', '9606', (11, 19))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))
48776	25714017	Villarroel et al reported a 61-year-old man with metastatic pancreatic cancer in the setting of a PALB2 mutation.	('man', 'Species', '9606', (40, 43))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('PALB2', 'Gene', '79728', (98, 103))	('PALB2', 'Gene', (98, 103))	('al', 'Chemical', 'MESH:D000535', (14, 16))	('mutation', 'Var', (104, 112))	('pancreatic cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))
48778	25714017	A 49-year-old woman with advanced pancreatic cancer in the setting of BRCA2 mutation who was treated with mitomycin C and capecitabine after progressing through two previous regimens also achieved a partial response.	('capecitabine', 'Chemical', 'MESH:D000069287', (122, 134))	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('mitomycin C', 'Chemical', 'MESH:D016685', (106, 117))	('BRCA2', 'Gene', '675', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('al', 'Chemical', 'MESH:D000535', (204, 206))	('woman', 'Species', '9606', (14, 19))	('al', 'Chemical', 'MESH:D000535', (183, 185))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('mutation', 'Var', (76, 84))	('BRCA2', 'Gene', (70, 75))	('pancreatic cancer', 'Disease', (34, 51))
48780	25714017	Patients with BRCA2 mutations may also be sensitive to PARP inhibitors.	('al', 'Chemical', 'MESH:D000535', (34, 36))	('PARP', 'Gene', '142', (55, 59))	('BRCA2', 'Gene', '675', (14, 19))	('sensitive', 'Reg', (42, 51))	('Patients', 'Species', '9606', (0, 8))	('PARP', 'Gene', (55, 59))	('BRCA2', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))
48781	25714017	Response has been seen in a variety of other tumors, including breast, prostate, and ovarian cancer harboring BRCA2 aberrations.	('ovarian cancer', 'Phenotype', 'HP:0100615', (85, 99))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('ovarian cancer', 'Disease', 'MESH:D010051', (85, 99))	('BRCA2', 'Gene', (110, 115))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('prostate', 'Disease', (71, 79))	('breast', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('BRCA2', 'Gene', '675', (110, 115))	('ovarian cancer', 'Disease', (85, 99))	('aberrations', 'Var', (116, 127))
48782	25714017	Abberations in STK11/LKB1 and FBXW7 are also potential targets.	('FBXW7', 'Gene', '55294', (30, 35))	('STK11', 'Gene', '6794', (15, 20))	('al', 'Chemical', 'MESH:D000535', (52, 54))	('LKB1', 'Gene', (21, 25))	('FBXW7', 'Gene', (30, 35))	('LKB1', 'Gene', '6794', (21, 25))	('STK11', 'molecular_function', 'GO:0033868', ('15', '20'))	('al', 'Chemical', 'MESH:D000535', (40, 42))	('STK11', 'Gene', (15, 20))	('Abberations', 'Var', (0, 11))
48784	25714017	Germline STK11/LKB1 loss-of function mutations are associated with Peutz-Jeghers Syndrome, which carries an increased risk for pancreatic neoplasms.	('STK11', 'Gene', '6794', (9, 14))	('pancreatic neoplasms', 'Disease', 'MESH:D010190', (127, 147))	('neoplasms', 'Phenotype', 'HP:0002664', (138, 147))	('mutations', 'Var', (37, 46))	('pancreatic neoplasms', 'Phenotype', 'HP:0002894', (127, 147))	('LKB1', 'Gene', '6794', (15, 19))	('STK11', 'molecular_function', 'GO:0033868', ('9', '14'))	('LKB1', 'Gene', (15, 19))	('STK11', 'Gene', (9, 14))	('Peutz-Jeghers Syndrome', 'Disease', (67, 89))	('pancreatic neoplasms', 'Disease', (127, 147))	('loss-of function', 'NegReg', (20, 36))
48787	25714017	In NSCLC cell lines with silenced FBXW7, taxane sensitivity can be restored when treated with the histone deacetylase inhibitor MS-275.	('taxane', 'Chemical', 'MESH:C080625', (41, 47))	('NSCLC', 'Disease', (3, 8))	('FBXW7', 'Gene', '55294', (34, 39))	('silenced', 'Var', (25, 33))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('taxane sensitivity', 'MPA', (41, 59))	('FBXW7', 'Gene', (34, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('MS-275', 'Chemical', 'MESH:C118739', (128, 134))
48788	25714017	Other potentially actionable aberrations that can be seen in small, but not insignificant subsets of patients include PIK3CA and BRAF mutations.	('patients', 'Species', '9606', (101, 109))	('al', 'Chemical', 'MESH:D000535', (13, 15))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('nab', 'Chemical', '-', (23, 26))	('al', 'Chemical', 'MESH:D000535', (63, 65))	('mutations', 'Var', (134, 143))	('PIK3CA', 'Gene', (118, 124))	('PIK3CA', 'Gene', '5290', (118, 124))
48793	25714017	Six used tissue biomarkers to assign patients among multiple conventional chemotherapy options, two sought patients with BRCA mutations for PARP inhibitors, one required a specific antigen for a corresponding investigational monoclonal antibody, and one sought patients with a specific HLA marker for a vaccine study.	('patients', 'Species', '9606', (261, 269))	('antibody', 'cellular_component', 'GO:0019814', ('236', '244'))	('al', 'Chemical', 'MESH:D000535', (233, 235))	('BRCA', 'Gene', '672', (121, 125))	('patients', 'Species', '9606', (37, 45))	('PARP', 'Gene', (140, 144))	('antibody', 'molecular_function', 'GO:0003823', ('236', '244'))	('BRCA', 'Gene', (121, 125))	('PARP', 'Gene', '142', (140, 144))	('antibody', 'cellular_component', 'GO:0042571', ('236', '244'))	('al', 'Chemical', 'MESH:D000535', (71, 73))	('mutations', 'Var', (126, 135))	('al', 'Chemical', 'MESH:D000535', (222, 224))	('antibody', 'cellular_component', 'GO:0019815', ('236', '244'))	('patients', 'Species', '9606', (107, 115))
48809	26053486	High podocalyxin expression associated significantly with higher risk of death from PDAC by both the polyclonal antibody (hazard ratio (HR) = 1.62; 95% confidence interval (CI) 1.12-2.33; p=0.01) and the monoclonal antibody (HR = 2.10, 95% CI 1.38-3.20; p<0.001).	('PDAC', 'Disease', (84, 88))	('High', 'Var', (0, 4))	('PDAC', 'Phenotype', 'HP:0006725', (84, 88))	('antibody', 'molecular_function', 'GO:0003823', ('215', '223'))	('antibody', 'cellular_component', 'GO:0019814', ('112', '120'))	('podocalyxin', 'Gene', (5, 16))	('antibody', 'molecular_function', 'GO:0003823', ('112', '120'))	('antibody', 'cellular_component', 'GO:0042571', ('215', '223'))	('PDAC', 'Chemical', '-', (84, 88))	('antibody', 'cellular_component', 'GO:0019815', ('215', '223'))	('podocalyxin', 'Gene', '5420', (5, 16))	('antibody', 'cellular_component', 'GO:0042571', ('112', '120'))	('death', 'Disease', 'MESH:D003643', (73, 78))	('death', 'Disease', (73, 78))	('antibody', 'cellular_component', 'GO:0019814', ('215', '223'))	('antibody', 'cellular_component', 'GO:0019815', ('112', '120'))
48817	26053486	Loss of normal PODXL expression is associated with glomerulopathies:mainly with nephrotic syndrome.	('nephrotic syndrome', 'Disease', 'MESH:D009404', (80, 98))	('glomerulopathies', 'Disease', (51, 67))	('nephrotic syndrome', 'Disease', (80, 98))	('associated', 'Reg', (35, 45))	('expression', 'MPA', (21, 31))	('Loss of normal', 'Var', (0, 14))	('nephrotic syndrome', 'Phenotype', 'HP:0000100', (80, 98))	('glomerulopathies', 'Disease', 'MESH:D007674', (51, 67))	('PODXL', 'Gene', '5420', (15, 20))	('PODXL', 'Gene', (15, 20))
48822	26053486	concluded that sialofucosylated PODXL is overexpressed by metastatic pancreatic cancer cells.	('PODXL', 'Gene', (32, 37))	('pancreatic cancer', 'Disease', (69, 86))	('overexpressed', 'PosReg', (41, 54))	('pancreatic cancer', 'Disease', 'MESH:D010190', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('PODXL', 'Gene', '5420', (32, 37))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (69, 86))	('sialofucosylated', 'Var', (15, 31))
48835	26053486	The novel monoclonal in-house antibody (HES9) used in this study recognizes amino acid residues 189-192 of PODXL.	('antibody', 'cellular_component', 'GO:0042571', ('30', '38'))	('PODXL', 'Gene', '5420', (107, 112))	('amino acid residues 189-192', 'Var', (76, 103))	('antibody', 'cellular_component', 'GO:0019815', ('30', '38'))	('antibody', 'cellular_component', 'GO:0019814', ('30', '38'))	('PODXL', 'Gene', (107, 112))	('antibody', 'molecular_function', 'GO:0003823', ('30', '38'))
48865	26053486	A combination of mAb and pAb showed a significantly poorer CSS for PDAC patients with high expression than for those with low expression (p = 0.001).	('CSS', 'Chemical', '-', (59, 62))	('PDAC', 'Phenotype', 'HP:0006725', (67, 71))	('poorer', 'NegReg', (52, 58))	('PDAC', 'Disease', (67, 71))	('CSS', 'MPA', (59, 62))	('high expression', 'Var', (86, 101))	('PDAC', 'Chemical', '-', (67, 71))	('pAb', 'Chemical', '-', (25, 28))	('patients', 'Species', '9606', (72, 80))
48869	26053486	High podocalyxin expression associated significantly with higher risk of death from PDAC by both the pAb (HR = 1.62; 95% CI 1.12-2.33; p = 0.01) and the mAb (HR = 2.10, 95% CI 1.38-3.20; p<0.001).	('PDAC', 'Disease', (84, 88))	('High', 'Var', (0, 4))	('PDAC', 'Phenotype', 'HP:0006725', (84, 88))	('pAb', 'Chemical', '-', (101, 104))	('podocalyxin', 'Gene', (5, 16))	('PDAC', 'Chemical', '-', (84, 88))	('podocalyxin', 'Gene', '5420', (5, 16))	('death', 'Disease', 'MESH:D003643', (73, 78))	('death', 'Disease', (73, 78))
48883	26053486	These findings are substantiated by earlier studies demonstrating that aberrant PODXL expression supports the disruption of cell-to-cell and cell-to-extracellular matrix adhesions, and in this way promotes tumor dissemination.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('disruption', 'CPA', (110, 120))	('tumor', 'Disease', (206, 211))	('PODXL', 'Gene', '5420', (80, 85))	('expression', 'MPA', (86, 96))	('PODXL', 'Gene', (80, 85))	('promotes', 'PosReg', (197, 205))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('aberrant', 'Var', (71, 79))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('149', '169'))
48891	26053486	Only a small difference existed between the two antibodies as prognostic markers: the hazard ratio for risk of death was greater for patients with high PODXL expression by the mAb than for those with membranous PODXL expression by the pAb.	('PODXL', 'Gene', (211, 216))	('patients', 'Species', '9606', (133, 141))	('PODXL', 'Gene', '5420', (152, 157))	('high', 'Var', (147, 151))	('pAb', 'Chemical', '-', (235, 238))	('PODXL', 'Gene', (152, 157))	('PODXL', 'Gene', '5420', (211, 216))	('death', 'Disease', 'MESH:D003643', (111, 116))	('death', 'Disease', (111, 116))
48894	26053486	Five-year CSS was lower for patients with high PODXL expression by the mAb than for patients with membranous PODXL expression by the pAb (4.4% vs. 14.0%).	('CSS', 'Chemical', '-', (10, 13))	('PODXL', 'Gene', (47, 52))	('PODXL', 'Gene', (109, 114))	('patients', 'Species', '9606', (84, 92))	('lower', 'NegReg', (18, 23))	('pAb', 'Chemical', '-', (133, 136))	('CSS', 'MPA', (10, 13))	('high', 'Var', (42, 46))	('PODXL', 'Gene', '5420', (47, 52))	('patients', 'Species', '9606', (28, 36))	('PODXL', 'Gene', '5420', (109, 114))
48905	25753158	Genomic deletion or mutation of FBW7 has frequently been identified in many human cancers but not in pancreatic ductal adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (101, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('pancreatic ductal adenocarcinoma', 'Disease', (101, 133))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (101, 133))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('FBW7', 'Gene', (32, 36))	('mutation', 'Var', (20, 28))	('cancers', 'Disease', (82, 89))	('human', 'Species', '9606', (76, 81))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('identified', 'Reg', (57, 67))	('FBW7', 'Gene', '55294', (32, 36))
48907	25753158	In this study, we first observed that low FBW7 expression correlated significantly with ERK activation in pancreatic cancer clinical samples, primarily due to KRAS mutations in pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (106, 123))	('KRAS mutations', 'Var', (159, 173))	('FBW7', 'Gene', (42, 46))	('clinical samples', 'Species', '191496', (124, 140))	('ERK', 'Gene', '5594', (88, 91))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (177, 194))	('FBW7', 'Gene', '55294', (42, 46))	('expression', 'MPA', (47, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('ERK', 'Gene', (88, 91))	('low', 'NegReg', (38, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (177, 194))	('mutations', 'Var', (164, 173))	('pancreatic cancer', 'Disease', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('activation', 'PosReg', (92, 102))	('pancreatic cancer', 'Disease', (177, 194))	('expression', 'Species', '29278', (47, 57))	('ERK', 'molecular_function', 'GO:0004707', ('88', '91'))
48909	25753158	Furthermore, the phospho-deficient T205A FBW7 mutant is resistant to ERK activation and could significantly suppress pancreatic cancer cell proliferation and tumorigenesis.	('tumor', 'Disease', (158, 163))	('ERK', 'Gene', '5594', (69, 72))	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cell proliferation', 'biological_process', 'GO:0008283', ('135', '153'))	('pancreatic cancer', 'Disease', (117, 134))	('FBW7', 'Gene', '55294', (41, 45))	('suppress', 'NegReg', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('ERK', 'molecular_function', 'GO:0004707', ('69', '72'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('FBW7', 'Gene', (41, 45))	('T205A', 'Var', (35, 40))	('ERK', 'Gene', (69, 72))	('T205A', 'Mutation', 'c.205T>A', (35, 40))
48910	25753158	These results collectively demonstrate how the oncogenic KRAS mutation inhibits the tumor suppressor FBW7, thus revealing an important function of KRAS mutations in promoting pancreatic cancer progression.	('FBW7', 'Gene', '55294', (101, 105))	('pancreatic cancer', 'Disease', 'MESH:D010190', (175, 192))	('pancreatic cancer', 'Disease', (175, 192))	('FBW7', 'Gene', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('mutations', 'Var', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('KRAS', 'Gene', (147, 151))	('tumor suppressor', 'biological_process', 'GO:0051726', ('84', '100'))	('KRAS', 'Gene', (57, 61))	('tumor', 'Disease', (84, 89))	('mutation', 'Var', (62, 70))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (175, 192))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('84', '100'))	('promoting', 'PosReg', (165, 174))	('inhibits', 'NegReg', (71, 79))
48917	25753158	For example, oncogenic mutations in genes such as KRAS and loss-of-function mutation of tumor suppressors, such as p53, CDNK2A/p16, DPC4/SMAD4 and BRCA2, are frequently observed in PDAC.	('BRCA2', 'Gene', (147, 152))	('PDAC', 'Chemical', '-', (181, 185))	('SMAD4', 'Gene', '4089', (137, 142))	('BRCA2', 'Gene', '675', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('p16', 'Gene', (127, 130))	('loss-of-function', 'NegReg', (59, 75))	('KRAS', 'Gene', (50, 54))	('p53', 'Gene', (115, 118))	('mutations', 'Var', (23, 32))	('PDAC', 'Disease', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('PDAC', 'Phenotype', 'HP:0006725', (181, 185))	('SMAD4', 'Gene', (137, 142))	('p16', 'Gene', '1029', (127, 130))	('mutation', 'Var', (76, 84))	('tumor', 'Disease', (88, 93))
48918	25753158	Mutations in KRAS were found in > 90% of patient specimens and were proposed to be initiators of PDAC.	('PDAC', 'Chemical', '-', (97, 101))	('patient', 'Species', '9606', (41, 48))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (13, 17))	('PDAC', 'Disease', (97, 101))	('PDAC', 'Phenotype', 'HP:0006725', (97, 101))
48919	25753158	In addition, inactivating mutations of CDKN2A were detected in almost 95% of PDAC cases, making this gene the most frequently mutated tumor suppressor.	('inactivating mutations', 'Var', (13, 35))	('CDKN2A', 'Gene', (39, 45))	('PDAC', 'Disease', (77, 81))	('PDAC', 'Phenotype', 'HP:0006725', (77, 81))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('134', '150'))	('CDKN2A', 'Gene', '1029', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('PDAC', 'Chemical', '-', (77, 81))	('tumor suppressor', 'biological_process', 'GO:0051726', ('134', '150'))	('tumor', 'Disease', (134, 139))
48920	25753158	In addition, mutations in p53, DPC4 and BRCA2 were identified in 75%, 50% and 5%-10% of PDAC cases, respectively.	('PDAC', 'Disease', (88, 92))	('DPC4', 'Gene', (31, 35))	('identified', 'Reg', (51, 61))	('PDAC', 'Phenotype', 'HP:0006725', (88, 92))	('p53', 'Gene', (26, 29))	('BRCA2', 'Gene', (40, 45))	('mutations', 'Var', (13, 22))	('PDAC', 'Chemical', '-', (88, 92))	('BRCA2', 'Gene', '675', (40, 45))
48921	25753158	Consistent with the genetic data, mouse models with activating KRAS mutations combined with p53 or DPC4 deletion exhibited accelerated PDAC development, supporting the idea of a complex synergistic pro-tumor effect involving the alteration of both oncogenes and tumor suppressor genes.	('PDAC', 'Phenotype', 'HP:0006725', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('262', '278'))	('tumor', 'Disease', (202, 207))	('PDAC development', 'CPA', (135, 151))	('tumor suppressor', 'biological_process', 'GO:0051726', ('262', '278'))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', (262, 267))	('accelerated', 'PosReg', (123, 134))	('activating', 'PosReg', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('KRAS', 'Gene', (63, 67))	('mouse', 'Species', '10090', (34, 39))	('p53', 'Gene', (92, 95))	('PDAC', 'Chemical', '-', (135, 139))	('mutations', 'Var', (68, 77))	('deletion', 'Var', (104, 112))	('DPC4', 'Gene', (99, 103))
48925	25753158	Indeed, deletion and mutation of FBW7 have been frequently identified in various human malignancies, such as gastric cancer, colon cancer, breast carcinoma, esophageal squamous cell carcinoma and intrahepatic cholangiocarcinoma.	('colon cancer', 'Disease', 'MESH:D015179', (125, 137))	('breast carcinoma', 'Disease', 'MESH:D001943', (139, 155))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (196, 227))	('identified', 'Reg', (59, 69))	('intrahepatic cholangiocarcinoma', 'Disease', (196, 227))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (209, 227))	('human', 'Species', '9606', (81, 86))	('colon cancer', 'Disease', (125, 137))	('breast carcinoma', 'Phenotype', 'HP:0003002', (139, 155))	('gastric cancer', 'Disease', (109, 123))	('FBW7', 'Gene', (33, 37))	('malignancies', 'Disease', 'MESH:D009369', (87, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('malignancies', 'Disease', (87, 99))	('breast carcinoma', 'Disease', (139, 155))	('FBW7', 'Gene', '55294', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('esophageal squamous cell carcinoma', 'Disease', (157, 191))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('colon cancer', 'Phenotype', 'HP:0003003', (125, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('mutation', 'Var', (21, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (157, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))	('deletion', 'Var', (8, 16))
48927	25753158	Overall, ~6% of human tumors harbor mutations in FBW7.	('FBW7', 'Gene', (49, 53))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('human', 'Disease', (16, 21))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('FBW7', 'Gene', '55294', (49, 53))	('human', 'Species', '9606', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (22, 28))
48928	25753158	Emerging evidence has also demonstrated that FBW7 is regulated by multiple protein factors, such as p53, Pin1, Hes-5 and Numb4, as well as microRNAs.	('Hes-5', 'Gene', (111, 116))	('Pin1', 'Gene', '5300', (105, 109))	('FBW7', 'Gene', '55294', (45, 49))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('Pin1', 'Gene', (105, 109))	('p53', 'Var', (100, 103))	('Hes-5', 'Gene', '388585', (111, 116))	('FBW7', 'Gene', (45, 49))
48935	25753158	Furthermore, overexpression of a phospho-deficient mutant of FBW7 (Thr205Ala) significantly reduced the tumorigenesis potential of PDAC cells both in vitro and in vivo.	('Thr205Ala', 'SUBSTITUTION', 'None', (67, 76))	('Thr205Ala', 'Var', (67, 76))	('expression', 'Species', '29278', (17, 27))	('FBW7', 'Gene', '55294', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('PDAC', 'Chemical', '-', (131, 135))	('overexpression', 'PosReg', (13, 27))	('FBW7', 'Gene', (61, 65))	('reduced', 'NegReg', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('PDAC', 'Phenotype', 'HP:0006725', (131, 135))
48938	25753158	To investigate the role of FBW7 in PDAC progression, we first determined the expression level of FBW7 in various human pancreatic cancer cell lines with KRAS mutations (Aspc-1, Capan-1, CFPAC-1, PANC-1, MIA PaCa-2 and SW1990).	('pancreatic cancer', 'Disease', (119, 136))	('PDAC', 'Phenotype', 'HP:0006725', (35, 39))	('FBW7', 'Gene', (97, 101))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (203, 213))	('FBW7', 'Gene', '55294', (27, 31))	('PDAC', 'Chemical', '-', (35, 39))	('Capan-1', 'CellLine', 'CVCL:0237', (177, 184))	('human', 'Species', '9606', (113, 118))	('PANC-1', 'CellLine', 'CVCL:0480', (195, 201))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (119, 136))	('CFPAC-1', 'CellLine', 'CVCL:1119', (186, 193))	('mutations', 'Var', (158, 167))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('FBW7', 'Gene', '55294', (97, 101))	('FBW7', 'Gene', (27, 31))	('expression', 'Species', '29278', (77, 87))	('SW1990', 'CellLine', 'CVCL:1723', (218, 224))	('pancreatic cancer', 'Disease', 'MESH:D010190', (119, 136))
48946	25753158	The Kaplan-Meier survival curves and log rank test showed that high FBW7 expression significantly correlated with better overall survival (OS) in PDAC (Figure 1C; n = 86, P = 0.029).	('FBW7', 'Gene', '55294', (68, 72))	('overall survival', 'MPA', (121, 137))	('PDAC', 'Chemical', '-', (146, 150))	('expression', 'Species', '29278', (73, 83))	('FBW7', 'Gene', (68, 72))	('expression', 'MPA', (73, 83))	('high', 'Var', (63, 67))	('better', 'PosReg', (114, 120))	('PDAC', 'Disease', (146, 150))	('PDAC', 'Phenotype', 'HP:0006725', (146, 150))
48952	25753158	To further support this point, an inverse correlation between the levels of Fbw7 and p-Erk was detected on slides containing samples derived from KrasG12D transgenic mice by IHC staining (Figure 2C).	('transgenic mice', 'Species', '10090', (155, 170))	('Erk', 'Gene', (87, 90))	('tween', 'Chemical', 'MESH:D011136', (56, 61))	('Erk', 'molecular_function', 'GO:0004707', ('87', '90'))	('KrasG12D', 'Var', (146, 154))	('Fbw7', 'Gene', (76, 80))	('G12D', 'Mutation', 'rs121913529', (150, 154))	('Erk', 'Gene', '26413', (87, 90))
48965	25753158	As expected, inhibition of the MAPK/ERK pathway dramatically extended the FBW7 half-life (Figure 3E and 3F).	('ERK', 'molecular_function', 'GO:0004707', ('36', '39'))	('ERK', 'Gene', '5594', (36, 39))	('FBW7', 'Gene', '55294', (74, 78))	('MAPK', 'molecular_function', 'GO:0004707', ('31', '35'))	('inhibition', 'Var', (13, 23))	('FBW7', 'Gene', (74, 78))	('ERK', 'Gene', (36, 39))	('extended', 'PosReg', (61, 69))
48972	25753158	According to a recent study, Threonine205-Proline206 is the only TP motif of FBW7, and this TP motif has been shown to be involved in FBW7 stability control.	('Threonine205', 'Chemical', '-', (29, 41))	('FBW7', 'Gene', '55294', (77, 81))	('TP', 'Chemical', '-', (65, 67))	('Threonine205-Proline206', 'Var', (29, 52))	('FBW7', 'Gene', '55294', (134, 138))	('Proline206', 'Chemical', '-', (42, 52))	('FBW7', 'Gene', (77, 81))	('TP', 'Chemical', '-', (92, 94))	('FBW7', 'Gene', (134, 138))
48976	25753158	After UO126 treatment, the phosphorylation of endogenous FBW7 in the PDAC cell line CFPAC-1 was significantly reduced when detected with a phospho-Threonine-Proline (TP) monoclonal antibody (p-Thr-Pro-101) that specifically recognizes the phosphorylated TP motif (Supplementary information, Figure S4B).	('PDAC', 'Phenotype', 'HP:0006725', (69, 73))	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('antibody', 'cellular_component', 'GO:0019815', ('181', '189'))	('FBW7', 'Gene', '55294', (57, 61))	('TP', 'Chemical', '-', (254, 256))	('reduced', 'NegReg', (110, 117))	('antibody', 'cellular_component', 'GO:0019814', ('181', '189'))	('PDAC', 'Chemical', '-', (69, 73))	('antibody', 'molecular_function', 'GO:0003823', ('181', '189'))	('TP', 'Chemical', '-', (166, 168))	('UO126', 'Var', (6, 11))	('phosphorylation', 'MPA', (27, 42))	('UO126', 'Chemical', 'MESH:C113580', (6, 11))	('Threonine-Proline', 'Chemical', '-', (147, 164))	('FBW7', 'Gene', (57, 61))	('antibody', 'cellular_component', 'GO:0042571', ('181', '189'))	('CFPAC-1', 'CellLine', 'CVCL:1119', (84, 91))
48981	25753158	Next, we conducted a series of experiments to determine whether T205 is indeed an ERK phosphorylation site.	('ERK', 'molecular_function', 'GO:0004707', ('82', '85'))	('phosphorylation', 'biological_process', 'GO:0016310', ('86', '101'))	('T205', 'Var', (64, 68))	('ERK', 'Gene', '5594', (82, 85))	('ERK', 'Gene', (82, 85))
48982	25753158	Notably, co-transfection of a constitutively active form of MEK1 (MEK1-CA) or ERK1 kinase dramatically increased the phosphorylation of wild-type FBW7 but not the T205A mutant, suggesting that MAPK kinase signaling indeed controls FBW7 phosphorylation status (Figure 5D and 5E).	('MEK1', 'Gene', '5604', (60, 64))	('T205A', 'Var', (163, 168))	('MAPK', 'molecular_function', 'GO:0004707', ('193', '197'))	('phosphorylation', 'biological_process', 'GO:0016310', ('236', '251'))	('FBW7', 'Gene', (146, 150))	('ERK1', 'molecular_function', 'GO:0004707', ('78', '82'))	('phosphorylation', 'biological_process', 'GO:0016310', ('117', '132'))	('ERK1', 'Gene', (78, 82))	('FBW7', 'Gene', '55294', (146, 150))	('ERK1', 'Gene', '5595', (78, 82))	('T205A', 'Mutation', 'c.205T>A', (163, 168))	('signaling', 'biological_process', 'GO:0023052', ('205', '214'))	('FBW7', 'Gene', (231, 235))	('phosphorylation', 'MPA', (117, 132))	('MEK1', 'Gene', '5604', (66, 70))	('FBW7', 'Gene', '55294', (231, 235))	('MEK1', 'Gene', (60, 64))	('MEK1', 'molecular_function', 'GO:0004708', ('60', '64'))	('MEK1', 'molecular_function', 'GO:0004708', ('66', '70'))	('increased', 'PosReg', (103, 112))	('MEK1-CA', 'Gene', (66, 73))	('MEK1', 'Gene', (66, 70))	('MEK1-CA', 'Gene', '5604', (66, 73))
48984	25753158	To prove that ERK kinase directly phosphorylates FBW7, glutathione S-transferase (GST)-fused recombinant FBW7 proteins, both wild type and T205A mutant, were incubated with purified HA-ERK1 kinase in the presence of ATP and detected with the p-FBW7 antibody.	('ERK', 'Gene', (14, 17))	('mutant', 'Var', (145, 151))	('T205A mutant', 'Var', (139, 151))	('FBW7', 'Gene', (105, 109))	('ERK', 'Gene', '5594', (185, 188))	('antibody', 'cellular_component', 'GO:0019815', ('249', '257'))	('FBW7', 'Gene', '55294', (105, 109))	('FBW7', 'Gene', (49, 53))	('GST', 'Gene', '373156', (82, 85))	('ERK1', 'molecular_function', 'GO:0004707', ('185', '189'))	('T205A', 'Mutation', 'c.205T>A', (139, 144))	('FBW7', 'Gene', '55294', (49, 53))	('glutathione S-transferase', 'Gene', '373156', (55, 80))	('ERK', 'Gene', (185, 188))	('antibody', 'cellular_component', 'GO:0019814', ('249', '257'))	('glutathione S-transferase', 'Gene', (55, 80))	('ERK', 'molecular_function', 'GO:0004707', ('14', '17'))	('ATP', 'Chemical', 'MESH:D000255', (216, 219))	('ERK1', 'Gene', (185, 189))	('ERK', 'Gene', '5594', (14, 17))	('FBW7', 'Gene', (244, 248))	('antibody', 'molecular_function', 'GO:0003823', ('249', '257'))	('ERK1', 'Gene', '5595', (185, 189))	('antibody', 'cellular_component', 'GO:0042571', ('249', '257'))	('FBW7', 'Gene', '55294', (244, 248))	('GST', 'Gene', (82, 85))
48985	25753158	As shown in Figure 5G, ERK kinase could also specifically phosphorylate FBW7 at T205 in vitro.	('T205', 'Var', (80, 84))	('FBW7', 'Gene', (72, 76))	('ERK', 'Gene', '5594', (23, 26))	('ERK', 'molecular_function', 'GO:0004707', ('23', '26'))	('ERK', 'Gene', (23, 26))	('FBW7', 'Gene', '55294', (72, 76))
48991	25753158	Notably, although MG132 treatment led to an increase in total FBW7 protein, the upregulation of phosphorylated FBW7 was much more dramatic (Supplementary information, Figure S5), suggesting that phosphorylated FBW7 is indeed highly unstable.	('MG132', 'Chemical', 'MESH:C072553', (18, 23))	('FBW7', 'Gene', (111, 115))	('upregulation', 'PosReg', (80, 92))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('MG132', 'Var', (18, 23))	('increase', 'PosReg', (44, 52))	('FBW7', 'Gene', '55294', (210, 214))	('protein', 'Protein', (67, 74))	('FBW7', 'Gene', '55294', (62, 66))	('FBW7', 'Gene', '55294', (111, 115))	('FBW7', 'Gene', (62, 66))	('FBW7', 'Gene', (210, 214))
48995	25753158	Furthermore, co-transfection of KrasG12D also significantly promoted the ubiquitination of FBW7 (Figure 6E).	('promoted', 'PosReg', (60, 68))	('FBW7', 'Gene', '55294', (91, 95))	('G12D', 'Mutation', 'rs121913529', (36, 40))	('KrasG12D', 'Var', (32, 40))	('FBW7', 'Gene', (91, 95))	('ubiquitination', 'MPA', (73, 87))
49000	25753158	Given the critical role of Thr205 phosphorylation in controlling FBW7 stability, we continued to assess how this phosphorylation inhibits FBW7 tumor suppressor function in PDAC.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('143', '159'))	('FBW7', 'Gene', '55294', (138, 142))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('PDAC', 'Chemical', '-', (172, 176))	('PDAC', 'Phenotype', 'HP:0006725', (172, 176))	('phosphorylation', 'biological_process', 'GO:0016310', ('113', '128'))	('phosphorylation', 'Var', (113, 128))	('PDAC', 'Disease', (172, 176))	('FBW7', 'Gene', '55294', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor suppressor', 'biological_process', 'GO:0051726', ('143', '159'))	('inhibits', 'NegReg', (129, 137))	('Thr205', 'Chemical', '-', (27, 33))	('FBW7', 'Gene', (65, 69))	('FBW7', 'Gene', (138, 142))
49001	25753158	First, we established SW1990 stable cell lines ectopically expressing wild-type FBW7 and a T205A phospho-deficient mutant, designated as SW1990/FBW7WT and SW1990/FBW7T205A respectively.	('SW1990', 'CellLine', 'CVCL:1723', (22, 28))	('FBW7', 'Gene', (162, 166))	('FBW7', 'Gene', (80, 84))	('T205A', 'Var', (91, 96))	('SW1990', 'CellLine', 'CVCL:1723', (137, 143))	('FBW7', 'Gene', '55294', (144, 148))	('T205A', 'Mutation', 'c.205T>A', (91, 96))	('SW1990', 'CellLine', 'CVCL:1723', (155, 161))	('FBW7', 'Gene', '55294', (162, 166))	('SW1990/FBW7T205A', 'CellLine', 'CVCL:1723', (155, 171))	('FBW7', 'Gene', '55294', (80, 84))	('FBW7', 'Gene', (144, 148))	('T205A', 'Mutation', 'c.205T>A', (166, 171))
49004	25753158	Furthermore, we also found that SW1990/FBW7T205A cells displayed a significant decrease in cell migration ability (Supplementary information, Figure S6A and S6B).	('cell migration', 'biological_process', 'GO:0016477', ('91', '105'))	('SW1990/FBW7T205A', 'CellLine', 'CVCL:1723', (32, 48))	('cell migration ability', 'CPA', (91, 113))	('decrease', 'NegReg', (79, 87))	('SW1990/FBW7T205A', 'Var', (32, 48))
49007	25753158	Taken together, these results suggested that the FBW7 T205A mutant conferred a growth disadvantage on pancreatic cancer cells both in vitro and in vivo.	('FBW7', 'Gene', (49, 53))	('T205A', 'Var', (54, 59))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('growth disadvantage', 'CPA', (79, 98))	('T205A', 'Mutation', 'c.205T>A', (54, 59))	('FBW7', 'Gene', '55294', (49, 53))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
49018	25753158	Generally, loss of function of tumor suppressors in cancer is frequently caused by mutation or deletion.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('deletion', 'Var', (95, 103))	('tumor', 'Disease', (31, 36))	('mutation', 'Var', (83, 91))	('loss of function', 'NegReg', (11, 27))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
49019	25753158	FBW7 is ranked among the most important tumor suppressors, with a relatively high mutation rate in cancer exceeded only by p53 and PTEN.	('PTEN', 'Gene', (131, 135))	('mutation', 'Var', (82, 90))	('PTEN', 'Gene', '5728', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('FBW7', 'Gene', '55294', (0, 4))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('FBW7', 'Gene', (0, 4))
49020	25753158	Mutation of FBW7 has previously been reported in several types of cancer.	('FBW7', 'Gene', '55294', (12, 16))	('FBW7', 'Gene', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Mutation', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('reported', 'Reg', (37, 45))	('cancer', 'Disease', (66, 72))
49021	25753158	Overall, ~6% of tumors exhibited mutations in FBW7, with the highest mutation rates found in cholangiocarcinoma (35%) and T-cell acute lymphoblastic leukemia (31%).	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (135, 157))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('cholangiocarcinoma', 'Disease', (93, 111))	('FBW7', 'Gene', (46, 50))	('mutations', 'Var', (33, 42))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (122, 157))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (122, 157))	('exhibited', 'Reg', (23, 32))	('T-cell acute lymphoblastic leukemia', 'Disease', (122, 157))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (93, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('leukemia', 'Phenotype', 'HP:0001909', (149, 157))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (129, 157))	('tumors', 'Disease', (16, 22))	('FBW7', 'Gene', '55294', (46, 50))
49022	25753158	However, in PDAC, FBW7 mutation was only reported in a study with limited samples (1 out of 11 samples).	('PDAC', 'Disease', (12, 16))	('mutation', 'Var', (23, 31))	('PDAC', 'Phenotype', 'HP:0006725', (12, 16))	('FBW7', 'Gene', '55294', (18, 22))	('PDAC', 'Chemical', '-', (12, 16))	('FBW7', 'Gene', (18, 22))
49024	25753158	Similarly, our own sequencing results from 60 individual patients showed that < 2% of specimens exhibited FBW7 mutation (1 out of 60 samples; Supplementary information, Table S2).	('exhibited', 'Reg', (96, 105))	('FBW7', 'Gene', '55294', (106, 110))	('patients', 'Species', '9606', (57, 65))	('FBW7', 'Gene', (106, 110))	('mutation', 'Var', (111, 119))
49025	25753158	These findings together suggest that FBW7 mutation is a rare event in PDAC.	('PDAC', 'Phenotype', 'HP:0006725', (70, 74))	('FBW7', 'Gene', '55294', (37, 41))	('FBW7', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('PDAC', 'Chemical', '-', (70, 74))
49031	25753158	KRAS mutation has been regarded as the most frequent oncogenic event in PDAC.	('PDAC', 'Disease', (72, 76))	('PDAC', 'Chemical', '-', (72, 76))	('KRAS', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('PDAC', 'Phenotype', 'HP:0006725', (72, 76))
49040	25753158	On one hand, ectopic expression of ERK1 significantly reduced the endogenous FBW7 protein level.	('ERK1', 'Gene', (35, 39))	('FBW7', 'Gene', '55294', (77, 81))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('expression', 'Species', '29278', (21, 31))	('ERK1', 'molecular_function', 'GO:0004707', ('35', '39'))	('reduced', 'NegReg', (54, 61))	('FBW7', 'Gene', (77, 81))	('ectopic expression', 'Var', (13, 31))	('ERK1', 'Gene', '5595', (35, 39))
49041	25753158	On the other hand, inhibition of the MAPK pathway dramatically increased endogenous FBW7 abundance.	('MAPK', 'molecular_function', 'GO:0004707', ('37', '41'))	('FBW7', 'Gene', '55294', (84, 88))	('increased', 'PosReg', (63, 72))	('inhibition', 'Var', (19, 29))	('MAPK pathway', 'Pathway', (37, 49))	('FBW7', 'Gene', (84, 88))	('endogenous', 'MPA', (73, 83))	('abundance', 'MPA', (89, 98))
49042	25753158	By contrast, inhibition of AKT kinase dramatically shortened Fbw7 half-life, indicating the PI3K/AKT pathway may play a different role in regulating Fbw7 stability (Supplementary information, Figure S3F and S3G).	('AKT', 'Gene', '207', (97, 100))	('AKT', 'Gene', (27, 30))	('Fbw7 half-life', 'MPA', (61, 75))	('inhibition', 'Var', (13, 23))	('AKT', 'Gene', (97, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('92', '96'))	('AKT', 'Gene', '207', (27, 30))	('shortened', 'NegReg', (51, 60))
49051	25753158	To dissect a possible role of self-ubiquitination in ERK-mediated FBW7 degradation, we generated a FBW7 R465H mutant that could not ubiquitinate substrates based on a previous report.	('FBW7', 'Gene', (66, 70))	('FBW7', 'Gene', '55294', (99, 103))	('ERK', 'Gene', '5594', (53, 56))	('ERK', 'molecular_function', 'GO:0004707', ('53', '56'))	('ERK', 'Gene', (53, 56))	('degradation', 'biological_process', 'GO:0009056', ('71', '82'))	('R465H', 'Mutation', 'rs1057519895', (104, 109))	('FBW7', 'Gene', '55294', (66, 70))	('FBW7', 'Gene', (99, 103))	('R465H', 'Var', (104, 109))
49052	25753158	As shown in Supplementary information, Figure S7A, R465H is more heavily ubiquitinated than WT FBW7, which is consistent with the previous report.	('FBW7', 'Gene', '55294', (95, 99))	('FBW7', 'Gene', (95, 99))	('R465H', 'Mutation', 'rs1057519895', (51, 56))	('R465H', 'Var', (51, 56))	('heavily ubiquitinated', 'MPA', (65, 86))
49053	25753158	Co-transfected ERK kinase could still promote poly-ubiquitination of the R465H mutant, which possibly indicates the involvement of other E3 ligases in FBW7 stability control, but the possibility of self-ubiquitination can not be formally excluded.	('ERK', 'molecular_function', 'GO:0004707', ('15', '18'))	('R465H', 'Var', (73, 78))	('ERK', 'Gene', '5594', (15, 18))	('ERK', 'Gene', (15, 18))	('poly-ubiquitination', 'MPA', (46, 65))	('FBW7', 'Gene', '55294', (151, 155))	('R465H', 'Mutation', 'rs1057519895', (73, 78))	('promote', 'PosReg', (38, 45))	('FBW7', 'Gene', (151, 155))
49054	25753158	Furthermore, we generated T205E FBW7 construct.	('T205E', 'Mutation', 'p.T205E', (26, 31))	('FBW7', 'Gene', (32, 36))	('FBW7', 'Gene', '55294', (32, 36))	('T205E', 'Var', (26, 31))
49055	25753158	As shown in Supplementary information, Figure S7B, T205E mutant failed to form homo-dimer as WT and T205A FBW7 did.	('FBW7', 'Gene', '55294', (106, 110))	('failed', 'NegReg', (64, 70))	('T205E', 'Mutation', 'p.T205E', (51, 56))	('FBW7', 'Gene', (106, 110))	('T205A', 'Var', (100, 105))	('T205A', 'Mutation', 'c.205T>A', (100, 105))	('T205E', 'Var', (51, 56))
49056	25753158	We also tested the ubiquitination potential of T205E, and interestingly T205E are less ubiquitinated than WT (Supplementary information, Figure S7C).	('tested', 'Reg', (8, 14))	('T205E', 'Mutation', 'p.T205E', (47, 52))	('ubiquitinated', 'MPA', (87, 100))	('T205E', 'Var', (47, 52))	('less', 'NegReg', (82, 86))	('T205E', 'Mutation', 'p.T205E', (72, 77))	('ubiquitination potential', 'MPA', (19, 43))	('T205E', 'Var', (72, 77))
49057	25753158	Although the T E mutation generated a negative charge at aa205, which is similar to what a phosphor group does after phosphorylation, Pin1 isomerase does not interact with EP motif and could not perform the cis-trans conversions.	('Pin1', 'Gene', (134, 138))	('phosphorylation', 'biological_process', 'GO:0016310', ('117', '132'))	('mutation', 'Var', (17, 25))	('aa205', 'Var', (57, 62))	('negative charge', 'MPA', (38, 53))	('Pin1', 'Gene', '5300', (134, 138))
49058	25753158	Thus, the T205E mutant may not be appropriate to be used to evaluate the regulatory effect involving Pin1.	('T205E', 'Mutation', 'p.T205E', (10, 15))	('Pin1', 'Gene', '5300', (101, 105))	('Pin1', 'Gene', (101, 105))	('T205E', 'Var', (10, 15))
49061	25753158	However, the functional role of FBW7 in PDAC progression has not yet been well studied, although a recent stem cell study reported that FBW7 deletion in the adult pancreatic ducts induces the direct conversion of ductal cells into beta cells.	('pancreatic', 'Disease', 'MESH:D010195', (163, 173))	('PDAC', 'Phenotype', 'HP:0006725', (40, 44))	('deletion', 'Var', (141, 149))	('pancreatic', 'Disease', (163, 173))	('FBW7', 'Gene', (32, 36))	('FBW7', 'Gene', '55294', (136, 140))	('PDAC', 'Chemical', '-', (40, 44))	('FBW7', 'Gene', (136, 140))	('induces', 'Reg', (180, 187))	('FBW7', 'Gene', '55294', (32, 36))
49067	25753158	Recent studies have shown that the expression levels of mutant KRAS and c-Myc share equal importance in the initiation and maintenance of pancreatic cancer.	('c-Myc', 'Gene', '4609', (72, 77))	('pancreatic cancer', 'Disease', (138, 155))	('expression', 'Species', '29278', (35, 45))	('mutant', 'Var', (56, 62))	('c-Myc', 'Gene', (72, 77))	('pancreatic cancer', 'Disease', 'MESH:D010190', (138, 155))	('expression', 'MPA', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))	('KRAS', 'Gene', (63, 67))
49068	25753158	Therefore, through the phosphorylation and inhibition of FBW7, the KRAS-MAPK axis may mainly rescue c-Myc expression to trigger a major alteration in the transcription profile towards malignancy and cell growth advantage.	('phosphorylation', 'biological_process', 'GO:0016310', ('23', '38'))	('MAPK', 'molecular_function', 'GO:0004707', ('72', '76'))	('FBW7', 'Gene', '55294', (57, 61))	('expression', 'Species', '29278', (106, 116))	('inhibition', 'NegReg', (43, 53))	('transcription profile', 'MPA', (154, 175))	('c-Myc', 'Gene', (100, 105))	('malignancy', 'Disease', 'MESH:D009369', (184, 194))	('cell growth', 'biological_process', 'GO:0016049', ('199', '210'))	('phosphorylation', 'Var', (23, 38))	('malignancy', 'Disease', (184, 194))	('rescue', 'NegReg', (93, 99))	('FBW7', 'Gene', (57, 61))	('transcription', 'biological_process', 'GO:0006351', ('154', '167'))	('c-Myc', 'Gene', '4609', (100, 105))
49070	25753158	In summary, by exploring signaling pathways unique to PDAC and absent from other types of cancer, we demonstrated for the first time that the oncogenic KRAS-MAPK signaling cascade, one of the major driving forces for PDAC progression, phosphorylates the tumor suppressor FBW7 at the T205 site and promotes FBW7 ubiquitination and destruction.	('destruction', 'MPA', (330, 341))	('signaling cascade', 'biological_process', 'GO:0007165', ('162', '179'))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('FBW7', 'Gene', (306, 310))	('PDAC', 'Phenotype', 'HP:0006725', (54, 58))	('tumor suppressor', 'biological_process', 'GO:0051726', ('254', '270'))	('FBW7', 'Gene', (271, 275))	('FBW7', 'Gene', '55294', (306, 310))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))	('ubiquitination', 'MPA', (311, 325))	('MAPK signaling', 'biological_process', 'GO:0000165', ('157', '171'))	('FBW7', 'Gene', '55294', (271, 275))	('phosphorylates', 'Var', (235, 249))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('promotes', 'PosReg', (297, 305))	('tumor', 'Disease', (254, 259))	('MAPK', 'molecular_function', 'GO:0004707', ('157', '161'))	('PDAC', 'Chemical', '-', (217, 221))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('PDAC', 'Phenotype', 'HP:0006725', (217, 221))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('254', '270'))	('PDAC', 'Chemical', '-', (54, 58))	('cancer', 'Disease', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
49071	25753158	Thus, the dysregulation of FBW7 substrates, such as c-Myc, promotes tumorigenesis and poor clinical prognosis (Figure 7H).	('tumor', 'Disease', (68, 73))	('c-Myc', 'Gene', '4609', (52, 57))	('poor clinical prognosis', 'CPA', (86, 109))	('c-Myc', 'Gene', (52, 57))	('dysregulation', 'Var', (10, 23))	('FBW7', 'Gene', '55294', (27, 31))	('clinical', 'Species', '191496', (91, 99))	('promotes', 'PosReg', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('FBW7', 'Gene', (27, 31))
49073	25753158	The human pancreatic cancer cell lines SW1990, PANC-1, CFPAC-1, Capan-1, MIA PaCa-2 and AsPC-1 with KRAS mutations were obtained from the American Type Culture Collection.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('human', 'Species', '9606', (4, 9))	('pancreatic cancer', 'Disease', 'MESH:D010190', (10, 27))	('pancreatic cancer', 'Disease', (10, 27))	('AsPC-1', 'CellLine', 'CVCL:0152', (88, 94))	('CFPAC-1', 'CellLine', 'CVCL:1119', (55, 62))	('PANC-1', 'CellLine', 'CVCL:0480', (47, 53))	('mutations', 'Var', (105, 114))	('Capan-1', 'CellLine', 'CVCL:0237', (64, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (10, 27))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (73, 83))	('SW1990', 'CellLine', 'CVCL:1723', (39, 45))
49089	25753158	The Flag-tagged coding sequence of human FBW7 or the relevant T205A mutant was cloned into the lentiviral vector pCDH-CMV-MCS-EF1-puro (SBI, USA) to generate FBW7 expression plasmids.	('MCS', 'cellular_component', 'GO:0044232', ('122', '125'))	('FBW7', 'Gene', (158, 162))	('FBW7', 'Gene', '55294', (41, 45))	('human', 'Species', '9606', (35, 40))	('FBW7', 'Gene', '55294', (158, 162))	('expression', 'Species', '29278', (163, 173))	('T205A', 'Var', (62, 67))	('T205A', 'Mutation', 'c.205T>A', (62, 67))	('FBW7', 'Gene', (41, 45))
49090	25753158	The first 300 amino acids of the human FBW7 protein and the T205A mutant were cloned into the pGEX-4T-1 vector to generate bacterial expression constructs.	('FBW7', 'Gene', '55294', (39, 43))	('T205A', 'Var', (60, 65))	('FBW7', 'Gene', (39, 43))	('T205A', 'Mutation', 'c.205T>A', (60, 65))	('human', 'Species', '9606', (33, 38))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('expression', 'Species', '29278', (133, 143))
49091	25753158	The expression vectors for HA-tagged MEK1 (WT-MEK) and constitutively active MEK1 (CA-MEK; in which the Raf1-dependent regulatory phosphorylation sites S218 and S222 were substituted by aspartic residues) were constructed as previously described.	('MEK1', 'Gene', '5604', (77, 81))	('MEK1', 'Gene', '5604', (37, 41))	('MEK', 'Gene', (86, 89))	('expression vectors', 'Species', '29278', (4, 22))	('MEK1', 'molecular_function', 'GO:0004708', ('77', '81'))	('MEK', 'Gene', (46, 49))	('MEK', 'Gene', (77, 80))	('Raf', 'Gene', (104, 107))	('MEK1', 'molecular_function', 'GO:0004708', ('37', '41'))	('MEK', 'Gene', '5609', (37, 40))	('MEK', 'Gene', (37, 40))	('MEK1', 'Gene', (37, 41))	('Raf', 'Gene', '22882', (104, 107))	('MEK1', 'Gene', (77, 81))	('phosphorylation', 'biological_process', 'GO:0016310', ('130', '145'))	('S218', 'Var', (152, 156))	('S222', 'Var', (161, 165))	('MEK', 'Gene', '5609', (86, 89))	('MEK', 'Gene', '5609', (46, 49))	('MEK', 'Gene', '5609', (77, 80))
49114	25753158	Forty-eight hours later, ERK1 was immunoprecipitated using an HA-matrix (Roche) and then incubated with 1 mug of GST-FBW7 protein (wild type and T205A mutant) in the presence of 200 muM cold ATP in kinase reaction buffer for 30 min.	('GST', 'Gene', '373156', (113, 116))	('FBW7', 'Gene', (117, 121))	('T205A', 'Mutation', 'c.205T>A', (145, 150))	('ERK1', 'molecular_function', 'GO:0004707', ('25', '29'))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('muM', 'Gene', (182, 185))	('ERK1', 'Gene', '5595', (25, 29))	('mug', 'molecular_function', 'GO:0043739', ('106', '109'))	('ERK1', 'Gene', (25, 29))	('GST', 'Gene', (113, 116))	('FBW7', 'Gene', '55294', (117, 121))	('muM', 'Gene', '56925', (182, 185))	('ATP', 'Chemical', 'MESH:D000255', (191, 194))	('T205A', 'Var', (145, 150))
49129	25310976	Deletion of two co-receptors (Gas1 and Boc) in fibroblasts reduces HH-responsiveness.	('HH-responsiveness', 'Disease', (67, 84))	('Boc', 'Gene', (39, 42))	('reduces', 'NegReg', (59, 66))	('HH-responsiveness', 'Disease', 'MESH:D006432', (67, 84))	('Gas1', 'Gene', (30, 34))	('Deletion', 'Var', (0, 8))
49131	25310976	In contrast, deletion of all three co-receptors (Gas1, Boc and Cdon) results in the near complete abrogation of HH signaling and a corresponding failure to promote tumorigenesis and angiogenesis.	('Cdon', 'Gene', '57810', (63, 67))	('tumor', 'Disease', (164, 169))	('Gas1', 'Gene', (49, 53))	('Cdon', 'Gene', (63, 67))	('deletion', 'Var', (13, 21))	('abrogation', 'NegReg', (98, 108))	('angiogenesis', 'CPA', (182, 194))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('angiogenesis', 'biological_process', 'GO:0001525', ('182', '194'))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('HH signaling', 'MPA', (112, 124))	('Boc', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('failure', 'NegReg', (145, 152))	('promote', 'PosReg', (156, 163))
49133	25310976	Pancreatic cancer, one of the deadliest human malignancies, is almost invariably associated with oncogenic mutations of Kras and the inappropriate activation of embryonic signaling pathways.	('embryonic signaling pathways', 'Pathway', (161, 189))	('Pancreatic cancer', 'Disease', (0, 17))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('signaling', 'biological_process', 'GO:0023052', ('171', '180'))	('Kras', 'Gene', (120, 124))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('malignancies', 'Disease', 'MESH:D009369', (46, 58))	('associated', 'Reg', (81, 91))	('malignancies', 'Disease', (46, 58))	('human', 'Species', '9606', (40, 45))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
49135	25310976	Notably, tissue-specific expression of mutant Kras in mice recapitulates the step-wise progression of the human disease and constitutes a reasonable mouse model of pancreatic cancer.	('recapitulates', 'Reg', (59, 72))	('Kras', 'Gene', (46, 50))	('pancreatic cancer', 'Disease', (164, 181))	('human', 'Species', '9606', (106, 111))	('pancreatic cancer', 'Disease', 'MESH:D010190', (164, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (164, 181))	('mouse', 'Species', '10090', (149, 154))	('mutant', 'Var', (39, 45))	('mice', 'Species', '10090', (54, 58))	('step-wise progression', 'CPA', (77, 98))
49139	25310976	De-repression of SMO results in a cascade of events that ultimately leads to the activation of GLI transcription factors and modulated target gene expression.	('modulated', 'Reg', (125, 134))	('SMO', 'Gene', (17, 20))	('GLI transcription factors', 'Gene', (95, 120))	('De-repression', 'Var', (0, 13))	('gene expression', 'biological_process', 'GO:0010467', ('142', '157'))	('transcription', 'biological_process', 'GO:0006351', ('99', '112'))	('activation', 'PosReg', (81, 91))	('SMO', 'Gene', '319757', (17, 20))
49144	25310976	While SMO inhibition in the clinic has met with initial success, the emergence of drug-resistant Smo mutations in tumors underscores the need for alternative approaches to restrict HH pathway function.	('SMO', 'Gene', (6, 9))	('SMO', 'Gene', '319757', (6, 9))	('Smo', 'Gene', (97, 100))	('mutations', 'Var', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('Smo', 'Gene', '319757', (97, 100))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
49151	25310976	Counter to prevailing paradigms, while deletion of two co-receptors (Gas1 and Boc) in pancreatic fibroblasts led to reduced HH-responsiveness, this resulted in increased tumor growth.	('pancreatic', 'Disease', (86, 96))	('Gas1', 'Gene', (69, 73))	('increased tumor', 'Disease', 'MESH:D009369', (160, 175))	('Boc', 'Gene', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('deletion', 'Var', (39, 47))	('HH-responsiveness', 'Disease', (124, 141))	('pancreatic', 'Disease', 'MESH:D010195', (86, 96))	('reduced', 'NegReg', (116, 123))	('HH-responsiveness', 'Disease', 'MESH:D006432', (124, 141))	('increased tumor', 'Disease', (160, 175))
49152	25310976	In contrast, deletion of all three co-receptors (Gas1, Boc and Cdon) abrogated HH signaling and blocked tumor promotion.	('Cdon', 'Gene', '57810', (63, 67))	('abrogated', 'NegReg', (69, 78))	('signaling', 'biological_process', 'GO:0023052', ('82', '91'))	('HH signaling', 'MPA', (79, 91))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Gas1', 'Gene', (49, 53))	('tumor', 'Disease', (104, 109))	('Cdon', 'Gene', (63, 67))	('deletion', 'Var', (13, 21))	('blocked', 'NegReg', (96, 103))	('Boc', 'Gene', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
49156	25310976	To determine if Gas1, Boc and Cdon were expressed in the normal pancreas, during pancreatitis, and/or in the neoplastic pancreas, we harvested pancreata from adult wildtype or Ptf1aCre;LSL-KrasG12D (KC) mice.	('Ptf1aCre', 'Var', (176, 184))	('pancreatitis', 'Disease', (81, 93))	('neoplastic pancreas', 'Disease', 'MESH:D010190', (109, 128))	('Cdon', 'Gene', (30, 34))	('mice', 'Species', '10090', (203, 207))	('neoplastic pancreas', 'Disease', (109, 128))	('neoplastic pancreas', 'Phenotype', 'HP:0002894', (109, 128))	('pancreatitis', 'Phenotype', 'HP:0001733', (81, 93))	('pancreatitis', 'Disease', 'MESH:D010195', (81, 93))	('Ptf1', 'Species', '32651', (176, 180))	('Cdon', 'Gene', '57810', (30, 34))
49171	25310976	Finally, we performed RT-qPCR analysis of primary mouse pancreatic tumor cells, fibroblasts, and flow-sorted macrophages from the Pft1a-Cre;LSL-KrasG12D;p53R172H/+(KPC) and iKras pancreatic cancer models.	('iKras pancreatic cancer', 'Disease', (173, 196))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (56, 72))	('p53R172H/+', 'Var', (153, 163))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('iKras pancreatic cancer', 'Disease', 'MESH:D010190', (173, 196))	('pancreatic tumor', 'Disease', 'MESH:D010190', (56, 72))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (179, 196))	('mouse', 'Species', '10090', (50, 55))	('pancreatic tumor', 'Disease', (56, 72))
49189	25310976	Thus, we predicted that Gas1-/-;Boc-/- fibroblasts would display reduced tumor-promoting ability compared to wildtype cells.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('reduced', 'NegReg', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Gas1-/-', 'Var', (24, 31))	('tumor', 'Disease', (73, 78))
49190	25310976	To test this hypothesis, we co-injected the human pancreatic cancer cell lines Hs766T and MiaPaCa with either wildtype or Gas1-/-;Boc-/- MEFs in immune compromised mice (Figure 2B).	('human', 'Species', '9606', (44, 49))	('Gas1-/-', 'Var', (122, 129))	('MEFs', 'CellLine', 'CVCL:9115', (137, 141))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 67))	('mice', 'Species', '10090', (164, 168))	('Hs766T', 'CellLine', 'CVCL:0334', (79, 85))	('pancreatic cancer', 'Disease', (50, 67))	('pancreatic cancer', 'Disease', 'MESH:D010190', (50, 67))	('MiaPaCa', 'CellLine', 'CVCL:0428', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
49191	25310976	Surprisingly, tumor cells co-injected with Gas1-/-;Boc-/- MEFs grew significantly larger than tumor cells injected alone or co-injected with wildtype fibroblasts (Figure 2C,D and Figure S2A).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', (94, 99))	('MEFs', 'CellLine', 'CVCL:9115', (58, 62))	('Gas1-/-;Boc-/-', 'Var', (43, 57))	('Boc-/-', 'Var', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('larger', 'PosReg', (82, 88))	('grew', 'CPA', (63, 67))
49193	25310976	However, blood vessel density was dramatically increased in tumors coinjected with Gas1-/-;Boc-/- fibroblasts compared to tumor cells alone or co-injected with wildtype fibroblasts (Figure 2C,E).	('Gas1-/-;Boc-/-', 'Var', (83, 97))	('blood vessel density', 'CPA', (9, 29))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('increased', 'PosReg', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (122, 127))	('tumors', 'Disease', (60, 66))
49203	25310976	However, CD31 immunostaining revealed a dramatic increase in vasculature within tumors co-injected with Gas1-/-;Boc-/- pancreatic fibroblasts (Figures 2G and 2I).	('CD31', 'Gene', '18613', (9, 13))	('increase', 'PosReg', (49, 57))	('vasculature within tumors', 'Disease', 'MESH:D001929', (61, 86))	('CD31', 'Gene', (9, 13))	('vasculature within tumors', 'Disease', (61, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('pancreatic', 'Disease', 'MESH:D010195', (119, 129))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('Gas1-/-', 'Var', (104, 111))	('pancreatic', 'Disease', (119, 129))
49205	25310976	Thus, stromal deletion of Gas1 and Boc results in attenuated HH-responsiveness that paradoxically increases tumor growth.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('HH-responsiveness', 'Disease', (61, 78))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('increases', 'PosReg', (98, 107))	('tumor', 'Disease', (108, 113))	('HH-responsiveness', 'Disease', 'MESH:D006432', (61, 78))	('Boc', 'Gene', (35, 38))	('attenuated', 'NegReg', (50, 60))	('deletion', 'Var', (14, 22))	('Gas1', 'Gene', (26, 30))
49211	25310976	We co-transplanted 1319 tumor cells alone, or with three different cohorts of MEFs: wildtype, Gas1-/-Boc-/- and Gas1-/-Boc-/-;Cdon-/- (Figure 3B).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('MEFs', 'CellLine', 'CVCL:9115', (78, 82))	('tumor', 'Disease', (24, 29))	('Cdon', 'Gene', (126, 130))	('Gas1-/-Boc-/-', 'Var', (94, 107))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('Cdon', 'Gene', '57810', (126, 130))
49212	25310976	Again, wildtype MEFs promoted tumor growth compared to tumor cells alone, and Gas1-/-Boc-/- MEFs promoted tumor growth further (Figure 3C).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('MEFs', 'CellLine', 'CVCL:9115', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('promoted', 'PosReg', (21, 29))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('Gas1-/-Boc-/-', 'Var', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (30, 35))	('promoted', 'PosReg', (97, 105))	('tumor', 'Disease', (106, 111))	('MEFs', 'CellLine', 'CVCL:9115', (92, 96))
49213	25310976	In contrast, tumors co-injected with Gas1-/-;Boc-/-;Cdon-/- MEFs were comparable both in growth rate and size at dissection to tumor cells alone (Figures 3C and 3D).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (13, 18))	('Gas1-/-', 'Var', (37, 44))	('MEFs', 'CellLine', 'CVCL:9115', (60, 64))	('tumors', 'Disease', (13, 19))	('Cdon', 'Gene', '57810', (52, 56))	('tumor', 'Disease', (127, 132))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('Cdon', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
49215	25310976	While cell death was similar in all experimental cohorts, we detected increased intratumoral proliferation in co-injections with tumor cells and Gas1-/-Boc-/- MEFs; this effect was abrogated in co-injections with Gas1-/-;Boc-/-;Cdon-/- MEFs (Figure S3A).	('tumor', 'Disease', (85, 90))	('MEFs', 'CellLine', 'CVCL:9115', (236, 240))	('tumor', 'Disease', (129, 134))	('increased', 'PosReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('MEFs', 'CellLine', 'CVCL:9115', (159, 163))	('Cdon', 'Gene', '57810', (228, 232))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cell death', 'biological_process', 'GO:0008219', ('6', '16'))	('Gas1-/-Boc-/- MEFs', 'Var', (145, 163))	('Cdon', 'Gene', (228, 232))
49220	25310976	Genetic inactivation of Shh in multiple mouse models of pancreatic cancer resulted in variable reduction of stroma accumulation in different settings.	('Genetic inactivation', 'Var', (0, 20))	('stroma accumulation', 'Disease', 'MESH:C579880', (108, 127))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (56, 73))	('pancreatic cancer', 'Disease', (56, 73))	('stroma accumulation', 'Disease', (108, 127))	('pancreatic cancer', 'Disease', 'MESH:D010190', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('reduction', 'NegReg', (95, 104))	('mouse', 'Species', '10090', (40, 45))	('Shh', 'Gene', (24, 27))	('Shh', 'Gene', '20423', (24, 27))
49224	25310976	While the accumulation of fibroblasts within the stroma did not change, the number of blood vessels was significantly increased in tumors co-injected with Gas1-/-Boc-/- MEFs but not in tumors co-injected with Gas1-/-;Boc-/-;Cdon-/- MEFs compared with control, as quantified by CD31 immunostaining (Figures 3E and 3F).	('MEFs', 'CellLine', 'CVCL:9115', (232, 236))	('CD31', 'Gene', '18613', (277, 281))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Disease', (185, 191))	('Cdon', 'Gene', (224, 228))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('CD31', 'Gene', (277, 281))	('number of blood vessels', 'CPA', (76, 99))	('increased', 'PosReg', (118, 127))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumors', 'Disease', (131, 137))	('Gas1-/-Boc-/- MEFs', 'Var', (155, 173))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('MEFs', 'CellLine', 'CVCL:9115', (169, 173))	('Cdon', 'Gene', '57810', (224, 228))
49225	25310976	A similar increase in vasculature was previously observed following genetic ablation of Shh or following drug-mediated inhibition of SMO, although the mechanism remained to be investigated.	('vasculature', 'MPA', (22, 33))	('genetic ablation', 'Var', (68, 84))	('Shh', 'Gene', (88, 91))	('SMO', 'Gene', '319757', (133, 136))	('Shh', 'Gene', '20423', (88, 91))	('SMO', 'Gene', (133, 136))	('increase', 'PosReg', (10, 18))
49229	25310976	In both Gas1-/- Boc-/- MEFs and pancreatic fibroblasts, Angpt2 was upregulated compared to control pancreatic fibroblasts and MEFs respectively; in contrast, Angpt2 expression in Gas1-/-;Boc-/-;Cdon-/- MEFs was comparable to wildtype MEFS (Figures 4A and 4B).	('Gas1-/-', 'Var', (179, 186))	('pancreatic', 'Disease', 'MESH:D010195', (99, 109))	('Angpt2', 'Gene', (158, 164))	('upregulated', 'PosReg', (67, 78))	('MEFs', 'CellLine', 'CVCL:9115', (23, 27))	('Angpt2', 'Gene', '11601', (56, 62))	('MEF', 'Gene', '56501', (23, 26))	('MEFs', 'CellLine', 'CVCL:9115', (126, 130))	('pancreatic', 'Disease', (99, 109))	('MEF', 'Gene', '56501', (126, 129))	('Angpt2', 'Gene', '11601', (158, 164))	('Cdon', 'Gene', (194, 198))	('pancreatic', 'Disease', 'MESH:D010195', (32, 42))	('MEF', 'Gene', (23, 26))	('MEFs', 'CellLine', 'CVCL:9115', (202, 206))	('MEF', 'Gene', (126, 129))	('Cdon', 'Gene', '57810', (194, 198))	('MEF', 'Gene', '56501', (234, 237))	('MEF', 'Gene', '56501', (202, 205))	('pancreatic', 'Disease', (32, 42))	('MEF', 'Gene', (202, 205))	('MEF', 'Gene', (234, 237))	('Angpt2', 'Gene', (56, 62))
49230	25310976	The expression of other angiogenic factors varied between MEFs and pancreatic fibroblasts, although in all cases, reduced HH signaling resulted in increased expression of angiogenic factors, while the abrogation of HH signaling inhibited angiogenic gene expression (Figures 4A and 4B).	('pancreatic', 'Disease', 'MESH:D010195', (67, 77))	('HH signaling', 'MPA', (122, 134))	('inhibited', 'NegReg', (228, 237))	('increased', 'PosReg', (147, 156))	('abrogation', 'Var', (201, 211))	('expression', 'MPA', (157, 167))	('gene expression', 'biological_process', 'GO:0010467', ('249', '264'))	('reduced', 'NegReg', (114, 121))	('pancreatic', 'Disease', (67, 77))	('MEFs', 'CellLine', 'CVCL:9115', (58, 62))	('signaling', 'biological_process', 'GO:0023052', ('218', '227'))	('angiogenic gene', 'Gene', (238, 253))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('reduced HH signaling', 'Phenotype', 'HP:0011905', (114, 134))	('angiogenic', 'Protein', (171, 181))
49231	25310976	For example, Angpt1 expression was significantly upregulated in Gas1-/-;Boc-/- pancreatic fibroblasts (Figure 4A), while VEGFa, previously described as a HH target in stromal perivascular cells was upregulated in Gas1-/-;Boc-/- MEFs (Figure 4B).	('Gas1-/-', 'Var', (64, 71))	('upregulated', 'PosReg', (198, 209))	('expression', 'MPA', (20, 30))	('VEGFa', 'Gene', (121, 126))	('VEGFa', 'Gene', '22339', (121, 126))	('pancreatic', 'Disease', 'MESH:D010195', (79, 89))	('Angpt1', 'Gene', (13, 19))	('upregulated', 'PosReg', (49, 60))	('pancreatic', 'Disease', (79, 89))	('MEFs', 'CellLine', 'CVCL:9115', (228, 232))	('Angpt1', 'Gene', '11600', (13, 19))
49237	25310976	Gas1-/-;Boc-/- pancreatic fibroblasts and MEFs implanted alone atop the CAM induced the formation of more blood vessels than wildtype MEFs.	('formation', 'biological_process', 'GO:0009058', ('88', '97'))	('CAM', 'Gene', (72, 75))	('pancreatic', 'Disease', (15, 25))	('Gas1-/-', 'Var', (0, 7))	('CAM', 'Gene', '71817', (72, 75))	('MEFs', 'CellLine', 'CVCL:9115', (134, 138))	('MEFs', 'CellLine', 'CVCL:9115', (42, 46))	('formation', 'CPA', (88, 97))	('pancreatic', 'Disease', 'MESH:D010195', (15, 25))
49263	25310976	Primary mouse pancreatic fibroblast lines were derived from E18.5 wildtype or Gas1-/-;Boc-/- pancreata.	('pancreatic', 'Disease', 'MESH:D010195', (14, 24))	('pancreatic', 'Disease', (14, 24))	('E18.5', 'Var', (60, 65))	('mouse', 'Species', '10090', (8, 13))
49267	25183455	miR-337 regulates the proliferation and invasion in pancreatic ductal adenocarcinoma by targeting HOXB7 miRNAs are involved in coordinating a variety of cellular processes by regulating their target genes.	('regulates', 'Reg', (8, 17))	('targeting', 'Var', (88, 97))	('invasion', 'CPA', (40, 48))	('regulating', 'Reg', (175, 185))	('miR-337', 'Gene', '442905', (0, 7))	('miR-337', 'Gene', (0, 7))	('proliferation', 'CPA', (22, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('involved', 'Reg', (115, 123))	('HOXB7', 'Gene', (98, 103))	('pancreatic ductal adenocarcinoma', 'Disease', (52, 84))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (52, 84))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (52, 84))
49268	25183455	Aberrant expression of miRNAs is correlated with various cancers.	('Aberrant expression', 'Var', (0, 19))	('miRNAs', 'Protein', (23, 29))	('correlated', '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))
49280	25183455	Aberrant expression of miRNAs has been found to be related to various human diseases, including cancers.	('Aberrant expression', 'Var', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('miRNAs', 'Gene', (23, 29))	('human', 'Species', '9606', (70, 75))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('related', 'Reg', (51, 58))	('cancers', 'Disease', (96, 103))
49288	25183455	The miRNA miR-337 may repress tumor cell proliferation and metastasis by targeting HOXB7.	('HOXB7', 'Gene', (83, 88))	('cell proliferation', 'biological_process', 'GO:0008283', ('36', '54'))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('targeting', 'Reg', (73, 82))	('miR-337', 'Gene', '442905', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('miR-337', 'Gene', (10, 17))	('repress', 'NegReg', (22, 29))	('tumor', 'Disease', (30, 35))	('HOXB7', 'Gene', '3217', (83, 88))	('miRNA', 'Var', (4, 9))
49299	25183455	Membranes were probed overnight at 4 C with antibody recognizing HOXB7 (1:600, Santa Cruz), or GAPDH (1:2000, Santa Cruz) in TBST containing 1% BSA (w/v).	('GAPDH', 'Gene', (95, 100))	('TBST', 'Chemical', '-', (125, 129))	('antibody', 'cellular_component', 'GO:0042571', ('44', '52'))	('HOXB7', 'Gene', (65, 70))	('1:2000', 'Var', (102, 108))	('antibody', 'molecular_function', 'GO:0003823', ('44', '52'))	('antibody', 'cellular_component', 'GO:0019815', ('44', '52'))	('antibody', 'cellular_component', 'GO:0019814', ('44', '52'))	('HOXB7', 'Gene', '3217', (65, 70))	('1:600', 'Var', (72, 77))
49311	25183455	In order to further support these results, two reporter plasmids carrying a wild-type HOXB7 3'UTR and a mutant HOXB7 3'UTR, respectively, were constructed.	('HOXB7', 'Gene', '3217', (86, 91))	('HOXB7', 'Gene', '3217', (111, 116))	('HOXB7', 'Gene', (86, 91))	('HOXB7', 'Gene', (111, 116))	('mutant', 'Var', (104, 110))
49313	25183455	The inhibitory effect was completely abrogated with pmirGLO-HOXB7-MUT, which contained a mutation in the miR-337 binding site (Figure 1C, D).	('binding', 'molecular_function', 'GO:0005488', ('113', '120'))	('miR-337', 'Gene', (105, 112))	('mutation', 'Var', (89, 97))	('abrogated', 'NegReg', (37, 46))	('HOXB7', 'Gene', '3217', (60, 65))	('inhibitory effect', 'MPA', (4, 21))	('HOXB7', 'Gene', (60, 65))	('miR-337', 'Gene', '442905', (105, 112))
49318	25183455	For a wound healing assay, PANC-1 (or As-PC-1) cells transfected with miR-337 mimics at 36 h after incubation exhibited a slower rate of invasion than that of miR-337 NC and untransfected group (Figure 3A).	('mimics', 'Var', (78, 84))	('slower', 'NegReg', (122, 128))	('wound healing', 'biological_process', 'GO:0042060', ('6', '19'))	('invasion', 'CPA', (137, 145))	('miR-337', 'Gene', '442905', (70, 77))	('miR-337', 'Gene', (70, 77))	('miR-337', 'Gene', '442905', (159, 166))	('As-PC-1', 'CellLine', 'CVCL:0152', (38, 45))	('miR-337', 'Gene', (159, 166))	('PANC-1', 'CellLine', 'CVCL:0480', (27, 33))
49324	25183455	Dysregulation of HOX gene expression is common in human cancers.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('Dysregulation', 'Var', (0, 13))	('HOX gene', 'Gene', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('gene expression', 'biological_process', 'GO:0010467', ('21', '36'))	('human', 'Species', '9606', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
49353	23603750	Mehlen and Puisieux have reviewed the importance of the development of inappropriate cell survival signalling for various steps in the metastatic process and have noted the particular importance of aberrant cell survival to successful colonization at the metastatic site.	('al', 'Chemical', 'MESH:D000535', (103, 105))	('al', 'Chemical', 'MESH:D000535', (96, 98))	('signalling', 'biological_process', 'GO:0023052', ('99', '109'))	('al', 'Chemical', 'MESH:D000535', (218, 220))	('cell survival signalling', 'MPA', (85, 109))	('aberrant', 'Var', (198, 206))
49398	23603750	PDPK1 phosphorylates Akt at Ser473 and PDK2 phosphorylates Akt at Thr308.	('Akt', 'Pathway', (21, 24))	('PDK2', 'Gene', (39, 43))	('Akt', 'Pathway', (59, 62))	('Thr308', 'Chemical', '-', (66, 72))	('Ser473', 'Chemical', '-', (28, 34))	('Ser473', 'Var', (28, 34))	('PDPK1', 'Gene', '5170', (0, 5))	('PDPK1', 'Gene', (0, 5))	('PDK2', 'molecular_function', 'GO:0004740', ('39', '43'))	('PDK2', 'Gene', '5164', (39, 43))	('Ser', 'cellular_component', 'GO:0005790', ('28', '31'))
49399	23603750	The dual activation of Akt at Ser473 and Thr308 phosphorylation sites elicits a broad range of downstream signalling events as shown in Figure 2.	('activation', 'PosReg', (9, 19))	('al', 'Chemical', 'MESH:D000535', (6, 8))	('elicits', 'Reg', (70, 77))	('al', 'Chemical', 'MESH:D000535', (110, 112))	('Thr308', 'Chemical', '-', (41, 47))	('Ser473', 'Var', (30, 36))	('signalling', 'biological_process', 'GO:0023052', ('106', '116'))	('Ser473', 'Chemical', '-', (30, 36))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))	('Ser', 'cellular_component', 'GO:0005790', ('30', '33'))	('Akt', 'Pathway', (23, 26))	('Thr308', 'Var', (41, 47))
49401	23603750	Deletion, mutation and hypermethylation of PTEN are observed in various cancer conditions thus resulting in elevated Akt activity.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('Deletion', 'Var', (0, 8))	('mutation', 'Var', (10, 18))	('PTEN', 'Gene', (43, 47))	('PTEN', 'Gene', '5728', (43, 47))	('Akt activity', 'CPA', (117, 129))	('hypermethylation', 'Var', (23, 39))	('elevated', 'PosReg', (108, 116))	('cancer', 'Disease', (72, 78))
49425	23603750	Variable phenotypic differences are observed following the genetic inactivation and/or removal of the Akt isoforms.	('al', 'Chemical', 'MESH:D000535', (92, 94))	('Akt', 'Protein', (102, 105))	('genetic inactivation', 'Var', (59, 79))	('removal', 'NegReg', (87, 94))
49426	23603750	Akt1 knockout mice exhibit retardation in growth and an increase in perinatal lethality.	('perinatal lethality', 'CPA', (68, 87))	('Akt1', 'Gene', (0, 4))	('growth', 'CPA', (42, 48))	('increase', 'PosReg', (56, 64))	('knockout', 'Var', (5, 13))	('mice', 'Species', '10090', (14, 18))	('retardation', 'Disease', (27, 38))	('retardation in growth', 'Phenotype', 'HP:0001510', (27, 48))	('al', 'Chemical', 'MESH:D000535', (75, 77))	('retardation', 'Disease', 'MESH:D008607', (27, 38))	('al', 'Chemical', 'MESH:D000535', (82, 84))
49427	23603750	Removal of Akt2 in mice results in insulin resistance and diabetes mellitus whereas Akt3 knockout results in reduction in brain size and development.	('insulin resistance', 'Phenotype', 'HP:0000855', (35, 53))	('diabetes mellitus', 'Disease', 'MESH:D003920', (58, 75))	('insulin', 'molecular_function', 'GO:0016088', ('35', '42'))	('Removal', 'Var', (0, 7))	('reduction', 'NegReg', (109, 118))	('results in', 'Reg', (24, 34))	('Akt3', 'Gene', (84, 88))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (58, 75))	('insulin', 'Gene', (35, 42))	('al', 'Chemical', 'MESH:D000535', (5, 7))	('Akt2', 'Gene', (11, 15))	('mice', 'Species', '10090', (19, 23))	('insulin', 'Gene', '3630', (35, 42))	('diabetes mellitus', 'Disease', (58, 75))
49430	23603750	Akt1 amplification is commonly observed in gastric cancer cells and knockdown of Akt1 increases the sensitivity of gastric cancer cells to chemotherapy as determined by treatment with cisplatin.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Akt1', 'Gene', (81, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('increases', 'PosReg', (86, 95))	('gastric cancer', 'Disease', 'MESH:D013274', (43, 57))	('gastric cancer', 'Disease', (43, 57))	('sensitivity', 'MPA', (100, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (184, 193))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('knockdown', 'Var', (68, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (43, 57))	('gastric cancer', 'Disease', (115, 129))
49431	23603750	Akt1 knockdown in gastric cancer cells increases the expression of Bax and reduces the expression of Bcl2 thus increasing cell death in vitro and in vivo.	('gastric cancer', 'Disease', (18, 32))	('Akt1', 'Gene', (0, 4))	('cell death', 'CPA', (122, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (18, 32))	('knockdown', 'Var', (5, 14))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('Bcl2', 'molecular_function', 'GO:0015283', ('101', '105'))	('Bcl2', 'Gene', (101, 105))	('expression', 'MPA', (87, 97))	('increasing', 'PosReg', (111, 121))	('reduces', 'NegReg', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('expression', 'MPA', (53, 63))	('increases', 'PosReg', (39, 48))	('Bax', 'Protein', (67, 70))	('cell death', 'biological_process', 'GO:0008219', ('122', '132'))
49441	23603750	However, CRC that originates due to DNA mismatch repair deficiency resulting in microsatellite instability (MSI) are usually associated with inactivating mutations of the pro-apoptotic BAX protein.	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('CRC', 'Disease', (9, 12))	('mismatch repair', 'biological_process', 'GO:0006298', ('40', '55'))	('BAX', 'Gene', (185, 188))	('microsatellite instability', 'MPA', (80, 106))	('associated', 'Reg', (125, 135))	('inactivating mutations', 'Var', (141, 163))	('BAX', 'Gene', '581', (185, 188))	('CRC', 'Phenotype', 'HP:0003003', (9, 12))	('deficiency', 'Var', (56, 66))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('al', 'Chemical', 'MESH:D000535', (120, 122))
49458	23603750	has shown that Akt1 stabilizes MDM2 by phosphorylating Ser166 and Ser188 residues, thus inhibiting its self-ubiquitination and increasing its stability..	('Ser166', 'Var', (55, 61))	('MDM2', 'Gene', '4193', (31, 35))	('Ser', 'cellular_component', 'GO:0005790', ('66', '69'))	('stability', 'MPA', (142, 151))	('increasing', 'PosReg', (127, 137))	('Ser166', 'Chemical', '-', (55, 61))	('self-ubiquitination', 'MPA', (103, 122))	('Ser', 'cellular_component', 'GO:0005790', ('55', '58'))	('Ser188', 'Chemical', '-', (66, 72))	('Akt1', 'Gene', (15, 19))	('Ser188 residues', 'Var', (66, 81))	('inhibiting', 'NegReg', (88, 98))	('MDM2', 'Gene', (31, 35))
49459	23603750	In contrast, Akt2 overexpression up-regulates beta1-integrin(a component of collagen IV- binding receptor; referred to here as beta1) expression both in vivo and in vitro.	('beta1', 'Gene', '10678', (46, 51))	('expression', 'MPA', (134, 144))	('beta1', 'Gene', '10678', (127, 132))	('binding', 'molecular_function', 'GO:0005488', ('89', '96'))	('Akt2', 'Gene', (13, 17))	('beta1-integrin', 'Gene', '3688', (46, 60))	('overexpression', 'Var', (18, 32))	('collagen', 'molecular_function', 'GO:0005202', ('76', '84'))	('up-regulates', 'PosReg', (33, 45))	('beta1-integrin', 'Gene', (46, 60))	('beta1', 'Gene', (127, 132))	('beta1', 'Gene', (46, 51))
49463	23603750	Amplification and overexpression of Akt2 has been shown to play a critical role in CRC metastatic colonization.	('Akt2', 'Gene', (36, 40))	('Amplification', 'Var', (0, 13))	('al', 'Chemical', 'MESH:D000535', (72, 74))	('CRC metastatic colonization', 'CPA', (83, 110))	('CRC', 'Phenotype', 'HP:0003003', (83, 86))	('overexpression', 'PosReg', (18, 32))
49465	23603750	Genetic inactivation of Akt2 has been shown to results in reduced ability of colon carcinoma cells to metastasize thus confirming that Akt2 is required for the establishment of colon cancer metastasis.	('Genetic inactivation', 'Var', (0, 20))	('colon cancer', 'Phenotype', 'HP:0003003', (177, 189))	('colon cancer metastasis', 'Disease', (177, 200))	('colon cancer metastasis', 'Disease', 'MESH:D009362', (177, 200))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('colon carcinoma', 'Disease', 'MESH:D015179', (77, 92))	('Akt2', 'Gene', (24, 28))	('colon carcinoma', 'Disease', (77, 92))	('reduced', 'NegReg', (58, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
49466	23603750	Genetic inactivation of Akt1 and Akt2 results in reduction in clonal growth of colon cancer cells in vitro, but this reduction was much more significant when the cells were cultured in media lacking growth factors.	('Genetic inactivation', 'Var', (0, 20))	('colon cancer', 'Disease', (79, 91))	('al', 'Chemical', 'MESH:D000535', (66, 68))	('Akt1', 'Gene', (24, 28))	('Akt2', 'Gene', (33, 37))	('reduction', 'NegReg', (49, 58))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('clonal growth of', 'CPA', (62, 78))
49467	23603750	This led to the conclusion that tumor microenvironment plays a significant role in regulating the effects of gene inactivation.	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('gene inactivation', 'Var', (109, 126))
49468	23603750	Inactivation of Akt1 and Akt2 also results in reduced metastasis to liver and reduced tumor burden.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('metastasis to', 'CPA', (54, 67))	('reduced', 'NegReg', (46, 53))	('Akt2', 'Gene', (25, 29))	('reduced', 'NegReg', (78, 85))	('al', 'Chemical', 'MESH:D000535', (30, 32))	('Akt1', 'Gene', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('Inactivation', 'Var', (0, 12))
49471	23603750	Phosphorylation of the 3 serine residues in turn phosphorylate the tyrosine residue (Tyr397) thus activating it.	('serine', 'Chemical', 'MESH:D012694', (25, 31))	('tyrosine', 'Chemical', 'MESH:D014443', (67, 75))	('Tyr397', 'Var', (85, 91))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('Tyr397', 'Chemical', '-', (85, 91))	('activating', 'PosReg', (98, 108))
49474	23603750	Sabatini laboratory have made the seminal discovery that mTOR is a direct substrate of Akt and identified Ser2448 residue as the Akt phosphorylation site on mTOR.	('Ser2448 residue', 'Var', (106, 121))	('Sabatini', 'Chemical', '-', (0, 8))	('al', 'Chemical', 'MESH:D000535', (39, 41))	('mTOR', 'Gene', (57, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('133', '148'))	('mTOR', 'Gene', '2475', (57, 61))	('Ser2448', 'Chemical', '-', (106, 113))	('Ser', 'cellular_component', 'GO:0005790', ('106', '109'))	('mTOR', 'Gene', (157, 161))	('mTOR', 'Gene', '2475', (157, 161))
49500	23603750	Akt3 siRNA knockdown reduced proliferation, survival and migration of lung cancer cells.	('reduced', 'NegReg', (21, 28))	('Akt3', 'Gene', (0, 4))	('survival', 'CPA', (44, 52))	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('lung cancer', 'Disease', (70, 81))	('proliferation', 'CPA', (29, 42))	('migration', 'CPA', (57, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('al', 'Chemical', 'MESH:D000535', (50, 52))	('knockdown', 'Var', (11, 20))
49501	23603750	In contrast, Akt1 siRNA knockdown resulted in a reduction in MEK/ERK1/2 activity and IkB protein expression leading to cell death.	('MEK', 'Gene', (61, 64))	('MEK', 'Gene', '5609', (61, 64))	('IkB protein', 'Protein', (85, 96))	('ERK1', 'molecular_function', 'GO:0004707', ('65', '69'))	('ERK1/2', 'Gene', (65, 71))	('ERK1/2', 'Gene', '5595;5594', (65, 71))	('cell death', 'CPA', (119, 129))	('activity', 'MPA', (72, 80))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('cell death', 'biological_process', 'GO:0008219', ('119', '129'))	('knockdown', 'Var', (24, 33))	('reduction', 'NegReg', (48, 57))	('Akt1', 'Gene', (13, 17))
49504	23603750	Recently, it was reported that non-small cell lung carcinoma (NSCLC) patients also possess E17K mutation in Akt1 although the frequency is very less.	('E17K', 'Var', (91, 95))	('al', 'Chemical', 'MESH:D000535', (78, 80))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (41, 60))	('NSCLC', 'Disease', (62, 67))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (31, 60))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('Akt1', 'Gene', (108, 112))	('cell lung carcinoma', 'Disease', (41, 60))	('al', 'Chemical', 'MESH:D000535', (37, 39))	('E17K', 'Mutation', 'rs121434592', (91, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('patients', 'Species', '9606', (69, 77))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (35, 60))	('al', 'Chemical', 'MESH:D000535', (113, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
49506	23603750	However, Sung et al reported that polymorphism in Akt2 and Akt3 is not associated by NSCLC.	('Akt2', 'Gene', (50, 54))	('Akt3', 'Gene', (59, 63))	('NSCLC', 'Disease', (85, 90))	('polymorphism', 'Var', (34, 46))	('al', 'Chemical', 'MESH:D000535', (17, 19))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('associated', 'Reg', (71, 81))
49507	23603750	Akt activation due to mutation of Kras or PTEN pathway is a potent survival signal in pancreatic cancer cell lines and correlates with the aggressiveness of tumor.	('aggressiveness', 'Phenotype', 'HP:0000718', (139, 153))	('PTEN', 'Gene', (42, 46))	('mutation', 'Var', (22, 30))	('PTEN', 'Gene', '5728', (42, 46))	('pancreatic cancer', 'Disease', (86, 103))	('al', 'Chemical', 'MESH:D000535', (80, 82))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('al', 'Chemical', 'MESH:D000535', (73, 75))	('aggressiveness of tumor', 'Disease', 'MESH:D001523', (139, 162))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Kras', 'Gene', (34, 38))	('aggressiveness of tumor', 'Disease', (139, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('Kras', 'Gene', '3845', (34, 38))	('activation', 'PosReg', (4, 14))	('Akt', 'Pathway', (0, 3))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
49510	23603750	Inhibition of Akt2 signaling by PI3K inhibitor results in the reduction in growth of pancreatic cancer cells in vitro and in vivo, by induction of apoptosis.	('pancreatic cancer', 'Disease', (85, 102))	('PI3K', 'molecular_function', 'GO:0016303', ('32', '36'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('PI3K inhibitor', 'Var', (32, 46))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('134', '156'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('induction', 'Reg', (134, 143))	('apoptosis', 'CPA', (147, 156))	('growth', 'CPA', (75, 81))	('al', 'Chemical', 'MESH:D000535', (23, 25))	('reduction', 'NegReg', (62, 71))	('Akt2 signaling', 'Pathway', (14, 28))
49512	23603750	It has been reported that Akt isoforms show differential role in pancreatic cancer, whereas Akt2 is responsible for poor prognosis, Akt1 is associated with favorable prognosis of pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (179, 196))	('Akt1', 'Var', (132, 136))	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('pancreatic cancer', 'Disease', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('al', 'Chemical', 'MESH:D000535', (54, 56))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (179, 196))	('pancreatic cancer', 'Disease', (179, 196))
49516	23603750	It was also reported that increased expression of PHLPP1 results in reduction in tumor growth confirming that it is the loss of phosphorylation of Akt2, that causes reduced growth of cancer cells.	('phosphorylation', 'biological_process', 'GO:0016310', ('128', '143'))	('al', 'Chemical', 'MESH:D000535', (7, 9))	('cancer', 'Disease', (183, 189))	('PHLPP1', 'Gene', (50, 56))	('PHLPP1', 'Gene', '23239', (50, 56))	('expression', 'Var', (36, 46))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('Akt2', 'Gene', (147, 151))	('increased', 'PosReg', (26, 35))	('phosphorylation', 'MPA', (128, 143))	('reduction', 'NegReg', (68, 77))	('tumor', 'Disease', (81, 86))	('loss', 'NegReg', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('reduced', 'NegReg', (165, 172))	('growth', 'MPA', (173, 179))
49519	23603750	Substantial reports from our laboratory have established a loss or epigenetic silencing of TGFbeta receptor expression in a wide range of cancer.	('cancer', 'Disease', (138, 144))	('TGFbeta', 'Gene', (91, 98))	('epigenetic silencing', 'Var', (67, 87))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('TGFbeta', 'Gene', '7040', (91, 98))	('expression', 'MPA', (108, 118))	('loss', 'NegReg', (59, 63))	('al', 'Chemical', 'MESH:D000535', (9, 11))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
49520	23603750	The mechanisms of epigenetic loss of TGFbeta receptors and their therapeutic implications have been reviewed in details.	('TGFbeta', 'Gene', (37, 44))	('epigenetic loss', 'Var', (18, 33))	('TGFbeta', 'Gene', '7040', (37, 44))
49538	23603750	Moreover, we have shown that Akt phosphorylation was higher in the highly metastatic CRC cells with attenuated TGFbeta receptor.	('higher', 'PosReg', (53, 59))	('attenuated', 'Var', (100, 110))	('TGFbeta', 'Gene', '7040', (111, 118))	('Akt', 'Pathway', (29, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('highly metastatic CRC', 'CPA', (67, 88))	('CRC', 'Phenotype', 'HP:0003003', (85, 88))	('TGFbeta', 'Gene', (111, 118))
49539	23603750	However, reconstitution of TGFbeta receptors in these CRC cells lead to a reduction in Akt phosphorylation followed by a reduction in metastatic colonization.	('reduction', 'NegReg', (74, 83))	('reconstitution', 'Var', (9, 23))	('metastatic colonization', 'CPA', (134, 157))	('TGFbeta', 'Gene', (27, 34))	('phosphorylation', 'biological_process', 'GO:0016310', ('91', '106'))	('CRC', 'Phenotype', 'HP:0003003', (54, 57))	('Akt', 'Protein', (87, 90))	('TGFbeta', 'Gene', '7040', (27, 34))	('reduction', 'NegReg', (121, 130))
49543	23603750	A recent study showed that MK-2206 has antitumor role in breast cancer in vivo, which was further augmented in the presence of paclitaxel.	('MK-2206', 'Chemical', 'MESH:C548887', (27, 34))	('breast cancer', 'Disease', (57, 70))	('MK-2206', 'Var', (27, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('paclitaxel', 'Chemical', 'MESH:D017239', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))
49545	23603750	A report on nasopharyngeal carcinoma (NPC) reveals that MK-2206 inhibits growth of NPC cells by inhibiting Akt and mTOR signaling.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('NPC', 'Disease', 'MESH:D052556', (83, 86))	('NPC', 'Disease', (38, 41))	('mTOR', 'Gene', (115, 119))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (12, 36))	('NPC', 'Phenotype', 'HP:0100630', (83, 86))	('mTOR', 'Gene', '2475', (115, 119))	('al', 'Chemical', 'MESH:D000535', (24, 26))	('Akt', 'Pathway', (107, 110))	('NPC', 'Disease', (83, 86))	('NPC', 'cellular_component', 'GO:0005643', ('83', '86'))	('al', 'Chemical', 'MESH:D000535', (47, 49))	('NPC', 'cellular_component', 'GO:0005643', ('38', '41'))	('MK-2206', 'Chemical', 'MESH:C548887', (56, 63))	('al', 'Chemical', 'MESH:D000535', (124, 126))	('MK-2206', 'Var', (56, 63))	('nasopharyngeal carcinoma', 'Disease', (12, 36))	('inhibiting', 'NegReg', (96, 106))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('growth', 'MPA', (73, 79))	('NPC', 'Disease', 'MESH:D052556', (38, 41))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (12, 36))	('inhibits', 'NegReg', (64, 72))	('NPC', 'Phenotype', 'HP:0100630', (38, 41))
49547	23603750	In T cell acute lymphoblastic leukemia it has been demonstrated that MK-2206 results in induction of apoptosis, autophagy and cell cycle arrest.	('leukemia', 'Phenotype', 'HP:0001909', (30, 38))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (126, 143))	('MK-2206', 'Chemical', 'MESH:C548887', (69, 76))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (10, 38))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (16, 38))	('MK-2206', 'Var', (69, 76))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (16, 38))	('autophagy', 'biological_process', 'GO:0016236', ('112', '121'))	('autophagy', 'biological_process', 'GO:0006914', ('112', '121'))	('apoptosis', 'CPA', (101, 110))	('lymphoblastic leukemia', 'Disease', (16, 38))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('126', '143'))	('induction', 'Reg', (88, 97))	('autophagy', 'CPA', (112, 121))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('88', '110'))	('cell cycle arrest', 'CPA', (126, 143))
49548	23603750	The treatment of MK-2206 in various cancer conditions as a single agent or in combination with other inhibitors has been effective in diminishing the tumor growth and reducing cell survival of cancer cells.	('MK-2206', 'Var', (17, 24))	('MK-2206', 'Chemical', 'MESH:C548887', (17, 24))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('reducing', 'NegReg', (167, 175))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('al', 'Chemical', 'MESH:D000535', (187, 189))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('diminishing', 'NegReg', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Disease', (150, 155))
49553	23603750	The role of perifosine was studied in hepatocellular carcinoma and it was found that this Akt inhibitor results in increased apoptosis by affecting the phosphorylation of ERK and JNK.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (38, 62))	('JNK', 'molecular_function', 'GO:0004705', ('179', '182'))	('ERK', 'Gene', (171, 174))	('apoptosis', 'CPA', (125, 134))	('phosphorylation', 'MPA', (152, 167))	('ERK', 'molecular_function', 'GO:0004707', ('171', '174'))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (38, 62))	('increased', 'PosReg', (115, 124))	('inhibitor', 'Var', (94, 103))	('affecting', 'Reg', (138, 147))	('ERK', 'Gene', '5595;5594;5595', (171, 174))	('phosphorylation', 'biological_process', 'GO:0016310', ('152', '167'))	('perifosine', 'Chemical', 'MESH:C105905', (12, 22))	('hepatocellular carcinoma', 'Disease', (38, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('125', '134'))	('apoptosis', 'biological_process', 'GO:0006915', ('125', '134'))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('JNK', 'Gene', (179, 182))	('JNK', 'Gene', '5599', (179, 182))
49564	23603750	A443654 is a potent ATP competitive inhibitor of Akt activity.	('A443654', 'Var', (0, 7))	('Akt', 'Pathway', (49, 52))	('ATP', 'Chemical', 'MESH:D000255', (20, 23))	('A443654', 'Chemical', 'MESH:C504035', (0, 7))
49569	23603750	It has also been shown that A443654 increases phosphorylation of Akt at Ser473 thus resulting in increase in Akt activity.	('phosphorylation', 'biological_process', 'GO:0016310', ('46', '61'))	('Ser473', 'Chemical', '-', (72, 78))	('increase', 'PosReg', (97, 105))	('al', 'Chemical', 'MESH:D000535', (7, 9))	('Akt', 'Pathway', (65, 68))	('A443654', 'Var', (28, 35))	('Ser', 'cellular_component', 'GO:0005790', ('72', '75'))	('increases', 'PosReg', (36, 45))	('phosphorylation', 'MPA', (46, 61))	('A443654', 'Chemical', 'MESH:C504035', (28, 35))	('Akt', 'CPA', (109, 112))
49573	23603750	Since all these mouse models had activated Akt, treatment with GSK690693 results in reduction in tumor progression, phosphorylation of Akt substrates, cell proliferation and increased apoptosis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('cell proliferation', 'biological_process', 'GO:0008283', ('151', '169'))	('phosphorylation', 'MPA', (116, 131))	('reduction', 'NegReg', (84, 93))	('apoptosis', 'CPA', (184, 193))	('al', 'Chemical', 'MESH:D000535', (6, 8))	('Akt', 'Protein', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('phosphorylation', 'biological_process', 'GO:0016310', ('116', '131'))	('cell proliferation', 'CPA', (151, 169))	('GSK', 'molecular_function', 'GO:0050321', ('63', '66'))	('tumor', 'Disease', (97, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('184', '193'))	('apoptosis', 'biological_process', 'GO:0006915', ('184', '193'))	('GSK690693', 'Chemical', 'MESH:C528328', (63, 72))	('mouse', 'Species', '10090', (16, 21))	('increased', 'PosReg', (174, 183))	('GSK690693', 'Var', (63, 72))
49575	23603750	It has been reported that long term use of this GSK690693 inhibits glycogen synthesis and activates glycogenolysis thus resulting in hyperglycemia as one of the major side effects thus making this drug unfit for further clinical trials.	('GSK690693', 'Chemical', 'MESH:C528328', (48, 57))	('resulting in', 'Reg', (120, 132))	('al', 'Chemical', 'MESH:D000535', (226, 228))	('activates', 'PosReg', (90, 99))	('glycogen', 'Chemical', 'MESH:D006003', (100, 108))	('hyperglycemia', 'Disease', 'MESH:D006943', (133, 146))	('glycogen synthesis', 'biological_process', 'GO:0005978', ('67', '85'))	('GSK', 'molecular_function', 'GO:0050321', ('48', '51'))	('glycogen synthesis', 'MPA', (67, 85))	('inhibits', 'NegReg', (58, 66))	('hyperglycemia', 'Disease', (133, 146))	('glycogenolysis', 'biological_process', 'GO:0005980', ('100', '114'))	('glycogenolysis', 'MPA', (100, 114))	('al', 'Chemical', 'MESH:D000535', (232, 234))	('hyperglycemia', 'Phenotype', 'HP:0003074', (133, 146))	('glycogen', 'Chemical', 'MESH:D006003', (67, 75))	('GSK690693', 'Var', (48, 57))
49581	23603750	It was reported that amino acid residues (229-309) of Akt are responsible for binding to HSP90.	('binding', 'Interaction', (78, 85))	('HSP90', 'Gene', (89, 94))	('HSP90', 'Gene', '3320', (89, 94))	('Akt', 'Gene', (54, 57))	('responsible', 'Reg', (62, 73))	('binding', 'molecular_function', 'GO:0005488', ('78', '85'))	('229-309', 'Var', (42, 49))
49609	23296709	Antibodies against components of the nuclear factor-kappa B (NF-kappaB) complex including p65 (catalog number 6956), IkappaBalpha (catalog number 34812), p-Stat1(Ser727) (catalog number 9177S), as well as p-Stat1(Tyr701) (catalog number 9167L) and p-Histone gammaH2AX (Ser139)(catalog number 2577S) were purchased from Cell Signaling Technology.	('IkappaBalpha', 'Gene', '4792', (117, 129))	('Ser', 'cellular_component', 'GO:0005790', ('162', '165'))	('Ser139', 'Chemical', '-', (269, 275))	('IkappaBalpha', 'Gene', (117, 129))	('Ser', 'cellular_component', 'GO:0005790', ('269', '272'))	('Ser727', 'Chemical', '-', (162, 168))	('p-Stat1', 'Var', (154, 161))	('Signaling', 'biological_process', 'GO:0023052', ('324', '333'))	('NF-kappaB) complex', 'cellular_component', 'GO:0071159', ('61', '79'))	('gammaH2AX', 'Chemical', '-', (258, 267))	('p-Histone', 'Chemical', '-', (248, 257))	('nuclear factor-kappa B', 'Gene', (37, 59))	('Tyr701', 'Chemical', '-', (213, 219))	('nuclear factor-kappa B', 'Gene', '4790', (37, 59))
49659	23296709	Furthermore, Ochi and colleagues recently reported that LPS accelerates tumorigenesis in the pancreas and that inhibition of TLR4 signaling significantly decreased the development of inflammation-related pancreatic tumors in vivo.	('decreased', 'NegReg', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('inflammation', 'biological_process', 'GO:0006954', ('183', '195'))	('accelerates', 'PosReg', (60, 71))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (204, 220))	('pancreatic tumors', 'Disease', 'MESH:D010190', (204, 221))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('pancreatic tumors', 'Disease', (204, 221))	('LPS', 'Var', (56, 59))	('TLR4', 'Gene', (125, 129))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (204, 221))	('development of', 'CPA', (168, 182))	('inhibition', 'Var', (111, 121))	('tumorigenesis in the pancreas', 'CPA', (72, 101))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('signaling', 'biological_process', 'GO:0023052', ('130', '139'))
49660	23296709	A critical role for the NF-kappaB pathway in the explanation of our findings is supported by the observation that pre-treatment with inhibitors of NF-kappaB signaling, PDTC and BAY117082, significantly decreased Duox2 expression following exposure to IFN-gamma and LPS (Fig.	('BAY117082', 'Var', (177, 186))	('Duox2', 'Gene', (212, 217))	('signaling', 'biological_process', 'GO:0023052', ('157', '166'))	('decreased', 'NegReg', (202, 211))	('pre', 'molecular_function', 'GO:0003904', ('114', '117'))	('expression', 'MPA', (218, 228))	('BAY117082', 'Chemical', 'MESH:C434003', (177, 186))
49671	22665051	A large number of genetic alterations have been ascribed to PDAC with mutations in the KRAS2 proto-oncogene thought to be an early event in the progression of disease.	('mutations', 'Var', (70, 79))	('KRAS2', 'Gene', '16653', (87, 92))	('PDAC', 'Disease', (60, 64))	('PDAC', 'Phenotype', 'HP:0006725', (60, 64))	('KRAS2', 'Gene', (87, 92))	('PDAC', 'Chemical', '-', (60, 64))
49672	22665051	Recent lineage-tracing studies have shown that acinar cells expressing mutant KrasG12D are induced to transdifferentiate, generating duct-like cells through a process known as acinar-ductal metaplasia (ADM).	('duct-like', 'MPA', (133, 142))	('KrasG12D', 'Gene', (78, 86))	('acinar-ductal metaplasia', 'Disease', 'MESH:D008679', (176, 200))	('metaplasia', 'biological_process', 'GO:0036074', ('190', '200'))	('mutant', 'Var', (71, 77))	('acinar-ductal metaplasia', 'Disease', (176, 200))
49678	22665051	Indeed, a number of genetic mutations associated with PDAC have been detected in PanINs at various stages including mutations in the KRAS2, TP53 and SMAD4 genes which also are hallmarks of advanced PDAC, consistent with a PanIN   PDAC step-wise progression model.	('PDAC', 'Chemical', '-', (230, 234))	('SMAD4', 'Gene', (149, 154))	('associated', 'Reg', (38, 48))	('TP53', 'Gene', (140, 144))	('PDAC', 'Disease', (54, 58))	('PDAC', 'Phenotype', 'HP:0006725', (54, 58))	('PDAC', 'Phenotype', 'HP:0006725', (198, 202))	('KRAS2', 'Gene', '16653', (133, 138))	('PDAC', 'Phenotype', 'HP:0006725', (230, 234))	('SMAD4', 'Gene', '17128', (149, 154))	('mutations', 'Var', (116, 125))	('PDAC', 'Chemical', '-', (198, 202))	('PDAC', 'Chemical', '-', (54, 58))	('TP53', 'Gene', '22059', (140, 144))	('KRAS2', 'Gene', (133, 138))
49683	22665051	Early efforts to model the disease by expressing Kras in pancreatic duct cells did not yield discenable pathology, although a recent study by Ray et al.	('Kras', 'Var', (49, 53))	('pancreatic', 'Disease', 'MESH:D010195', (57, 67))	('pancreatic', 'Disease', (57, 67))
49684	22665051	has shown that activation of endogenous KrasG12D in large pancreatic ducts leads to rare early PanIN lesions.	('activation', 'PosReg', (15, 25))	('pancreatic', 'Disease', 'MESH:D010195', (58, 68))	('KrasG12D', 'Var', (40, 48))	('pancreatic', 'Disease', (58, 68))	('early PanIN lesions', 'Disease', (89, 108))
49686	22665051	The transition from acinar to ductal cell properties has been termed acinar-ductal metaplasia (ADM) and lineage-tracing studies have confirmed that this process results from direct transdifferentiation of adult acinar cells that convert to a duct cell phenotype upon KrasG12D expression.	('transdifferentiation', 'biological_process', 'GO:0060290', ('181', '201'))	('KrasG12D expression', 'Var', (267, 286))	('convert', 'Reg', (229, 236))	('acinar-ductal metaplasia', 'Disease', 'MESH:D008679', (69, 93))	('metaplasia', 'biological_process', 'GO:0036074', ('83', '93'))	('acinar-ductal metaplasia', 'Disease', (69, 93))
49689	22665051	Although it is clear that KrasG12D expression in adult acinar cells can generate ADM lesions that progress to PanINs and PDAC, the molecular signaling pathways that are instrumental in these conversion events remain poorly defined.	('KrasG12D expression', 'Var', (26, 45))	('PDAC', 'Chemical', '-', (121, 125))	('progress', 'Reg', (98, 106))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('ADM', 'Disease', (81, 84))	('PDAC', 'Disease', (121, 125))	('PDAC', 'Phenotype', 'HP:0006725', (121, 125))	('PanINs', 'Disease', (110, 116))
49690	22665051	Indeed, KrasG12D expression alone does not guarantee ADM/PanIN development because in mouse PDAC models where ~95% of acinar cells express KrasG12D only a small cohort of cells generate detectable ADM/PanINs after a significant latent period (months), demonstrating that differentiated acinar cells are not universally responsive to KRAS signaling.	('PDAC', 'Phenotype', 'HP:0006725', (92, 96))	('mouse', 'Species', '10090', (86, 91))	('PDAC', 'Chemical', '-', (92, 96))	('KRAS', 'Gene', '16653', (333, 337))	('KRAS', 'Gene', (333, 337))	('KrasG12D', 'Var', (139, 147))	('signaling', 'biological_process', 'GO:0023052', ('338', '347'))	('ADM/PanINs', 'MPA', (197, 207))
49691	22665051	Analysis of RAS signaling components demonstrated that activation of the Raf/MEK/ERK pathway was essential for KrasG12D-induced ADM.	('signaling', 'biological_process', 'GO:0023052', ('16', '25'))	('ADM', 'Disease', (128, 131))	('KrasG12D-induced', 'Var', (111, 127))	('ERK', 'Gene', (81, 84))	('MEK', 'Gene', '17242', (77, 80))	('ERK', 'Gene', '26413', (81, 84))	('Raf', 'Gene', (73, 76))	('MEK', 'Gene', (77, 80))	('Raf', 'Gene', '387609', (73, 76))	('ERK', 'molecular_function', 'GO:0004707', ('81', '84'))
49692	22665051	Kras mutations are virtually universal in human PDAC, although identification of the initial adult cell (duct, acinar, centroacinar) that acquires the mutation and initiates the transformation cascade remains unknown.	('human', 'Species', '9606', (42, 47))	('PDAC', 'Chemical', '-', (48, 52))	('mutations', 'Var', (5, 14))	('Kras', 'Gene', (0, 4))	('PDAC', 'Phenotype', 'HP:0006725', (48, 52))
49694	22665051	Lineage-tracing of Elastase-CreER; LSL-KrasG12D/+; R26RmTmG mice confirmed that activation of KrasG12D in adult acinar cells induces acinar-ductal metaplasia (ADM), which can progress to pancreatic intraepithelial neoplasia (PanIN) and on to PDAC (Figure 1A).	('metaplasia', 'biological_process', 'GO:0036074', ('147', '157'))	('progress', 'PosReg', (175, 183))	('acinar-ductal metaplasia', 'Disease', (133, 157))	('PDAC', 'Phenotype', 'HP:0006725', (242, 246))	('acinar-ductal metaplasia', 'Disease', 'MESH:D008679', (133, 157))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (198, 223))	('pancreatic intraepithelial neoplasia', 'Disease', 'MESH:D018290', (187, 223))	('neoplasia', 'Phenotype', 'HP:0002664', (214, 223))	('KrasG12D', 'Var', (94, 102))	('pancreatic intraepithelial neoplasia', 'Disease', (187, 223))	('activation', 'Var', (80, 90))	('PDAC', 'Chemical', '-', (242, 246))	('induces', 'Reg', (125, 132))	('mice', 'Species', '10090', (60, 64))
49705	22665051	It is well established that KrasG12D expression induces cellular transformation by activating downstream signaling events, including the Raf/MEK/ERK, PI3K/AKT and RalGDS/Ral pathways (Figure 4A).	('Raf', 'Gene', (137, 140))	('MEK', 'Gene', (141, 144))	('KrasG12D expression', 'Var', (28, 47))	('induces', 'Reg', (48, 55))	('PI3', 'Gene', '20702', (150, 153))	('ERK', 'Gene', (145, 148))	('AKT', 'Gene', (155, 158))	('Ral', 'Gene', '56044', (163, 166))	('Ral', 'Gene', (163, 166))	('Raf', 'Gene', '387609', (137, 140))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('PI3K', 'molecular_function', 'GO:0016303', ('150', '154'))	('ERK', 'Gene', '26413', (145, 148))	('PI3', 'Gene', (150, 153))	('RalGDS', 'Gene', '19730', (163, 169))	('RalGDS', 'Gene', (163, 169))	('Ral', 'Gene', '56044', (170, 173))	('Ral', 'Gene', (170, 173))	('ERK', 'molecular_function', 'GO:0004707', ('145', '148'))	('cellular transformation', 'CPA', (56, 79))	('AKT', 'Gene', '11651', (155, 158))	('MEK', 'Gene', '17242', (141, 144))	('activating', 'PosReg', (83, 93))
49707	22665051	In an effort to dissect the importance of the PI3K/AKT and Raf/MEK/ERK pathways prior to tumor formation, we examined Mist1CreER/+; LSL-KrasG12D/+ (HET/Kras) pancreata 3 months post-TM to ascertain if ADM/PanIN regions exhibited elevated KRAS signaling.	('ERK', 'Gene', (67, 70))	('MEK', 'Gene', (63, 66))	('KRAS', 'Gene', '16653', (238, 242))	('formation', 'biological_process', 'GO:0009058', ('95', '104'))	('Raf', 'Gene', '387609', (59, 62))	('Mist1CreER/+', 'Var', (118, 130))	('ERK', 'Gene', '26413', (67, 70))	('TM', 'Chemical', 'MESH:D013629', (182, 184))	('PI3', 'Gene', '20702', (46, 49))	('tumor', 'Disease', (89, 94))	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('AKT', 'Gene', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('signaling', 'biological_process', 'GO:0023052', ('243', '252'))	('HET', 'Gene', '224480', (148, 151))	('MEK', 'Gene', '17242', (63, 66))	('elevated', 'PosReg', (229, 237))	('PI3', 'Gene', (46, 49))	('ERK', 'molecular_function', 'GO:0004707', ('67', '70'))	('HET', 'Gene', (148, 151))	('KRAS', 'Gene', (238, 242))	('Raf', 'Gene', (59, 62))	('AKT', 'Gene', '11651', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
49709	22665051	Thus, expression of KrasG12D in acinar cells (for up to 3 months) is not sufficient to uniformly activate the PI3K/AKT and Raf/MEK/ERK arms of the KRAS pathway in all cells.	('KrasG12D', 'Var', (20, 28))	('ERK', 'molecular_function', 'GO:0004707', ('131', '134'))	('MEK', 'Gene', (127, 130))	('AKT', 'Gene', '11651', (115, 118))	('Raf', 'Gene', '387609', (123, 126))	('PI3K', 'molecular_function', 'GO:0016303', ('110', '114'))	('Raf', 'Gene', (123, 126))	('ERK', 'Gene', (131, 134))	('ERK', 'Gene', '26413', (131, 134))	('AKT', 'Gene', (115, 118))	('activate', 'PosReg', (97, 105))	('KRAS', 'Gene', '16653', (147, 151))	('PI3', 'Gene', '20702', (110, 113))	('KRAS', 'Gene', (147, 151))	('MEK', 'Gene', '17242', (127, 130))	('PI3', 'Gene', (110, 113))
49712	22665051	As expected, inhibition of EGFR by the EGFR tyrosine kinase inhibitor PD153035 completely blocked ductal cyst formation of wildtype acinar cells but had no effect on HET/Kras ductal cyst formation, confirming that KRAS functions downstream of EGFR (Figure 4A,C).	('EGFR', 'Gene', (27, 31))	('EGFR', 'Gene', '13649', (27, 31))	('KRAS', 'Gene', '16653', (214, 218))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('53', '69'))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('formation', 'biological_process', 'GO:0009058', ('187', '196'))	('PD153035', 'Chemical', 'MESH:C088860', (70, 78))	('HET', 'Gene', '224480', (166, 169))	('PD153035', 'Var', (70, 78))	('blocked', 'NegReg', (90, 97))	('ductal', 'CPA', (98, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('243', '247'))	('HET', 'Gene', (166, 169))	('EGFR', 'Gene', (39, 43))	('EGFR', 'Gene', '13649', (39, 43))	('formation', 'biological_process', 'GO:0009058', ('110', '119'))	('inhibition', 'Var', (13, 23))	('KRAS', 'Gene', (214, 218))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('EGFR', 'Gene', (243, 247))	('EGFR', 'Gene', '13649', (243, 247))
49714	22665051	As predicted, elevated pAKT was observed in KrasG12D-isolated acinar cells when compared to control cells isolated from corn oil treated littermates (Figure 4D).	('AKT', 'Gene', (24, 27))	('elevated', 'PosReg', (14, 22))	('KrasG12D-isolated', 'Var', (44, 61))	('corn', 'Species', '4577', (120, 124))	('AKT', 'Gene', '11651', (24, 27))
49715	22665051	Treatment of the cultures with the PI3K inhibitor LY294002 led to a ~70% reduction in pAKT levels but had no significant effect on ductal cyst formation in the 3D culture model.	('PI3', 'Gene', (35, 38))	('LY294002', 'Chemical', 'MESH:C085911', (50, 58))	('AKT', 'Gene', (87, 90))	('PI3', 'Gene', '20702', (35, 38))	('LY294002', 'Var', (50, 58))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))	('formation', 'biological_process', 'GO:0009058', ('143', '152'))	('reduction', 'NegReg', (73, 82))	('AKT', 'Gene', '11651', (87, 90))
49720	22665051	Treatment of cells with the MEK inhibitor PD98059 efficiently blocked accumulation of pERK at concentrations as low as 20 muM.	('MEK', 'Gene', '17242', (28, 31))	('pERK', 'Gene', '13666', (86, 90))	('PD98059', 'Var', (42, 49))	('MEK', 'Gene', (28, 31))	('PD98059', 'Chemical', 'MESH:C093973', (42, 49))	('pERK', 'Gene', (86, 90))	('blocked', 'NegReg', (62, 69))
49724	22665051	Previous studies have shown that human acinar cells lose Mist1 expression upon ADM/PanIN formation, and in mouse models devoid of the Mist1 gene, KrasG12D-expressing acinar cells rapidly undergo ADM and develop extensive PanIN lesions through a pathway that involves elevated pERK activity.	('Mist1', 'Gene', (57, 62))	('KrasG12D-expressing', 'Var', (146, 165))	('mouse', 'Species', '10090', (107, 112))	('PanIN lesions', 'MPA', (221, 234))	('develop', 'PosReg', (203, 210))	('undergo', 'PosReg', (187, 194))	('pERK', 'Gene', '13666', (276, 280))	('expression', 'MPA', (63, 73))	('human', 'Species', '9606', (33, 38))	('ADM', 'CPA', (195, 198))	('pERK', 'Gene', (276, 280))	('lose', 'NegReg', (52, 56))	('formation', 'biological_process', 'GO:0009058', ('89', '98'))
49729	22665051	As shown in Figure 5C, loss of Mist1 (KO) led to elevated pERK levels, even in the absence of KrasG12D expression.	('pERK', 'Gene', '13666', (58, 62))	('pERK', 'Gene', (58, 62))	('Mist1', 'Gene', (31, 36))	('elevated', 'PosReg', (49, 57))	('loss', 'Var', (23, 27))
49730	22665051	However, sustained Mist1myc expression in the KO/Kras/Mist1myc pancreata generated lower pERK levels when compared to KO/Kras littermates (Figure 5C).	('Mist1myc', 'Var', (19, 27))	('pERK', 'Gene', (89, 93))	('lower', 'NegReg', (83, 88))	('pERK', 'Gene', '13666', (89, 93))
49731	22665051	As expected, Mist1+/- (HET) and Mist1-/- (KO) acini generated few ductal cysts when placed in collagen matrix for 5 days (Figure 5D).	('HET', 'Gene', '224480', (23, 26))	('collagen', 'molecular_function', 'GO:0005202', ('94', '102'))	('ductal cysts', 'CPA', (66, 78))	('Mist1+/-', 'Var', (13, 21))	('Mist1-/-', 'Var', (32, 40))	('HET', 'Gene', (23, 26))
49733	22665051	These results demonstrate that sustained Mist1 expression lowers pERK levels and protects acinar cells from TGFalpha- or KrasG12D-induced ADM formation in vitro.	('pERK', 'Gene', '13666', (65, 69))	('lowers', 'NegReg', (58, 64))	('pERK', 'Gene', (65, 69))	('expression', 'Var', (47, 57))	('Mist1', 'Gene', (41, 46))	('formation', 'biological_process', 'GO:0009058', ('142', '151'))
49734	22665051	Finally, to determine if sustained Mist1 expression could similarly deter ADM/PanIN development in vivo, adult KO/Kras/Mist1myc mice and their littermate controls were treated with TM and pancreata were examined three months post-TM for the presence of ADM and PanIN lesions.	('ADM/PanIN development', 'CPA', (74, 95))	('mice', 'Species', '10090', (128, 132))	('deter', 'NegReg', (68, 73))	('Mist1', 'Gene', (35, 40))	('expression', 'Var', (41, 51))	('TM', 'Chemical', 'MESH:D013629', (230, 232))	('TM', 'Chemical', 'MESH:D013629', (181, 183))
49737	22665051	In contrast, sustained Mist1myc expression greatly attenuated ADM/PanIN development in the KO/Kras/Mist1myc mice as the majority of the organ consisted of normal appearing acinar tissue with only isolated areas of ADM/PanINs (Figure 6A,B).	('Mist1myc expression', 'Var', (23, 42))	('ADM/PanIN development', 'CPA', (62, 83))	('attenuated', 'NegReg', (51, 61))	('mice', 'Species', '10090', (108, 112))
49739	22665051	The MIST1myc-dependent reduction in ADM/PanIN formation was also reflected in the expression profiles of key acinar vs. ductal genes where MIST1myc significantly reduced ductal gene activity while maintaining acinar gene expression to levels approaching, or exceeding, those obtained with HET/Kras mice (Figure 6C).	('ductal gene activity', 'MPA', (170, 190))	('mice', 'Species', '10090', (298, 302))	('MIST1myc', 'Var', (139, 147))	('gene expression', 'biological_process', 'GO:0010467', ('216', '231'))	('reduced', 'NegReg', (162, 169))	('acinar gene expression', 'MPA', (209, 231))	('HET', 'Gene', (289, 292))	('reduction', 'NegReg', (23, 32))	('HET', 'Gene', '224480', (289, 292))	('formation', 'biological_process', 'GO:0009058', ('46', '55'))
49742	22665051	Consistent with this hypothesis, ADM occurrence precedes PanIN development in PDAC mouse models.	('PDAC', 'Phenotype', 'HP:0006725', (78, 82))	('ADM', 'Var', (33, 36))	('mouse', 'Species', '10090', (83, 88))	('PanIN development', 'CPA', (57, 74))	('PDAC', 'Chemical', '-', (78, 82))
49743	22665051	Mutant Kras is often detected in ADM and low-grade PanIN lesions in human diseased organs but these mutations are not universally present, suggesting that additional underlying events can influence ADM formation.	('human', 'Species', '9606', (68, 73))	('influence', 'Reg', (188, 197))	('formation', 'biological_process', 'GO:0009058', ('202', '211'))	('Kras', 'Gene', (7, 11))	('Mutant', 'Var', (0, 6))	('ADM', 'Disease', (198, 201))
49745	22665051	Similarly, EGFR activity is a hallmark of Kras-induced ADM/PanIN lesions, implying a central role for this pathway in Kras-dependent and Kras-independent ADM. ADM is also commonly associated with acute and chronic pancreatitis in both humans and rodents, suggesting that inflammation and/or cell damage can simultaneously generate an ADM response without Kras activity.	('EGFR', 'molecular_function', 'GO:0005006', ('11', '15'))	('inflammation', 'biological_process', 'GO:0006954', ('271', '283'))	('EGFR', 'Gene', (11, 15))	('EGFR', 'Gene', '13649', (11, 15))	('pancreatitis', 'Phenotype', 'HP:0001733', (214, 226))	('acute', 'Disease', (196, 201))	('humans', 'Species', '9606', (235, 241))	('pancreatitis', 'Disease', 'MESH:D010195', (214, 226))	('ADM', 'Var', (159, 162))	('inflammation', 'Disease', 'MESH:D007249', (271, 283))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (206, 226))	('associated with', 'Reg', (180, 195))	('pancreatitis', 'Disease', (214, 226))	('inflammation', 'Disease', (271, 283))
49746	22665051	Although a number of studies have shown that metaplastic cells in pancreatitis settings eventually resume an acinar cell phenotype, the presence of Kras mutations efficiently redirects metaplastic cells toward PanIN development.	('metaplastic cells', 'CPA', (185, 202))	('pancreatitis', 'Disease', 'MESH:D010195', (66, 78))	('redirects', 'Reg', (175, 184))	('PanIN development', 'CPA', (210, 227))	('mutations', 'Var', (153, 162))	('acinar cell phenotype', 'MPA', (109, 130))	('pancreatitis', 'Disease', (66, 78))	('Kras', 'Gene', (148, 152))	('presence', 'Var', (136, 144))	('pancreatitis', 'Phenotype', 'HP:0001733', (66, 78))
49748	22665051	Using inhibitors that specifically blocked individual signaling components, we also demonstrated that Raf/MEK/ERK represent a critical downstream effector pathway through which KRAS operates to induce ADM. Interestingly, BrafV599E and KrasG12D, the predominant raf and ras gene mutations, respectively, in pancreatic cancer operate in a mutually exclusive pattern in pancreatic tumors, suggesting that upstream (KrasG12D) or downstream (BrafV599E) effectors of the Raf/MEK/ERK pathway exhibit interchangeable functions in converting acinar cells to ADM lesions.	('Raf', 'Gene', '387609', (465, 468))	('ERK', 'Gene', '26413', (110, 113))	('ERK', 'molecular_function', 'GO:0004707', ('110', '113'))	('ERK', 'Gene', (473, 476))	('pancreatic tumors', 'Disease', 'MESH:D010190', (367, 384))	('pancreatic tumors', 'Disease', (367, 384))	('tumors', 'Phenotype', 'HP:0002664', (378, 384))	('pancreatic cancer', 'Disease', 'MESH:D010190', (306, 323))	('raf', 'Gene', (438, 441))	('MEK', 'Gene', '17242', (106, 109))	('ERK', 'Gene', '26413', (473, 476))	('tumor', 'Phenotype', 'HP:0002664', (378, 383))	('ERK', 'molecular_function', 'GO:0004707', ('473', '476'))	('raf', 'Gene', '387609', (438, 441))	('raf', 'Gene', (261, 264))	('KrasG12D', 'Var', (412, 420))	('Raf', 'Gene', (102, 105))	('pancreatic cancer', 'Disease', (306, 323))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('KRAS', 'Gene', (177, 181))	('MEK', 'Gene', '17242', (469, 472))	('raf', 'Gene', (222, 225))	('raf', 'Gene', '387609', (261, 264))	('signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (367, 384))	('ERK', 'Gene', (110, 113))	('Raf', 'Gene', (465, 468))	('MEK', 'Gene', (106, 109))	('Raf', 'Gene', '387609', (102, 105))	('KRAS', 'Gene', '16653', (177, 181))	('raf', 'Gene', '387609', (222, 225))	('MEK', 'Gene', (469, 472))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (306, 323))
49751	22665051	Future studies will test if individual dominant-negative mutants of the MAPK pathway similarly block ADM in models of tumorigenesis and pancreatitis.	('MAPK', 'molecular_function', 'GO:0004707', ('72', '76'))	('MAPK pathway', 'Pathway', (72, 84))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('pancreatitis', 'Disease', (136, 148))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('ADM', 'Disease', (101, 104))	('tumor', 'Disease', (118, 123))	('pancreatitis', 'Phenotype', 'HP:0001733', (136, 148))	('pancreatitis', 'Disease', 'MESH:D010195', (136, 148))	('mutants', 'Var', (57, 64))	('block', 'NegReg', (95, 100))
49761	22665051	Similarly, Mist1 exhibits a protective role not only in KrasG12D-induced ADM but also in ADM associated with acute pancreatitis, where Mist1 null pancreata endure more severe damage following caerulein treatment.	('pancreatitis', 'Phenotype', 'HP:0001733', (115, 127))	('pancreatitis', 'Disease', 'MESH:D010195', (115, 127))	('acute pancreatitis', 'Phenotype', 'HP:0001735', (109, 127))	('ADM', 'Disease', (73, 76))	('KrasG12D-induced', 'Var', (56, 72))	('Mist1', 'Gene', (11, 16))	('Mist1', 'Gene', (135, 140))	('pancreatitis', 'Disease', (115, 127))
49763	22665051	Indeed, Mist1 is silenced in pancreatitis-associated acinar cells (unpublished results) and Mist1KO acinar cells exhibit increased MEK and ERK phosphorylation.	('increased', 'PosReg', (121, 130))	('MEK', 'Gene', '17242', (131, 134))	('pancreatitis', 'Phenotype', 'HP:0001733', (29, 41))	('ERK', 'Gene', (139, 142))	('phosphorylation', 'MPA', (143, 158))	('pancreatitis', 'Disease', 'MESH:D010195', (29, 41))	('ERK', 'molecular_function', 'GO:0004707', ('139', '142'))	('Mist1KO', 'Var', (92, 99))	('ERK', 'Gene', '26413', (139, 142))	('MEK', 'Gene', (131, 134))	('silenced', 'NegReg', (17, 25))	('phosphorylation', 'biological_process', 'GO:0016310', ('143', '158'))	('pancreatitis', 'Disease', (29, 41))	('Mist1', 'Gene', (8, 13))
49764	22665051	Given the central role of the MAPK pathway in ADM and the observation that pancreatitis enhances KrasG12D-induced tumorigenesis, it is likely that Mist1 inhibits ADM by maintaining basal levels of these MAPK effectors.	('pancreatitis', 'Disease', (75, 87))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('MAPK', 'molecular_function', 'GO:0004707', ('203', '207'))	('MAPK', 'molecular_function', 'GO:0004707', ('30', '34'))	('enhances', 'PosReg', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('pancreatitis', 'Phenotype', 'HP:0001733', (75, 87))	('KrasG12D-induced', 'Var', (97, 113))	('tumor', 'Disease', (114, 119))	('pancreatitis', 'Disease', 'MESH:D010195', (75, 87))
49921	19243145	Also, we have found that the InP/ZnS QDs have very low cytotoxic effect on the cells, thereby justifying our strategy of using them for targeted bioimaging.	('ZnS', 'Chemical', 'MESH:D015032', (33, 36))	('low', 'NegReg', (51, 54))	('InP/ZnS QDs', 'Var', (29, 40))	('cytotoxic effect on the cells', 'CPA', (55, 84))
49931	19243145	The PL quantum yield (QY) of the InP/ZnS QDs is estimated to be 25 - 30%.	('PL quantum yield', 'MPA', (4, 20))	('ZnS', 'Chemical', 'MESH:D015032', (37, 40))	('PL', 'Chemical', '-', (4, 6))	('InP/ZnS', 'Var', (33, 40))
49972	19243145	have reported the cytotoxic effects of CdSe/ZnS QDs with different sizes on three different cell types.	('cytotoxic effects', 'CPA', (18, 35))	('CdSe', 'Chemical', '-', (39, 43))	('CdSe/ZnS', 'Var', (39, 47))	('ZnS', 'Chemical', 'MESH:D015032', (44, 47))
49976	19243145	This result strongly indicates that the InP/ZnS QDs have a relatively low cellular cytotoxicity, thereby justifying our strategy of using them as non-cadmium based targeted optical probes for biomedical applications.	('InP/ZnS', 'Var', (40, 47))	('cytotoxicity', 'Disease', 'MESH:D064420', (83, 95))	('cadmium', 'Chemical', 'MESH:D002104', (150, 157))	('cytotoxicity', 'Disease', (83, 95))	('low', 'NegReg', (70, 73))	('ZnS', 'Chemical', 'MESH:D015032', (44, 47))
49985	19243145	reported that no acute toxicity was observed after injecting CdSe/ZnS QDs into the mice and hypothesized that CdSe/ZnS QDs successfully excrete from the body before the breakdown of surface coating that will cause the leakeage of heavy metals from the core materials.	('toxicity', 'Disease', (23, 31))	('core', 'cellular_component', 'GO:0019013', ('252', '256'))	('CdSe', 'Chemical', '-', (61, 65))	('breakdown', 'biological_process', 'GO:0009056', ('169', '178'))	('ZnS', 'Chemical', 'MESH:D015032', (66, 69))	('mice', 'Species', '10090', (83, 87))	('CdSe', 'Chemical', '-', (110, 114))	('ZnS', 'Chemical', 'MESH:D015032', (115, 118))	('leakeage', 'MPA', (218, 226))	('CdSe/ZnS', 'Var', (110, 118))	('toxicity', 'Disease', 'MESH:D064420', (23, 31))	('cause', 'Reg', (208, 213))
49986	19243145	However, it is still debatable whether cadmium-based QDs will eventually degrade in biological environment and causes acute toxicicity in long term.	('cadmium-based', 'Var', (39, 52))	('acute toxicicity', 'Disease', 'MESH:D000208', (118, 134))	('causes', 'Reg', (111, 117))	('acute toxicicity', 'Disease', (118, 134))	('cadmium', 'Chemical', 'MESH:D002104', (39, 46))	('degrade', 'NegReg', (73, 80))
50106	19531250	CA 19-9 has been shown to be correlated with clinical efficacy of GEM in pancreatic cancer.	('GEM', 'Chemical', 'MESH:C056507', (66, 69))	('CA 19-9', 'Var', (0, 7))	('pancreatic cancer', 'Disease', (73, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))
50109	19531250	It has been reported that pancreatic cancer patients with high hENT1 protein or mRNA expression in surgical specimens or biopsies have significantly longer survival after GEM treatment, as compared to those with low levels of hENT1.	('hENT1', 'Gene', '2030', (226, 231))	('hENT1', 'Gene', '2030', (63, 68))	('patients', 'Species', '9606', (44, 52))	('hENT1', 'Gene', (226, 231))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (26, 43))	('hENT1', 'Gene', (63, 68))	('longer', 'PosReg', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('survival', 'CPA', (156, 164))	('high', 'Var', (58, 62))	('pancreatic cancer', 'Disease', (26, 43))	('GEM', 'Chemical', 'MESH:C056507', (171, 174))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('mRNA expression', 'MPA', (80, 95))	('pancreatic cancer', 'Disease', 'MESH:D010190', (26, 43))
50110	19531250	In in vitro experiments, high hENT1 mRNA levels have been shown to be associated with GEM sensitivity, as represented by IC50 values.	('hENT1', 'Gene', '2030', (30, 35))	('GEM', 'Chemical', 'MESH:C056507', (86, 89))	('GEM sensitivity', 'CPA', (86, 101))	('hENT1', 'Gene', (30, 35))	('associated', 'Reg', (70, 80))	('high', 'Var', (25, 29))
50121	19531250	Our results suggested that high dCK mRNA expression is a predictor of GEM efficacy.	('dCK', 'Gene', '43828', (32, 35))	('GEM', 'Chemical', 'MESH:C056507', (70, 73))	('dCK', 'Gene', (32, 35))	('high', 'Var', (27, 31))
50190	33735191	As depicted in the Kaplan-Meier curves (Fig 6), patients who received CTx showed higher OS compared to those who did not receive or complete CTx (OS with CTx = 26.7, 20.4-33.0; without CTx = 9.7, 5.2-14.1; test statistic (1) = 12.751; p < .001).	('CTx', 'Var', (70, 73))	('higher', 'PosReg', (81, 87))	('patients', 'Species', '9606', (48, 56))
50209	33735191	In our case, margin positivity according to RCP guidelines, chemotherapy and nodal status have the strongest influence on patients  long-term survival.	('influence', 'Reg', (109, 118))	('patients', 'Species', '9606', (122, 130))	('nodal', 'Gene', '4838', (77, 82))	('nodal', 'Gene', (77, 82))	('margin positivity', 'Var', (13, 30))
50294	33067432	Importantly, we observed that autofluorescence, CD133, and CD24 significantly increased by more than twofold and CXCR4 and TEM8 significantly increased by threefold in 14-day Gal-CC compared to Gluc-CC (Fig.	('CD133', 'Gene', (48, 53))	('CD133', 'Gene', '8842', (48, 53))	('Gluc-CC', 'Chemical', '-', (194, 201))	('Gal-CC', 'Chemical', '-', (175, 181))	('increased', 'PosReg', (142, 151))	('CXCR4', 'Gene', '7852', (113, 118))	('TEM8', 'Gene', '84168', (123, 127))	('CXCR4', 'molecular_function', 'GO:0038147', ('113', '118'))	('increased', 'PosReg', (78, 87))	('CXCR4', 'Gene', (113, 118))	('TEM8', 'Gene', (123, 127))	('Gal-CC', 'Var', (175, 181))	('TEM', 'cellular_component', 'GO:0097197', ('123', '126'))	('autofluorescence', 'MPA', (30, 46))	('CD24', 'MPA', (59, 63))
50295	33067432	Moreover, CD90 and SSEA-4, PaCSC biomarkers present only on PANC286 and PANC185scd, respectively, significantly increased by more than fourfold (CD90) or twofold (SSEA-4) in 14-day Gal-CC (Supplementary Fig.	('PANC185', 'CellLine', 'CVCL:E284', (72, 79))	('Gal-CC', 'Chemical', '-', (181, 187))	('CD90', 'MPA', (10, 14))	('increased', 'PosReg', (112, 121))	('PANC185scd', 'Var', (72, 82))
50303	33067432	However, at times >4 days post-sorting, a sharp decrease in the percentage of CSC biomarker-positive cells was observed in Gluc-CC, while in Gal-CC the percentages either remained constant or increased, and at day 11 were ~2-fold higher than Gluc-CC (Supplementary Fig.	('Gluc-CC', 'Var', (123, 130))	('percentage of CSC biomarker-positive cells', 'MPA', (64, 106))	('Gluc-CC', 'Chemical', '-', (123, 130))	('Gal-CC', 'Chemical', '-', (141, 147))	('decrease', 'NegReg', (48, 56))	('Gluc-CC', 'Chemical', '-', (242, 249))	('increased', 'PosReg', (192, 201))
50309	33067432	First, we measured self-renewal capacity and observed significantly increased sphere-forming capacity for Gal-CC compared to Gluc-CC (Fig.	('Gal-CC', 'Chemical', '-', (106, 112))	('sphere-forming capacity', 'CPA', (78, 101))	('self-renewal capacity', 'CPA', (19, 40))	('increased', 'PosReg', (68, 77))	('Gal-CC', 'Var', (106, 112))	('Gluc-CC', 'Chemical', '-', (125, 132))
50310	33067432	2e), although spheres from Gluc-CC were consistently larger (Fig.	('larger', 'PosReg', (53, 59))	('Gluc-CC', 'Chemical', '-', (27, 34))	('Gluc-CC', 'Var', (27, 34))
50314	33067432	2h) cells were significantly higher in Gal-CC (more than threefold) compared to Gluc-CC in first- and second-generation spheres.	('higher', 'PosReg', (29, 35))	('Gal-CC', 'Var', (39, 45))	('Gal-CC', 'Chemical', '-', (39, 45))	('Gluc-CC', 'Chemical', '-', (80, 87))
50315	33067432	2f), genes related to stemness (e.g., SOX9) and pluripotency (e.g., NANOG) were significantly increased 2-3-fold in Gal-CC compared to Gluc-CC (Fig.	('Gluc-CC', 'Chemical', '-', (135, 142))	('SOX9', 'Gene', (38, 42))	('Gal-CC', 'Chemical', '-', (116, 122))	('pluripotency', 'Disease', (48, 60))	('NANOG', 'Gene', '79923', (68, 73))	('increased', 'PosReg', (94, 103))	('SOX9', 'Gene', '6662', (38, 42))	('pluripotency', 'Disease', 'None', (48, 60))	('NANOG', 'Gene', (68, 73))	('Gal-CC', 'Var', (116, 122))
50318	33067432	Analysis of the expression levels of a subset of lncRNAs revealed a significant 2-3-fold increase in their expression in Gal-CC compared to Gluc-CC (Supplementary Fig.	('Gal-CC', 'Var', (121, 127))	('expression', 'MPA', (107, 117))	('Gluc-CC', 'Chemical', '-', (140, 147))	('Gal-CC', 'Chemical', '-', (121, 127))	('increase', 'PosReg', (89, 97))
50320	33067432	While the size, weight, and percentage of mCherry-H2B+ Gluc-CC-derived tumors were slightly greater or equal to those of the Gal-CC-derived tumors (Supplementary Fig.	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('Gal-CC', 'Chemical', '-', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumors', 'Disease', (71, 77))	('mCherry-H2B+', 'Var', (42, 54))	('Gluc-CC', 'Chemical', '-', (55, 62))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
50322	33067432	Moreover, the percentage of CD133+ cells inside the mCherry-H2B+ cell population was significantly higher in the vast majority of tumors derived from Gal-CC versus Gluc-CC (Fig.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('CD133', 'Gene', '8842', (28, 33))	('Gal-CC', 'Chemical', '-', (150, 156))	('higher', 'PosReg', (99, 105))	('Gluc-CC', 'Chemical', '-', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Gal-CC', 'Var', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('CD133', 'Gene', (28, 33))
50330	33067432	Baseline OCR was significantly higher in Gal-CC compared to Gluc-CC, and both the maximal respiration and the spare respiratory capacity (SRC) significantly increased in Gal-CC compared to Gluc-CC (Fig.	('Gluc-CC', 'Chemical', '-', (60, 67))	('respiration', 'biological_process', 'GO:0007585', ('90', '101'))	('Baseline OCR', 'MPA', (0, 12))	('spare respiratory capacity', 'MPA', (110, 136))	('maximal respiration', 'MPA', (82, 101))	('Gal-CC', 'Var', (170, 176))	('Gluc-CC', 'Chemical', '-', (189, 196))	('Gal-CC', 'Chemical', '-', (41, 47))	('respiration', 'biological_process', 'GO:0045333', ('90', '101'))	('increased', 'PosReg', (157, 166))	('higher', 'PosReg', (31, 37))	('Gal-CC', 'Chemical', '-', (170, 176))
50331	33067432	Proton leak was also significantly higher in Gluc-CC, indicating decreased mitochondrial efficiency (Fig.	('decreased', 'NegReg', (65, 74))	('Proton leak', 'MPA', (0, 11))	('mitochondrial efficiency', 'MPA', (75, 99))	('Gluc-CC', 'Var', (45, 52))	('Gluc-CC', 'Chemical', '-', (45, 52))	('higher', 'PosReg', (35, 41))
50332	33067432	As expected, extracellular acidification rate (ECAR) revealed more acidification by glucose fermentation in Gluc-CC compared to Gal-CC (Supplementary Fig.	('acidification', 'biological_process', 'GO:0045851', ('27', '40'))	('glucose', 'Chemical', 'MESH:D005947', (84, 91))	('extracellular', 'cellular_component', 'GO:0005576', ('13', '26'))	('more', 'PosReg', (62, 66))	('extracellular acidification rate', 'MPA', (13, 45))	('Gluc-CC', 'Var', (108, 115))	('fermentation', 'biological_process', 'GO:0006113', ('92', '104'))	('acidification', 'MPA', (67, 80))	('Gal-CC', 'Chemical', '-', (128, 134))	('acidification', 'biological_process', 'GO:0045851', ('67', '80'))	('Gluc-CC', 'Chemical', '-', (108, 115))
50341	33067432	In line with the latter, we observed a significant increase in the percentage of MTDR and MT-CMXRos fluorescent area in Gal-CC compared to Gluc-CC (Fig.	('increase', 'PosReg', (51, 59))	('MTDR', 'MPA', (81, 85))	('Gal-CC', 'Chemical', '-', (120, 126))	('MT-CMXRos fluorescent area', 'MPA', (90, 116))	('Gal-CC', 'Var', (120, 126))	('Gluc-CC', 'Chemical', '-', (139, 146))
50344	33067432	3j, k), which was also used to show that the mitochondrial network in Gal-CC was more extensive compared to Gluc-CC (Supplementary Fig.	('Gal-CC', 'Var', (70, 76))	('mitochondrial network', 'CPA', (45, 66))	('Gal-CC', 'Chemical', '-', (70, 76))	('Gluc-CC', 'Chemical', '-', (108, 115))	('extensive', 'PosReg', (86, 95))
50353	33067432	4c), but the percentage of beta-galactosidase-positive area was significantly lower (twofold) in Gal-CC compared to Gluc-CC (Fig.	('Gluc-CC', 'Chemical', '-', (116, 123))	('Gal-CC', 'Var', (97, 103))	('beta-galactosidase', 'Gene', '2720', (27, 45))	('Gal-CC', 'Chemical', '-', (97, 103))	('beta-galactosidase', 'Gene', (27, 45))	('lower', 'NegReg', (78, 83))
50366	33067432	IF analysis of LC3B I-II and LAMP-1, both essential proteins related to the autophagic process, revealed that Gal-CC had a higher percentage of LC3B I-II and LAMP-1 fluorescent area compared to Gluc-CC (Fig.	('LAMP-1', 'Gene', '3916', (29, 35))	('LAMP-1', 'Gene', (158, 164))	('LC3B', 'Gene', (144, 148))	('Gluc-CC', 'Chemical', '-', (194, 201))	('LC3B', 'Gene', '81631', (15, 19))	('higher', 'PosReg', (123, 129))	('Gal-CC', 'Var', (110, 116))	('LAMP-1', 'Gene', '3916', (158, 164))	('LC3B', 'Gene', (15, 19))	('Gal-CC', 'Chemical', '-', (110, 116))	('LC3B', 'Gene', '81631', (144, 148))	('LAMP-1', 'Gene', (29, 35))
50399	33067432	While at 1 day post-injection (dpi) PANCA6L mCherry-H2B Gluc-CC migrated more efficiently to the tail compared to Gal-CC (Fig.	('Gal-CC', 'Chemical', '-', (114, 120))	('Gluc-CC', 'Chemical', '-', (56, 63))	('migrated', 'CPA', (64, 72))	('PANCA6L', 'Var', (36, 43))
50404	33067432	However, at 3 months pi, we found that mice injected with Gal-CC presented with significantly higher percentages of mCherry-positive cells in most organs compared to mice injected with Gluc-CC, including the liver, one of the main metastatic sites in PDAC patients (Fig.	('Gal-CC', 'Var', (58, 64))	('PDAC', 'Chemical', '-', (251, 255))	('Gal-CC', 'Chemical', '-', (58, 64))	('patients', 'Species', '9606', (256, 264))	('Gluc-CC', 'Chemical', '-', (185, 192))	('PDAC', 'Phenotype', 'HP:0006725', (251, 255))	('mice', 'Species', '10090', (166, 170))	('higher', 'PosReg', (94, 100))	('mice', 'Species', '10090', (39, 43))
50406	33067432	Interestingly, we found numerous and abnormally large lymphatic nodes in mice injected with Gal-CC, which were not detected in the mice injected with Gluc-CC (Fig.	('Gal-CC', 'Chemical', '-', (92, 98))	('Gluc-CC', 'Chemical', '-', (150, 157))	('mice', 'Species', '10090', (73, 77))	('Gal-CC', 'Var', (92, 98))	('mice', 'Species', '10090', (131, 135))	('lymphatic nodes', 'CPA', (54, 69))
50422	33067432	Moreover, we also observed increased autophagy in Gal-CC, suggesting that autophagy is also likely an important mechanism used by OXPHOS-dependent cells in metabolically restrictive conditions, such as those faced by CSCs in the tumor microenvironment (TME) where oxygen and nutrients are reduced.	('OXPHOS', 'biological_process', 'GO:0002082', ('130', '136'))	('autophagy', 'biological_process', 'GO:0006914', ('74', '83'))	('increased', 'PosReg', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('Gal-CC', 'Var', (50, 56))	('tumor', 'Disease', (229, 234))	('oxygen', 'Chemical', 'MESH:D010100', (264, 270))	('autophagy', 'biological_process', 'GO:0016236', ('37', '46'))	('autophagy', 'CPA', (37, 46))	('autophagy', 'biological_process', 'GO:0016236', ('74', '83'))	('autophagy', 'biological_process', 'GO:0006914', ('37', '46'))	('Gal-CC', 'Chemical', '-', (50, 56))
50474	33067432	356234, Corning) were subcutaneously injected into 8-week-old female nude mice (Hsd:Athymic Nude-Foxn1nu/Foxn1+; Envigo) and tracked for 10-14 weeks for tumor formation.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('Foxn1', 'Gene', (97, 102))	('356234', 'Var', (0, 6))	('Foxn1', 'Gene', '15218', (105, 110))	('Foxn1', 'Gene', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('formation', 'biological_process', 'GO:0009058', ('159', '168'))	('nude mice', 'Species', '10090', (69, 78))	('Foxn1', 'Gene', '15218', (97, 102))
50478	33067432	For in vivo tail vein injection invasion assays, 8-week-old NOD-SCID mice (Instituto de Investigaciones Biomedicas "Alberto Sols" CSIC-UAM) were injected intravenously via the tail vein with either 5 x 105 mCherry-H2B-labeled PANC185scd or PANCA6L Gluc-CC or Gal-CC (resuspended in 0.9% physiological saline solution) using a 27-G needle.	('saline', 'Chemical', 'MESH:D012965', (301, 307))	('mice', 'Species', '10090', (69, 73))	('PANCA6L Gluc-CC', 'Var', (240, 255))	('Gluc-CC', 'Chemical', '-', (248, 255))	('Gal-CC', 'Chemical', '-', (259, 265))	('PANC185scd', 'Var', (226, 236))	('PANC185', 'CellLine', 'CVCL:E284', (226, 233))
50482	33067432	For all in vivo experiments, mice were housed according to institutional guidelines and all experimental procedures were performed in compliance with the institutional guidelines for the welfare of experimental animals approved by the Universidad Autonoma de Madrid Ethics Committee (CEI 60-1057-A068 and CEI 103-1958-A337) and La Comunidad de Madrid (PROEX 335/14 and PROEX 294/19) and in accordance with the guidelines for Ethical Conduct in the Care and Use of Animals as stated in The International Guiding Principles for Biomedical Research involving Animals, developed by the Council for International Organizations of Medical Sciences (CIOMS).	('Autonoma de Madrid', 'Disease', (247, 265))	('mice', 'Species', '10090', (29, 33))	('CEI', 'Var', (284, 287))	('Autonoma de Madrid', 'Disease', 'MESH:D005862', (247, 265))
50512	33067432	E7760) as recommended by the kit manufacturer.	('kit', 'Gene', '3815', (29, 32))	('E7760', 'Var', (0, 5))	('kit', 'Gene', (29, 32))
50524	33067432	Imaging of the injected embryos was performed using a fluorescence stereomicroscope (AZ-100, Nikon) at 1, 4, and 6 dpi in order to measure the proliferation of the PANC185scd- and PANCA6L-injected human cancer cells inside the zebrafish circulation in each of the conditions assayed.	('PANC185scd-', 'Var', (164, 175))	('zebrafish', 'Species', '7955', (227, 236))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('human', 'Species', '9606', (197, 202))	('PANC185', 'CellLine', 'CVCL:E284', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
50579	32648540	For example, sorting can induce mechanical and oxidative stress and reduce the levels of certain metabolites, and even adding small amounts of bovine serum to the sorting buffer was not sufficient to prevent changes in some metabolite levels during cell sorting.	('induce', 'Reg', (25, 31))	('mechanical', 'CPA', (32, 42))	('sorting', 'Var', (13, 20))	('oxidative stress', 'Phenotype', 'HP:0025464', (47, 63))	('reduce', 'NegReg', (68, 74))	('stress', 'Disease', (57, 63))	('stress', 'Disease', 'MESH:D000079225', (57, 63))	('levels of certain metabolites', 'MPA', (79, 108))
50586	32648540	Furthermore, deletion of PC was insufficient to account for all pyruvate carboxylation activity within cancer cells in a mixed population, revealing that malic enzyme 1 (ME1) also contributes to pyruvate carboxylation in cancer cells when fibroblasts are present and is required for PDAC tumor growth.	('malic enzyme 1', 'Gene', '17436', (154, 168))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (221, 227))	('PDAC tumor', 'Disease', 'MESH:C537768', (283, 293))	('pyruvate', 'Chemical', 'MESH:D019289', (195, 203))	('PDAC tumor', 'Disease', (283, 293))	('deletion', 'Var', (13, 21))	('malic enzyme', 'molecular_function', 'GO:0004471', ('154', '166'))	('malic enzyme 1', 'Gene', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('pyruvate carboxylation', 'MPA', (195, 217))	('contributes', 'Reg', (180, 191))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('malic enzyme', 'molecular_function', 'GO:0004473', ('154', '166'))	('pyruvate', 'Chemical', 'MESH:D019289', (64, 72))
50588	32648540	To better understand glucose metabolism of PDAC tumor tissue in vivo, we infused U-13C-glucose into conscious, unrestrained mice bearing PDAC tumors from autochthonous models that are driven by activating mutations in Kras and disruption of Trp53 function.	('PDAC tumors', 'Disease', (137, 148))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('glucose', 'Chemical', 'MESH:D005947', (87, 94))	('Kras', 'Gene', (218, 222))	('function', 'MPA', (247, 255))	('mice', 'Species', '10090', (124, 128))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('glucose', 'Chemical', 'MESH:D005947', (21, 28))	('Kras', 'Gene', '16653', (218, 222))	('disruption', 'Var', (227, 237))	('13C', 'Chemical', 'MESH:C000615229', (83, 86))	('PDAC tumors', 'Disease', 'MESH:C537768', (137, 148))	('mutations', 'Var', (205, 214))	('Trp53', 'Gene', '22059', (241, 246))	('Trp53', 'Gene', (241, 246))	('glucose metabolism of PDAC tumor', 'Disease', (21, 53))	('glucose metabolism', 'biological_process', 'GO:0006006', ('21', '39'))	('glucose metabolism of PDAC tumor', 'Disease', 'MESH:C537768', (21, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
50589	32648540	Similar to what has been observed with other mouse cancer models and in humans, extensive labeling of multiple metabolic intermediates is observed from U-13C-glucose in pancreatic tumors and normal pancreas (Figure 1, Figure 1:figure supplements 1-3, Figure 1:source data 1, Figure 1:figure supplement 1:source data 1, Figure 1:figure supplement 2:source data 1, Figure 1:figure supplement 3:source data 1).	('pancreatic tumors', 'Phenotype', 'HP:0002894', (169, 186))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (169, 185))	('13C', 'Chemical', 'MESH:C000615229', (154, 157))	('mouse', 'Species', '10090', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('pancreatic tumors', 'Disease', 'MESH:D010190', (169, 186))	('pancreatic tumors', 'Disease', (169, 186))	('glucose', 'Chemical', 'MESH:D005947', (158, 165))	('U-13C-glucose', 'Var', (152, 165))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('humans', 'Species', '9606', (72, 78))
50593	32648540	Under these conditions, labeling of pyruvate and lactate, as well as the glucose-derived amino acids alanine and serine, from U-13C-glucose was observed in normal pancreas tissue and in tumors arising in both models (Figure 1C-F, Figure 1:source data 1).	('serine', 'Chemical', 'MESH:D012694', (113, 119))	('lactate', 'MPA', (49, 56))	('glucose', 'Chemical', 'MESH:D005947', (73, 80))	('glucose', 'Chemical', 'MESH:D005947', (132, 139))	('serine', 'MPA', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('alanine', 'Chemical', 'MESH:D000409', (101, 108))	('U-13C-glucose', 'Var', (126, 139))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('pyruvate', 'Chemical', 'MESH:D019289', (36, 44))	('lactate', 'Chemical', 'MESH:D019344', (49, 56))	('13C', 'Chemical', 'MESH:C000615229', (128, 131))
50603	32648540	To further study glucose metabolism in PDAC tumor tissue, we infused control and tumor-bearing KP-/-C mice with U-13C-glucose at a higher rate in an attempt to increase plasma enrichment of labeled glucose (; Figure 1:figure supplement 2, Figure 1:figure supplement 3A-K, Figure 1:figure supplement 2:source data 1, Figure 1:figure supplement 3:source data 1).	('mice', 'Species', '10090', (102, 106))	('glucose metabolism', 'biological_process', 'GO:0006006', ('17', '35'))	('glucose', 'Chemical', 'MESH:D005947', (118, 125))	('U-13C-glucose', 'Var', (112, 125))	('glucose', 'Chemical', 'MESH:D005947', (198, 205))	('glucose metabolism', 'Disease', (17, 35))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('PDAC tumor', 'Disease', (39, 49))	('13C', 'Chemical', 'MESH:C000615229', (114, 117))	('glucose metabolism', 'Disease', 'MESH:D044882', (17, 35))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('glucose', 'Chemical', 'MESH:D005947', (17, 24))	('PDAC tumor', 'Disease', 'MESH:C537768', (39, 49))	('increase', 'PosReg', (160, 168))	('plasma enrichment of labeled glucose', 'MPA', (169, 205))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
50606	32648540	Despite both being driven by mutant Kras and loss of normal Trp53 function, differences in the autochthonous KP-/-C and KPC PDAC models are known and have been attributed to differences in tumor latency and p53 status, as well as differences in how stromal cell populations interact with cancer cells to support tumor growth.	('PDAC', 'Chemical', '-', (124, 128))	('cancer', 'Disease', (288, 294))	('tumor', 'Disease', (312, 317))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('p53', 'Gene', (207, 210))	('p53', 'Gene', (62, 65))	('driven by', 'Reg', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('mutant', 'Var', (29, 35))	('Trp53', 'Gene', '22059', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('Trp53', 'Gene', (60, 65))	('Kras', 'Gene', (36, 40))	('tumor', 'Disease', (189, 194))	('p53', 'Gene', '22059', (207, 210))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('loss', 'NegReg', (45, 49))	('p53', 'Gene', '22059', (62, 65))	('Kras', 'Gene', '16653', (36, 40))
50656	32648540	M+3 labeling from U-13C-glucose is often used as a surrogate for pyruvate carboxylation activity, but can also occur from multiple rounds of TCA cycling.	('glucose', 'Chemical', 'MESH:D005947', (24, 31))	('M+3', 'MPA', (0, 3))	('pyruvate carboxylation activity', 'MPA', (65, 96))	('pyruvate', 'Chemical', 'MESH:D019289', (65, 73))	('U-13C-glucose', 'Var', (18, 31))	('TCA', 'Chemical', 'MESH:D014233', (141, 144))	('13C', 'Chemical', 'MESH:C000615229', (20, 23))
50659	32648540	Compared to U-13C-glucose labeling, a greater difference and significantly higher M+1 aspartate labeling in protein was observed using 1-13C-pyruvate or 3,4-13C-glucose in sorted cancer cells compared to PSCs from organoid-PSC co-cultures, further supporting that pyruvate carboxylation activity is higher in these cells (Figure 4J-K, Figure 4:figure supplement 1H).	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('13C', 'Chemical', 'MESH:C000615229', (157, 160))	('13C', 'Chemical', 'MESH:C000615229', (14, 17))	('pyruvate', 'Chemical', 'MESH:D019289', (264, 272))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('higher', 'PosReg', (299, 305))	('1-13C-pyruvate', 'Chemical', '-', (135, 149))	('higher', 'PosReg', (75, 81))	('M+1 aspartate labeling in protein', 'MPA', (82, 115))	('1H', 'Chemical', '-', (362, 364))	('13C', 'Chemical', 'MESH:C000615229', (137, 140))	('aspartate', 'Chemical', 'MESH:D001224', (86, 95))	('glucose', 'Chemical', 'MESH:D005947', (161, 168))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('1-13C-pyruvate', 'Var', (135, 149))	('glucose', 'Chemical', 'MESH:D005947', (18, 25))	('pyruvate', 'Chemical', 'MESH:D019289', (141, 149))	('cancer', 'Disease', (179, 185))	('pyruvate carboxylation activity', 'MPA', (264, 295))
50663	32648540	To label protein in PDAC tumors in vivo, autochthonous tumor-bearing mice were infused with U-13C-glucose for 24 hr (Figure 5:figure supplement 1C-D), with aspartate labeling observed in protein hydrolysates from bulk tumors in this time frame (Figure 5G).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('mice', 'Species', '10090', (69, 73))	('tumor', 'Disease', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('PDAC tumors', 'Disease', 'MESH:C537768', (20, 31))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Disease', (25, 30))	('U-13C-glucose', 'Var', (92, 105))	('glucose', 'Chemical', 'MESH:D005947', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('aspartate', 'Chemical', 'MESH:D001224', (156, 165))	('tumors', 'Disease', (218, 224))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('PDAC tumors', 'Disease', (20, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Disease', (55, 60))	('bulk tumor', 'Disease', 'MESH:D009369', (213, 223))	('bulk tumor', 'Disease', (213, 223))	('13C', 'Chemical', 'MESH:C000615229', (94, 97))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
50669	32648540	First, CRISPRi was used to knock down PC expression in a PDAC cancer cell line derived from KP-/-C mice (Figure 6:figure supplement 1A).	('mice', 'Species', '10090', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('PDAC', 'Chemical', '-', (57, 61))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('knock', 'Var', (27, 32))
50670	32648540	The ratio of M+1 aspartate to M+1 pyruvate derived from 1-13C-pyruvate or 3,4-13C-glucose has been used as a way to approximate pyruvate carboxylation activity.	('pyruvate', 'Chemical', 'MESH:D019289', (34, 42))	('pyruvate', 'Chemical', 'MESH:D019289', (62, 70))	('pyruvate carboxylation activity', 'MPA', (128, 159))	('13C', 'Chemical', 'MESH:C000615229', (58, 61))	('aspartate', 'Chemical', 'MESH:D001224', (17, 26))	('13C', 'Chemical', 'MESH:C000615229', (78, 81))	('pyruvate', 'Chemical', 'MESH:D019289', (128, 136))	('glucose', 'Chemical', 'MESH:D005947', (82, 89))	('1-13C-pyruvate', 'Chemical', '-', (56, 70))	('1-13C-pyruvate', 'Var', (56, 70))
50671	32648540	As expected, PC knockdown in these PDAC cells resulted in a decrease in aspartate labeling from 1-13C-pyruvate and relative pyruvate carboxylation activity compared to control cells as assessed by the ratio of M+1 labeled aspartate to M+1 labeled pyruvate (Figure 6:figure supplement 1B-C), but did not affect proliferation in culture (Figure 6:figure supplement 1D).	('decrease', 'NegReg', (60, 68))	('pyruvate', 'Chemical', 'MESH:D019289', (102, 110))	('pyruvate', 'Chemical', 'MESH:D019289', (247, 255))	('aspartate', 'Chemical', 'MESH:D001224', (222, 231))	('aspartate labeling from 1-13C-pyruvate', 'MPA', (72, 110))	('pyruvate carboxylation activity', 'MPA', (124, 155))	('PDAC', 'Chemical', '-', (35, 39))	('pyruvate', 'Chemical', 'MESH:D019289', (124, 132))	('knockdown', 'Var', (16, 25))	('aspartate', 'Chemical', 'MESH:D001224', (72, 81))	('1-13C-pyruvate', 'Chemical', '-', (96, 110))
50672	32648540	However, knockdown of PC in PDAC organoids reduced growth of these cells in organoid-PSC co-cultures (Figure 6:figure supplement 1E-G).	('PDAC organoids', 'Chemical', '-', (28, 42))	('reduced', 'NegReg', (43, 50))	('knockdown', 'Var', (9, 18))	('growth', 'CPA', (51, 57))
50674	32648540	When transplanted subcutaneously, PDAC cell lines with PC knockdown formed tumors that grew similarly to control cells (Figure 6:figure supplement 1K); however, PC expression was similar or increased in the tumors formed from PC knockdown cells compared to control tumors (Figure 6:figure supplement 1L).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('PDAC', 'Chemical', '-', (34, 38))	('knockdown', 'Var', (229, 238))	('expression', 'MPA', (164, 174))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('increased', 'PosReg', (190, 199))	('tumors', 'Disease', (265, 271))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('knockdown', 'Var', (58, 67))
50675	32648540	These data suggest that over time, cells that grew into tumors were selected for reversal of PC knockdown and that PC is required for PDAC tumor growth in vivo even though it is dispensable in culture, as has been observed previously in lung cancer.	('knockdown', 'Var', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('lung cancer', 'Disease', (237, 248))	('lung cancer', 'Disease', 'MESH:D008175', (237, 248))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('PDAC tumor', 'Disease', 'MESH:C537768', (134, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (237, 248))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('PDAC tumor', 'Disease', (134, 144))
50676	32648540	To further test the requirement for PC in PDAC tumors, we generated cancer cell clones with complete CRISPR/Cas9 disruption of PC expression (Figure 6:figure supplement 1M-N).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('disruption', 'Var', (113, 123))	('PDAC tumors', 'Disease', (42, 53))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('PDAC tumors', 'Disease', 'MESH:C537768', (42, 53))	('cancer', 'Disease', (68, 74))	('Cas', 'cellular_component', 'GO:0005650', ('108', '111'))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
50677	32648540	Similar to knockdown experiments, loss of PC had no effect on proliferation of PDAC cells in culture (Figure 6A), whereas loss of PC reduced the growth of organoid co-cultures (Figure 6B-C).	('loss', 'Var', (34, 38))	('PDAC', 'Chemical', '-', (79, 83))	('growth of organoid co-cultures', 'CPA', (145, 175))	('loss', 'Var', (122, 126))	('reduced', 'NegReg', (133, 140))
50678	32648540	CRISPR/Cas9 was also used to knockout PC in PSCs, and despite loss of PC expression and reduced pyruvate carboxylation activity (Figure 6:figure supplement 2A-C), PC knockout PSCs retained the ability to enhance PDAC organoid growth or growth of PDAC cancer cells as tumors in subcutaneous transplants, although the effect was reduced compared to sgControl PSCs (Figure 6:figure supplement 2D-F).	('loss', 'NegReg', (62, 66))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('pyruvate carboxylation activity', 'MPA', (96, 127))	('pyruvate', 'Chemical', 'MESH:D019289', (96, 104))	('Cas', 'cellular_component', 'GO:0005650', ('7', '10'))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('expression', 'MPA', (73, 83))	('enhance', 'PosReg', (204, 211))	('reduced', 'NegReg', (88, 95))	('tumors', 'Disease', (267, 273))	('PDAC organoid growth', 'CPA', (212, 232))	('growth', 'CPA', (236, 242))	('cancer', 'Disease', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('knockout', 'Var', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('reduced pyruvate carboxylation activity', 'Phenotype', 'HP:0003209', (88, 127))	('PDAC', 'Chemical', '-', (246, 250))	('PDAC', 'Chemical', '-', (212, 216))
50681	32648540	Taken together, these data argue that loss of PC in cancer cells can impact tumor growth, but another enzyme must also contribute to pyruvate carboxylation activity in these cells.	('loss', 'Var', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('contribute', 'Reg', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('impact', 'Reg', (69, 75))	('cancer', 'Disease', (52, 58))	('pyruvate carboxylation activity', 'MPA', (133, 164))	('pyruvate', 'Chemical', 'MESH:D019289', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
50684	32648540	Thus, we tested whether malic enzyme activity could sustain M+1 labeling of aspartate in PDAC cancer cells lacking PC by using CRISPR/Cas9 to knock out malic enzyme 1 (ME1).	('PDAC', 'Chemical', '-', (89, 93))	('malic enzyme 1', 'Gene', (152, 166))	('aspartate', 'Chemical', 'MESH:D001224', (76, 85))	('malic enzyme 1', 'Gene', '17436', (152, 166))	('M+1 labeling of aspartate', 'MPA', (60, 85))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('malic enzyme activity', 'molecular_function', 'GO:0004470', ('24', '45'))	('ME1', 'Gene', (168, 171))	('Cas', 'cellular_component', 'GO:0005650', ('134', '137'))	('knock out', 'Var', (142, 151))	('malic enzyme', 'molecular_function', 'GO:0004471', ('152', '164'))	('malic enzyme', 'molecular_function', 'GO:0004473', ('152', '164'))	('tested', 'Reg', (9, 15))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
50685	32648540	After knockout of both PC and ME1 in PDAC cell lines, aspartate labeling from 1-13C-pyruvate is virtually abolished, suggesting that ME1 activity can contribute to pyruvate carboxylation activity in these cells (Figure 7A-B, Figure 7:figure supplement 1A).	('pyruvate carboxylation activity', 'MPA', (164, 195))	('contribute', 'Reg', (150, 160))	('pyruvate', 'Chemical', 'MESH:D019289', (164, 172))	('1-13C-pyruvate', 'Chemical', '-', (78, 92))	('aspartate labeling from', 'MPA', (54, 77))	('activity', 'MPA', (137, 145))	('knockout', 'Var', (6, 14))	('PDAC', 'Chemical', '-', (37, 41))	('pyruvate', 'Chemical', 'MESH:D019289', (84, 92))	('aspartate', 'Chemical', 'MESH:D001224', (54, 63))	('abolished', 'NegReg', (106, 115))
50687	32648540	We used CRISPR/Cas9 to knockout or knockdown both PC and ME1 in organoids, which also resulted in decreased M+1 aspartate labeling from 1-13C-pyruvate and decreased pyruvate carboxylation activity (Figure 7:figure supplement 1B-D).	('knockdown', 'Var', (35, 44))	('pyruvate carboxylation activity', 'MPA', (165, 196))	('Cas', 'cellular_component', 'GO:0005650', ('15', '18'))	('1-13C-pyruvate', 'Chemical', '-', (136, 150))	('pyruvate', 'Chemical', 'MESH:D019289', (165, 173))	('M+1 aspartate labeling from 1-13C-pyruvate', 'MPA', (108, 150))	('aspartate', 'Chemical', 'MESH:D001224', (112, 121))	('decreased pyruvate carboxylation activity', 'Phenotype', 'HP:0003209', (155, 196))	('ME1', 'Gene', (57, 60))	('decreased', 'NegReg', (155, 164))	('pyruvate', 'Chemical', 'MESH:D019289', (142, 150))	('decreased', 'NegReg', (98, 107))
50690	32648540	This aspartate labeling was also increased after exogenous expression of ME1 in ME1 knockdown cells (Figure 7:figure supplement 1L-N).	('ME1', 'Gene', (73, 76))	('aspartate', 'Chemical', 'MESH:D001224', (5, 14))	('increased', 'PosReg', (33, 42))	('aspartate labeling', 'MPA', (5, 23))	('exogenous expression', 'Var', (49, 69))
50691	32648540	Interestingly, ME1 expression in KP-/-C mouse and human PDAC tumors and organoids mimics that of PC in that it is more highly expressed in cancer cells compared to stroma, suggesting that ME1 could also contribute to the higher pyruvate carboxylation seen in cancer cells compared to PSCs (Figure 7C-E, Figure 7:figure supplement 2A-E).	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('higher', 'PosReg', (221, 227))	('ME1', 'Gene', (15, 18))	('ME1', 'Var', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('pyruvate carboxylation', 'MPA', (228, 250))	('cancer', 'Disease', (139, 145))	('human', 'Species', '9606', (50, 55))	('PDAC tumors', 'Disease', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mouse', 'Species', '10090', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('PDAC tumors', 'Disease', 'MESH:C537768', (56, 67))	('pyruvate', 'Chemical', 'MESH:D019289', (228, 236))	('cancer', 'Disease', (259, 265))
50693	32648540	Similar to loss of PC, loss of ME1 had minimal effect on cancer cell proliferation in monoculture (Figure 7F, Figure 7:figure supplement 1F), but reduced growth of organoid co-cultures compared to controls (Figure 7G-H, Figure 7:figure supplement 1E).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('reduced', 'NegReg', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('loss', 'Var', (23, 27))	('ME1', 'Gene', (31, 34))	('growth', 'CPA', (154, 160))
50724	32648540	While loss of ME activity might be expected to impact pyruvate carboxylation activity when both enzymes are present, the fact that residual pyruvate carboxylation activity is observed in the absence of PC, and that this is lost upon ME1 disruption argues that PC and ME may have redundant metabolic functions under some conditions.	('loss', 'NegReg', (6, 10))	('impact', 'Reg', (47, 53))	('pyruvate', 'Chemical', 'MESH:D019289', (140, 148))	('disruption', 'Var', (237, 247))	('ME1', 'Gene', (233, 236))	('pyruvate carboxylation activity', 'MPA', (54, 85))	('activity', 'MPA', (17, 25))	('pyruvate', 'Chemical', 'MESH:D019289', (54, 62))	('pyruvate carboxylation activity', 'MPA', (140, 171))
50757	32648540	PSCs were isolated from beta-actin-GFP mice in a C57Bl6/J background (006567) as previously described: 3 mL of 1.3 mg/mL cold collagenase P (Sigma 11213865001) and 0.01 mg/mL DNAse (Sigma D5025) in GBSS (Sigma G9779) were injected into the pancreas.	('Sigma', 'Var', (182, 187))	('P (Sigma 11213865001', 'Var', (138, 158))	('mice', 'Species', '10090', (39, 43))	('GBSS', 'molecular_function', 'GO:0033840', ('198', '202'))
50762	32648540	Tumors were minced and digested overnight with collagenase XI (Sigma C9407) and dispase II (Roche 04942078001) and embedded in 50 muL domes of growth factor reduced (GFR) matrigel (Corning 356231) covered with 500 muL of complete media.	('muL', 'Gene', '68729', (214, 217))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('muL', 'Gene', '68729', (130, 133))	('muL', 'Gene', (214, 217))	('Sigma', 'Var', (63, 68))	('muL', 'Gene', (130, 133))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
50818	32648540	Knocking out either enzyme reduced tumor growth.	('reduced tumor', 'Disease', (27, 40))	('reduced tumor', 'Disease', 'MESH:C536418', (27, 40))	('Knocking out', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))
50837	32648540	The isotope labeling data from those ME1 null cells unexpectedly showed a larger decrease in labeling consistent with pyruvate carboxylation than was observed in PC null cells (with ME1 left intact).	('ME1', 'Var', (37, 40))	('decrease', 'NegReg', (81, 89))	('pyruvate carboxylation', 'MPA', (118, 140))	('labeling consistent', 'MPA', (93, 112))	('pyruvate', 'Chemical', 'MESH:D019289', (118, 126))
50842	32648540	The effects of ME1 knockout show a similar effect to PC knockout, with minimal effects on cell proliferation in culture (Figure 7F), but a reduction in organoid growth (Figure 7G-H) and tumor formation (Figure 7I).	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('ME1', 'Gene', (15, 18))	('reduction', 'NegReg', (139, 148))	('knockout', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('cell proliferation', 'CPA', (90, 108))	('tumor', 'Disease', (186, 191))	('organoid growth', 'CPA', (152, 167))	('formation', 'biological_process', 'GO:0009058', ('192', '201'))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))
50864	32364676	For example, miR-577 inhibits cell proliferation and epithelial-mesenchymal transition (EMT) in NSCLC.6 Conversely, miR-21 promotes cell proliferation, migration and invasion in NSCLC.7 Now, due to the dysregulation of miR-374b function in human cancer, it has attracted our attention.	('NSCLC', 'Disease', (96, 101))	('miR-374b', 'Gene', (219, 227))	('human', 'Species', '9606', (240, 245))	('miR-577', 'Gene', '693162', (13, 20))	('miR-21', 'Gene', (116, 122))	('inhibits', 'NegReg', (21, 29))	('promotes', 'PosReg', (123, 131))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('53', '86'))	('cancer', 'Disease', (246, 252))	('miR-577', 'Gene', (13, 20))	('miR-374b', 'Gene', '100126317', (219, 227))	('dysregulation', 'Var', (202, 215))	('EMT', 'biological_process', 'GO:0001837', ('88', '91'))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cell proliferation', 'biological_process', 'GO:0008283', ('30', '48'))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('invasion', 'CPA', (166, 174))	('NSCLC', 'Disease', (178, 183))	('migration', 'CPA', (152, 161))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cell proliferation', 'CPA', (30, 48))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('miR-21', 'Gene', '406991', (116, 122))	('cell proliferation', 'CPA', (132, 150))	('cell proliferation', 'biological_process', 'GO:0008283', ('132', '150'))	('epithelial-mesenchymal transition', 'CPA', (53, 86))
50884	32364676	The pcDNA3.1 plasmid vector (Promega, Madison, USA) was inserted into the 3'-UTR of wild-type or mutant ITGB1.	('ITGB1', 'Gene', '3688', (104, 109))	('ITGB1', 'Gene', (104, 109))	('mutant', 'Var', (97, 103))
50945	32373132	Their dysregulated expression has been associated with many human diseases, notably inflammation and cancer.	('dysregulated', 'Var', (6, 18))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('inflammation', 'Disease', 'MESH:D007249', (84, 96))	('cancer', 'Disease', (101, 107))	('inflammation', 'biological_process', 'GO:0006954', ('84', '96'))	('inflammation', 'Disease', (84, 96))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('human', 'Species', '9606', (60, 65))
50977	32373132	Interestingly, although IL-17B and IL-17E (IL-25) share a common receptor, IL-17RB, IL-17B, and IL-17E deficiency lead to opposite results in a model of acute colitis induced by dextran sulfate sodium.	('IL-17B', 'Gene', (84, 90))	('IL-17E', 'Gene', (96, 102))	('IL-17E', 'molecular_function', 'GO:0030380', ('96', '102'))	('colitis', 'Disease', (159, 166))	('IL-25', 'molecular_function', 'GO:0045521', ('43', '48'))	('IL-17', 'molecular_function', 'GO:0030367', ('75', '80'))	('IL-17E', 'Gene', '64806', (35, 41))	('colitis', 'Disease', 'MESH:D003092', (159, 166))	('dextran sulfate sodium', 'Chemical', 'MESH:D016264', (178, 200))	('IL-17E', 'Gene', '64806', (96, 102))	('IL-25', 'Gene', (43, 48))	('acute colitis', 'Phenotype', 'HP:0100282', (153, 166))	('colitis', 'Phenotype', 'HP:0002583', (159, 166))	('IL-25', 'Gene', '64806', (43, 48))	('IL-17E', 'Gene', (35, 41))	('IL-17', 'molecular_function', 'GO:0030367', ('84', '89'))	('IL-17E', 'molecular_function', 'GO:0030380', ('35', '41'))	('deficiency', 'Var', (103, 113))	('IL-17RB', 'Gene', (75, 82))	('IL-17', 'molecular_function', 'GO:0030367', ('24', '29'))
50984	32373132	High expression of IL-17B or its receptor has been associated with poor patient prognosis in different cancer types (see Table 1).	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('IL-17B', 'Gene', (19, 25))	('High', 'Var', (0, 4))	('patient', 'Species', '9606', (72, 79))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('IL-17', 'molecular_function', 'GO:0030367', ('19', '24'))
50990	32373132	Then, we analyzed microarray data of 1809 patients with breast cancer, and found that high IL-17B expression was significantly correlated with poorer prognosis in the whole population and in the basal-like subtype, but not in other breast cancer subtypes.	('breast cancer', 'Disease', (232, 245))	('breast cancer', 'Phenotype', 'HP:0003002', (232, 245))	('IL-17B', 'Gene', (91, 97))	('poorer', 'NegReg', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (232, 245))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('IL-17', 'molecular_function', 'GO:0030367', ('91', '96'))	('breast cancer', 'Disease', (56, 69))	('patients', 'Species', '9606', (42, 50))	('high', 'Var', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('expression', 'MPA', (98, 108))
50991	32373132	Conversely, IL-17A expression was associated with favorable outcomes in the whole population and in the different molecular subtypes from this cohort.	('IL-17', 'molecular_function', 'GO:0030367', ('12', '17'))	('IL-17A', 'Gene', (12, 18))	('expression', 'Var', (19, 29))	('IL-17A', 'Gene', '3605', (12, 18))
50993	32373132	They found that in patients with high IL-17RB expression, prognosis is worse and malignancy is enhanced.	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (19, 27))	('IL-17RB', 'Protein', (38, 45))	('prognosis', 'CPA', (58, 67))	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('enhanced', 'PosReg', (95, 103))	('expression', 'MPA', (46, 56))	('malignancy', 'Disease', (81, 91))	('IL-17', 'molecular_function', 'GO:0030367', ('38', '43'))
51012	32373132	Similarly, IL-17B or IL-17RB silencing in cancer cells or treatment with antibodies targeting IL-17RB reduced proliferation of MDA-MB361 breast cancer cells and MOLM-13 AML cells in vitro and tumor growth in vivo in xenograft models based on these cell lines.	('AML', 'Phenotype', 'HP:0004808', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('AML', 'Disease', (169, 172))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('IL-17', 'molecular_function', 'GO:0030367', ('94', '99'))	('silencing', 'Var', (29, 38))	('IL-17', 'molecular_function', 'GO:0030367', ('11', '16'))	('proliferation', 'CPA', (110, 123))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('MDA-MB361', 'CellLine', 'CVCL:0620', (127, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('tumor', 'Disease', (192, 197))	('IL-17RB', 'Gene', (94, 101))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('reduced', 'NegReg', (102, 109))	('IL-17RB', 'Gene', (21, 28))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Disease', (137, 150))	('cancer', 'Disease', (42, 48))	('IL-17', 'molecular_function', 'GO:0030367', ('21', '26'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('AML', 'Disease', 'MESH:D015470', (169, 172))
51013	32373132	Interestingly, IL-17RB knockdown in MOLM-13 AML cells had a stronger effect than IL-17B knockdown in vivo, reflecting the potential contribution of the microenvironment-derived IL-17B to the signal delivered to IL-17RB-positive leukemia cells.	('IL-17', 'molecular_function', 'GO:0030367', ('177', '182'))	('leukemia', 'Disease', 'MESH:D007938', (228, 236))	('IL-17', 'molecular_function', 'GO:0030367', ('211', '216'))	('AML', 'Disease', 'MESH:D015470', (44, 47))	('knockdown', 'Var', (23, 32))	('AML', 'Disease', (44, 47))	('IL-17RB', 'Gene', (15, 22))	('AML', 'Phenotype', 'HP:0004808', (44, 47))	('leukemia', 'Phenotype', 'HP:0001909', (228, 236))	('IL-17', 'molecular_function', 'GO:0030367', ('81', '86'))	('IL-17', 'molecular_function', 'GO:0030367', ('15', '20'))	('leukemia', 'Disease', (228, 236))
51022	32373132	Specifically, in A549 an CL1-5 lung cancer cell lines that spontaneously expressed high level of IL-17RB, Snail and Twist expression was decreased upon IL-17RB knockdown.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('Twist', 'Gene', '7291', (116, 121))	('Snail', 'Gene', '6615', (106, 111))	('Twist', 'Gene', (116, 121))	('knockdown', 'Var', (160, 169))	('Snail', 'Gene', (106, 111))	('IL-17', 'molecular_function', 'GO:0030367', ('152', '157'))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('IL-17', 'molecular_function', 'GO:0030367', ('97', '102'))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('decreased', 'NegReg', (137, 146))	('A549', 'CellLine', 'CVCL:0023', (17, 21))
51031	32373132	In pancreatic cancer, high IL-17RB expression has been associated with postoperative metastases in patients.	('pancreatic cancer', 'Disease', (3, 20))	('IL-17RB', 'Protein', (27, 34))	('postoperative metastases', 'Disease', 'MESH:D009362', (71, 95))	('high', 'Var', (22, 26))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('associated', 'Reg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('expression', 'MPA', (35, 45))	('patients', 'Species', '9606', (99, 107))	('IL-17', 'molecular_function', 'GO:0030367', ('27', '32'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('postoperative metastases', 'Disease', (71, 95))
51032	32373132	Conversely, IL-17RB or IL-17B knockdown in CFPAC-1 and BxPC3 pancreatic cancer cell reduces their soft agar colony formation in soft agar and cell invasion in vitro.	('soft agar colony formation in soft agar', 'CPA', (98, 137))	('BxPC3', 'CellLine', 'CVCL:0186', (55, 60))	('IL-17RB', 'Gene', (12, 19))	('IL-17B', 'Gene', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('IL-17', 'molecular_function', 'GO:0030367', ('23', '28'))	('formation', 'biological_process', 'GO:0009058', ('115', '124'))	('IL-17', 'molecular_function', 'GO:0030367', ('12', '17'))	('knockdown', 'Var', (30, 39))	('reduces', 'NegReg', (84, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('pancreatic cancer', 'Disease', (61, 78))	('cell invasion in vitro', 'CPA', (142, 164))
51033	32373132	In vivo studies showed that tumor growth and metastasis formation are reduced in mice xenografted with IL-17RB or IL-17B knockdown cells compared with parental CFPAC-1 and BxPC3 cells.	('knockdown', 'Var', (121, 130))	('IL-17B', 'Gene', (114, 120))	('IL-17', 'molecular_function', 'GO:0030367', ('103', '108'))	('reduced', 'NegReg', (70, 77))	('tumor', 'Disease', (28, 33))	('mice', 'Species', '10090', (81, 85))	('IL-17RB', 'Gene', (103, 110))	('BxPC3', 'CellLine', 'CVCL:0186', (172, 177))	('IL-17', 'molecular_function', 'GO:0030367', ('114', '119'))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('formation', 'biological_process', 'GO:0009058', ('56', '65'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
51037	32373132	In agreement, shRNA-mediated of CCL20, CXCL1, or TFF1 depletion in CFPAC-1 pancreatic cancer cells significantly decreased the percentage of macrophages that interact with tumor cells in vivo, while IL-8 depletion reduced CD31+ endothelial cell recruitment.	('CXCL1', 'Gene', (39, 44))	('tumor', 'Disease', (172, 177))	('CCL20', 'Gene', '6364', (32, 37))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (75, 92))	('CD31', 'Gene', '5175', (222, 226))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('decreased', 'NegReg', (113, 122))	('CCL20', 'Gene', (32, 37))	('IL-8', 'Gene', (199, 203))	('pancreatic cancer', 'Disease', 'MESH:D010190', (75, 92))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('TFF1', 'Gene', '7031', (49, 53))	('CD31', 'Gene', (222, 226))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('IL-8', 'molecular_function', 'GO:0005153', ('199', '203'))	('reduced', 'NegReg', (214, 221))	('pancreatic cancer', 'Disease', (75, 92))	('TFF1', 'Gene', (49, 53))	('depletion', 'Var', (54, 63))	('IL-8', 'Gene', '3576', (199, 203))	('CXCL1', 'Gene', '2919', (39, 44))	('CCL', 'molecular_function', 'GO:0044101', ('32', '35'))
51042	32373132	In fact, our own unpublished data in mouse models suggest that IL-17B-driven alterations in the TME are the major contributors of the anticancer effect after IL-17B neutralization.	('cancer', 'Disease', (138, 144))	('IL-17B', 'Gene', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('IL-17', 'molecular_function', 'GO:0030367', ('158', '163'))	('TME', 'Gene', '110080', (96, 99))	('IL-17', 'molecular_function', 'GO:0030367', ('63', '68'))	('mouse', 'Species', '10090', (37, 42))	('TME', 'Gene', (96, 99))	('neutralization', 'Var', (165, 179))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
51064	32323034	Biomolecular analysis of our cases detected KRAS mutation.	('KRAS', 'Gene', '3845', (44, 48))	('detected', 'Reg', (35, 43))	('KRAS', 'Gene', (44, 48))	('mutation', 'Var', (49, 57))
51122	31102348	The detailed HR and p-value were presented in Figure S2, in which low-expressed DNAH10 and KIAA0513 were proved to be robust for prognosis prediction.	('DNAH10', 'Gene', (80, 86))	('DNAH10', 'Gene', '196385', (80, 86))	('KIAA0513', 'Gene', (91, 99))	('KIAA0513', 'Gene', '9764', (91, 99))	('low-expressed', 'Var', (66, 79))
51225	30823544	In their study it also emerged that in patients undergoing CRT, the IOA drastically dropped in staging and in the determination of resectability compared to patients not treated with CRT.	('dropped', 'NegReg', (84, 91))	('CRT', 'Var', (59, 62))	('patients', 'Species', '9606', (39, 47))	('patients', 'Species', '9606', (157, 165))	('staging', 'CPA', (95, 102))
51228	30823544	In fact, as shown by Cassinotto et al., changes in tumor major diameter are not always associated with R0 resection.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('changes', 'Var', (40, 47))	('tumor', 'Disease', (51, 56))	('associated', 'Reg', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
51275	30650541	However, recent findings have demonstrated that grafting polymers to a liposome surface can only reduce protein binding, but cannot fully prevent it.	('protein binding', 'molecular_function', 'GO:0005515', ('104', '119'))	('grafting', 'Var', (48, 56))	('protein', 'Protein', (104, 111))	('polymers', 'Chemical', 'MESH:D011108', (57, 65))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('reduce', 'NegReg', (97, 103))
51306	30650541	On the other hand, molecular recognition between endogenous plasma proteins (i.e., recruited from the blood) and cancer cell receptors could promote selective accumulation at the tumor site.	('molecular recognition', 'Var', (19, 40))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('selective', 'CPA', (149, 158))	('cancer', 'Disease', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('promote', 'PosReg', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Disease', (179, 184))
51328	30650541	Consequently, we envision that the manipulation of liposome surface chemistry can dictate the selective binding of plasma proteins with the possibility of identifying cancer at the early stages.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('binding', 'Interaction', (104, 111))	('plasma proteins', 'Protein', (115, 130))	('dictate', 'Reg', (82, 89))	('binding', 'molecular_function', 'GO:0005488', ('104', '111'))	('manipulation', 'Var', (35, 47))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
51357	30405887	However, due to the possible cardiac side effects (lengthening of the electrocardiographic (ECG) QT interval and triggering of ventricular arrhythmia) that hERG1 blockade may produce, this channel is generally considered an undesirable pharmacologic target.	('ventricular arrhythmia', 'Phenotype', 'HP:0004308', (127, 149))	('electrocardiographic', 'MPA', (70, 90))	('ventricular arrhythmia', 'Disease', (127, 149))	('hERG1', 'Gene', '3757', (156, 161))	('hERG1', 'Gene', (156, 161))	('blockade', 'Var', (162, 170))	('ECG', 'Chemical', '-', (92, 95))	('ventricular arrhythmia', 'Disease', 'MESH:D001145', (127, 149))	('arrhythmia', 'Phenotype', 'HP:0011675', (139, 149))
51379	30405887	The immunoreactivity of both "native" scFv-hERG1 and mutagenized scFv-hERG1-Cys was first tested through a sandwich ELISA assay, using the immobilized S5-Pore peptide as antigen.	('hERG1', 'Gene', '3757', (70, 75))	('scFv', 'Gene', '652070', (38, 42))	('hERG1', 'Gene', (70, 75))	('scFv', 'Gene', (65, 69))	('scFv', 'Gene', (38, 42))	('scFv', 'Gene', '652070', (65, 69))	('Pore', 'cellular_component', 'GO:0046930', ('152', '156'))	('hERG1', 'Gene', '3757', (43, 48))	('hERG1', 'Gene', (43, 48))	('mutagenized', 'Var', (53, 64))
51382	30405887	Overall, the mutagenized scFv-hERG1-Cys displayed higher binding capacity towards the antigenic peptide, compared to the "native" scFv-hERG1.	('scFv', 'Gene', '652070', (130, 134))	('scFv', 'Gene', '652070', (25, 29))	('higher', 'PosReg', (50, 56))	('binding', 'Interaction', (57, 64))	('scFv', 'Gene', (25, 29))	('mutagenized', 'Var', (13, 24))	('hERG1', 'Gene', '3757', (135, 140))	('hERG1', 'Gene', (135, 140))	('hERG1', 'Gene', '3757', (30, 35))	('hERG1', 'Gene', (30, 35))	('binding', 'molecular_function', 'GO:0005488', ('57', '64'))	('scFv', 'Gene', (130, 134))
51392	30405887	Both scFv antibodies showed correct core folding with very little conformational differences in the region carrying the mutation.	('scFv', 'Gene', (5, 9))	('core folding', 'MPA', (36, 48))	('scFv', 'Gene', '652070', (5, 9))	('mutation', 'Var', (120, 128))
51394	30405887	In conclusion, the mutagenized scFv-hERG1-Cys displayed higher stability, purity and affinity towards the raising peptide, compared to the "native" scFv-hERG1, and was hence chosen for further characterizations, both in vitro and in vivo.	('hERG1', 'Gene', '3757', (36, 41))	('mutagenized', 'Var', (19, 30))	('purity', 'MPA', (74, 80))	('stability', 'MPA', (63, 72))	('hERG1', 'Gene', '3757', (153, 158))	('scFv', 'Gene', (148, 152))	('scFv', 'Gene', (31, 35))	('hERG1', 'Gene', (153, 158))	('scFv', 'Gene', '652070', (31, 35))	('scFv', 'Gene', '652070', (148, 152))	('affinity', 'MPA', (85, 93))	('hERG1', 'Gene', (36, 41))	('higher', 'PosReg', (56, 62))
51447	30405887	In particular, the anti-ABPC48 antibody, although lacking the Cys in position 92, maintains it functionality beacuse the Cys residue is replaced by a strong hydrophobic residue, Tyrosine, which preserves the hydrophobic core and hence antibody performances.	('antibody', 'cellular_component', 'GO:0019815', ('31', '39'))	('core', 'cellular_component', 'GO:0019013', ('220', '224'))	('antibody', 'cellular_component', 'GO:0042571', ('235', '243'))	('antibody', 'cellular_component', 'GO:0019814', ('31', '39'))	('antibody', 'molecular_function', 'GO:0003823', ('31', '39'))	('anti-ABPC48', 'Var', (19, 30))	('hydrophobic core', 'MPA', (208, 224))	('Tyrosine', 'Chemical', 'MESH:D014443', (178, 186))	('antibody', 'cellular_component', 'GO:0019815', ('235', '243'))	('Cys', 'Chemical', 'MESH:D003545', (62, 65))	('antibody', 'cellular_component', 'GO:0042571', ('31', '39'))	('antibody', 'cellular_component', 'GO:0019814', ('235', '243'))	('antibody', 'molecular_function', 'GO:0003823', ('235', '243'))	('Cys', 'Chemical', 'MESH:D003545', (121, 124))
51452	30405887	On the contrary, the mutagenesis procedure we applied was capable to generate a single chain antibody, the scFv-hERG1-Cys, with advantageous affinity constants, closer to those of the bivalent monoclonal antibody (KD 62 nM).	('antibody', 'cellular_component', 'GO:0042571', ('204', '212'))	('antibody', 'cellular_component', 'GO:0019815', ('93', '101'))	('scFv', 'Gene', '652070', (107, 111))	('antibody', 'cellular_component', 'GO:0019814', ('93', '101'))	('antibody', 'molecular_function', 'GO:0003823', ('93', '101'))	('scFv', 'Gene', (107, 111))	('antibody', 'cellular_component', 'GO:0019814', ('204', '212'))	('antibody', 'cellular_component', 'GO:0019815', ('204', '212'))	('mutagenesis', 'biological_process', 'GO:0006280', ('21', '32'))	('antibody', 'molecular_function', 'GO:0003823', ('204', '212'))	('antibody', 'cellular_component', 'GO:0042571', ('93', '101'))	('mutagenesis', 'Var', (21, 32))
51453	30405887	In addition, the mutagenized scFv was more stable, without aggregates or degraded forms (Figure 1E), and hence with higher manufacturing performances.	('manufacturing', 'MPA', (123, 136))	('higher', 'PosReg', (116, 122))	('mutagenized', 'Var', (17, 28))	('more', 'PosReg', (38, 42))	('scFv', 'Gene', (29, 33))	('scFv', 'Gene', '652070', (29, 33))
51459	30405887	Indeed, the mutagenized scFv-hERG1-Cys also showed good performances when tested in living systems.	('mutagenized', 'Var', (12, 23))	('scFv', 'Gene', (24, 28))	('performances', 'MPA', (56, 68))	('scFv', 'Gene', '652070', (24, 28))
51556	29273875	Patients with histology codes 8453, intraductal papillary mucinous carcinoma and 8480 mucinous adenocarcinoma represented only 8% of the patients who underwent a robotic total pancreatectomy.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('patients', 'Species', '9606', (137, 145))	('intraductal papillary mucinous carcinoma', 'Disease', (36, 76))	('8480', 'Var', (81, 85))	('Patients', 'Species', '9606', (0, 8))	('mucinous adenocarcinoma', 'Disease', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (86, 109))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (58, 76))	('intraductal papillary mucinous carcinoma', 'Disease', 'MESH:D000077779', (36, 76))
51585	29273875	The association of robotic TP with decreased mortality was significant even after multivariate logistic regression analysis (table2).	('robotic', 'Var', (19, 26))	('TP', 'Chemical', '-', (27, 29))	('decreased', 'NegReg', (35, 44))	('mortality', 'MPA', (45, 54))
51590	29273875	Evaluation of the National Cancer Database on TP cases, revealed that the use of robotic TP was associated with decreased hospital stay and postoperative mortality at 30 and 90 days compared to open TP and similar to laparoscopic TP.	('robotic', 'Var', (81, 88))	('Cancer', 'Disease', (27, 33))	('postoperative mortality', 'CPA', (140, 163))	('TP', 'Chemical', '-', (46, 48))	('Cancer', 'Disease', 'MESH:D009369', (27, 33))	('TP', 'Chemical', '-', (89, 91))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('hospital stay', 'CPA', (122, 135))	('decreased', 'NegReg', (112, 121))	('TP', 'Chemical', '-', (199, 201))	('TP', 'Chemical', '-', (230, 232))
51602	29273875	In our report, robotic and laparoscopic TP were associated with shorter hospital stay and improved 30 and 90 day mortality compared to open TP.	('robotic', 'Var', (15, 22))	('laparoscopic', 'Disease', (27, 39))	('improved', 'PosReg', (90, 98))	('TP', 'Chemical', '-', (40, 42))	('TP', 'Chemical', '-', (140, 142))	('shorter', 'NegReg', (64, 71))
51603	29273875	We similarly have shown improved postoperative outcome and shorted hospital stay for minimally invasive distal pancreatectomies with frail patients deriving the greatest benefit.	('improved', 'PosReg', (24, 32))	('minimally', 'Var', (85, 94))	('patients', 'Species', '9606', (139, 147))
51611	29273875	NCDB data support that the utilization of robotic TP has tripled from 2010 to 2014 and is associated, similarly to laparoscopic TP, with decreased hospitalization and postoperative mortality compared to open TP.	('TP', 'Chemical', '-', (128, 130))	('TP', 'Chemical', '-', (208, 210))	('TP', 'Chemical', '-', (50, 52))	('robotic', 'Var', (42, 49))	('decreased', 'NegReg', (137, 146))	('hospitalization', 'MPA', (147, 162))
51618	29854071	miR-21 silencing attenuated ROS-induced activation, invasion, migration, and glycolysis of PSCs, whereas the overexpression of miR-21 rescued the responses of PSCs treated with RSV.	('migration', 'CPA', (62, 71))	('miR-21', 'Gene', (127, 133))	('attenuated', 'NegReg', (17, 27))	('glycolysis', 'biological_process', 'GO:0006096', ('77', '87'))	('miR-21', 'Gene', (0, 6))	('miR-21', 'Gene', '406991', (0, 6))	('RSV', 'Chemical', 'MESH:D000077185', (177, 180))	('ROS', 'Chemical', 'MESH:D017382', (28, 31))	('glycolysis', 'CPA', (77, 87))	('miR-21', 'Gene', '406991', (127, 133))	('invasion', 'CPA', (52, 60))	('ROS-induced', 'Protein', (28, 39))	('activation', 'MPA', (40, 50))	('silencing', 'Var', (7, 16))	('rat', 'Species', '10116', (65, 68))
51619	29854071	Moreover, RSV or N-acetyl-L-cysteine (NAC) administration or miR-21 knockdown in PSCs reduced the invasion and migration of PCCs in coculture, and the effects of RSV were partly reversed by miR-21 upregulation.	('RSV', 'Chemical', 'MESH:D000077185', (10, 13))	('reduced', 'NegReg', (86, 93))	('miR-21', 'Gene', '406991', (190, 196))	('rat', 'Species', '10116', (114, 117))	('PCC', 'Gene', '1421', (124, 127))	('RSV', 'Chemical', 'MESH:D000077185', (162, 165))	('rat', 'Species', '10116', (51, 54))	('miR-21', 'Gene', '406991', (61, 67))	('NAC', 'cellular_component', 'GO:0005854', ('38', '41'))	('knockdown', 'Var', (68, 77))	('NAC', 'Gene', (38, 41))	('miR-21', 'Gene', (190, 196))	('NAC', 'Gene', '7504', (38, 41))	('PCC', 'Gene', (124, 127))	('miR-21', 'Gene', (61, 67))
51620	29854071	Collectively, RSV inhibits PCC invasion and migration through suppression of ROS/miR-21-mediated activation and glycolysis in PSCs.	('miR-21', 'Gene', (81, 87))	('suppression', 'NegReg', (62, 73))	('RSV', 'Chemical', 'MESH:D000077185', (14, 17))	('inhibits', 'NegReg', (18, 26))	('glycolysis', 'MPA', (112, 122))	('PCC', 'Gene', (27, 30))	('PCC', 'cellular_component', 'GO:0120205', ('27', '30'))	('RSV', 'Var', (14, 17))	('miR-21', 'Gene', '406991', (81, 87))	('rat', 'Species', '10116', (47, 50))	('glycolysis', 'biological_process', 'GO:0006096', ('112', '122'))	('ROS', 'Chemical', 'MESH:D017382', (77, 80))	('migration', 'CPA', (44, 53))	('activation', 'MPA', (97, 107))	('PCC', 'Gene', '1421', (27, 30))
51630	29854071	The interaction between PSCs (cancer-associated fibroblasts) and tumor cells is mediated by diverse secreted soluble factors such as extracellular matrix proteins, cytokines, and integrins, and disrupting this connection may provide novel approaches to cancer therapy.	('interaction', 'Interaction', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('soluble', 'cellular_component', 'GO:0005625', ('109', '116'))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('133', '153'))	('cancer', 'Disease', (253, 259))	('disrupting', 'Var', (194, 204))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
51635	29854071	Inhibition of miR-21 induces apoptosis and cell cycle arrest and enhances the chemotherapeutic sensitivity of tumors by positively modulating PTEN, PDCD4, and BCL-2 and other target genes.	('miR-21', 'Gene', '406991', (14, 20))	('PTEN', 'Gene', '5728', (142, 146))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (43, 60))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('enhances', 'PosReg', (65, 73))	('arrest', 'Disease', (54, 60))	('apoptosis', 'CPA', (29, 38))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('43', '60'))	('induces', 'Reg', (21, 28))	('miR-21', 'Gene', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('BCL-2', 'Gene', '596', (159, 164))	('BCL-2', 'Gene', (159, 164))	('BCL-2', 'molecular_function', 'GO:0015283', ('159', '164'))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('arrest', 'Disease', 'MESH:D006323', (54, 60))	('Inhibition', 'Var', (0, 10))	('PDCD4', 'Gene', (148, 153))	('PTEN', 'Gene', (142, 146))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('modulating', 'Reg', (131, 141))	('PDCD4', 'Gene', '27250', (148, 153))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))
51637	29854071	However, whether aberrant miR-21 expression promotes glycolysis and the invasiveness of PSCs remains unclear.	('promotes', 'PosReg', (44, 52))	('aberrant', 'Var', (17, 25))	('PSCs', 'Disease', (88, 92))	('glycolysis', 'MPA', (53, 63))	('miR-21', 'Gene', '406991', (26, 32))	('glycolysis', 'biological_process', 'GO:0006096', ('53', '63'))	('miR-21', 'Gene', (26, 32))
51639	29854071	RSV inhibits tumor growth, invasion, and epithelial-mesenchymal transition and enhances chemosensitivity.	('tumor', 'Disease', (13, 18))	('inhibits', 'NegReg', (4, 12))	('RSV', 'Var', (0, 3))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('41', '74'))	('epithelial-mesenchymal transition', 'CPA', (41, 74))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('invasion', 'CPA', (27, 35))	('enhances', 'PosReg', (79, 87))	('chemosensitivity', 'CPA', (88, 104))	('RSV', 'Chemical', 'MESH:D000077185', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
51641	29854071	Furthermore, RSV induces apoptosis and cell cycle arrest in tumor cells by enhancing expression of p21, p27, Bim, and cleaved caspase-3 and by inhibiting the expression of cyclin D1.	('Bim', 'Gene', '10018', (109, 112))	('cyclin', 'molecular_function', 'GO:0016538', ('172', '178'))	('apoptosis', 'biological_process', 'GO:0097194', ('25', '34'))	('apoptosis', 'biological_process', 'GO:0006915', ('25', '34'))	('arrest', 'Disease', 'MESH:D006323', (50, 56))	('tumor', 'Disease', (60, 65))	('RSV', 'Chemical', 'MESH:D000077185', (13, 16))	('cleaved', 'MPA', (118, 125))	('Bim', 'Gene', (109, 112))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('39', '56'))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('apoptosis', 'CPA', (25, 34))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (39, 56))	('expression', 'MPA', (158, 168))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('arrest', 'Disease', (50, 56))	('p21', 'Gene', (99, 102))	('cyclin D1', 'Gene', (172, 181))	('p21', 'Gene', '644914', (99, 102))	('expression', 'MPA', (85, 95))	('induces', 'Reg', (17, 24))	('enhancing', 'PosReg', (75, 84))	('inhibiting', 'NegReg', (143, 153))	('p27', 'Gene', '3429', (104, 107))	('p27', 'Gene', (104, 107))	('cyclin D1', 'Gene', '595', (172, 181))	('caspase-3', 'Protein', (126, 135))	('RSV', 'Var', (13, 16))
51644	29854071	Glycolysis of tumor cells is disrupted by RSV via the modulation of glucose consumption and glycolytic enzymes such as hexokinase 2.	('glucose consumption', 'Disease', (68, 87))	('hexokinase 2', 'Gene', (119, 131))	('tumor', 'Disease', (14, 19))	('RSV', 'Chemical', 'MESH:D000077185', (42, 45))	('RSV', 'Var', (42, 45))	('modulation', 'Reg', (54, 64))	('glycolytic enzymes', 'Enzyme', (92, 110))	('Glycolysis', 'MPA', (0, 10))	('hexokinase 2', 'Gene', '3099', (119, 131))	('disrupted', 'Reg', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('glucose consumption', 'Disease', 'MESH:D014397', (68, 87))	('Glycolysis', 'biological_process', 'GO:0006096', ('0', '10'))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
51687	29854071	Exogenous H2O2, a traditional cellular ROS inducer, exhibited growth-promoting action up to a concentration of approximately 50 muM (Figure 1(b)).	('H2O2', 'Var', (10, 14))	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('rat', 'Species', '10116', (101, 104))	('muM', 'Gene', '56925', (128, 131))	('muM', 'Gene', (128, 131))	('growth-promoting action', 'CPA', (62, 85))	('H2O2', 'Chemical', 'MESH:D006861', (10, 14))
51689	29854071	Oil Red O staining showed that 50 muM H2O2 efficiently transferred the quiescent state of PSCs to the activated state with a considerable decline of lipid droplets (Figure S1).	('H2O2', 'Var', (38, 42))	('muM', 'Gene', '56925', (34, 37))	('decline', 'NegReg', (138, 145))	('quiescent state', 'MPA', (71, 86))	('muM', 'Gene', (34, 37))	('lipid droplets', 'MPA', (149, 163))	('Oil Red O', 'Chemical', 'MESH:C011049', (0, 9))	('lipid', 'Chemical', 'MESH:D008055', (149, 154))	('H2O2', 'Chemical', 'MESH:D006861', (38, 42))
51692	29854071	The expression of alpha-SMA was increased after H2O2 incubation, whereas NAC or RSV reversed this effect, indicating that H2O2-driven ROS-promoted PSC activation could be inhibited by RSV.	('H2O2', 'Chemical', 'MESH:D006861', (48, 52))	('H2O2', 'Var', (48, 52))	('ROS', 'Chemical', 'MESH:D017382', (134, 137))	('H2O2-driven', 'Var', (122, 133))	('NAC', 'cellular_component', 'GO:0005854', ('73', '76'))	('expression', 'MPA', (4, 14))	('RSV', 'Chemical', 'MESH:D000077185', (80, 83))	('RSV', 'Chemical', 'MESH:D000077185', (184, 187))	('PSC', 'CPA', (147, 150))	('increased', 'PosReg', (32, 41))	('NAC', 'Gene', (73, 76))	('NAC', 'Gene', '7504', (73, 76))	('alpha-SMA', 'Protein', (18, 27))	('H2O2', 'Chemical', 'MESH:D006861', (122, 126))	('activation', 'PosReg', (151, 161))
51694	29854071	As shown in Figures 1(g) and 1(h), cell migratory ability was enhanced by H2O2 incubation, whereas NAC and RSV efficiently repressed this effect.	('NAC', 'Gene', (99, 102))	('NAC', 'Gene', '7504', (99, 102))	('RSV', 'Chemical', 'MESH:D000077185', (107, 110))	('rat', 'Species', '10116', (43, 46))	('enhanced', 'PosReg', (62, 70))	('NAC', 'cellular_component', 'GO:0005854', ('99', '102'))	('H2O2', 'Chemical', 'MESH:D006861', (74, 78))	('H2O2', 'Var', (74, 78))	('cell migratory ability', 'CPA', (35, 57))
51695	29854071	The number of cells that invaded into the lower chamber was also increased by H2O2 stimulation but markedly decreased when the cells were pretreated with NAC or RSV (Figures 1(i) and 1(j)).	('increased', 'PosReg', (65, 74))	('NAC', 'Gene', (154, 157))	('NAC', 'Gene', '7504', (154, 157))	('H2O2', 'Chemical', 'MESH:D006861', (78, 82))	('H2O2', 'Var', (78, 82))	('decreased', 'NegReg', (108, 117))	('NAC', 'cellular_component', 'GO:0005854', ('154', '157'))	('RSV', 'Chemical', 'MESH:D000077185', (161, 164))
51700	29854071	As shown in Figures 2(c) and 2(d), glucose transporter 1 (Glut1), hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA) levels were elevated under ROS treatment but decreased if cells were pretreated with NAC or RSV.	('hexokinase 2', 'Gene', '3099', (66, 78))	('Glut1', 'Gene', '6513', (58, 63))	('NAC', 'Gene', '7504', (233, 236))	('hexokinase 2', 'Gene', (66, 78))	('NAC', 'cellular_component', 'GO:0005854', ('233', '236'))	('ROS', 'Chemical', 'MESH:D017382', (175, 178))	('LDHA', 'Gene', (142, 146))	('HK2', 'molecular_function', 'GO:0008256', ('80', '83'))	('pyruvate kinase M2', 'Gene', (86, 104))	('Glut1', 'Gene', (58, 63))	('ROS', 'Var', (175, 178))	('lactate dehydrogenase A', 'Gene', '3939', (117, 140))	('HK2', 'Gene', (80, 83))	('elevated', 'PosReg', (160, 168))	('HK2', 'Gene', '3099', (80, 83))	('pyruvate kinase M2', 'Gene', '5315', (86, 104))	('lactate dehydrogenase A', 'Gene', (117, 140))	('PKM2', 'Gene', (106, 110))	('RSV', 'Chemical', 'MESH:D000077185', (240, 243))	('glucose transporter 1', 'Gene', '6513', (35, 56))	('PKM2', 'Gene', '5315', (106, 110))	('NAC', 'Gene', (233, 236))	('LDHA', 'Gene', '3939', (142, 146))	('glucose transporter 1', 'Gene', (35, 56))
51703	29854071	miR-21 levels are reportedly upregulated by H2O2 treatment in cardiac myocytes, and RSV inhibits miR-21 expression in several types of cancer cells.	('cancer', 'Disease', (135, 141))	('upregulated', 'PosReg', (29, 40))	('miR-21', 'Gene', '406991', (97, 103))	('miR-21', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('miR-21', 'Gene', (97, 103))	('RSV', 'Chemical', 'MESH:D000077185', (84, 87))	('expression', 'MPA', (104, 114))	('H2O2', 'Chemical', 'MESH:D006861', (44, 48))	('H2O2', 'Var', (44, 48))	('inhibits', 'NegReg', (88, 96))	('miR-21', 'Gene', '406991', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
51705	29854071	Our results showed that PSCs treated with H2O2 displayed higher levels of miR-21, and this enhancement was reversed by NAC or RSV (Figure 3(a)).	('H2O2', 'Chemical', 'MESH:D006861', (42, 46))	('H2O2', 'Var', (42, 46))	('NAC', 'cellular_component', 'GO:0005854', ('119', '122'))	('higher', 'PosReg', (57, 63))	('NAC', 'Gene', (119, 122))	('NAC', 'Gene', '7504', (119, 122))	('miR-21', 'Gene', '406991', (74, 80))	('miR-21', 'Gene', (74, 80))	('RSV', 'Chemical', 'MESH:D000077185', (126, 129))
51710	29854071	Our results further demonstrated that the enhancement of cell migratory ability by H2O2 incubation was reduced by miR-21 inhibitor pretreatment (Figures 4(g) and 4(h).	('miR-21', 'Gene', '406991', (114, 120))	('H2O2', 'Var', (83, 87))	('H2O2', 'Chemical', 'MESH:D006861', (83, 87))	('enhancement', 'PosReg', (42, 53))	('cell migratory ability', 'CPA', (57, 79))	('reduced', 'NegReg', (103, 110))	('miR-21', 'Gene', (114, 120))	('rat', 'Species', '10116', (27, 30))	('rat', 'Species', '10116', (65, 68))
51713	29854071	To further examine whether miR-21 mediates the RSV-induced responses of PSCs, PSCs were treated with RSV for 24 h and then transfected with miR-21 mimics or scrambled mimics (Figure 5(a)) prior to incubation with H2O2.	('miR-21', 'Gene', (140, 146))	('miR-21', 'Gene', (27, 33))	('RSV', 'Chemical', 'MESH:D000077185', (101, 104))	('mimics', 'Var', (147, 153))	('miR-21', 'Gene', '406991', (140, 146))	('miR-21', 'Gene', '406991', (27, 33))	('RSV', 'Chemical', 'MESH:D000077185', (47, 50))	('H2O2', 'Chemical', 'MESH:D006861', (213, 217))
51727	29854071	RSV inhibits proliferation, induces apoptosis, represses invasion and migration, and impairs tumor-initiating stem-like properties via several signaling pathways, such as the sonic hedgehog pathway and the PI3K/Akt/NF-kappaB pathway.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('hedgehog', 'Gene', (181, 189))	('Akt', 'Gene', (211, 214))	('NF-kappaB', 'Gene', (215, 224))	('signaling', 'biological_process', 'GO:0023052', ('143', '152'))	('NF-kappaB', 'Gene', '4790', (215, 224))	('inhibits', 'NegReg', (4, 12))	('Akt', 'Gene', '207', (211, 214))	('proliferation', 'CPA', (13, 26))	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('apoptosis', 'CPA', (36, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('PI3K', 'molecular_function', 'GO:0016303', ('206', '210'))	('induces', 'Reg', (28, 35))	('rat', 'Species', '10116', (20, 23))	('impairs tumor', 'Disease', 'MESH:D015417', (85, 98))	('impairs tumor', 'Disease', (85, 98))	('RSV', 'Var', (0, 3))	('hedgehog', 'Gene', '6469', (181, 189))	('represses', 'NegReg', (47, 56))	('RSV', 'Chemical', 'MESH:D000077185', (0, 3))	('rat', 'Species', '10116', (73, 76))
51728	29854071	Together with these classical regulatory pathways, RSV has been shown to regulate the expression of microRNAs (miRNAs) by which RSV may exert anti-inflammation and antitumor effects.	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('RSV', 'Chemical', 'MESH:D000077185', (51, 54))	('RSV', 'Chemical', 'MESH:D000077185', (128, 131))	('inflammation', 'biological_process', 'GO:0006954', ('147', '159'))	('RSV', 'Var', (128, 131))	('expression', 'MPA', (86, 96))	('inflammation', 'Disease', 'MESH:D007249', (147, 159))	('regulate', 'Reg', (73, 81))	('inflammation', 'Disease', (147, 159))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
51737	29854071	Cancer cells can secrete H2O2, which triggers oxidative stress in adjacent PSCs, and oxidative stress is essential in promoting PSC activation, and our data showed that H2O2-induced ROS promoted the expression of alpha-SMA in PSCs.	('PSC', 'Disease', (128, 131))	('ROS', 'Chemical', 'MESH:D017382', (182, 185))	('H2O2-induced', 'Var', (169, 181))	('expression', 'MPA', (199, 209))	('H2O2', 'Chemical', 'MESH:D006861', (169, 173))	('PSCs', 'Disease', (226, 230))	('oxidative stress', 'Phenotype', 'HP:0025464', (85, 101))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('alpha-SMA', 'Protein', (213, 222))	('H2O2', 'Chemical', 'MESH:D006861', (25, 29))	('promoted', 'PosReg', (186, 194))	('oxidative stress', 'Phenotype', 'HP:0025464', (46, 62))
51738	29854071	reported that the transformation of freshly isolated PSCs into the activated phenotype is not initiated by H2O2; this discrepancy may be explained by differences in culture conditions and the potential for further promotion of PSC activation by H2O2-induced ROS once the PSCs were preactivated in culture.	('H2O2', 'Chemical', 'MESH:D006861', (107, 111))	('H2O2-induced', 'Var', (245, 257))	('PSC', 'MPA', (227, 230))	('ROS', 'Chemical', 'MESH:D017382', (258, 261))	('activation', 'PosReg', (231, 241))	('H2O2', 'Chemical', 'MESH:D006861', (245, 249))	('promotion', 'PosReg', (214, 223))
51747	29854071	RSV can impede glycolysis in tumor cells, but its effects on the glycolytic phenotypes of PSCs have not been explored.	('glycolysis', 'MPA', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('RSV', 'Var', (0, 3))	('impede', 'NegReg', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('glycolysis', 'biological_process', 'GO:0006096', ('15', '25'))	('RSV', 'Chemical', 'MESH:D000077185', (0, 3))
51748	29854071	Here, we found that H2O2-induced ROS promoted glycolysis in PSCs, whereas RSV downregulated the expression of key glycolytic enzymes and, more importantly, decreased lactate production.	('lactate', 'Chemical', 'MESH:D019344', (166, 173))	('glycolysis', 'biological_process', 'GO:0006096', ('46', '56'))	('PSCs', 'Disease', (60, 64))	('glycolysis', 'MPA', (46, 56))	('lactate production', 'MPA', (166, 184))	('promoted', 'PosReg', (37, 45))	('expression', 'MPA', (96, 106))	('decreased', 'NegReg', (156, 165))	('RSV', 'Chemical', 'MESH:D000077185', (74, 77))	('ROS', 'Chemical', 'MESH:D017382', (33, 36))	('ROS', 'Var', (33, 36))	('H2O2', 'Chemical', 'MESH:D006861', (20, 24))	('H2O2-induced ROS', 'Var', (20, 36))	('downregulated', 'NegReg', (78, 91))
51750	29854071	It has been reported that miR-21 and CCN2 compose a positive feedback loop during PSC activation and that inhibition of miR-21 leads to decreased migration and invasion of PSCs.	('miR-21', 'Gene', (120, 126))	('rat', 'Species', '10116', (149, 152))	('migration', 'CPA', (146, 155))	('CCN2', 'Gene', '1490', (37, 41))	('invasion', 'CPA', (160, 168))	('miR-21', 'Gene', '406991', (26, 32))	('inhibition', 'Var', (106, 116))	('miR-21', 'Gene', '406991', (120, 126))	('PSC', 'Disease', (82, 85))	('miR-21', 'Gene', (26, 32))	('CCN2', 'Gene', (37, 41))	('decreased', 'NegReg', (136, 145))
51769	27916875	The final outcome of the TGF-beta response is determined by cell-autonomous mechanisms and genetic alterations such as genomic instability and somatic mutations, but also by a plethora of external signals derived from the tumor microenvironment, such as cell-to-cell interactions, growth factors and extracellular matrix proteins and proteolytic enzymes.	('plethora', 'Phenotype', 'HP:0001050', (176, 184))	('rat', 'Species', '10116', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('300', '320'))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('mutations', 'Var', (151, 160))
51785	27916875	Biologically, PDAC is characterized by genomic instability and somatic mutations in KRAS, p16INK4A, TP53, and DPC4, together accounting for its aggressive nature.	('TP53', 'Gene', '7157', (100, 104))	('PDAC', 'Chemical', '-', (14, 18))	('p16INK4A', 'Gene', '1029', (90, 98))	('TP53', 'Gene', (100, 104))	('DPC4', 'Gene', '4089', (110, 114))	('DPC4', 'Gene', (110, 114))	('KRAS', 'Gene', (84, 88))	('mutations', 'Var', (71, 80))	('KRAS', 'Gene', '3845', (84, 88))	('PDAC', 'Phenotype', 'HP:0006725', (14, 18))	('PDAC', 'Disease', (14, 18))	('p16INK4A', 'Gene', (90, 98))
51786	27916875	The DPC4 encoded Smad4 protein is a central mediator of transforming growth factor (TGF)-beta signaling and mutated in approximately 50% of invasive pancreatic carcinomas.	('Smad4', 'Gene', (17, 22))	('mutated', 'Var', (108, 115))	('DPC4', 'Gene', '4089', (4, 8))	('DPC4', 'Gene', (4, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('signaling', 'biological_process', 'GO:0023052', ('94', '103'))	('invasive pancreatic carcinomas', 'Disease', (140, 170))	('invasive pancreatic carcinomas', 'Disease', 'MESH:C562463', (140, 170))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))
51787	27916875	TGF-beta signaling has a central role in the cancer progression of PDAC because (i) the TGF-beta pathway naturally contains mutations and other well-defined alterations; and (ii) it belongs to only four signaling pathways that are mutated (with at least one gene) in 100% of tumors.	('TGF-beta pathway', 'Gene', (88, 104))	('mutations', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('PDAC', 'Phenotype', 'HP:0006725', (67, 71))	('PDAC', 'Disease', (67, 71))	('tumors', 'Disease', (275, 281))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('signaling', 'biological_process', 'GO:0023052', ('203', '212'))	('tumors', 'Disease', 'MESH:D009369', (275, 281))	('rat', 'Species', '10116', (161, 164))	('PDAC', 'Chemical', '-', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('signaling', 'biological_process', 'GO:0023052', ('9', '18'))
51788	27916875	Moreover, mouse models of PDAC have shown that mutations in the pathway e.g., in Smad4 and TGF-beta type II receptor (TbetaRII) are causative in the development of aggressive/metastatic PDAC by cooperating with members of the Ras/Rac family of small GTPases and other non-Smad pathways to induce neoangiogenesis, host immune suppression, invasion and metastasis.	('mouse', 'Species', '10090', (10, 15))	('aggressive/metastatic', 'CPA', (164, 185))	('host immune suppression', 'CPA', (313, 336))	('metastasis', 'CPA', (351, 361))	('TGF-beta type II receptor', 'Gene', '21813', (91, 116))	('mutations', 'Var', (47, 56))	('PDAC', 'Chemical', '-', (186, 190))	('PDAC', 'Phenotype', 'HP:0006725', (26, 30))	('Smad4', 'Gene', (81, 86))	('neoangiogenesis', 'CPA', (296, 311))	('induce', 'PosReg', (289, 295))	('TGF-beta type II receptor', 'Gene', (91, 116))	('rat', 'Species', '10116', (199, 202))	('PDAC', 'Phenotype', 'HP:0006725', (186, 190))	('PDAC', 'Chemical', '-', (26, 30))
51797	27916875	Moreover, PAR2 and TGF-beta/ALK5 activate the same intracellular signaling pathways (ERK1/2 and p38 mitogen-activated protein kinase (MAPK), protein kinase C, Rac/PAK, c-Src, NFkappaB) and intermediates (reactive oxygen species, Ca2+), while others are receptor (class)-specific such as phosphatidylinositol (3-5)-trisphosphate and beta-arrestin-2 signaling for PAR2 and signaling through Smad proteins for TGF-beta/ALK5.	('TGF-beta/ALK5', 'Var', (19, 32))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('Smad proteins', 'Protein', (389, 402))	('MAPK', 'molecular_function', 'GO:0004707', ('134', '138'))	('protein', 'Enzyme', (141, 148))	('ERK1', 'molecular_function', 'GO:0004707', ('85', '89'))	('beta-arrestin-2', 'Gene', (332, 347))	('c-Src', 'Gene', (168, 173))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))	('signaling', 'biological_process', 'GO:0023052', ('348', '357'))	('intracellular', 'cellular_component', 'GO:0005622', ('51', '64'))	('MAPK', 'Gene', '5595;5594;5595', (134, 138))	('NFkappaB', 'Gene', '4790', (175, 183))	('Ca2+', 'Chemical', 'MESH:D000069285', (229, 233))	('ERK1/2', 'Gene', (85, 91))	('signaling', 'biological_process', 'GO:0023052', ('371', '380'))	('ERK1/2', 'Gene', '5595;5594', (85, 91))	('c-Src', 'Gene', '6714', (168, 173))	('activate', 'PosReg', (33, 41))	('beta-arrestin-2', 'Gene', '409', (332, 347))	('MAPK', 'Gene', (134, 138))	('NFkappaB', 'Gene', (175, 183))	('p38 mitogen-activated protein kinase', 'Gene', (96, 132))	('intracellular', 'MPA', (51, 64))	('p38 mitogen-activated protein kinase', 'Gene', '1432', (96, 132))
51800	27916875	With respect to primary tumor growth, PAR2-/- mice subcutaneously inoculated with B16 melanoma cells exhibited larger primary tumors, while orthotopic xenografts of the human PDAC cell line Panc1 expressing a kinase-active mutant of the TGF-beta type I receptor ALK5 in scid/bg mice presented with smaller primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', (314, 319))	('human', 'Species', '9606', (169, 174))	('primary tumors', 'Disease', 'MESH:D009369', (306, 320))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('kinase-active', 'PosReg', (209, 222))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('mutant', 'Var', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('tumor', 'Disease', (24, 29))	('TGF-beta type I receptor', 'Gene', (237, 261))	('primary tumors', 'Disease', (118, 132))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (126, 131))	('PDAC', 'Chemical', '-', (175, 179))	('primary tumors', 'Disease', (306, 320))	('mice', 'Species', '10090', (278, 282))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('PDAC', 'Phenotype', 'HP:0006725', (175, 179))	('mice', 'Species', '10090', (46, 50))	('TGF-beta type I receptor', 'Gene', '7046', (237, 261))	('ALK5', 'Gene', (262, 266))	('primary tumors', 'Disease', 'MESH:D009369', (118, 132))
51801	27916875	However, in PAR2-/- mice, the transplanted B16 melanoma cells generated less distant metastases and allowed for a longer survival time of their hosts compared with strain-matched wild-type controls, while Panc1 xenografts with kinase-active ALK5 generated more distant metastases.	('kinase-active', 'Var', (227, 240))	('ALK5', 'Gene', (241, 245))	('rat', 'Species', '10116', (250, 253))	('mice', 'Species', '10090', (20, 24))	('metastases', 'Disease', 'MESH:D009362', (269, 279))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('survival', 'CPA', (121, 129))	('metastases', 'Disease', (85, 95))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('longer', 'PosReg', (114, 120))	('metastases', 'Disease', 'MESH:D009362', (85, 95))	('rat', 'Species', '10116', (66, 69))	('less', 'NegReg', (72, 76))	('metastases', 'Disease', (269, 279))
51812	27916875	Using siRNA-mediated silencing of PAR2 and real-time analysis of random cell migration and invasion, we have verified that PAR2 protein expression was required for TGF-beta1-mediated cell motility in several (TGF-beta-sensitive) cell lines of PDAC origin.	('cell motility', 'biological_process', 'GO:0048870', ('183', '196'))	('TGF-beta1', 'Gene', '7040', (164, 173))	('TGF-beta1', 'Gene', (164, 173))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('PDAC', 'Phenotype', 'HP:0006725', (243, 247))	('rat', 'Species', '10116', (80, 83))	('PAR2', 'Gene', (34, 38))	('cell migration', 'biological_process', 'GO:0016477', ('72', '86'))	('silencing', 'Var', (21, 30))	('PAR2', 'Gene', (123, 127))
51813	27916875	In search of the molecular basis, we found that PAR2 depletion blunted the TGF-beta response of several TGF-beta target genes involved in the regulation of cell motility, including the prototypical TGF-beta response gene serpine1, encoding plasminogen activator inhibitor-1 (PAI-1).	('PAI-1', 'Gene', '5054', (275, 280))	('depletion', 'Var', (53, 62))	('PAR2', 'Gene', (48, 52))	('regulation of cell motility', 'biological_process', 'GO:2000145', ('142', '169'))	('plasminogen activator inhibitor-1', 'Gene', '5054', (240, 273))	('PAI-1', 'Gene', (275, 280))	('TGF-beta response', 'MPA', (75, 92))	('serpine1', 'Gene', '5054', (221, 229))	('plasminogen activator inhibitor-1', 'Gene', (240, 273))	('blunted', 'NegReg', (63, 70))	('serpine1', 'Gene', (221, 229))
51820	27916875	Moreover, reconstitution by ectopic expression of wild-type and kinase-active versions of ALK5 (ALK5-T204D) but not of a Smad binding-defective mutant (RImL45-T204D) was able to rescue cells from losing sensitivity to TGF-beta1 as demonstrated by their ability to restore TGF-beta1-induced Smad3C phosphorylation, reporter gene activity and cell migration.	('TGF-beta1', 'Gene', (272, 281))	('TGF-beta1', 'Gene', '7040', (218, 227))	('rat', 'Species', '10116', (349, 352))	('TGF-beta1', 'Gene', '7040', (272, 281))	('T204D', 'Var', (159, 164))	('cell migration', 'biological_process', 'GO:0016477', ('341', '355'))	('T204D', 'Mutation', 'p.T204D', (159, 164))	('phosphorylation', 'biological_process', 'GO:0016310', ('297', '312'))	('cell migration', 'CPA', (341, 355))	('T204D', 'Var', (101, 106))	('Smad binding', 'molecular_function', 'GO:0046332', ('121', '133'))	('T204D', 'Mutation', 'p.T204D', (101, 106))	('T204D', 'SUBSTITUTION', 'None', (159, 164))	('ALK5', 'Gene', (90, 94))	('Smad3', 'Gene', '4088', (290, 295))	('Smad3', 'Gene', (290, 295))	('reporter gene activity', 'MPA', (314, 336))	('restore', 'PosReg', (264, 271))	('TGF-beta1', 'Gene', (218, 227))	('rat', 'Species', '10116', (238, 241))	('T204D', 'SUBSTITUTION', 'None', (101, 106))
51823	27916875	Interestingly, cells depleted of PAR2 protein lost the ability to autoinduce TGF-beta1 at both the mRNA and protein level in response to stimulation with exogenous TGF-beta, suggesting that inhibiting PAR2 expression or function is a suitable strategy to interfere with a TGF-beta autostimulatory loop in the tumor tissue.	('tumor', 'Disease', (309, 314))	('response to', 'MPA', (125, 136))	('autoinduce', 'MPA', (66, 76))	('rat', 'Species', '10116', (245, 248))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('function', 'MPA', (220, 228))	('inhibiting', 'Var', (190, 200))	('PAR2', 'Gene', (201, 205))	('TGF-beta1', 'Gene', '7040', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('TGF-beta1', 'Gene', (77, 86))	('lost', 'NegReg', (46, 50))	('ability', 'MPA', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('PAR2', 'Gene', (33, 37))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
51835	27916875	TGF-beta depletion compromises cell survival in response to radiation and impairs activation of the DDR because of severely reduced activity of ataxia telangiectasia mutated (ATM), a serine/threonine protein kinase that is rapidly activated by DNA double-strand breaks.	('compromises', 'NegReg', (19, 30))	('ataxia telangiectasia mutated', 'Gene', (144, 173))	('response to radiation', 'MPA', (48, 69))	('ATM', 'Gene', (175, 178))	('telangiectasia', 'Phenotype', 'HP:0001009', (151, 165))	('depletion', 'Var', (9, 18))	('ataxia', 'Phenotype', 'HP:0001251', (144, 150))	('impairs', 'NegReg', (74, 81))	('activity', 'MPA', (132, 140))	('DDR', 'Gene', (100, 103))	('response to radiation', 'biological_process', 'GO:0009314', ('48', '69'))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('ataxia telangiectasia mutated', 'Gene', '472', (144, 173))	('TGF-beta', 'Gene', (0, 8))	('activation', 'MPA', (82, 92))	('reduced', 'NegReg', (124, 131))	('cell survival', 'CPA', (31, 44))	('DNA', 'cellular_component', 'GO:0005574', ('244', '247'))	('ATM', 'Gene', '472', (175, 178))
51839	27916875	In addition, we are currently analyzing if depletion of PAR2 by either siRNA transfection or CRISPR/Cas9 technology can sensitize tumor cells to apoptotic cell death following irradiation and can mimic conventional forms of TGF-beta pathway inhibition, e.g., ALK5 kinase inhibition with small molecules.	('death', 'Disease', 'MESH:D003643', (160, 165))	('death', 'Disease', (160, 165))	('depletion', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('sensitize', 'Reg', (120, 129))	('ALK5 kinase', 'Pathway', (259, 270))	('PAR2', 'Gene', (56, 60))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('145', '165'))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('TGF-beta pathway', 'Pathway', (224, 240))	('tumor', 'Disease', (130, 135))	('Cas', 'cellular_component', 'GO:0005650', ('100', '103'))
51852	27916875	Previous results have also shown that PAR2 depletion abrogated the ability of TGF-beta1 to induce the expression of extracellular matrix genes in vitro.	('induce', 'PosReg', (91, 97))	('ability', 'MPA', (67, 74))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('116', '136'))	('depletion', 'Var', (43, 52))	('expression', 'MPA', (102, 112))	('abrogated', 'NegReg', (53, 62))	('TGF-beta1', 'Gene', '7040', (78, 87))	('TGF-beta1', 'Gene', (78, 87))	('extracellular matrix genes', 'Gene', (116, 142))
51853	27916875	If inhibitors of PAR2 are able to halt this profibrotic TGF-beta effect in vivo, then they would hold great promise in fighting desmoplasia, one of the hallmarks of PDAC.	('PAR2', 'Gene', (17, 21))	('PDAC', 'Chemical', '-', (165, 169))	('desmoplasia', 'Disease', (128, 139))	('inhibitors', 'Var', (3, 13))	('PDAC', 'Phenotype', 'HP:0006725', (165, 169))	('desmoplasia', 'Disease', 'None', (128, 139))
51858	27916875	ENMD-1068 attenuates PAR2-mediated murine joint inflammation in vivo, while K-14585 and GB88 inhibit PAR2-dependent calcium and pro-inflammatory signaling and effectively attenuate inflammation in a rat model of colitis, respectively.	('inflammation', 'Disease', (48, 60))	('colitis', 'Phenotype', 'HP:0002583', (212, 219))	('calcium', 'Chemical', 'MESH:D002118', (116, 123))	('rat', 'Species', '10116', (199, 202))	('inflammation', 'Disease', (181, 193))	('attenuate', 'NegReg', (171, 180))	('PAR2-dependent calcium', 'MPA', (101, 123))	('K-14585', 'Var', (76, 83))	('inflammation', 'biological_process', 'GO:0006954', ('181', '193'))	('GB88', 'Chemical', '-', (88, 92))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))	('inhibit', 'NegReg', (93, 100))	('colitis', 'Disease', (212, 219))	('inflammation', 'biological_process', 'GO:0006954', ('48', '60'))	('attenuates', 'NegReg', (10, 20))	('colitis', 'Disease', 'MESH:D003092', (212, 219))	('murine', 'Species', '10090', (35, 41))	('GB88', 'Gene', (88, 92))	('inflammation', 'Disease', 'MESH:D007249', (48, 60))	('K-14585', 'Chemical', 'MESH:C547641', (76, 83))	('inflammation', 'Disease', 'MESH:D007249', (181, 193))	('joint inflammation', 'Phenotype', 'HP:0001369', (42, 60))	('pro-inflammatory signaling', 'MPA', (128, 154))
51859	27916875	K-14585 and GB88 are both signal pathway-specific antagonists that inhibit PAR2-induced intracellular calcium release, cyclic adenosine monophosphate stimulation, receptor internalization and pro-inflammatory cytokine release without affecting PAR2-mediated MAPK phosphorylation.	('receptor internalization', 'biological_process', 'GO:0031623', ('163', '187'))	('inhibit', 'NegReg', (67, 74))	('cyclic adenosine monophosphate stimulation', 'MPA', (119, 161))	('receptor internalization', 'MPA', (163, 187))	('phosphorylation', 'biological_process', 'GO:0016310', ('263', '278'))	('MAPK', 'molecular_function', 'GO:0004707', ('258', '262'))	('MAPK', 'Gene', (258, 262))	('K-14585', 'Chemical', 'MESH:C547641', (0, 7))	('intracellular', 'cellular_component', 'GO:0005622', ('88', '101'))	('PAR2-induced', 'Gene', (75, 87))	('MAPK', 'Gene', '5595;5594;5595', (258, 262))	('GB88', 'Chemical', '-', (12, 16))	('cyclic adenosine monophosphate', 'Chemical', 'MESH:D000242', (119, 149))	('calcium', 'Chemical', 'MESH:D002118', (102, 109))	('pro-inflammatory cytokine release', 'MPA', (192, 225))	('K-14585', 'Var', (0, 7))	('GB88', 'Gene', (12, 16))
51863	27916875	If ALK5 transactivation of PAR2 also operates in vivo in the tumor tissue to drive PAR2-dependent invasion and metastasis, then small molecule inhibitors of the ALK5 kinase, such as SB431542, LY2157299, or SD-208 would add another level of potency to a combined TGF-beta/PAR2 inhibition approach.	('LY2157299', 'Var', (192, 201))	('LY2157299', 'Chemical', 'MESH:C557799', (192, 201))	('invasion', 'CPA', (98, 106))	('rat', 'Species', '10116', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('SD-208', 'Var', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('PAR2-dependent', 'Gene', (83, 97))	('SB431542', 'Var', (182, 190))	('tumor', 'Disease', (61, 66))	('transactivation', 'biological_process', 'GO:2000144', ('8', '23'))
51895	27896637	Only a small proportion of pancreatic cancers are related to a genetic alteration (5-10%).	('related', 'Reg', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (27, 45))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('genetic alteration', 'Var', (63, 81))	('pancreatic cancers', 'Disease', 'MESH:D010190', (27, 45))	('pancreatic cancers', 'Disease', (27, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (27, 44))
51896	27896637	Germline mutations in BRCA2, p16, ATM, STK11, PRSS1/PRSS2, SPINK1, PALB2, and DNA mismatch repair genes are associated with varying degrees of increased risk for pancreatic carcinoma.	('p16', 'Gene', (29, 32))	('Germline mutations', 'Var', (0, 18))	('pancreatic carcinoma', 'Disease', (162, 182))	('SPINK1', 'Gene', (59, 65))	('STK11', 'Gene', '6794', (39, 44))	('p16', 'Gene', '1029', (29, 32))	('ATM', 'Gene', (34, 37))	('SPINK1', 'Gene', '6690', (59, 65))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('PRSS2', 'Gene', '5645', (52, 57))	('PRSS2', 'Gene', (52, 57))	('STK11', 'molecular_function', 'GO:0033868', ('39', '44'))	('PALB2', 'Gene', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('BRCA2', 'Gene', (22, 27))	('associated', 'Reg', (108, 118))	('PRSS1', 'Gene', (46, 51))	('STK11', 'Gene', (39, 44))	('ATM', 'Gene', '472', (34, 37))	('PALB2', 'Gene', '79728', (67, 72))	('PRSS1', 'Gene', '5644', (46, 51))	('mismatch repair', 'biological_process', 'GO:0006298', ('82', '97'))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (162, 182))	('increased risk for pancreatic carcinoma', 'Phenotype', 'HP:0002894', (143, 182))	('BRCA2', 'Gene', '675', (22, 27))
51897	27896637	Mutation in BRCA2 is probably the most common inherited disorder in familial pancreatic cancer.	('BRCA2', 'Gene', (12, 17))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('Mutation', 'Var', (0, 8))	('inherited disorder', 'Disease', 'MESH:D030342', (46, 64))	('familial pancreatic cancer', 'Disease', (68, 94))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (68, 94))	('BRCA2', 'Gene', '675', (12, 17))	('inherited disorder', 'Disease', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
51946	27896637	PC patients with mutation in BRAC1, BRAC2 or PALB2 with a prevalence of 10% would be especially sensitive to this combination, an issue that should be tested prospectively.	('PALB2', 'Gene', '79728', (45, 50))	('mutation', 'Var', (17, 25))	('sensitive', 'Reg', (96, 105))	('patients', 'Species', '9606', (3, 11))	('BRAC1', 'Gene', (29, 34))	('BRAC2', 'Gene', (36, 41))	('PALB2', 'Gene', (45, 50))
51983	27318148	Conversely, disruption of Etv1 in PDAC mice (Pdx1Cre;KrasG12D/+;p53fl/+;Rosa26YFP;Cre;Etv1fl/fl) reduced levels of SPARC and hyaluronic acid in the stroma.	('SPARC', 'Gene', '20692', (115, 120))	('disruption', 'Var', (12, 22))	('PDAC', 'Chemical', '-', (34, 38))	('Etv1', 'Gene', (26, 30))	('Kras', 'Gene', (53, 57))	('p53', 'Gene', (64, 67))	('Kras', 'Gene', '3845', (53, 57))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (125, 140))	('reduced', 'NegReg', (97, 104))	('PDAC', 'Phenotype', 'HP:0006725', (34, 38))	('p53', 'Gene', '22059', (64, 67))	('SPARC', 'Gene', (115, 120))	('mice', 'Species', '10090', (39, 43))
52006	27318148	Indeed, genetic in vivo experiments demonstrated that the loss of Sparc completely abrogated the dramatic phenotype of increased primary tumor volume, stromal expansion, and increased metastasis associated with Etv1 overexpression.	('abrogated', 'NegReg', (83, 92))	('metastasis', 'CPA', (184, 194))	('loss', 'Var', (58, 62))	('stromal expansion', 'CPA', (151, 168))	('Sparc', 'Gene', (66, 71))	('primary tumor', 'Disease', 'MESH:D009369', (129, 142))	('primary tumor', 'Disease', (129, 142))	('increased', 'PosReg', (174, 183))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('increased', 'PosReg', (119, 128))
52010	27318148	In addition, cell lines from PDAC-bearing mice with a global SPARC deletion that have been previously described and characterized were utilized (termed KPfC Sparc-/-).	('PDAC', 'Phenotype', 'HP:0006725', (29, 33))	('Sparc-/-)', 'Gene', '20692', (157, 166))	('SPARC', 'Gene', (61, 66))	('mice', 'Species', '10090', (42, 46))	('Sparc-/-', 'Gene', (157, 165))	('deletion', 'Var', (67, 75))	('SPARC', 'Gene', '20692', (61, 66))	('PDAC', 'Chemical', '-', (29, 33))
52030	27318148	We examined Etv1 expression in a TMA of human PanIN which demonstrated similar expression in 88% (15/17) of low-grade PanIN and 100% (5/5) of high-grade PanIN lesions (Supplemental Figure 1A).	('human', 'Species', '9606', (40, 45))	('TMA', 'Chemical', '-', (33, 36))	('low-grade', 'Var', (108, 117))	('Etv1', 'Gene', (12, 16))
52038	27318148	We found a stepwise increase in mEtv1 gene expression by qPCR in comparing wild type pancreatic ductal cells (PDC) with parental cell lines from KC and KPfC animals (Supplemental Figure 2A).	('pancreatic ductal', 'Disease', 'MESH:D021441', (85, 102))	('mEtv1', 'Gene', '14009', (32, 37))	('qPCR', 'Var', (57, 61))	('mEtv1', 'Gene', (32, 37))	('expression', 'MPA', (43, 53))	('gene expression', 'biological_process', 'GO:0010467', ('38', '53'))	('pancreatic ductal', 'Disease', (85, 102))	('increase', 'PosReg', (20, 28))
52039	27318148	With regards to overexpression, in comparison to the 184-fold increase in mEtv1 observed between PDC and KPfC parental cell lines, transduced cell lines had a 6-8 fold increase over their respective controls (Supplemental Figure 2A).	('increase', 'PosReg', (168, 176))	('mEtv1', 'Gene', (74, 79))	('transduced', 'Var', (131, 141))	('mEtv1', 'Gene', '14009', (74, 79))
52066	27318148	Conversely, knockdown of Etv1 was associated with significant reductions in Zeb1 in vitro (Supplemental Figure 4F).	('Zeb1', 'Gene', '21417', (76, 80))	('Etv1', 'Gene', (25, 29))	('knockdown', 'Var', (12, 21))	('Zeb1', 'Gene', (76, 80))	('reductions', 'NegReg', (62, 72))
52072	27318148	In vitro, we observed that while Etv1 overexpression was associated with increases in levels of EMT regulators like Snail, Zeb1, and Zeb2, the loss of Sparc abrogated the capacity of Etv1 to induce these factors (Supplemental Figure 5B).	('Zeb1', 'Gene', (123, 127))	('Snail', 'Gene', (116, 121))	('Snail', 'Gene', '20613', (116, 121))	('increases', 'PosReg', (73, 82))	('Sparc', 'Gene', (151, 156))	('Zeb2', 'Gene', '24136', (133, 137))	('induce', 'MPA', (191, 197))	('Zeb2', 'Gene', (133, 137))	('abrogated', 'NegReg', (157, 166))	('overexpression', 'PosReg', (38, 52))	('levels of EMT regulators', 'MPA', (86, 110))	('Zeb1', 'Gene', '21417', (123, 127))	('EMT', 'biological_process', 'GO:0001837', ('96', '99'))	('loss', 'Var', (143, 147))	('Etv1', 'Gene', (33, 37))	('capacity', 'MPA', (171, 179))
52076	27318148	Strikingly, the loss of Sparc in KPfC Sparc-/- mEtv1 cells completely abrogated this increase in tumor volume (Figure 4B,C) and the expansion of the tumor stroma (Figure 4D).	('mEtv1', 'Gene', (47, 52))	('Sparc', 'Gene', (24, 29))	('abrogated', 'NegReg', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('expansion', 'CPA', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (97, 102))	('mEtv1', 'Gene', '14009', (47, 52))	('loss', 'Var', (16, 20))	('tumor', 'Disease', (149, 154))	('tumor stroma', 'Disease', 'MESH:D009369', (149, 161))	('increase', 'PosReg', (85, 93))	('tumor stroma', 'Disease', (149, 161))
52081	27318148	In addition to the abrogation of stromal expansion and increased tumor volume, the loss of Sparc also abrogated significant Etv1 associated increases in the frequency and grade of ascites present in the animals at sacrifice (Supplemental Figure 5D).	('increases', 'PosReg', (140, 149))	('stromal expansion', 'CPA', (33, 50))	('tumor', 'Disease', (65, 70))	('loss', 'Var', (83, 87))	('Etv1', 'Gene', (124, 128))	('abrogated', 'NegReg', (102, 111))	('ascites', 'Phenotype', 'HP:0001541', (180, 187))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Sparc', 'Gene', (91, 96))	('ascites', 'Disease', 'MESH:D001201', (180, 187))	('ascites', 'Disease', (180, 187))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
52083	27318148	In comparison, the loss of Sparc returned the frequency of liver metastasis to levels similar to the control group (4/9 vs 3/9, p<NS).	('liver metastasis', 'Disease', 'MESH:D009362', (59, 75))	('liver metastasis', 'Disease', (59, 75))	('loss', 'Var', (19, 23))	('Sparc', 'Gene', (27, 32))
52102	27318148	Interestingly, in a qualitative analysis by IF, SPARC expression appeared dramatically decreased in KPfCYEtv1fl/fl mice in comparison with KPfCY controls (Figure 6A).	('mice', 'Species', '10090', (115, 119))	('decreased', 'NegReg', (87, 96))	('SPARC', 'Gene', '20692', (48, 53))	('SPARC', 'Gene', (48, 53))	('KPfCYEtv1fl/fl', 'Var', (100, 114))
52109	27318148	Utilizing 3D pancreatic organoids, we demonstrate that Etv1 in concert with an oncogenic KrasG12D mutation disrupt cyst architecture, induce known EMT associated genes, and increase invasive capacity.	('invasive capacity', 'CPA', (182, 199))	('induce', 'PosReg', (134, 140))	('mutation', 'Var', (98, 106))	('EMT', 'biological_process', 'GO:0001837', ('147', '150'))	('Etv1', 'Gene', (55, 59))	('Kras', 'Gene', '3845', (89, 93))	('disrupt', 'NegReg', (107, 114))	('pancreatic', 'Disease', 'MESH:D010195', (13, 23))	('increase', 'PosReg', (173, 181))	('Kras', 'Gene', (89, 93))	('cyst', 'MPA', (115, 119))	('pancreatic', 'Disease', (13, 23))	('EMT', 'CPA', (147, 150))
52120	27318148	We found that expression of Etv1 induces a remarkable increase of ECM in pancreatic orthotopic tumors through Sparc and Has2, suggesting that Etv1 might be an important regulator within the transcriptional networks that control the ECM in the tumor stroma of pancreatic cancer.	('pancreatic orthotopic tumors', 'Disease', (73, 101))	('expression', 'Var', (14, 24))	('tumor stroma of pancreatic cancer', 'Disease', (243, 276))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (259, 276))	('Has2', 'Gene', (120, 124))	('pancreatic orthotopic tumors', 'Disease', 'MESH:D010190', (73, 101))	('increase', 'PosReg', (54, 62))	('Etv1', 'Gene', (28, 32))	('ECM in', 'CPA', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor stroma of pancreatic cancer', 'Disease', 'MESH:D010190', (243, 276))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
52122	27318148	Very interestingly, we found that the loss of Sparc abrogated the increased hyaluronic acid deposition associated with Etv1 over-expression, suggesting an interplay between Sparc, Has2, and Etv1 in governing the ECM and tumor stroma.	('abrogated', 'NegReg', (52, 61))	('Etv1', 'Gene', (119, 123))	('loss', 'Var', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('increased', 'PosReg', (66, 75))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (76, 91))	('tumor stroma', 'Disease', 'MESH:D009369', (220, 232))	('over-expression', 'PosReg', (124, 139))	('tumor stroma', 'Disease', (220, 232))	('Sparc', 'Gene', (46, 51))	('hyaluronic acid deposition', 'MPA', (76, 102))
52128	27318148	In our model, Etv1 drives the development of significantly larger primary tumors, more frequent metastasis and expansion of the tumor stroma, all of which are completely abrogated by the loss of Sparc.	('expansion', 'CPA', (111, 120))	('metastasis', 'CPA', (96, 106))	('larger', 'PosReg', (59, 65))	('more', 'PosReg', (82, 86))	('loss', 'Var', (187, 191))	('primary tumors', 'Disease', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Etv1', 'Gene', (14, 18))	('primary tumors', 'Disease', 'MESH:D009369', (66, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor stroma', 'Disease', 'MESH:D009369', (128, 140))	('tumor stroma', 'Disease', (128, 140))	('Sparc', 'Gene', (195, 200))
52131	27318148	Moreover, expression of Sparc via Etv1 confers invasive and metastatic capacity to at least a subset of pancreatic tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('pancreatic tumor', 'Disease', 'MESH:D010190', (104, 120))	('Etv1', 'Gene', (34, 38))	('pancreatic tumor', 'Disease', (104, 120))	('Sparc via Etv1', 'Gene', (24, 38))	('expression', 'Var', (10, 20))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (104, 120))
52134	27318148	High amounts of HA and expression of Has2 in PDAC have been associated with shorter survival after resection, but the molecular mechanisms that lead to increased expression of HA in PDAC have not been elucidated.	('Has2', 'Gene', (37, 41))	('PDAC', 'Chemical', '-', (45, 49))	('PDAC', 'Chemical', '-', (182, 186))	('HA', 'Chemical', 'MESH:D006820', (176, 178))	('survival after', 'CPA', (84, 98))	('expression', 'Var', (23, 33))	('PDAC', 'Phenotype', 'HP:0006725', (45, 49))	('PDAC', 'Phenotype', 'HP:0006725', (182, 186))	('HA', 'Chemical', 'MESH:D006820', (16, 18))	('shorter', 'NegReg', (76, 83))
52185	27019331	The spectral regions delta9.7-0.7 were integrally segmented into discrete regions of 0.002 ppm, and the spectral regions of delta4.74-4.92 and delta3.33-3.39 were removed to eliminate the interference of water and methanol signals for analysis.	('delta3.33-3.39', 'Var', (143, 157))	('methanol', 'Chemical', 'MESH:D000432', (214, 222))	('delta4.74-4.92', 'Var', (124, 138))	('water', 'Chemical', 'MESH:D014867', (204, 209))
52228	27019331	Given the high relevance with progression of PDAC,33 the discrepancy of ABC transporters metabolism may enhance the transport of nutritions into cells and promote intracellular anabolism.	('intracellular', 'cellular_component', 'GO:0005622', ('163', '176'))	('PDAC', 'Chemical', '-', (45, 49))	('transport', 'biological_process', 'GO:0006810', ('116', '125'))	('ABC', 'Gene', (72, 75))	('enhance', 'PosReg', (104, 111))	('transport of nutritions into cells', 'MPA', (116, 150))	('intracellular anabolism', 'MPA', (163, 186))	('anabolism', 'biological_process', 'GO:0009058', ('177', '186'))	('PDAC', 'Phenotype', 'HP:0006725', (45, 49))	('promote', 'PosReg', (155, 162))	('metabolism', 'biological_process', 'GO:0008152', ('89', '99'))	('discrepancy', 'Var', (57, 68))
52231	27019331	It is meaningful to find those with the same trends in the variation of PanIN, which may serve as biomarkers not only for PDAC but also for pancreatic precancerous lesions.	('PDAC', 'Chemical', '-', (122, 126))	('variation', 'Var', (59, 68))	('PanIN', 'Gene', (72, 77))	('pancreatic precancerous lesions', 'Disease', 'MESH:D011230', (140, 171))	('PDAC', 'Disease', (122, 126))	('PDAC', 'Phenotype', 'HP:0006725', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('pancreatic precancerous lesions', 'Disease', (140, 171))
52235	27019331	Considering being a crucial participator in tryptophan metabolism, the content variation of kynurenate can be associated with the disorder of tryptophan metabolism which can further affect the nicotinamide metabolism and glycolysis.	('tryptophan metabolism', 'biological_process', 'GO:0006568', ('44', '65'))	('kynurenate', 'Chemical', 'MESH:D007736', (92, 102))	('glycolysis', 'MPA', (221, 231))	('nicotinamide metabolism', 'biological_process', 'GO:0006769', ('193', '216'))	('affect', 'Reg', (182, 188))	('glycolysis', 'biological_process', 'GO:0006096', ('221', '231'))	('associated', 'Reg', (110, 120))	('content variation', 'Var', (71, 88))	('tryptophan metabolism', 'MPA', (142, 163))	('nicotinamide', 'Chemical', 'MESH:D009536', (193, 205))	('tryptophan', 'Chemical', 'MESH:D014364', (142, 152))	('tryptophan', 'Chemical', 'MESH:D014364', (44, 54))	('kynurenate', 'Gene', (92, 102))	('tryptophan metabolism', 'biological_process', 'GO:0006568', ('142', '163'))	('nicotinamide metabolism', 'MPA', (193, 216))
52264	27391842	Dysregulated EGFR signaling (such as cell-surface overexpression, autocrine activation and EGFR gene mutation) contributes to the formation of several epithelial malignancies in humans.	('EGFR', 'Gene', (91, 95))	('cell-surface', 'cellular_component', 'GO:0009986', ('37', '49'))	('formation', 'biological_process', 'GO:0009058', ('130', '139'))	('mutation', 'Var', (101, 109))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('malignancies', 'Disease', 'MESH:D009369', (162, 174))	('EGFR', 'molecular_function', 'GO:0005006', ('91', '95'))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (151, 174))	('humans', 'Species', '9606', (178, 184))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('contributes', 'Reg', (111, 122))	('malignancies', 'Disease', (162, 174))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('EGFR', 'Gene', '1956', (91, 95))
52265	27391842	There is increasing recognition that epidermal growth factor receptor variant III (EGFRvIII), the most common form of mutant EGFR, is an important target for cancer therapy.	('EGFR', 'Gene', '1956', (83, 87))	('epidermal growth factor receptor', 'Gene', '1956', (37, 69))	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', (83, 87))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('EGFR', 'Gene', (125, 129))	('mutant', 'Var', (118, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('37', '60'))	('epidermal growth factor receptor', 'Gene', (37, 69))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
52301	27391842	A significant association between AREG/EGFR co-expression and tumor differentiation was observed in our study (P = 0.032).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('co-expression', 'Var', (44, 57))	('tumor', 'Disease', (62, 67))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('EGFR', 'Gene', '1956', (39, 43))	('AREG', 'Gene', (34, 38))	('EGFR', 'Gene', (39, 43))	('AREG', 'Gene', '374', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
52308	27391842	PDAC patients with positive expression for AREG showed significantly shorter DFS and OS (AREG-positive, 8 months vs. AREG-negative, 12 months; AREG-positive, 16 months vs. AREG-negative, 23 months).	('AREG', 'Gene', (172, 176))	('AREG', 'Gene', (117, 121))	('DFS', 'MPA', (77, 80))	('patients', 'Species', '9606', (5, 13))	('PDAC', 'Chemical', '-', (0, 4))	('shorter', 'NegReg', (69, 76))	('AREG', 'Gene', '374', (43, 47))	('AREG', 'Gene', (143, 147))	('AREG', 'Gene', (43, 47))	('AREG', 'Gene', '374', (143, 147))	('AREG', 'Gene', '374', (172, 176))	('AREG', 'Gene', '374', (117, 121))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('AREG', 'Gene', '374', (89, 93))	('OS', 'Chemical', '-', (85, 87))	('AREG', 'Gene', (89, 93))	('positive', 'Var', (19, 27))
52319	27391842	In our study, we showed that AREG/EGFR co-expression were associated with poor tumor differentiation.	('co-expression', 'Var', (39, 52))	('tumor', 'Disease', (79, 84))	('EGFR', 'Gene', (34, 38))	('associated', 'Reg', (58, 68))	('AREG', 'Gene', '374', (29, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('AREG', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('EGFR', 'Gene', '1956', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
52331	27391842	found that expression of EGFRvIII was detected in 17 % of SCCHN patients, expression of EGFRvIII was significantly associated with shortened PFS but not with OS.	('SCCHN', 'Disease', (58, 63))	('EGFR', 'Gene', (25, 29))	('patients', 'Species', '9606', (64, 72))	('expression', 'Var', (74, 84))	('shortened PFS', 'Disease', (131, 144))	('associated', 'Reg', (115, 125))	('EGFR', 'Gene', '1956', (88, 92))	('OS', 'Chemical', '-', (158, 160))	('EGFR', 'Gene', (88, 92))	('EGFR', 'Gene', '1956', (25, 29))
52339	27391842	Moreover, the concomitant expression of AREG and EGFR was associated with enhanced tumor aggressiveness and shorter survival periods following tumor resection in PDAC.	('AREG', 'Gene', '374', (40, 44))	('tumor', 'Disease', (83, 88))	('shorter', 'NegReg', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('EGFR', 'Gene', (49, 53))	('PDAC', 'Chemical', '-', (162, 166))	('tumor aggressiveness', 'Disease', (83, 103))	('aggressiveness', 'Phenotype', 'HP:0000718', (89, 103))	('PDAC', 'Phenotype', 'HP:0006725', (162, 166))	('survival periods', 'CPA', (116, 132))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('expression', 'Var', (26, 36))	('AREG', 'Gene', (40, 44))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (83, 103))	('EGFR', 'Gene', '1956', (49, 53))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('enhanced', 'PosReg', (74, 82))
52342	27391842	Consistent with these results, our study demonstrated that high AREG expression was an independent prognosticator of poor OS in PDAC.	('PDAC', 'Chemical', '-', (128, 132))	('poor OS', 'Disease', (117, 124))	('AREG', 'Gene', '374', (64, 68))	('AREG', 'Gene', (64, 68))	('high', 'Var', (59, 63))	('OS', 'Chemical', '-', (122, 124))	('PDAC', 'Phenotype', 'HP:0006725', (128, 132))	('PDAC', 'Disease', (128, 132))
52343	27391842	We also found that AREG/EGFR co-expression was associated with poor tumor differentiation, which is similar to that demonstrated in previous studies.	('tumor', 'Disease', (68, 73))	('EGFR', 'Gene', '1956', (24, 28))	('AREG', 'Gene', (19, 23))	('EGFR', 'Gene', (24, 28))	('AREG', 'Gene', '374', (19, 23))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('co-expression', 'Var', (29, 42))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
52345	27391842	enrolled 88 PDAC patients and stained EGFR, AREG, VEGF, p-c-met, MMP2, MMP7, MMP9, CXCR3, and CXCR4 antibodies on tissue microarray (TMA).	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('MMP7', 'Gene', '4316', (71, 75))	('p-c-met', 'Var', (56, 63))	('AREG', 'Gene', (44, 48))	('CXCR3', 'Gene', (83, 88))	('VEGF', 'Gene', '7422', (50, 54))	('CXCR4', 'Gene', '7852', (94, 99))	('CXCR3', 'Gene', '2833', (83, 88))	('EGFR', 'Gene', '1956', (38, 42))	('CXCR4', 'Gene', (94, 99))	('VEGF', 'Gene', (50, 54))	('MMP2', 'Gene', (65, 69))	('MMP9', 'Gene', '4318', (77, 81))	('PDAC', 'Chemical', '-', (12, 16))	('MMP9', 'Gene', (77, 81))	('MMP2', 'molecular_function', 'GO:0004228', ('65', '69'))	('MMP7', 'Gene', (71, 75))	('PDAC', 'Phenotype', 'HP:0006725', (12, 16))	('AREG', 'Gene', '374', (44, 48))	('MMP9', 'molecular_function', 'GO:0004229', ('77', '81'))	('patients', 'Species', '9606', (17, 25))	('MMP2', 'Gene', '4313', (65, 69))	('MMP7', 'molecular_function', 'GO:0004235', ('71', '75'))	('EGFR', 'Gene', (38, 42))	('CXCR4', 'molecular_function', 'GO:0038147', ('94', '99'))
52351	27391842	Our results showed that although no significant association was observed between AREG expression alone and the clinicopathological characteristics in PDAC, there was a significant association between AREG/EGFR co-expression and poor tumor differentiation.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('PDAC', 'Chemical', '-', (150, 154))	('AREG', 'Gene', '374', (200, 204))	('tumor', 'Disease', (233, 238))	('AREG', 'Gene', (200, 204))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'molecular_function', 'GO:0005006', ('205', '209'))	('EGFR', 'Gene', (205, 209))	('PDAC', 'Disease', (150, 154))	('co-expression', 'Var', (210, 223))	('AREG', 'Gene', '374', (81, 85))	('PDAC', 'Phenotype', 'HP:0006725', (150, 154))	('AREG', 'Gene', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
52380	26568964	In addition to their function in the detection of CRC, peptides have also demonstrated their ability to treat CRC.	('CRC', 'Disease', (110, 113))	('rat', 'Species', '10116', (81, 84))	('CRC', 'Disease', (50, 53))	('CRC', 'Phenotype', 'HP:0003003', (110, 113))	('CRC', 'Phenotype', 'HP:0003003', (50, 53))	('peptides', 'Var', (55, 63))
52388	26568964	In addition, researchers from the same team also found that the peptides in NDF from common beans could cause different gene expression in a human CRC cell line, which was related to cell death and survival, the cell cycle, cell proliferation, and so forth, leading to the induction of apoptosis and cell death.	('peptides', 'Var', (64, 72))	('death', 'Disease', 'MESH:D003643', (188, 193))	('gene expression', 'MPA', (120, 135))	('related', 'Reg', (172, 179))	('cause', 'Reg', (104, 109))	('NDF', 'Chemical', '-', (76, 79))	('gene expression', 'biological_process', 'GO:0010467', ('120', '135'))	('cell proliferation', 'biological_process', 'GO:0008283', ('224', '242'))	('CRC', 'Phenotype', 'HP:0003003', (147, 150))	('death', 'Disease', 'MESH:D003643', (305, 310))	('rat', 'Species', '10116', (236, 239))	('cell death', 'biological_process', 'GO:0008219', ('300', '310'))	('death', 'Disease', (188, 193))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('273', '295'))	('human', 'Species', '9606', (141, 146))	('induction', 'Reg', (273, 282))	('death', 'Disease', (305, 310))	('cell death', 'biological_process', 'GO:0008219', ('183', '193'))	('NDF', 'Gene', (76, 79))	('apoptosis', 'CPA', (286, 295))	('cell cycle', 'biological_process', 'GO:0007049', ('212', '222'))
52393	26568964	Then, in the following research, Hazama and colleagues found that the interleukin-6 level was increased due to the peptide vaccine, and it could also predict good prognosis in patients who accepted the peptide vaccine.	('patients', 'Species', '9606', (176, 184))	('increased', 'PosReg', (94, 103))	('interleukin-6', 'Gene', (70, 83))	('interleukin-6', 'Gene', '3569', (70, 83))	('peptide vaccine', 'Var', (115, 130))
52406	26568964	Peptides can also be used to treat lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('Peptides', 'Var', (0, 8))	('lung cancer', 'Disease', (35, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
52413	26568964	The peptide fractions from high oleic acid soybean showed an inhibitory effect in cancer cells (including colon cancer, liver cancer, and lung cancer), and this effect was dose dependent.	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('cancer', 'Disease', (112, 118))	('colon cancer', 'Phenotype', 'HP:0003003', (106, 118))	('cancer', 'Disease', (82, 88))	('soybean', 'Species', '3847', (43, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (126, 132))	('colon cancer', 'Disease', 'MESH:D015179', (106, 118))	('cancer', 'Disease', (143, 149))	('high oleic acid', 'Var', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('liver cancer', 'Disease', 'MESH:D006528', (120, 132))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('lung cancer', 'Disease', (138, 149))	('colon cancer', 'Disease', (106, 118))	('liver cancer', 'Phenotype', 'HP:0002896', (120, 132))	('inhibitory effect', 'NegReg', (61, 78))	('liver cancer', 'Disease', (120, 132))	('oleic acid', 'Chemical', 'MESH:D019301', (32, 42))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
52414	26568964	Additionally, peptides from the venom of the Eastern green mamba have toxic effects against the human NSCLC cell line A549.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('SCLC', 'Phenotype', 'HP:0030357', (103, 107))	('toxic effects', 'MPA', (70, 83))	('human', 'Species', '9606', (96, 101))	('Eastern green mamba', 'Species', '8618', (45, 64))	('A549', 'CellLine', 'CVCL:0023', (118, 122))	('peptides', 'Var', (14, 22))	('NSCLC', 'Disease', (102, 107))
52497	26568964	confirmed the safety and immunological response against prostate tumors by using of a multipeptide, dual-adjuvant telomerase vaccine called GX301, which is composed of four telomerase peptides (peptide540-548, peptide611-626, peptide672-686, and peptide766-780) and two adjuvants, MontanideISA-51 and Imiquimod.	('Montanide', 'Chemical', '-', (281, 290))	('prostate tumors', 'Disease', 'MESH:D011471', (56, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('peptide672-686', 'Var', (226, 240))	('peptide540-548', 'Var', (194, 208))	('peptide611-626', 'Var', (210, 224))	('peptide766-780', 'Var', (246, 260))	('prostate tumor', 'Phenotype', 'HP:0100787', (56, 70))	('prostate tumors', 'Disease', (56, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
52520	26568964	Additionally, Ohtake and his colleagues validated that an artificial long peptide consisting of survivin-18 (SU18) and SU22 connected by a glycine linker was able to induce IFN-gamma producing Th1 and Tc1 cells better than mixed short peptides.	('Th1', 'Gene', '51497', (193, 196))	('Th1', 'Gene', (193, 196))	('IFN-gamma', 'Gene', '3458', (173, 182))	('IFN-gamma', 'Gene', (173, 182))	('glycine', 'Chemical', 'MESH:D005998', (139, 146))	('induce', 'PosReg', (166, 172))	('SU22', 'Var', (119, 123))
52521	26568964	reported that the combination of E75 and granulocyte-macrophage colony-stimulating factor (GM-CSF) is safe and inhibits tumor recurrence.	('granulocyte-macrophage colony-stimulating factor', 'Gene', (41, 89))	('GM-CSF', 'Gene', (91, 97))	('GM-CSF', 'Gene', '1437', (91, 97))	('inhibits', 'NegReg', (111, 119))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('granulocyte-macrophage colony-stimulating factor', 'Gene', '1437', (41, 89))	('granulocyte-macrophage colony-stimulating factor', 'molecular_function', 'GO:0005129', ('41', '89'))	('E75', 'Var', (33, 36))	('tumor', 'Disease', (120, 125))
52543	26568964	reported that the peptides derived from the melanocortin 1 receptor could elicit cytotoxic T-lymphocyte responses to kill melanoma cells.	('melanocortin 1 receptor', 'Gene', '4157', (44, 67))	('elicit', 'Reg', (74, 80))	('peptides derived', 'Var', (18, 34))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('cytotoxic T-lymphocyte responses', 'CPA', (81, 113))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('melanocortin 1 receptor', 'Gene', (44, 67))
52550	26568964	found that the peptide Myr-NR2B9c could be used to reduce bone cancer pain, suggesting that this peptide could be used in patients with advanced bone cancer.	('bone cancer pain', 'Disease', (58, 74))	('Myr-NR2B9c', 'Var', (23, 33))	('bone cancer', 'Disease', (145, 156))	('pain', 'Phenotype', 'HP:0012531', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (122, 130))	('bone cancer', 'Disease', 'MESH:D001859', (58, 69))	('reduce', 'NegReg', (51, 57))	('bone cancer pain', 'Disease', 'MESH:D001859', (58, 74))	('bone cancer', 'Disease', 'MESH:D001859', (145, 156))	('bone cancer pain', 'Phenotype', 'HP:0002653', (58, 74))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
52554	26568964	(2) Peptides can induce specific T cell responses to tumor cells, as Gonzalez et al.	('induce', 'Reg', (17, 23))	('Peptides', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
52555	26568964	Interestingly, peptides could also target tumor vessel as well as targeting tumor cells.	('peptides', 'Var', (15, 23))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('target', 'Reg', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
52577	26451384	The pancreatic CSCs express a wide array of markers such as CD44, CD24, ESA, CD133, c-MET, CXCR4, PD2/Paf1 and ALDH1.	('CXCR4', 'molecular_function', 'GO:0038147', ('91', '96'))	('ALDH1', 'Gene', '216', (111, 116))	('Paf1', 'Gene', '54623', (102, 106))	('pancreatic CSCs', 'Disease', (4, 19))	('ESA', 'Disease', (72, 75))	('PD2', 'Gene', '54623', (98, 101))	('PD2', 'Gene', (98, 101))	('Paf1', 'Gene', (102, 106))	('ALDH', 'molecular_function', 'GO:0004030', ('111', '115'))	('c-MET', 'Gene', '4233', (84, 89))	('CXCR4', 'Gene', '7852', (91, 96))	('ALDH1', 'Gene', (111, 116))	('c-MET', 'Gene', (84, 89))	('CXCR4', 'Gene', (91, 96))	('CD133', 'Gene', (77, 82))	('CD133', 'Gene', '8842', (77, 82))	('CD24', 'Gene', (66, 70))	('pancreatic CSCs', 'Disease', 'MESH:D010195', (4, 19))	('CD44', 'Var', (60, 64))
52597	26451384	Many genetic alterations were defined in pancreatic cancer such as earlier events including K-ras point mutation, EGFR overexpression and gene amplification and HER2/neu overexpression and later events such as inactivation of p16, p53, DPC4 and BRCA.	('p16', 'Gene', (226, 229))	('K-ras', 'Gene', (92, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (41, 58))	('HER2/neu', 'Gene', '2064', (161, 169))	('BRCA', 'Gene', (245, 249))	('p16', 'Gene', '1029', (226, 229))	('overexpression', 'PosReg', (170, 184))	('inactivation', 'Var', (210, 222))	('p53', 'Gene', (231, 234))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))	('pancreatic cancer', 'Disease', 'MESH:D010190', (41, 58))	('K-ras', 'Gene', '3845', (92, 97))	('HER2/neu', 'Gene', (161, 169))	('point mutation', 'Var', (98, 112))	('DPC4', 'Gene', (236, 240))	('pancreatic cancer', 'Disease', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('overexpression', 'PosReg', (119, 133))	('gene amplification', 'Var', (138, 156))	('EGFR', 'Gene', '1956', (114, 118))	('BRCA', 'Gene', '672', (245, 249))	('rat', 'Species', '10116', (17, 20))	('DPC4', 'Gene', '4089', (236, 240))
52600	26451384	In the recent past various animal models have been developed using the Cre-Lox technology such as Pdx1-Cre; LSL-KrasG12D, Ptf1/p48-Cre; LSL-KrasG12D and LSL-KrasG12D/+/Mist1Cre-ER/.	('Ptf1', 'Species', '32651', (122, 126))	('LSL-KrasG12D', 'Var', (136, 148))	('Pdx1', 'Gene', (98, 102))	('LSL-KrasG12D/+/Mist1Cre-ER/', 'Var', (153, 180))	('Pdx1', 'Gene', '18609', (98, 102))
52601	26451384	Eventually, animal models harboring additional modifications such as inactivation/mutation of p16, p19, p53, transforming growth factor (TGFbeta) and smad4 were developed.	('p19', 'Gene', '1029', (99, 102))	('p53', 'Gene', (104, 107))	('p19', 'cellular_component', 'GO:0070743', ('99', '102'))	('p16', 'Gene', '1029', (94, 97))	('TGFbeta', 'Gene', (137, 144))	('p19', 'Gene', (99, 102))	('p16', 'Gene', (94, 97))	('smad4', 'Gene', '4089', (150, 155))	('smad4', 'Gene', (150, 155))	('inactivation/mutation', 'Var', (69, 90))
52608	26451384	Pancreatic CSCs were characterized by CD44+ CD24+ and ESA+ markers.	('Pancreatic CSCs', 'Disease', 'MESH:D010195', (0, 15))	('CD44+ CD24+', 'Var', (38, 49))	('Pancreatic CSCs', 'Disease', (0, 15))
52615	26451384	Li et al., demonstrated that the CD44+ CD24+ESA+ cells isolated from human PDAC could self-renew, had differentiation potential, and had enhanced Shh expression.	('enhanced', 'PosReg', (137, 145))	('rat', 'Species', '10116', (18, 21))	('expression', 'MPA', (150, 160))	('CD44+ CD24+ESA+', 'Var', (33, 48))	('self-renew', 'CPA', (86, 96))	('differentiation potential', 'CPA', (102, 127))	('Shh', 'Gene', '6469', (146, 149))	('human', 'Species', '9606', (69, 74))	('PDAC', 'Chemical', '-', (75, 79))	('Shh', 'Gene', (146, 149))
52616	26451384	Subcutaneous injection of 500 cells (positive for CD44, CD24 and ESA) in mice could generate tumors (7/12 mice) whereas implantation of pancreatic cancer cells negative for these markers could not.	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('mice', 'Species', '10090', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', (93, 99))	('mice', 'Species', '10090', (73, 77))	('rat', 'Species', '10116', (88, 91))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('CD24', 'Var', (56, 60))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('CD44', 'Var', (50, 54))	('pancreatic cancer', 'Disease', (136, 153))
52664	26451384	Using this assay, Rasheed et al., claimed that the ALDH+ cells have enhanced tumorigenic potential and they are comparatively more invasive than the CD44+CD24+ pancreatic CSCs.	('enhanced', 'PosReg', (68, 76))	('rat', 'Species', '10116', (117, 120))	('invasive', 'CPA', (131, 139))	('pancreatic CSCs', 'Disease', (160, 175))	('pancreatic CSCs', 'Disease', 'MESH:D010195', (160, 175))	('ALDH', 'molecular_function', 'GO:0004030', ('51', '55'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ALDH+', 'Var', (51, 56))	('tumor', 'Disease', (77, 82))
52685	26451384	They have isolated the CD44+/CD24+/ESA+ pancreatic CSCs from the pancreatic tumors which accounted for 0.2-0.8% of pancreatic cancer cells that displayed the CSC features such as the self-renewal property and enhanced tumorigenic potential as opposed to the marker-negative population.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('tumor', 'Disease', (76, 81))	('enhanced', 'PosReg', (209, 217))	('tumor', 'Disease', (218, 223))	('self-renewal property', 'CPA', (183, 204))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('pancreatic CSCs', 'Disease', 'MESH:D010195', (40, 55))	('pancreatic tumors', 'Disease', 'MESH:D010190', (65, 82))	('pancreatic tumors', 'Disease', (65, 82))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('CD44+/CD24+/ESA+', 'Var', (23, 39))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pancreatic CSCs', 'Disease', (40, 55))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('pancreatic cancer', 'Disease', (115, 132))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (65, 81))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (65, 82))
52702	26451384	In pancreatic cancer, it has been shown that 50% of the mice developed tumor when 100 CD44+CD24+ESA+ cells were injected in mice.	('pancreatic cancer', 'Disease', (3, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('mice', 'Species', '10090', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('mice', 'Species', '10090', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('CD44+CD24+ESA+', 'Var', (86, 100))
52725	26451384	They have observed that knockdown of Hes1 using shRNA and inhibition of the Notch pathway components by gamma secretase resulted in the reduction of the self-renewal capacity of pancreatic CSCs.	('pancreatic CSCs', 'Disease', 'MESH:D010195', (178, 193))	('Hes1', 'Gene', (37, 41))	('Hes1', 'Gene', '3280', (37, 41))	('pancreatic CSCs', 'Disease', (178, 193))	('reduction', 'NegReg', (136, 145))	('inhibition', 'NegReg', (58, 68))	('knockdown', 'Var', (24, 33))
52730	26451384	It has been reported that a nine fold increase in Shh mRNA levels has been found in the CD44+ CD24+ESA+ cells when compared to the unsorted pancreatic cancer cells.	('increase', 'PosReg', (38, 46))	('pancreatic cancer', 'Disease', 'MESH:D010190', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('Shh', 'Gene', (50, 53))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('mRNA levels', 'MPA', (54, 65))	('Shh', 'Gene', '6469', (50, 53))	('CD44+', 'Var', (88, 93))	('pancreatic cancer', 'Disease', (140, 157))
52753	26451384	On silencing Zeb-1 in the mesenchymal cell lines, the expression of the epithelial markers such as E-cadherin, EVA1 and MAL2 was increased and most importantly the pancreatic cancer cells gained sensitivity to chemotherapeutic drugs.	('expression', 'MPA', (54, 64))	('silencing', 'Var', (3, 12))	('gained', 'PosReg', (188, 194))	('Zeb-1', 'Gene', (13, 18))	('EVA1', 'Gene', (111, 115))	('pancreatic cancer', 'Disease', (164, 181))	('cadherin', 'molecular_function', 'GO:0008014', ('101', '109'))	('sensitivity', 'MPA', (195, 206))	('pancreatic cancer', 'Disease', 'MESH:D010190', (164, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('Zeb-1', 'Gene', '6935', (13, 18))	('increased', 'PosReg', (129, 138))	('MAL2', 'Gene', '114569', (120, 124))	('E-cadherin', 'Gene', (99, 109))	('E-cadherin', 'Gene', '999', (99, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (164, 181))	('EVA1', 'Gene', '10205', (111, 115))	('MAL2', 'Gene', (120, 124))
52758	26451384	Another study showed that miRNAs such as miR99a, miR100, miR-125b, miR-192 and miR-429 were differentially expressed in pancreatic CSCs.	('miR-125b', 'Var', (57, 65))	('pancreatic CSCs', 'Disease', 'MESH:D010195', (120, 135))	('miR100', 'Gene', (49, 55))	('miR-429', 'Gene', '554210', (79, 86))	('pancreatic CSCs', 'Disease', (120, 135))	('miR-429', 'Gene', (79, 86))	('miR99a', 'Gene', '407055', (41, 47))	('miR99a', 'Gene', (41, 47))	('miR100', 'Gene', '406892', (49, 55))	('miR-192', 'Gene', (67, 74))	('miR-192', 'Gene', '406967', (67, 74))
52764	26451384	Metformin was able to increase the reactive oxygen species production in CSCs and reduce its mitochondrial transmembrane potential.	('reactive oxygen species production', 'MPA', (35, 69))	('reduce', 'NegReg', (82, 88))	('Metformin', 'Var', (0, 9))	('increase', 'PosReg', (22, 30))	('transmembrane', 'cellular_component', 'GO:0044214', ('107', '120'))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (35, 58))	('mitochondrial transmembrane potential', 'MPA', (93, 130))	('transmembrane', 'cellular_component', 'GO:0016021', ('107', '120'))	('increase the reactive oxygen species production', 'Phenotype', 'HP:0025464', (22, 69))
52766	26451384	Interestingly, they have shown that metformin retarded the formation of secondary and tertiary tumorspheres by hampering the self-renewal capacity of these CSCs.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('retarded', 'Disease', 'MESH:D008607', (46, 54))	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('hampering', 'NegReg', (111, 120))	('metformin', 'Chemical', 'MESH:D008687', (36, 45))	('metformin', 'Var', (36, 45))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('retarded', 'Disease', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('self-renewal capacity of these CSCs', 'CPA', (125, 160))	('tumors', 'Disease', (95, 101))
52826	26151762	Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile.	('Ptf1a', 'Gene', '19213', (8, 13))	('metaplasia', 'biological_process', 'GO:0036074', ('61', '71'))	('Ptf1a', 'Gene', (8, 13))	('induce', 'Reg', (102, 108))	('KRAS-permissive', 'MPA', (111, 126))	('inflammation', 'Disease', 'MESH:D007249', (84, 96))	('metaplasia', 'Disease', 'MESH:D008679', (61, 71))	('PDAC', 'Chemical', '-', (128, 132))	('inflammation', 'biological_process', 'GO:0006954', ('84', '96'))	('inflammation', 'Disease', (84, 96))	('metaplasia', 'Disease', (61, 71))	('gene expression', 'biological_process', 'GO:0010467', ('138', '153'))	('induce', 'PosReg', (37, 43))	('potentiate', 'PosReg', (73, 83))	('Loss', 'Var', (0, 4))
52832	26151762	Together, these mutations cause cells to over-proliferate and disrupt the structure of the pancreas.	('disrupt', 'NegReg', (62, 69))	('cause', 'Reg', (26, 31))	('mutations', 'Var', (16, 25))	('over-proliferate', 'PosReg', (41, 57))	('rat', 'Species', '10116', (53, 56))	('structure', 'MPA', (74, 83))
52838	26151762	Additionally, when an oncogene mutation was activated at the same time as the gene for PTF1A was deleted, Krah et al.	('deleted', 'Var', (97, 104))	('PTF1A', 'Gene', '19213', (87, 92))	('PTF1A', 'Gene', (87, 92))	('mutation', 'Var', (31, 39))
52848	26151762	Notably, the progression of PanINs to PDAC is accompanied by additional mutations in tumor suppressor genes, such as INK4A, CDKN2A, TRP53 (commonly referred to as P53), and DPC4/SMAD4.	('tumor', 'Disease', (85, 90))	('CDKN2A', 'Gene', (124, 130))	('INK4A', 'Gene', (117, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('85', '101'))	('PDAC', 'Chemical', '-', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('mutations', 'Var', (72, 81))	('P53', 'Gene', (134, 137))	('P53', 'Gene', '22059', (134, 137))	('PanINs', 'Disease', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('P53', 'Gene', (163, 166))	('P53', 'Gene', '22059', (163, 166))	('PDAC', 'Disease', (38, 42))	('TRP53', 'Gene', '22059', (132, 137))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('85', '101'))	('TRP53', 'Gene', (132, 137))	('SMA', 'Gene', '20589', (178, 181))	('SMA', 'Gene', (178, 181))
52854	26151762	Consistent with acinar cells as the cell of origin in PDAC, and acinar cell identity being a protective mechanism against KrasG12D-mediated transformation, recent genome-wide association studies identified PDAC risk-associated single-nucleotide polymorphisms in the non-coding region of the gene encoding the acinar differentiation transcription factor NR5A2, also known as LRH-1.	('NR5A2', 'Gene', '26424', (353, 358))	('PDAC', 'Chemical', '-', (206, 210))	('transcription factor', 'molecular_function', 'GO:0000981', ('332', '352'))	('PDAC', 'Disease', (206, 210))	('transcription', 'biological_process', 'GO:0006351', ('332', '345'))	('NR5A2', 'Gene', (353, 358))	('PDAC', 'Chemical', '-', (54, 58))	('single-nucleotide polymorphisms', 'Var', (227, 258))
52865	26151762	Consistent with the central role of this transcription factor in defining and maintaining acinar cell identity, we have shown that PTF1A is downregulated in acinar cells transformed by KrasG12D and Notch activation.	('transcription', 'biological_process', 'GO:0006351', ('41', '54'))	('KrasG12D', 'Var', (185, 193))	('transcription factor', 'molecular_function', 'GO:0000981', ('41', '61'))	('downregulated', 'NegReg', (140, 153))	('PTF1A', 'Gene', (131, 136))	('PTF1A', 'Gene', '19213', (131, 136))
52867	26151762	Based on the studies described above, we hypothesized that loss of PTF1A is a necessary and sufficient step in acinar cell reprogramming, the initiation of PanINs, and the progression of PDAC.	('PTF1A', 'Gene', (67, 72))	('PTF1A', 'Gene', '19213', (67, 72))	('PDAC', 'Chemical', '-', (187, 191))	('loss', 'Var', (59, 63))	('PDAC', 'Disease', (187, 191))
52880	26151762	In order to determine whether PTF1A downregulation was a functionally important step in PanIN initiation, or a side effect of acinar cell transformation itself, we used an inducible system to delete Ptf1a both in the absence and presence of oncogenic KrasG12D.	('downregulation', 'NegReg', (36, 50))	('PTF1A', 'Gene', (30, 35))	('Ptf1a', 'Gene', '19213', (199, 204))	('Ptf1a', 'Gene', (199, 204))	('PTF1A', 'Gene', '19213', (30, 35))	('delete', 'Var', (192, 198))
52892	26151762	Interestingly, ADM in Ptf1a cKO mice was associated with no or scant inflammatory infiltrates, and the surrounding areas did not stain positively with Sirius Red (Figure 2W), a histochemical stain that highlights fibrotic collagen matrix.	('Ptf1a', 'Gene', '19213', (22, 27))	('cKO', 'Var', (28, 31))	('Ptf1a', 'Gene', (22, 27))	('collagen', 'molecular_function', 'GO:0005202', ('222', '230'))	('Sirius Red', 'Chemical', '-', (151, 161))	('rat', 'Species', '10116', (88, 91))	('mice', 'Species', '10090', (32, 36))
52893	26151762	We next tested if inactivation of Ptf1a sensitized acinar cells to oncogenic KRAS-mediated transformation and PanIN initiation.	('tested', 'Reg', (8, 14))	('inactivation', 'Var', (18, 30))	('oncogenic KRAS-mediated transformation', 'CPA', (67, 105))	('Ptf1a', 'Gene', '19213', (34, 39))	('Ptf1a', 'Gene', (34, 39))	('sensitized', 'Reg', (40, 50))
52894	26151762	While intermittent PanIN formation was observed in KrasG12D mice (Figure 2D), pancreata from Ptf1a cKO; KrasG12D mice were uniformly composed of extensively distributed PanINs embedded in fibrotic stroma, with almost no remaining normal acinar tissue (Figure 2E).	('fibrotic stroma', 'Disease', 'None', (188, 203))	('fibrotic stroma', 'Disease', (188, 203))	('mice', 'Species', '10090', (60, 64))	('KrasG12D', 'Var', (104, 112))	('Ptf1a', 'Gene', '19213', (93, 98))	('formation', 'biological_process', 'GO:0009058', ('25', '34'))	('Ptf1a', 'Gene', (93, 98))	('PanINs', 'Protein', (169, 175))	('mice', 'Species', '10090', (113, 117))
52895	26151762	PanINs in both KrasG12D and Ptf1a cKO; KrasG12D mice were positive for the duct marker Cytokeratin-19 (Figure 2H,I) and the duct-cell transcription factor SOX9 (Figure 2L,M), as well as the PanIN markers CLDN18 (Figure 2P,Q) and Alcian Blue acidic mucin staining (Figure 2T,U).	('positive', 'Reg', (58, 66))	('CLDN18', 'Gene', '56492', (204, 210))	('Alcian Blue acidic mucin', 'MPA', (229, 253))	('CLDN18', 'Gene', (204, 210))	('mice', 'Species', '10090', (48, 52))	('Ptf1a', 'Gene', (28, 33))	('Ptf1a', 'Gene', '19213', (28, 33))	('Alcian Blue', 'Chemical', 'MESH:D000423', (229, 240))	('transcription factor', 'molecular_function', 'GO:0000981', ('134', '154'))	('transcription', 'biological_process', 'GO:0006351', ('134', '147'))	('KrasG12D', 'Var', (39, 47))
52897	26151762	Taken together, these data indicate that loss of Ptf1a sensitizes acinar cells to ADM and dramatically increases their susceptibility to oncogenic KRAS transformation and PDAC initiation.	('PDAC initiation', 'CPA', (171, 186))	('loss', 'Var', (41, 45))	('increases', 'PosReg', (103, 112))	('oncogenic KRAS transformation', 'CPA', (137, 166))	('susceptibility', 'MPA', (119, 133))	('Ptf1a', 'Gene', '19213', (49, 54))	('Ptf1a', 'Gene', (49, 54))	('sensitizes', 'Reg', (55, 65))	('PDAC', 'Chemical', '-', (171, 175))
52898	26151762	Given the severity and robustness of PanIN formation in Ptf1a cKO; KrasG12D mice 9 months after TM administration, we next determined if loss of Ptf1a had a more acute effect on acinar cell transformation.	('Ptf1a', 'Gene', (56, 61))	('mice', 'Species', '10090', (76, 80))	('formation', 'biological_process', 'GO:0009058', ('43', '52'))	('Ptf1a', 'Gene', '19213', (145, 150))	('Ptf1a', 'Gene', '19213', (56, 61))	('Ptf1a', 'Gene', (145, 150))	('loss', 'Var', (137, 141))	('TM', 'Chemical', 'MESH:D013629', (96, 98))	('acinar cell transformation', 'CPA', (178, 204))	('rat', 'Species', '10116', (107, 110))
52903	26151762	3 days after TM administration (0.17 mg/g), there was a ~20% decrease in the number of PTF1A+ cells detected by immunofluorescence (Figure 2:figure supplement 2).	('decrease', 'NegReg', (61, 69))	('0.17', 'Var', (32, 36))	('PTF1A', 'Gene', (87, 92))	('TM', 'Chemical', 'MESH:D013629', (13, 15))	('PTF1A', 'Gene', '19213', (87, 92))	('rat', 'Species', '10116', (24, 27))
52904	26151762	Importantly, the majority (~75%) of EYFP+ cells were PTF1A-negative at this dose of TM (Figure 2:figure supplement 2), indicating that activation of EYFP provides an approximate surrogate for deletion of Ptf1a.	('activation', 'PosReg', (135, 145))	('PTF1A', 'Gene', '19213', (53, 58))	('EYFP', 'Var', (149, 153))	('TM', 'Chemical', 'MESH:D013629', (84, 86))	('PTF1A', 'Gene', (53, 58))	('deletion', 'Var', (192, 200))	('Ptf1a', 'Gene', '19213', (204, 209))	('Ptf1a', 'Gene', (204, 209))
52905	26151762	Interestingly, this level of Ptf1a deletion alone did not produce ADM or other histologically detectable effects at 2 weeks post-TM, compared to control mice (Figure 3B,C).	('ADM', 'Disease', (66, 69))	('TM', 'Chemical', 'MESH:D013629', (129, 131))	('deletion', 'Var', (35, 43))	('mice', 'Species', '10090', (153, 157))	('Ptf1a', 'Gene', '19213', (29, 34))	('Ptf1a', 'Gene', (29, 34))
52906	26151762	While KrasG12D pancreata exhibited few or no PanINs at this time point, there was widespread induction of ADM, leukocyte infiltration, fibrosis, and PanIN initiation in Ptf1a cKO; KrasG12D pancreata (Figure 3D,E and Figure 3:figure supplement 1).	('cKO; KrasG12D', 'Var', (175, 188))	('Ptf1a', 'Gene', (169, 174))	('fibrosis', 'Disease', 'MESH:D005355', (135, 143))	('ADM', 'MPA', (106, 109))	('initiation', 'PosReg', (155, 165))	('rat', 'Species', '10116', (127, 130))	('PanIN', 'MPA', (149, 154))	('Ptf1a', 'Gene', '19213', (169, 174))	('fibrosis', 'Disease', (135, 143))
52910	26151762	Following a counting procedure established in our lab, we observed a ~sixfold increase in the frequency of PanINs in Ptf1a cKO; KrasG12D mice compared to mice expressing KrasG12D alone (Figure 3N).	('cKO; KrasG12D', 'Var', (123, 136))	('mice', 'Species', '10090', (154, 158))	('Ptf1a', 'Gene', '19213', (117, 122))	('PanINs', 'Protein', (107, 113))	('increase', 'PosReg', (78, 86))	('Ptf1a', 'Gene', (117, 122))	('mice', 'Species', '10090', (137, 141))
52917	26151762	Staining with the fibrosis marker Sirius Red confirmed that PanIN-associated fibroblasts of Ptf1a cKO; KrasG12D pancreata were actively secreting collagenous matrix (Figure 3:figure supplement 1), indicating activation of stellate cells only 2 weeks after Cre-mediated recombination.	('Ptf1a', 'Gene', '19213', (92, 97))	('Ptf1a', 'Gene', (92, 97))	('activation', 'PosReg', (208, 218))	('Sirius Red', 'Chemical', '-', (34, 44))	('KrasG12D', 'Var', (103, 111))	('fibrosis', 'Disease', 'MESH:D005355', (18, 26))	('fibrosis', 'Disease', (18, 26))	('cKO; KrasG12D', 'Var', (98, 111))
52919	26151762	In order to determine the acinar cell-intrinsic consequences of Ptf1a deletion, we used a 3D culture system in which acini can undergo metaplasia into ductal cysts in response to mutant Kras or EGF receptor (EGFR) ligand stimulation, without the influence of other cell types.	('deletion', 'Var', (70, 78))	('mutant', 'Var', (179, 185))	('metaplasia', 'Disease', (135, 145))	('Ptf1a', 'Gene', '19213', (64, 69))	('ligand', 'molecular_function', 'GO:0005488', ('214', '220'))	('Ptf1a', 'Gene', (64, 69))	('metaplasia', 'Disease', 'MESH:D008679', (135, 145))	('metaplasia', 'biological_process', 'GO:0036074', ('135', '145'))	('EGFR', 'molecular_function', 'GO:0005006', ('208', '212'))	('Kras', 'Gene', '16653', (186, 190))	('Kras', 'Gene', (186, 190))	('EGF', 'molecular_function', 'GO:0005154', ('194', '197'))
52920	26151762	To induce widespread, acinar-specific Kras activation and/or Ptf1a deletion, we treated mice with three daily doses of tamoxifen at 0.25 mg/ml, a treatment paradigm that we found to drive widespread recombination (see below).	('Ptf1a', 'Gene', '19213', (61, 66))	('Ptf1a', 'Gene', (61, 66))	('deletion', 'Var', (67, 75))	('Kras', 'Gene', '16653', (38, 42))	('Kras', 'Gene', (38, 42))	('tamoxifen', 'Chemical', 'MESH:D013629', (119, 128))	('mice', 'Species', '10090', (88, 92))
52922	26151762	Neither control nor Ptf1a cKO acinar clusters underwent spontaneous cyst conversion, in the absence of added growth factors, implying that loss of Ptf1a is not sufficient for acinar-ductal reprogramming.	('Ptf1a', 'Gene', '19213', (20, 25))	('Ptf1a', 'Gene', (20, 25))	('Ptf1a', 'Gene', '19213', (147, 152))	('Ptf1a', 'Gene', (147, 152))	('loss', 'Var', (139, 143))
52923	26151762	As expected, acini of both genotypes generated CK19+ ductal cysts in response to the EGFR ligand TGFalpha (data not shown).	('CK19+', 'Var', (47, 52))	('ligand', 'molecular_function', 'GO:0005488', ('90', '96'))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('rat', 'Species', '10116', (41, 44))	('response', 'MPA', (69, 77))
52925	26151762	These results are consistent with our in vivo data and suggest that acinar cell loss of Ptf1a enhances KRAS-mediated transformation independent of effects on the stromal microenvironment.	('Ptf1a', 'Gene', (88, 93))	('enhances', 'PosReg', (94, 102))	('KRAS-mediated transformation', 'CPA', (103, 131))	('loss', 'Var', (80, 84))	('Ptf1a', 'Gene', '19213', (88, 93))
52926	26151762	A generally similar synergy between KrasG12D and Ptf1a cKO was observed in vivo at the 6-week post-tamoxifen time point.	('tamoxifen', 'Chemical', 'MESH:D013629', (99, 108))	('Ptf1a', 'Gene', (49, 54))	('KrasG12D', 'Var', (36, 44))	('Ptf1a', 'Gene', '19213', (49, 54))
52927	26151762	Ptf1a cKO pancreata remained histologically unchanged compared to control, as at 2 weeks post-TM, while intermittent PanIN-1 lesions were observed in KrasG12D pancreata (Figure 3O-Q).	('TM', 'Chemical', 'MESH:D013629', (94, 96))	('Ptf1a', 'Gene', (0, 5))	('Ptf1a', 'Gene', '19213', (0, 5))	('KrasG12D', 'Var', (150, 158))
52929	26151762	Quantifying PanIN lesions by Alcian Blue staining, we observed a >15-fold increase in Ptf1a cKO; KrasG12D compared to mice expressing KrasG12D alone (Figure 3W).	('increase', 'PosReg', (74, 82))	('Ptf1a', 'Gene', '19213', (86, 91))	('Alcian Blue', 'Chemical', 'MESH:D000423', (29, 40))	('Ptf1a', 'Gene', (86, 91))	('mice', 'Species', '10090', (118, 122))	('cKO; KrasG12D', 'Var', (92, 105))
52931	26151762	Altogether, the dramatic acceleration of PanIN development upon Ptf1a deletion suggests that downregulation of this TF is a rate-limiting step for KRAS-driven pancreatic tumorigenesis.	('deletion', 'Var', (70, 78))	('rat', 'Species', '10116', (124, 127))	('pancreatic tumorigenesis', 'Disease', (159, 183))	('Ptf1a', 'Gene', '19213', (64, 69))	('Ptf1a', 'Gene', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('rat', 'Species', '10116', (31, 34))	('PanIN development', 'CPA', (41, 58))	('pancreatic tumorigenesis', 'Disease', 'MESH:D010190', (159, 183))	('acceleration', 'PosReg', (25, 37))
52932	26151762	As we were surprised that a moderate level of acinar cell recombination (~25%) failed to produce an overt, short-term phenotype in Ptf1a cKO pancreata (Figure 3), we tested if more pervasive deletion of Ptf1a would produce a more robust reprogramming phenotype.	('deletion', 'Var', (191, 199))	('tested', 'Reg', (166, 172))	('rat', 'Species', '10116', (32, 35))	('produce', 'Reg', (215, 222))	('Ptf1a', 'Gene', '19213', (203, 208))	('Ptf1a', 'Gene', (203, 208))	('Ptf1a', 'Gene', '19213', (131, 136))	('Ptf1a', 'Gene', (131, 136))
52936	26151762	As with low-dose TM, described above, the majority (>90%) of EYFP+ cells were PTF1A-negative at 3 days post-TM, confirming that EYFP expression highlights acinar cells deleted for Ptf1a (Figure 2:figure supplement 2).	('TM', 'Chemical', 'MESH:D013629', (108, 110))	('PTF1A', 'Gene', (78, 83))	('PTF1A', 'Gene', '19213', (78, 83))	('Ptf1a', 'Gene', '19213', (180, 185))	('TM', 'Chemical', 'MESH:D013629', (17, 19))	('Ptf1a', 'Gene', (180, 185))	('EYFP', 'Var', (128, 132))
52941	26151762	CK19+ acinar cells (defined by EYFP co-expression) were consistently surrounded by CD45+ leukocytes (Figure 4:figure supplement 2A-C), consistent with an intimate association between metaplasia and inflammatory cell recruitment.	('metaplasia', 'biological_process', 'GO:0036074', ('183', '193'))	('CK19+', 'Var', (0, 5))	('metaplasia', 'Disease', (183, 193))	('metaplasia', 'Disease', 'MESH:D008679', (183, 193))	('CD45', 'Gene', (83, 87))	('CD45', 'Gene', '19264', (83, 87))
52945	26151762	Surprisingly, we also observed a significant (~fourfold) increase in the fraction of Ki67+ epithelial cells in Ptf1a cKO pancreata compared with control, suggesting that loss of PTF1A results in deregulation of proliferation as well as differentiation (Figure 4:figure supplement 2G-I).	('Ki67', 'Gene', '17345', (85, 89))	('Ki67', 'Gene', (85, 89))	('loss', 'Var', (170, 174))	('PTF1A', 'Gene', (178, 183))	('proliferation', 'CPA', (211, 224))	('differentiation', 'CPA', (236, 251))	('increase', 'PosReg', (57, 65))	('rat', 'Species', '10116', (218, 221))	('deregulation', 'MPA', (195, 207))	('Ptf1a', 'Gene', '19213', (111, 116))	('PTF1A', 'Gene', '19213', (178, 183))	('Ptf1a', 'Gene', (111, 116))
52951	26151762	Given our finding that loss of Ptf1a strongly potentiates KRAS-induced PanIN initiation (Figures 2, 3), we analyzed the expression of genes previously implicated in KRAS signaling and PDAC development.	('KRAS-induced PanIN initiation', 'MPA', (58, 87))	('potentiates', 'PosReg', (46, 57))	('signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('PDAC', 'Chemical', '-', (184, 188))	('Ptf1a', 'Gene', '19213', (31, 36))	('Ptf1a', 'Gene', (31, 36))	('loss', 'Var', (23, 27))
52956	26151762	The preferential upregulation of RAS dependency genes in Ptf1a cKO was confirmed by Gene Set Enrichment Analysis (GSEA) (Figure 5B), and suggests that loss of PTF1A results in a phenotypic shift toward a KRAS-permissive phenotype.	('upregulation', 'PosReg', (17, 29))	('Ptf1a', 'Gene', '19213', (57, 62))	('Ptf1a', 'Gene', (57, 62))	('GSEA', 'Chemical', '-', (114, 118))	('PTF1A', 'Gene', (159, 164))	('PTF1A', 'Gene', '19213', (159, 164))	('loss', 'Var', (151, 155))
52958	26151762	We find that the classical PDAC signature is also preferentially upregulated upon Ptf1a deletion, while the distinct 'exocrine-like' PDAC signature, largely comprising acinar-specific secreted proteins, is downregulated (Figure 5A,B).	('PDAC', 'Chemical', '-', (27, 31))	('Ptf1a', 'Gene', '19213', (82, 87))	('Ptf1a', 'Gene', (82, 87))	('deletion', 'Var', (88, 96))	('downregulated', 'NegReg', (206, 219))	('preferentially', 'PosReg', (50, 64))	('upregulated', 'PosReg', (65, 76))	('PDAC', 'Chemical', '-', (133, 137))
52960	26151762	To identify biological pathways that were activated or attenuated by Ptf1a deletion, we analyzed this RNA-seq data set using Qiagen's Ingenuity Pathway Analysis (IPA, QIAGEN Redwood City, www.ingenuity.com).	('attenuated', 'NegReg', (55, 65))	('deletion', 'Var', (75, 83))	('activated', 'PosReg', (42, 51))	('RNA', 'cellular_component', 'GO:0005562', ('102', '105'))	('Ptf1a', 'Gene', '19213', (69, 74))	('Ptf1a', 'Gene', (69, 74))	('Redwood', 'Species', '28980', (174, 181))	('biological pathways', 'Pathway', (12, 31))
52961	26151762	At an upregulation threshold of 2.0, deletion of Ptf1a significantly affected over 300 pathways, several of which have an established role in PDAC initiation.	('deletion', 'Var', (37, 45))	('PDAC', 'Chemical', '-', (142, 146))	('affected', 'Reg', (69, 77))	('Ptf1a', 'Gene', '19213', (49, 54))	('Ptf1a', 'Gene', (49, 54))
52965	26151762	Thus, we propose that loss of Ptf1a alters cell state at multiple levels, ultimately promoting gene expression and signaling activities that are supportive of KRAS transformation.	('gene expression', 'MPA', (95, 110))	('Ptf1a', 'Gene', '19213', (30, 35))	('signaling activities', 'MPA', (115, 135))	('Ptf1a', 'Gene', (30, 35))	('gene expression', 'biological_process', 'GO:0010467', ('95', '110'))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('loss', 'Var', (22, 26))	('promoting', 'PosReg', (85, 94))
52967	26151762	As Ptf1a deletion upregulates other pathways characteristic of pancreatic injury, such as stellate-cell activation, TGF-beta signaling, and dendritic cell maturation, we were interested to determine if loss of Ptf1a would sensitize acinar cells to injury-induced reprogramming even without oncogenic KRAS.	('loss', 'Var', (202, 206))	('upregulates', 'PosReg', (18, 29))	('cell activation', 'biological_process', 'GO:0001775', ('99', '114'))	('deletion', 'Var', (9, 17))	('pancreatic injury', 'Disease', 'MESH:D010195', (63, 80))	('sensitize', 'Reg', (222, 231))	('Ptf1a', 'Gene', '19213', (3, 8))	('Ptf1a', 'Gene', (3, 8))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('injury-induced reprogramming', 'CPA', (248, 276))	('Ptf1a', 'Gene', '19213', (210, 215))	('Ptf1a', 'Gene', (210, 215))	('cell maturation', 'biological_process', 'GO:0048469', ('150', '165'))	('rat', 'Species', '10116', (159, 162))	('pancreatic injury', 'Disease', (63, 80))
52968	26151762	To test this hypothesis in vivo, we deleted Ptf1a via high-dose TM administration (three doses of 0.17 mg/g), which induced a recombination rate of ~65% (Figure 4:figure supplement 1).	('Ptf1a', 'Gene', '19213', (44, 49))	('Ptf1a', 'Gene', (44, 49))	('rat', 'Species', '10116', (75, 78))	('induced', 'Reg', (116, 123))	('TM', 'Chemical', 'MESH:D013629', (64, 66))	('deleted', 'Var', (36, 43))	('rat', 'Species', '10116', (140, 143))
52970	26151762	As a control for caerulein injections, additional TM-treated Ptf1a cKO and control mice were administered saline vehicle alone.	('Ptf1a', 'Gene', '19213', (61, 66))	('Ptf1a', 'Gene', (61, 66))	('saline', 'Chemical', 'MESH:D012965', (106, 112))	('cKO', 'Var', (67, 70))	('TM', 'Chemical', 'MESH:D013629', (50, 52))	('mice', 'Species', '10090', (83, 87))	('caerulein', 'Chemical', 'MESH:D002108', (17, 26))
52975	26151762	Acinar-derived EYFP+ cells in caerulein-treated Ptf1a cKO pancreata were instead integrated within CK19+ duct-like structures, suggesting that pancreatitis synergizes with loss of Ptf1a to cause a rapid loss of acinar gene expression and complete reprogramming to a duct-like fate (Figure 6I-L).	('pancreatitis', 'Disease', (143, 155))	('acinar', 'Protein', (211, 217))	('loss', 'Var', (172, 176))	('reprogramming to a duct-like fate', 'CPA', (247, 280))	('expression', 'MPA', (223, 233))	('caerulein', 'Chemical', 'MESH:D002108', (30, 39))	('Ptf1a', 'Gene', '19213', (48, 53))	('pancreatitis', 'Phenotype', 'HP:0001733', (143, 155))	('Ptf1a', 'Gene', (48, 53))	('Ptf1a', 'Gene', '19213', (180, 185))	('gene expression', 'biological_process', 'GO:0010467', ('218', '233'))	('pancreatitis', 'Disease', 'MESH:D010195', (143, 155))	('Ptf1a', 'Gene', (180, 185))	('rat', 'Species', '10116', (86, 89))	('loss', 'NegReg', (203, 207))
52976	26151762	As our findings in Ptf1a cKO; KrasG12D mice indicate that loss of PTF1A enhances the transforming activity of mutant KRAS, we were interested to determine if development of mucinous metaplasia involved enhanced signaling through endogenous RAS.	('Ptf1a', 'Gene', '19213', (19, 24))	('signaling', 'MPA', (211, 220))	('mucinous metaplasia', 'Disease', (173, 192))	('Ptf1a', 'Gene', (19, 24))	('loss', 'Var', (58, 62))	('enhanced', 'PosReg', (202, 210))	('mucinous metaplasia', 'Phenotype', 'HP:0031495', (173, 192))	('mutant', 'Var', (110, 116))	('signaling', 'biological_process', 'GO:0023052', ('211', '220'))	('transforming activity', 'CPA', (85, 106))	('PTF1A', 'Gene', (66, 71))	('metaplasia', 'biological_process', 'GO:0036074', ('182', '192'))	('PTF1A', 'Gene', '19213', (66, 71))	('enhances', 'PosReg', (72, 80))	('mice', 'Species', '10090', (39, 43))	('mucinous metaplasia', 'Disease', 'MESH:D008679', (173, 192))
52978	26151762	Phospho-ERK was undetectable in saline-treated Ptf1a cKO mice, or control mice under either treatment.	('mice', 'Species', '10090', (57, 61))	('Ptf1a', 'Gene', '19213', (47, 52))	('ERK', 'molecular_function', 'GO:0004707', ('8', '11'))	('Ptf1a', 'Gene', (47, 52))	('cKO', 'Var', (53, 56))	('mice', 'Species', '10090', (74, 78))	('saline', 'Chemical', 'MESH:D012965', (32, 38))
52981	26151762	The above studies rely on genetic deletion of Ptf1a, a process without clear parallel in human disease: somatic mutations of PTF1A are not observed in human PDAC, according to the Catalogue of Somatic Mutations in Cancer (COSMIC) database (cancer.sanger.ac.uk).	('human', 'Species', '9606', (89, 94))	('Ptf1a', 'Gene', '19213', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('human', 'Species', '9606', (151, 156))	('deletion', 'Var', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('PTF1A', 'Gene', (125, 130))	('Ptf1a', 'Gene', (46, 51))	('cancer', 'Disease', (240, 246))	('Cancer', 'Phenotype', 'HP:0002664', (214, 220))	('PTF1A', 'Gene', '19213', (125, 130))	('PDAC', 'Chemical', '-', (157, 161))
52984	26151762	To determine if the role of Ptf1a itself is dosage-sensitive, we generated mice of the 'KC' genotype, using the Pdx1-Cre driver to activate KrasLSL-G12D throughout the pancreas, and which were either heterozygous for a germ line deletion of Ptf1a (Pdx1-Cre; KrasLSL-G12D; Ptf1aDelta/+) or remained homozygous Ptf1a wild type.	('Ptf1a', 'Gene', '19213', (272, 277))	('Pdx1', 'Gene', '18609', (248, 252))	('Kras', 'Gene', '16653', (140, 144))	('Ptf1a', 'Gene', (309, 314))	('Ptf1a', 'Gene', '19213', (241, 246))	('Kras', 'Gene', '16653', (258, 262))	('Pdx1', 'Gene', '18609', (112, 116))	('Pdx1', 'Gene', (248, 252))	('deletion', 'Var', (229, 237))	('Ptf1a', 'Gene', '19213', (309, 314))	('Pdx1', 'Gene', (112, 116))	('rat', 'Species', '10116', (69, 72))	('mice', 'Species', '10090', (75, 79))	('Ptf1a', 'Gene', (28, 33))	('G12D', 'Mutation', 'rs121913529', (148, 152))	('G12D', 'Mutation', 'rs121913529', (266, 270))	('Ptf1a', 'Gene', (272, 277))	('Kras', 'Gene', (140, 144))	('Ptf1a', 'Gene', '19213', (28, 33))	('Ptf1a', 'Gene', (241, 246))	('Kras', 'Gene', (258, 262))
52994	26151762	Importantly, despite the earlier onset of PDAC in KPC mice with Ptf1a heterozygosity, once tumors arose they were histologically indistinguishable between genotypes (Figure 7E-H).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Ptf1a', 'Gene', '19213', (64, 69))	('Ptf1a', 'Gene', (64, 69))	('PDAC', 'Chemical', '-', (42, 46))	('PDAC', 'Disease', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('heterozygosity', 'Var', (70, 84))	('mice', 'Species', '10090', (54, 58))
52995	26151762	They contained classical features of human PDAC, including abundant fibrotic stroma surrounding CK19+ epithelial cells (Figure 7I,J) and substantial areas of necrosis.	('fibrotic stroma', 'Disease', 'None', (68, 83))	('fibrotic stroma', 'Disease', (68, 83))	('necrosis', 'Disease', (158, 166))	('PDAC', 'Disease', (43, 47))	('necrosis', 'Disease', 'MESH:D009336', (158, 166))	('necrosis', 'biological_process', 'GO:0070265', ('158', '166'))	('necrosis', 'biological_process', 'GO:0008219', ('158', '166'))	('necrosis', 'biological_process', 'GO:0019835', ('158', '166'))	('CK19+', 'Var', (96, 101))	('human', 'Species', '9606', (37, 42))	('PDAC', 'Chemical', '-', (43, 47))	('necrosis', 'biological_process', 'GO:0008220', ('158', '166'))	('necrosis', 'biological_process', 'GO:0001906', ('158', '166'))
52998	26151762	Here, we demonstrate that the loss of a principal regulator of acinar cell identity, PTF1A, is sufficient to prompt rapid and extensive acinar-to-ductal metaplasia even in the absence of other exocrine insults (Figure 4).	('metaplasia', 'Disease', 'MESH:D008679', (153, 163))	('PTF1A', 'Gene', (85, 90))	('metaplasia', 'Disease', (153, 163))	('prompt', 'PosReg', (109, 115))	('rat', 'Species', '10116', (16, 19))	('PTF1A', 'Gene', '19213', (85, 90))	('metaplasia', 'biological_process', 'GO:0036074', ('153', '163'))	('loss', 'Var', (30, 34))
53000	26151762	Deletion of Ptf1a alone at moderate frequency (~25%) did not produce detectable histological changes in the pancreas over the course of 2-6 weeks (Figure 3).	('rat', 'Species', '10116', (31, 34))	('Ptf1a', 'Gene', '19213', (12, 17))	('Ptf1a', 'Gene', (12, 17))	('Deletion', 'Var', (0, 8))
53001	26151762	By contrast, we observed rapid de-differentiation of Ptf1a cKO acinar cells generated under a high-TM dose regimen that produced >65% deletion (Figure 4).	('Ptf1a', 'Gene', '19213', (53, 58))	('Ptf1a', 'Gene', (53, 58))	('rat', 'Species', '10116', (80, 83))	('deletion', 'Var', (134, 142))	('TM', 'Chemical', 'MESH:D013629', (99, 101))	('de-differentiation', 'NegReg', (31, 49))
53005	26151762	However, with increasing TM-driven deletion, the fraction of Ptf1a WT acinar cells passes a tipping point, the community effect cannot be sustained, and ductal metaplasia is correspondingly rapid.	('Ptf1a', 'Gene', '19213', (61, 66))	('Ptf1a', 'Gene', (61, 66))	('metaplasia', 'Disease', 'MESH:D008679', (160, 170))	('metaplasia', 'Disease', (160, 170))	('metaplasia', 'biological_process', 'GO:0036074', ('160', '170'))	('deletion', 'Var', (35, 43))	('TM', 'Chemical', 'MESH:D013629', (25, 27))
53008	26151762	These resemble tubular complexes observed in human and mouse chronic pancreatitis, suggesting that dysregulation of PTF1A expression or function might be involved in the etiology of this disease and its well-known contribution to PDAC risk.	('PDAC', 'Chemical', '-', (230, 234))	('pancreatitis', 'Phenotype', 'HP:0001733', (69, 81))	('function', 'MPA', (136, 144))	('PTF1A', 'Gene', (116, 121))	('involved', 'Reg', (154, 162))	('dysregulation', 'Var', (99, 112))	('pancreatitis', 'Disease', (69, 81))	('human', 'Species', '9606', (45, 50))	('PTF1A', 'Gene', '19213', (116, 121))	('mouse', 'Species', '10090', (55, 60))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (61, 81))	('PDAC', 'Disease', (230, 234))	('pancreatitis', 'Disease', 'MESH:D010195', (69, 81))
53009	26151762	We additionally demonstrate that inflammation and loss of Ptf1a synergize to drive sustained activation of the MEK-ERK pathway, a major effector of oncogenic and endogenous KRAS.	('activation', 'PosReg', (93, 103))	('rat', 'Species', '10116', (23, 26))	('inflammation', 'Disease', 'MESH:D007249', (33, 45))	('Ptf1a', 'Gene', '19213', (58, 63))	('Ptf1a', 'Gene', (58, 63))	('loss', 'Var', (50, 54))	('inflammation', 'biological_process', 'GO:0006954', ('33', '45'))	('MEK-ERK pathway', 'Pathway', (111, 126))	('inflammation', 'Disease', (33, 45))	('ERK', 'molecular_function', 'GO:0004707', ('115', '118'))
53010	26151762	Going forward, it will interesting to test whether MEK inhibitors are able to prevent acinar cell reprogramming in the context of chronic pancreatitis and/or decrease the risk of chronic pancreatitis progressing to PDAC.	('pancreatitis', 'Disease', 'MESH:D010195', (138, 150))	('prevent', 'NegReg', (78, 85))	('pancreatitis', 'Phenotype', 'HP:0001733', (187, 199))	('PDAC', 'Disease', (215, 219))	('acinar cell reprogramming', 'CPA', (86, 111))	('pancreatitis', 'Disease', 'MESH:D010195', (187, 199))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (179, 199))	('MEK', 'Gene', (51, 54))	('pancreatitis', 'Disease', (138, 150))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (130, 150))	('pancreatitis', 'Disease', (187, 199))	('decrease', 'NegReg', (158, 166))	('inhibitors', 'Var', (55, 65))	('PDAC', 'Chemical', '-', (215, 219))	('pancreatitis', 'Phenotype', 'HP:0001733', (138, 150))
53011	26151762	Given the dramatic effects of Ptf1a deletion on transformation and inflammation, it will be important to determine which genes in our RNA-seq data set are directly suppressed or activated by PTF1A.	('PTF1A', 'Gene', (191, 196))	('deletion', 'Var', (36, 44))	('Ptf1a', 'Gene', '19213', (30, 35))	('Ptf1a', 'Gene', (30, 35))	('suppressed', 'NegReg', (164, 174))	('PTF1A', 'Gene', '19213', (191, 196))	('RNA', 'cellular_component', 'GO:0005562', ('134', '137'))	('inflammation', 'Disease', 'MESH:D007249', (67, 79))	('inflammation', 'biological_process', 'GO:0006954', ('67', '79'))	('activated', 'PosReg', (178, 187))	('effects', 'Reg', (19, 26))	('inflammation', 'Disease', (67, 79))
53015	26151762	It will also be useful to understand how KRAS, together with inflammatory and other insults, is capable of downregulating the expression and/or function of PTF1-network components during tumor initiation.	('PTF1-network', 'Gene', (156, 168))	('expression', 'MPA', (126, 136))	('tumor initiation', 'Disease', 'MESH:D009369', (187, 203))	('function', 'MPA', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('downregulating', 'NegReg', (107, 121))	('tumor initiation', 'Disease', (187, 203))	('KRAS', 'Var', (41, 45))	('PTF1', 'Species', '32651', (156, 160))
53016	26151762	Of note, recent studies indicate that oncogenic KRAS induces specific pathways dedicated to silencing tumor suppressor genes; a similar process may drive downregulation of Ptf1a and its partners during acinar cell reprogramming.	('KRAS', 'Var', (48, 52))	('tumor suppressor', 'biological_process', 'GO:0051726', ('102', '118'))	('downregulation', 'NegReg', (154, 168))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('102', '118'))	('Ptf1a', 'Gene', '19213', (172, 177))	('Ptf1a', 'Gene', (172, 177))	('silencing', 'MPA', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('induces', 'Reg', (53, 60))
53017	26151762	Because loss of Ptf1a strongly potentiated KRAS-mediated transformation (Figures 2, 3), we hypothesized that PTF1A inhibits KRAS-signaling activity in some capacity.	('Ptf1a', 'Gene', (16, 21))	('PTF1A', 'Gene', (109, 114))	('signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('PTF1A', 'Gene', '19213', (109, 114))	('loss', 'Var', (8, 12))	('inhibits', 'NegReg', (115, 123))	('potentiated', 'PosReg', (31, 42))	('KRAS-mediated transformation', 'CPA', (43, 71))	('KRAS-signaling activity', 'MPA', (124, 147))	('Ptf1a', 'Gene', '19213', (16, 21))
53018	26151762	Here, we demonstrate that loss of Ptf1a leads to upregulation of genes associated with KRAS-dependency in human cancer cells.	('human', 'Species', '9606', (106, 111))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('rat', 'Species', '10116', (16, 19))	('KRAS-dependency', 'Disease', 'MESH:D019966', (87, 102))	('Ptf1a', 'Gene', '19213', (34, 39))	('Ptf1a', 'Gene', (34, 39))	('KRAS-dependency', 'Disease', (87, 102))	('loss', 'Var', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('upregulation', 'PosReg', (49, 61))
53019	26151762	Future investigations should therefore move forward to test if different subtypes of human PDAC exhibit different extents of PTF1A repression, and whether variation in PTF1A expression within human PDAC correlates with KRAS-dependency or disease prognosis.	('PDAC', 'Chemical', '-', (91, 95))	('KRAS-dependency', 'Disease', (219, 234))	('human', 'Species', '9606', (192, 197))	('correlates', 'Reg', (203, 213))	('PTF1A', 'Gene', (168, 173))	('PTF1A', 'Gene', '19213', (168, 173))	('variation', 'Var', (155, 164))	('PTF1A', 'Gene', (125, 130))	('KRAS-dependency', 'Disease', 'MESH:D019966', (219, 234))	('PDAC', 'Chemical', '-', (198, 202))	('PTF1A', 'Gene', '19213', (125, 130))	('human', 'Species', '9606', (85, 90))
53024	26151762	The fact that removal of a single allele of Ptf1a accelerates mouse PDAC development (Figure 7D) suggests that even incomplete inhibition of human PTF1A could promote acinar transformation and subsequent tumorigenesis.	('accelerates', 'PosReg', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('rat', 'Species', '10116', (56, 59))	('Ptf1a', 'Gene', '19213', (44, 49))	('mouse', 'Species', '10090', (62, 67))	('Ptf1a', 'Gene', (44, 49))	('removal', 'Var', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('PTF1A', 'Gene', (147, 152))	('tumor', 'Disease', (204, 209))	('human', 'Species', '9606', (141, 146))	('mouse PDAC development', 'CPA', (62, 84))	('PTF1A', 'Gene', '19213', (147, 152))	('promote', 'PosReg', (159, 166))	('PDAC', 'Chemical', '-', (68, 72))	('acinar transformation', 'CPA', (167, 188))
53026	26151762	Additionally, our data suggest that PTF1A restoration may reduce inflammatory pathways that feed forward to synergize with oncogenic KRAS.	('PTF1A', 'Gene', (36, 41))	('restoration', 'Var', (42, 53))	('PTF1A', 'Gene', '19213', (36, 41))	('rat', 'Species', '10116', (47, 50))	('reduce', 'NegReg', (58, 64))	('inflammatory pathways', 'Pathway', (65, 86))
53033	26151762	The mouse PanIN-PDAC model provides a new experimental system to relate genetic changes in cancer, such as KRAS mutation, to epigenetic changes such as PTF1A downregulation.	('mouse', 'Species', '10090', (4, 9))	('PTF1A', 'Gene', '19213', (152, 157))	('mutation', 'Var', (112, 120))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('downregulation', 'NegReg', (158, 172))	('PTF1A', 'Gene', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('PDAC', 'Chemical', '-', (16, 20))	('KRAS', 'Disease', (107, 111))
53035	26151762	Experimental mice of the following genotypes have been previously described: Ptf1aCreERT (Ptf1atm2(cre/ESR1)Cvw), Pdx1-Cre (Tg(Pdx1-cre)89.1Dam), KrasLSL-G12D (Krastm4Tyj), p53lox (Trp53tm1Brn), and R26REYFP (Gt(ROSA)26Sortm1(EYFP)Cos).	('mice', 'Species', '10090', (13, 17))	('R26REYFP', 'Var', (199, 207))	('p53', 'Gene', '22059', (173, 176))	('Trp53', 'Gene', '22059', (181, 186))	('Pdx1', 'Gene', '18609', (114, 118))	('Ptf1a', 'Gene', '19213', (90, 95))	('G12D', 'Mutation', 'rs121913529', (154, 158))	('Kras', 'Gene', (160, 164))	('Kras', 'Gene', '16653', (146, 150))	('Pdx1', 'Gene', '18609', (127, 131))	('Trp53', 'Gene', (181, 186))	('p53', 'Gene', (183, 186))	('Pdx1', 'Gene', (114, 118))	('Pdx1', 'Gene', (127, 131))	('Kras', 'Gene', '16653', (160, 164))	('Ptf1a', 'Gene', (77, 82))	('p53', 'Gene', (173, 176))	('Ptf1a', 'Gene', '19213', (77, 82))	('p53', 'Gene', '22059', (183, 186))	('Ptf1a', 'Gene', (90, 95))	('Kras', 'Gene', (146, 150))
53061	26151762	Using ImageJ software (NIH), cells co-expressing EYFP with the acinar differentiation markers Amylase or CPA1 were detected by additive image overlay of their staining with DAPI and anti-GFP, and counted using the Analyze Particles function, as described previously.	('CPA1', 'Gene', (105, 109))	('EYFP', 'Var', (49, 53))	('DAPI', 'Chemical', 'MESH:C007293', (173, 177))	('CPA1', 'Gene', '100351403', (105, 109))
53070	26151762	To identify regulatory pathways altered upon Ptf1a deletion, significantly increased and decreased genes were analyzed by IPA (QIAGEN, Redwood City, CA, www.ingenuity.com) at expression thresholds of 1.5-, 2.0,- and 3.0-fold (Supplementary files 3-5).	('Redwood', 'Species', '28980', (135, 142))	('altered', 'Reg', (32, 39))	('Ptf1a', 'Gene', '19213', (45, 50))	('Ptf1a', 'Gene', (45, 50))	('deletion', 'Var', (51, 59))
53084	26151762	Intriguingly, loss of Ptf1a facilitates the onset of acinar-ductal metaplasia (ADM), and the onset of KRAS-driven pancreatic carcinogenesis.	('Ptf1a', 'Gene', '19213', (22, 27))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (114, 139))	('Ptf1a', 'Gene', (22, 27))	('loss', 'Var', (14, 18))	('acinar-ductal metaplasia', 'Disease', (53, 77))	('metaplasia', 'biological_process', 'GO:0036074', ('67', '77'))	('facilitates', 'PosReg', (28, 39))	('KRAS-driven', 'CPA', (102, 113))	('pancreatic carcinogenesis', 'Disease', (114, 139))	('acinar-ductal metaplasia', 'Disease', 'MESH:D008679', (53, 77))
53089	26151762	The authors note that recombination in 15-20% of acinar cells is not sufficient to induce ADM, but recombination in a higher percentage of cells does indeed induce ADM, and interpret these findings as a "field" effect, or, in other words, a non-cell autonomous effect of Ptf1 loss.	('induce', 'Reg', (157, 163))	('Ptf1', 'Gene', (271, 275))	('Ptf1', 'Species', '32651', (271, 275))	('loss', 'NegReg', (276, 280))	('ADM', 'MPA', (164, 167))	('recombination', 'Var', (99, 112))
53094	26151762	2) High level-tamoxifen induces ADM while low-level tamoxifen does not.	('induces', 'Reg', (24, 31))	('ADM', 'Disease', (32, 35))	('tamoxifen', 'Chemical', 'MESH:D013629', (14, 23))	('tamoxifen', 'Chemical', 'MESH:D013629', (52, 61))	('High level-tamoxifen', 'Var', (3, 23))
53113	26151762	Importantly, in both low- and high-dose TM conditions, the majority of EYFP+ cells had lost Ptf1a protein expression (~75% with low-dose, ~90% with high-dose).	('Ptf1a', 'Gene', '19213', (92, 97))	('Ptf1a', 'Gene', (92, 97))	('TM', 'Chemical', 'MESH:D013629', (40, 42))	('lost', 'NegReg', (87, 91))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('EYFP+', 'Var', (71, 76))	('protein', 'Protein', (98, 105))
53114	26151762	Therefore, EYFP induction does represent a reasonable surrogate for Ptf1a deletion (if anything, it may underestimate the extent of Ptf1a deletion), and the lack of ADM within EYFP+ cells following low-dose TM is very unlikely to represent a non-deleted Ptf1a allele in EYFP+ cells.	('deletion', 'Var', (74, 82))	('Ptf1a', 'Gene', '19213', (68, 73))	('TM', 'Chemical', 'MESH:D013629', (207, 209))	('Ptf1a', 'Gene', (68, 73))	('lack', 'Var', (157, 161))	('Ptf1a', 'Gene', '19213', (254, 259))	('Ptf1a', 'Gene', (254, 259))	('Ptf1a', 'Gene', '19213', (132, 137))	('Ptf1a', 'Gene', (132, 137))
53115	26151762	Instead, we infer that ADM requires a non-cell- autonomous effect produced by widespread Ptf1a deletion, consistent with some sort of "field" effect.	('Ptf1a', 'Gene', (89, 94))	('ADM', 'Disease', (23, 26))	('deletion', 'Var', (95, 103))	('Ptf1a', 'Gene', '19213', (89, 94))
53119	26151762	We found that pancreata of mice receiving either high-dose corn oil or high-dose TM were indistinguishable from untreated controls, in terms of overall histology as well as frequency of infiltrating CD45+ leukocytes.	('mice', 'Species', '10090', (27, 31))	('rat', 'Species', '10116', (192, 195))	('TM', 'Chemical', 'MESH:D013629', (81, 83))	('corn', 'Species', '4577', (59, 63))	('high-dose TM', 'Var', (71, 83))	('CD45', 'Gene', (199, 203))	('CD45', 'Gene', '19264', (199, 203))
53121	26151762	We therefore conclude that high dose TM treatment alone does not induce pancreatic inflammation, suggesting that the ADM observed upon widespread Ptf1a deletion is unlikely to be caused by tamoxifen delivery itself.	('deletion', 'Var', (152, 160))	('TM', 'Chemical', 'MESH:D013629', (37, 39))	('ADM', 'Disease', (117, 120))	('pancreatic inflammation', 'Phenotype', 'HP:0001733', (72, 95))	('tamoxifen', 'Chemical', 'MESH:D013629', (189, 198))	('pancreatic inflammation', 'Disease', 'MESH:D007249', (72, 95))	('inflammation', 'biological_process', 'GO:0006954', ('83', '95'))	('Ptf1a', 'Gene', '19213', (146, 151))	('Ptf1a', 'Gene', (146, 151))	('pancreatic inflammation', 'Disease', (72, 95))
53122	26151762	We prepared acinar cell cultures from mice of the following genotypes: control, KrasG12D, Ptf1a cKO, and Ptf1a cKO; KrasG12D.	('Ptf1a', 'Gene', '19213', (105, 110))	('mice', 'Species', '10090', (38, 42))	('Ptf1a', 'Gene', (105, 110))	('Ptf1a', 'Gene', '19213', (90, 95))	('Ptf1a', 'Gene', (90, 95))	('KrasG12D', 'Var', (116, 124))
53123	26151762	Acinar clusters under the influence of KrasG12D or EGFR signaling have been previously shown to undergo metaplasia into ductal cysts, and we therefore used KrasG12D pancreata as a baseline to assess metaplasia.	('metaplasia', 'biological_process', 'GO:0036074', ('199', '209'))	('metaplasia', 'Disease', (104, 114))	('metaplasia', 'biological_process', 'GO:0036074', ('104', '114'))	('EGFR signaling', 'Gene', (51, 65))	('metaplasia', 'Disease', 'MESH:D008679', (199, 209))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('KrasG12D', 'Var', (156, 164))	('metaplasia', 'Disease', (199, 209))	('metaplasia', 'Disease', 'MESH:D008679', (104, 114))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))
53124	26151762	While Ptf1a cKO pancreata did not robustly form metaplastic spherules in this assay, in the absence of added TGFalpha, both KrasG12D and Ptf1a cKO; KrasG12D acinar clusters formed robust cysts without added growth factors.	('Ptf1a', 'Gene', '19213', (6, 11))	('Ptf1a', 'Gene', (6, 11))	('KrasG12D', 'Var', (124, 132))	('Ptf1a', 'Gene', '19213', (137, 142))	('Ptf1a', 'Gene', (137, 142))
53125	26151762	Importantly, the cysts from Ptf1a cKO; KrasG12D were significantly larger than those derived from Kras G12D pancreata (Figure 3-figure supplement 2) .	('G12D', 'Var', (43, 47))	('larger', 'PosReg', (67, 73))	('G12D', 'SUBSTITUTION', 'None', (103, 107))	('Ptf1a', 'Gene', '19213', (28, 33))	('Ptf1a', 'Gene', (28, 33))	('cysts', 'CPA', (17, 22))	('G12D', 'Var', (103, 107))	('G12D', 'SUBSTITUTION', 'None', (43, 47))
53126	26151762	Importantly, these results suggest that loss of Ptf1a has a direct effect on the ability of KrasG12D to transform acinar cells, independent of inflammation (Figure 6) and other non-cell autonomous pathways (Figure 5).	('Ptf1a', 'Gene', '19213', (48, 53))	('Ptf1a', 'Gene', (48, 53))	('loss', 'Var', (40, 44))	('inflammation', 'Disease', 'MESH:D007249', (143, 155))	('inflammation', 'Disease', (143, 155))	('transform', 'Reg', (104, 113))	('inflammation', 'biological_process', 'GO:0006954', ('143', '155'))
53128	26151762	Based on phospho-ERK immunostaining, we observe MAPK activation specifically in the ductal lesions of caerulein-treated Ptf1a cKO mice, but not in the normal acini of saline-treated cKO mice (nor in control mice, regardless of treatment).	('MAPK', 'molecular_function', 'GO:0004707', ('48', '52'))	('caerulein-treated', 'Var', (102, 119))	('mice', 'Species', '10090', (130, 134))	('activation', 'PosReg', (53, 63))	('Ptf1a', 'Gene', '19213', (120, 125))	('caerulein', 'Chemical', 'MESH:D002108', (102, 111))	('Ptf1a', 'Gene', (120, 125))	('MAPK activation', 'biological_process', 'GO:0000187', ('48', '63'))	('ERK', 'molecular_function', 'GO:0004707', ('17', '20'))	('MAPK', 'Gene', (48, 52))	('mice', 'Species', '10090', (207, 211))	('mice', 'Species', '10090', (186, 190))	('ductal lesions', 'Disease', (84, 98))	('cKO', 'Var', (126, 129))	('saline', 'Chemical', 'MESH:D012965', (167, 173))
53130	26151762	Our SMA staining data suggest that the stromal reaction observed after only two weeks of simultaneous Ptf1a deletion and KRASG12D activation is a response to lesion formation, rather than a reaction to Ptf1a deletion itself.	('SMA', 'Gene', (4, 7))	('rat', 'Species', '10116', (176, 179))	('Ptf1a', 'Gene', '19213', (102, 107))	('Ptf1a', 'Gene', (102, 107))	('formation', 'biological_process', 'GO:0009058', ('165', '174'))	('stromal reaction', 'CPA', (39, 55))	('lesion', 'MPA', (158, 164))	('Ptf1a', 'Gene', '19213', (202, 207))	('Ptf1a', 'Gene', (202, 207))	('SMA', 'Gene', '20589', (4, 7))	('deletion', 'Var', (108, 116))
53131	26151762	We also observe local SMA staining around lesions in mice with oncogenic KRASG12D alone, suggesting that this is not a specific reaction to Ptf1a loss, per se, but to PanIN formation.	('loss', 'NegReg', (146, 150))	('Ptf1a', 'Gene', '19213', (140, 145))	('Ptf1a', 'Gene', (140, 145))	('SMA', 'Gene', '20589', (22, 25))	('SMA', 'Gene', (22, 25))	('formation', 'biological_process', 'GO:0009058', ('173', '182'))	('KRASG12D', 'Var', (73, 81))	('mice', 'Species', '10090', (53, 57))
53132	26151762	Nonetheless, our gene expression profiling provides evidence that stellate cell signaling is upregulated in response to Ptf1a deletion (Figure 5C), suggesting that Ptf1a deletion results in a priming signal to stellate cells that enhances their activation when other insults, such as KRASG12D activation, drive acinar cell transformation.	('gene expression', 'biological_process', 'GO:0010467', ('17', '32'))	('Ptf1a', 'Gene', '19213', (120, 125))	('Ptf1a', 'Gene', (120, 125))	('priming signal', 'MPA', (192, 206))	('Ptf1a', 'Gene', '19213', (164, 169))	('Ptf1a', 'Gene', (164, 169))	('activation', 'MPA', (245, 255))	('deletion', 'Var', (126, 134))	('enhances', 'PosReg', (230, 238))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))	('acinar cell transformation', 'CPA', (311, 337))	('deletion', 'Var', (170, 178))
53134	26151762	This is an important concern, given that gene expression profiling suggests upregulation of fibro-inflammatory pathways upon Ptf1a deletion (Figure 5).	('upregulation', 'PosReg', (76, 88))	('gene expression', 'biological_process', 'GO:0010467', ('41', '56'))	('fibro-inflammatory pathways', 'Pathway', (92, 119))	('Ptf1a', 'Gene', '19213', (125, 130))	('Ptf1a', 'Gene', (125, 130))	('deletion', 'Var', (131, 139))
53138	26151762	However, we conclude that the loss of Ptf1a does not confer a full-blown pancreatitis phenotype, but instead creates the potential for locally-enhanced inflammation (which is dramatically realized upon caerulein treatment).	('pancreatitis', 'Disease', 'MESH:D010195', (73, 85))	('inflammation', 'Disease', 'MESH:D007249', (152, 164))	('creates', 'Reg', (109, 116))	('inflammation', 'Disease', (152, 164))	('Ptf1a', 'Gene', '19213', (38, 43))	('Ptf1a', 'Gene', (38, 43))	('pancreatitis', 'Disease', (73, 85))	('locally-enhanced', 'MPA', (135, 151))	('inflammation', 'biological_process', 'GO:0006954', ('152', '164'))	('caerulein', 'Chemical', 'MESH:D002108', (202, 211))	('loss', 'Var', (30, 34))	('pancreatitis', 'Phenotype', 'HP:0001733', (73, 85))	('locally-enhanced', 'PosReg', (135, 151))
53140	26151762	Altogether, our results suggest that widespread Ptf1a deletion is accompanied by both transdifferentiation and proliferation.	('transdifferentiation', 'biological_process', 'GO:0060290', ('86', '106'))	('rat', 'Species', '10116', (118, 121))	('deletion', 'Var', (54, 62))	('Ptf1a', 'Gene', '19213', (48, 53))	('Ptf1a', 'Gene', (48, 53))
53151	24977113	Dozens of preclinical studies nearly uniformly demonstrate that inhibition of VEGF-A or its receptors potentiates the effects of radiation therapy against solid tumors, and this potentiation is generally independent of the type or schedule of radiation and timing of VEGF-A inhibitor delivery.	('VEGF-A', 'Gene', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('solid tumors', 'Disease', (155, 167))	('inhibition', 'Var', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('potentiates', 'PosReg', (102, 113))	('effects', 'MPA', (118, 125))	('solid tumors', 'Disease', 'MESH:D009369', (155, 167))
53174	24977113	Cells may respond to DNA damage by initiating apoptosis within hours of radiation injury, or DNA damage may lead to death through abnormal chromosomal segregation during mitosis.	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('apoptosis', 'CPA', (46, 55))	('radiation injury', 'Disease', (72, 88))	('mitosis', 'Disease', (170, 177))	('mitosis', 'Disease', 'None', (170, 177))	('radiation injury', 'Disease', 'MESH:D011832', (72, 88))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('mitosis', 'biological_process', 'GO:0000278', ('170', '177'))	('initiating', 'Reg', (35, 45))	('damage', 'Var', (97, 103))	('abnormal chromosomal segregation', 'Phenotype', 'HP:0002916', (130, 162))	('lead to', 'Reg', (108, 115))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('abnormal chromosomal segregation', 'CPA', (130, 162))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('death', 'CPA', (116, 121))
53176	24977113	Dysfunction of p53 related machinery prevents cells from initiating rapid apoptotic death in response to radiation, and predisposes to premature entry into M phase, before DNA damage is repaired.	('Dysfunction', 'Var', (0, 11))	('prevents', 'NegReg', (37, 45))	('M phase', 'biological_process', 'GO:0000279', ('156', '163'))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('rapid apoptotic death', 'MPA', (68, 89))	('premature entry', 'MPA', (135, 150))	('response to radiation', 'biological_process', 'GO:0009314', ('93', '114'))
53226	24977113	One possible mechanism is via the stabilization of HIF-1alpha and the subsequent expression of genes that promote invasion, including c-MET.	('c-MET', 'Gene', '4233', (134, 139))	('HIF-1alpha', 'Gene', (51, 61))	('stabilization', 'Var', (34, 47))	('c-MET', 'Gene', (134, 139))	('HIF-1alpha', 'Gene', '3091', (51, 61))	('expression', 'MPA', (81, 91))
53230	24977113	It is important to note that the vast majority of cancer patients treated with VEGF-A inhibitors have established metastatic disease and relatively few studies have examined the use of VEGF-A inhibitors in patients with primary tumors and no clinically evident metastases.	('metastases', 'Disease', (261, 271))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('patients', 'Species', '9606', (57, 65))	('primary tumors', 'Disease', (220, 234))	('metastases', 'Disease', 'MESH:D009362', (261, 271))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('patients', 'Species', '9606', (206, 214))	('VEGF-A', 'Gene', (79, 85))	('primary tumors', 'Disease', 'MESH:D009369', (220, 234))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('inhibitors', 'Var', (86, 96))	('metastatic disease', 'CPA', (114, 132))
53231	24977113	For anti-angiogenic agents to be more broadly used in the neoadjuvant setting with radiation or chemoradiation, it is vital to determine under what circumstances VEGF-A inhibitors may increase the invasiveness and metastatic potential of primary tumors.	('increase', 'PosReg', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('primary tumors', 'Disease', (238, 252))	('VEGF-A', 'Gene', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('invasiveness', 'Disease', 'MESH:D009362', (197, 209))	('invasiveness', 'Disease', (197, 209))	('primary tumors', 'Disease', 'MESH:D009369', (238, 252))	('inhibitors', 'Var', (169, 179))
53233	24977113	These studies examine several different agents including neutralizing antibodies to VEGF-A, neutralizing antibodies to VEGF receptors, and small molecule inhibitors of angiogenic factor signaling.	('VEGF', 'Gene', '7422', (119, 123))	('neutralizing', 'Var', (92, 104))	('neutralizing', 'Var', (57, 69))	('signaling', 'biological_process', 'GO:0023052', ('186', '195'))	('VEGF', 'Gene', (84, 88))	('VEGF', 'Gene', (119, 123))	('VEGF', 'Gene', '7422', (84, 88))
53236	24977113	As one example, DC101 increased hypoxia in mammary carcinoma xenografts, but produced a window of decreased hypoxia in orthotopic gliomas.	('DC101', 'Var', (16, 21))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('hypoxia', 'Disease', 'MESH:D000860', (108, 115))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('hypoxia', 'Disease', 'MESH:D000860', (32, 39))	('increased', 'PosReg', (22, 31))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (43, 60))	('carcinoma xenografts', 'Disease', (51, 71))	('carcinoma xenografts', 'Disease', 'MESH:D002277', (51, 71))	('hypoxia', 'Disease', (108, 115))	('decreased', 'NegReg', (98, 107))	('hypoxia', 'Disease', (32, 39))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
53244	24977113	Neutralization of VEGF-A reduces these abnormalities in preclinical tumor models.	('tumor', 'Disease', (68, 73))	('reduces', 'NegReg', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('Neutralization', 'Var', (0, 14))	('VEGF-A', 'Gene', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
53255	24977113	A combination of anti-VEGF-A antibody and radiation shown to work on tumors in control mice had no effect on tumors in mice unable to generate ceramide through both genetic and antibody-based manipulation.	('antibody', 'molecular_function', 'GO:0003823', ('177', '185'))	('antibody', 'cellular_component', 'GO:0019815', ('29', '37'))	('antibody', 'cellular_component', 'GO:0042571', ('177', '185'))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('antibody', 'cellular_component', 'GO:0019814', ('29', '37'))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('antibody', 'cellular_component', 'GO:0019815', ('177', '185'))	('tumors', 'Disease', (109, 115))	('ceramide', 'Chemical', 'MESH:D002518', (143, 151))	('anti-VEGF-A antibody', 'Var', (17, 37))	('tumors', 'Disease', (69, 75))	('antibody', 'molecular_function', 'GO:0003823', ('29', '37'))	('antibody', 'cellular_component', 'GO:0019814', ('177', '185'))	('mice', 'Species', '10090', (119, 123))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('antibody', 'cellular_component', 'GO:0042571', ('29', '37'))	('antibody', 'Var', (29, 37))	('mice', 'Species', '10090', (87, 91))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
53397	24293293	When three outliers were excluded, there was an average of 64 somatic mutations per tumor (range 12-189).	('somatic mutations', 'Var', (62, 79))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))
53399	24293293	Genes altered in other neoplasms of the pancreas were occasionally targeted in carcinomas with acinar differentiation; SMAD4 was mutated in six tumors (26%), TP53 in three (13%), GNAS in two (9%), RNF43 in one (4%) and MEN1 in one tumor (4%).	('tumors', 'Disease', (144, 150))	('TP53', 'Gene', (158, 162))	('neoplasms of the pancreas', 'Phenotype', 'HP:0002894', (23, 48))	('SMAD4', 'Gene', (119, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('carcinomas', 'Disease', 'MESH:D002277', (79, 89))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('RNF43', 'Gene', '54894', (197, 202))	('tumor', 'Disease', (231, 236))	('neoplasms of the pancreas', 'Disease', 'MESH:D010190', (23, 48))	('TP53', 'Gene', '7157', (158, 162))	('SMAD4', 'Gene', '4089', (119, 124))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('MEN1', 'Gene', '4221', (219, 223))	('GNAS', 'Gene', (179, 183))	('neoplasms of the pancreas', 'Disease', (23, 48))	('RNF43', 'Gene', (197, 202))	('mutated', 'Var', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('GNAS', 'Gene', '2778', (179, 183))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('MEN1', 'Gene', (219, 223))	('carcinomas', 'Disease', (79, 89))	('neoplasms', 'Phenotype', 'HP:0002664', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('neoplasm', 'Phenotype', 'HP:0002664', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
53400	24293293	Somatic mutations were identified in genes in which constitutional alterations are associated with familial pancreatic ductal adenocarcinoma, such as ATM, BRCA2, and PALB2 (one tumor each), as well as in genes altered in extra-pancreatic neoplasms, such as JAK1 in four tumors (17%) BRAF in three (13%), RB1 in three (13%), APC in two (9%), PTEN in two (9%), ARID1A in two (9%), MLL3 in two (9%), and BAP1 in one (4%).	('PTEN', 'Gene', '5728', (341, 345))	('BRCA2', 'Gene', '675', (155, 160))	('alterations', 'Var', (67, 78))	('pancreatic neoplasms', 'Disease', 'MESH:D010190', (227, 247))	('MLL3', 'Gene', '58508', (379, 383))	('APC', 'Disease', 'MESH:D011125', (324, 327))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('ARID1A', 'Gene', (359, 365))	('JAK1', 'Gene', '3716', (257, 261))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('APC', 'Disease', (324, 327))	('PALB2', 'Gene', '79728', (166, 171))	('pancreatic neoplasms', 'Disease', (227, 247))	('tumors', 'Disease', (270, 276))	('ATM', 'Gene', (150, 153))	('ARID1A', 'Gene', '8289', (359, 365))	('APC', 'cellular_component', 'GO:0005680', ('324', '327'))	('BAP1', 'Gene', '8314', (401, 405))	('tumor', 'Disease', (177, 182))	('MLL3', 'Gene', (379, 383))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('familial pancreatic ductal adenocarcinoma', 'Disease', (99, 140))	('JAK', 'molecular_function', 'GO:0004713', ('257', '260'))	('BRAF', 'Gene', (283, 287))	('BRAF', 'Gene', '673', (283, 287))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('neoplasm', 'Phenotype', 'HP:0002664', (238, 246))	('JAK1', 'Gene', (257, 261))	('RB1', 'Gene', (304, 307))	('tumor', 'Disease', (270, 275))	('familial pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (99, 140))	('BRCA2', 'Gene', (155, 160))	('pancreatic neoplasms', 'Phenotype', 'HP:0002894', (227, 247))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (108, 140))	('PTEN', 'Gene', (341, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('BAP1', 'Gene', (401, 405))	('neoplasms', 'Phenotype', 'HP:0002664', (238, 247))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('associated', 'Reg', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('ATM', 'Gene', '472', (150, 153))	('RB1', 'Gene', '5925', (304, 307))	('PALB2', 'Gene', (166, 171))	('pancreatic neoplasm', 'Phenotype', 'HP:0002894', (227, 246))
53401	24293293	Perhaps most importantly, we found that more than a third of these carcinomas have potentially targetable genetic alterations including mutations in BRCA2, PALB2, ATM, BAP1, BRAF and JAK1.	('JAK1', 'Gene', '3716', (183, 187))	('BAP1', 'Gene', '8314', (168, 172))	('BRCA2', 'Gene', (149, 154))	('PALB2', 'Gene', '79728', (156, 161))	('JAK', 'molecular_function', 'GO:0004713', ('183', '186'))	('ATM', 'Gene', '472', (163, 166))	('PALB2', 'Gene', (156, 161))	('BRAF', 'Gene', '673', (174, 178))	('BAP1', 'Gene', (168, 172))	('carcinomas', 'Disease', 'MESH:D002277', (67, 77))	('BRCA2', 'Gene', '675', (149, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('BRAF', 'Gene', (174, 178))	('carcinomas', 'Disease', (67, 77))	('mutations', 'Var', (136, 145))	('JAK1', 'Gene', (183, 187))	('ATM', 'Gene', (163, 166))
53415	24293293	In addition, microsatellite instability has been identified in a small subset of acinar cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('identified', 'Reg', (49, 59))	('acinar cell carcinomas', 'Disease', (81, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (81, 103))	('microsatellite instability', 'Var', (13, 39))
53416	24293293	At the individual gene level, alterations in genes coding for members of the APC/beta (beta)-catenin pathway have been identified in 20-25% of acinar cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (143, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('alterations', 'Var', (30, 41))	('acinar cell carcinomas', 'Disease', (143, 165))	('APC/beta (beta)-catenin', 'Gene', (77, 100))	('APC/beta (beta)-catenin', 'Gene', '1499', (77, 100))	('APC', 'cellular_component', 'GO:0005680', ('77', '80'))	('identified', 'Reg', (119, 129))
53417	24293293	These included inactivating mutations in APC as well as activating mutations in CTNNB1.	('activating mutations', 'Var', (56, 76))	('CTNNB1', 'Gene', '1499', (80, 86))	('APC', 'Disease', 'MESH:D011125', (41, 44))	('inactivating mutations', 'Var', (15, 37))	('APC', 'Disease', (41, 44))	('APC', 'cellular_component', 'GO:0005680', ('41', '44'))	('CTNNB1', 'Gene', (80, 86))
53419	24293293	Only rare mutations in KRAS and TP53, and only rare loss of Smad4 protein expression have been reported in acinar cell carcinomas.	('expression', 'MPA', (74, 84))	('loss', 'NegReg', (52, 56))	('protein', 'Protein', (66, 73))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (107, 129))	('TP53', 'Gene', '7157', (32, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('KRAS', 'Gene', (23, 27))	('Smad4', 'Gene', '4089', (60, 65))	('acinar cell carcinomas', 'Disease', (107, 129))	('TP53', 'Gene', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('Smad4', 'Gene', (60, 65))	('reported', 'Reg', (95, 103))	('mutations', 'Var', (10, 19))	('KRAS', 'Gene', '3845', (23, 27))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
53422	24293293	The majority of pancreatoblastomas have somatic alterations in the APC/beta (beta)-catenin pathway, including inactivating mutations in APC and activating mutations in CTNNB1.	('APC', 'Disease', (67, 70))	('pancreatoblastomas', 'Disease', 'MESH:C537162', (16, 34))	('alterations', 'Reg', (48, 59))	('APC/beta (beta)-catenin', 'Gene', '1499', (67, 90))	('pancreatoblastoma', 'Phenotype', 'HP:0100757', (16, 33))	('APC', 'Disease', 'MESH:D011125', (136, 139))	('CTNNB1', 'Gene', (168, 174))	('pancreatoblastomas', 'Disease', (16, 34))	('inactivating mutations', 'Var', (110, 132))	('APC', 'cellular_component', 'GO:0005680', ('67', '70'))	('APC', 'Disease', (136, 139))	('APC/beta (beta)-catenin', 'Gene', (67, 90))	('APC', 'cellular_component', 'GO:0005680', ('136', '139'))	('CTNNB1', 'Gene', '1499', (168, 174))	('APC', 'Disease', 'MESH:D011125', (67, 70))	('activating', 'Reg', (144, 154))
53423	24293293	Loss of chromosome 11p also occurs frequently in pancreatoblastomas.	('pancreatoblastoma', 'Phenotype', 'HP:0100757', (49, 66))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('pancreatoblastomas', 'Disease', 'MESH:C537162', (49, 67))	('Loss', 'Var', (0, 4))	('pancreatoblastomas', 'Disease', (49, 67))
53439	24293293	One sample (ACINAR28) was tested with additional mononucleotide repeat loci, including BAT-40, NR-22, NR-27 and CAT-25 as previously reported.	('CAT-25', 'Gene', (112, 118))	('BAT-40', 'Gene', (87, 93))	('NR-22', 'Gene', (95, 100))	('NR-27', 'Gene', (102, 107))	('NR-22', 'CellLine', 'CVCL:6689', (95, 100))	('mononucleotide', 'Chemical', '-', (49, 63))	('NR-27', 'CellLine', 'CVCL:6689', (102, 107))	('CAT', 'molecular_function', 'GO:0004096', ('112', '115'))	('mononucleotide repeat', 'Var', (49, 70))
53445	24293293	The proximal probes for chromosome 15 were BACs RP11-294O11 and RP11-562A8 (band 15q21.2), and the distal probes were CTD-2071N1 and RP11-285A1 (band 15q24.3-25.1).	('RP11', 'Gene', (48, 52))	('chromosome', 'cellular_component', 'GO:0005694', ('24', '34'))	('RP11', 'Gene', '26121', (48, 52))	('BACs', 'Var', (43, 47))	('RP11', 'Gene', (64, 68))	('RP11', 'Gene', (133, 137))	('RP11', 'Gene', '26121', (133, 137))	('RP11', 'Gene', '26121', (64, 68))
53459	24293293	These carcinomas had a mean of 119 non-synonymous somatic mutations.	('non-synonymous', 'Var', (35, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (6, 16))	('carcinomas', 'Disease', 'MESH:D002277', (6, 16))	('carcinomas', 'Disease', (6, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (6, 15))
53465	24293293	This number is higher than the average number of mutations in pancreatic ductal adenocarcinoma and other primary pancreatic neoplasms but not higher than the average number of mutations in other solid tumors such as colorectal and breast cancers.	('neoplasm', 'Phenotype', 'HP:0002664', (124, 132))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))	('pancreatic neoplasms', 'Disease', 'MESH:D010190', (113, 133))	('neoplasms', 'Phenotype', 'HP:0002664', (124, 133))	('mutations', 'Var', (49, 58))	('solid tumors', 'Disease', (195, 207))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('pancreatic neoplasms', 'Disease', (113, 133))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (62, 94))	('pancreatic neoplasm', 'Phenotype', 'HP:0002894', (113, 132))	('pancreatic ductal adenocarcinoma', 'Disease', (62, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('solid tumors', 'Disease', 'MESH:D009369', (195, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('colorectal and breast cancers', 'Disease', 'MESH:D015179', (216, 245))	('pancreatic neoplasms', 'Phenotype', 'HP:0002894', (113, 133))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (62, 94))	('breast cancers', 'Phenotype', 'HP:0003002', (231, 245))
53466	24293293	All of the carcinomas were enriched for C:G-to-T:A transitions (35% of mutations in remaining 20 carcinomas after the 3 outliers were excluded), and this enrichment was even more striking in the carcinomas with microsatellite instability, with C:G-to-T:A transitions accounting for 63% and 54% mutations in these two samples (ACINAR01 and ACINAR03).	('carcinomas', 'Disease', (195, 205))	('carcinomas', 'Disease', 'MESH:D002277', (11, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('carcinomas', 'Disease', (11, 21))	('C:G-to-T', 'Var', (40, 48))	('mutations', 'Var', (71, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('carcinomas', 'Disease', (97, 107))	('men', 'Species', '9606', (160, 163))	('carcinomas', 'Disease', 'MESH:D002277', (97, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('carcinomas', 'Phenotype', 'HP:0030731', (195, 205))	('carcinomas', 'Disease', 'MESH:D002277', (195, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))
53467	24293293	As expected, the carcinomas with microsatellite instability were also enriched for single base deletions, accounting for 14% and 18% of mutations in these two samples (ACINAR01 and ACINAR03), compared to 4% of the remaining 20 samples.	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('carcinomas', 'Disease', (17, 27))	('carcinomas', 'Disease', 'MESH:D002277', (17, 27))	('microsatellite instability', 'Var', (33, 59))	('mutations', 'Var', (136, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('single base deletions', 'Var', (83, 104))
53479	24293293	Remarkably, three (ACINAR06, ACINAR07, and ACINAR15) of the seven carcinomas analyzed showed dramatic intratumoral heterogeneity and polysomy in five of six regions assayed (Figure 1).	('ACINAR15', 'Var', (43, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('carcinomas', 'Disease', (66, 76))	('tumor', 'Disease', (107, 112))	('carcinomas', 'Disease', 'MESH:D002277', (66, 76))	('ACINAR07', 'Var', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('ACINAR06', 'Var', (19, 27))
53482	24293293	For this purpose, we reviewed our whole exome sequencing data to identify somatic mutations in genes known to cause base pair and chromosomal instability in other tumor types.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('mutations', 'Var', (82, 91))	('tumor', 'Disease', (163, 168))	('chromosomal instability', 'Phenotype', 'HP:0040012', (130, 153))
53483	24293293	One of the acinar cell carcinomas with microsatellite instability (ACINAR01) contained a somatic mutation in MSH2, a gene whose constitutional alteration causes Lynch syndrome (also known as hereditary non-polyposis colon cancer or HNPCC), an inherited cancer predisposition syndrome caused by mutations in DNA mismatch repair genes.	('Lynch syndrome', 'Disease', 'MESH:D003123', (161, 175))	('colon cancer', 'Phenotype', 'HP:0003003', (216, 228))	('inherited cancer predisposition syndrome', 'Disease', (243, 283))	('hereditary non-polyposis colon cancer', 'Phenotype', 'HP:0006716', (191, 228))	('MSH2', 'Gene', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('HNPCC', 'Disease', 'None', (232, 237))	('HNPCC', 'Disease', (232, 237))	('acinar cell carcinomas', 'Disease', (11, 33))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('mutation', 'Var', (97, 105))	('MSH2', 'Gene', '4436', (109, 113))	('mismatch repair', 'biological_process', 'GO:0006298', ('311', '326'))	('non-polyposis colon cancer', 'Disease', 'MESH:D015179', (202, 228))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('Lynch syndrome', 'Disease', (161, 175))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (11, 33))	('causes', 'Reg', (154, 160))	('inherited cancer predisposition syndrome', 'Disease', 'MESH:D020022', (243, 283))	('DNA', 'cellular_component', 'GO:0005574', ('307', '310'))	('non-polyposis colon cancer', 'Disease', (202, 228))
53484	24293293	As >90% of the total sequenced tags in the region contained the mutation, we concluded that MSH2 was biallelically inactivated in this tumor.	('MSH2', 'Gene', (92, 96))	('MSH2', 'Gene', '4436', (92, 96))	('mutation', 'Var', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('contained', 'Reg', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
53486	24293293	The MSH3 mutation also occurred in ACINAR01, which had microsatellite instability and somatic MSH2 mutation.	('mutation', 'Var', (9, 17))	('microsatellite instability', 'MPA', (55, 81))	('MSH3', 'Gene', (4, 8))	('occurred', 'Reg', (23, 31))	('mutation', 'Var', (99, 107))	('MSH3', 'Gene', '4437', (4, 8))	('MSH2', 'Gene', (94, 98))	('MSH2', 'Gene', '4436', (94, 98))
53487	24293293	However, because the other tumors with these mutations did not have particularly high numbers of somatic mutations, the role of these mutations in base pair instability was unclear.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (45, 54))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))
53488	24293293	No mutations were identified in POLE or POLD1, DNA polymerase genes whose constitutional alterations were recently associated with colorectal cancer predisposition.	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('POLD1', 'Gene', '5424', (40, 45))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('associated', 'Reg', (115, 125))	('POLD1', 'Gene', (40, 45))	('colorectal cancer', 'Disease', (131, 148))	('alterations', 'Var', (89, 100))
53489	24293293	We also reviewed our whole exome sequencing data for somatic mutations in genes involved in the spindle checkpoint and DNA double-strand break repair, such as MAD1, MAD2, MAD3, BUB1, BUB3, MPSI, CDC20, MRE11, RAD50, NBS1, ROD, ZW10, ZWILCH and FBXW7, as mutations in these genes have been associated with chromosomal instability in other tumor types.	('RAD50', 'Gene', (209, 214))	('MAD', 'biological_process', 'GO:0072671', ('171', '174'))	('tumor', 'Disease', (338, 343))	('MAD2', 'Gene', (165, 169))	('ZWILCH', 'Gene', '55055', (233, 239))	('MAD2', 'Gene', '4087', (165, 169))	('ROD', 'Gene', '9735', (222, 225))	('RAD', 'biological_process', 'GO:1990116', ('209', '212'))	('CDC20', 'Gene', (195, 200))	('chromosomal', 'MPA', (305, 316))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('ZWILCH', 'Gene', (233, 239))	('RAD50', 'Gene', '10111', (209, 214))	('ZW10', 'Gene', (227, 231))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('BUB3', 'Gene', (183, 187))	('BUB3', 'Gene', '9184', (183, 187))	('FBXW7', 'Gene', (244, 249))	('MRE11', 'Gene', (202, 207))	('MPSI', 'Disease', 'None', (189, 193))	('MAD3', 'Gene', '4088', (171, 175))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('BUB1', 'Gene', '699', (177, 181))	('mutations', 'Var', (61, 70))	('spindle', 'cellular_component', 'GO:0005819', ('96', '103'))	('double-strand break repair', 'biological_process', 'GO:0006302', ('123', '149'))	('BUB1', 'Gene', (177, 181))	('MRE11', 'Gene', '4361', (202, 207))	('chromosomal instability', 'Phenotype', 'HP:0040012', (305, 328))	('NBS1', 'Gene', '4683', (216, 220))	('FBXW7', 'Gene', '55294', (244, 249))	('spindle checkpoint', 'biological_process', 'GO:0031577', ('96', '114'))	('NBS1', 'Gene', (216, 220))	('MAD', 'biological_process', 'GO:0072671', ('165', '168'))	('MAD1', 'Gene', '4084', (159, 163))	('associated', 'Reg', (289, 299))	('MAD1', 'Gene', (159, 163))	('CDC20', 'Gene', '991', (195, 200))	('MPSI', 'Disease', (189, 193))	('MAD', 'biological_process', 'GO:0072671', ('159', '162'))	('MAD3', 'Gene', (171, 175))	('ROD', 'Gene', (222, 225))	('ZW10', 'Gene', '9183', (227, 231))
53491	24293293	Because genes governing DNA repair can also be epigenetically inactivated in tumors with genomic instability, we analyzed the tumors for methylation of the MLH1 and BRCA1 genes, which have been reported to be methylated in tumors with microsatellite and chromosomal instability, respectively.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Disease', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('microsatellite', 'Var', (235, 249))	('MLH1', 'Gene', (156, 160))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('chromosomal instability', 'Phenotype', 'HP:0040012', (254, 277))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('MLH1', 'Gene', '4292', (156, 160))	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('DNA repair', 'biological_process', 'GO:0006281', ('24', '34'))	('BRCA1', 'Gene', '672', (165, 170))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('BRCA1', 'Gene', (165, 170))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))
53494	24293293	Methylation at MLH1 did not correlate with microsatellite instability or with increased number of mutations in the whole exome sequencing data.	('Methylation', 'Var', (0, 11))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('microsatellite instability', 'MPA', (43, 69))	('MLH1', 'Gene', '4292', (15, 19))	('MLH1', 'Gene', (15, 19))
53497	24293293	Mutations were identified in genes altered in other pancreatic neoplasms, including SMAD4 in six tumors (26%), TP53 in three tumors (13%), GNAS in two tumors (9%, both at the previously described oncogenic hotspot in codon 201), RNF43 in one tumor (4%) and MEN1 in one tumor (4%) (Table 1).	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('pancreatic neoplasm', 'Phenotype', 'HP:0002894', (52, 71))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('RNF43', 'Gene', '54894', (229, 234))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('pancreatic neoplasms', 'Disease', 'MESH:D010190', (52, 72))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Disease', (97, 103))	('tumor', 'Disease', (242, 247))	('pancreatic neoplasms', 'Disease', (52, 72))	('SMAD4', 'Gene', (84, 89))	('RNF43', 'Gene', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('TP53', 'Gene', '7157', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', (125, 131))	('tumor', 'Disease', (97, 102))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('MEN1', 'Gene', '4221', (257, 261))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('neoplasms', 'Phenotype', 'HP:0002664', (63, 72))	('SMAD4', 'Gene', '4089', (84, 89))	('GNAS', 'Gene', (139, 143))	('pancreatic neoplasms', 'Phenotype', 'HP:0002894', (52, 72))	('MEN1', 'Gene', (257, 261))	('neoplasm', 'Phenotype', 'HP:0002664', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (269, 274))	('TP53', 'Gene', (111, 115))	('tumor', 'Disease', (125, 130))	('GNAS', 'Gene', '2778', (139, 143))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
53498	24293293	The MEN1 mutation occurred in a mixed acinar-ductal carcinoma, but there were no features of neuroendocrine differentiation in this carcinoma.	('mutation', 'Var', (9, 17))	('acinar-ductal carcinoma', 'Disease', (38, 61))	('MEN1', 'Gene', (4, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('MEN1', 'Gene', '4221', (4, 8))	('carcinoma', 'Disease', 'MESH:D002277', (132, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('acinar-ductal carcinoma', 'Disease', 'MESH:D018267', (38, 61))	('carcinoma', 'Disease', (52, 61))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (45, 61))	('carcinoma', 'Disease', (132, 141))	('carcinoma', 'Disease', 'MESH:D002277', (52, 61))	('occurred in', 'Reg', (18, 29))
53499	24293293	Except for MEN1, mutations in genes altered in other pancreatic neoplasms did not occur in the mixed acinar-ductal carcinomas, and no carcinoma in our study was associated with a cystic lesion such as an intraductal papillary mucinous neoplasm or mucinous cystic neoplasm, which have previously been reported to harbor GNAS and RNF43 mutations.	('MEN1', 'Gene', (11, 15))	('associated', 'Reg', (161, 171))	('GNAS', 'Gene', (319, 323))	('cystic lesion', 'Disease', (179, 192))	('pancreatic neoplasms', 'Disease', (53, 73))	('neoplasm', 'Phenotype', 'HP:0002664', (235, 243))	('carcinoma', 'Disease', 'MESH:D002277', (115, 124))	('mutations', 'Var', (334, 343))	('GNAS', 'Gene', '2778', (319, 323))	('cystic lesion', 'Disease', 'MESH:D052177', (179, 192))	('acinar-ductal carcinomas', 'Disease', 'MESH:D018267', (101, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('papillary mucinous neoplasm', 'Disease', (216, 243))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (108, 124))	('carcinoma', 'Disease', (134, 143))	('RNF43', 'Gene', '54894', (328, 333))	('pancreatic neoplasms', 'Phenotype', 'HP:0002894', (53, 73))	('acinar-ductal carcinomas', 'Disease', (101, 125))	('neoplasm', 'Phenotype', 'HP:0002664', (64, 72))	('neoplasm', 'Phenotype', 'HP:0002664', (263, 271))	('mucinous neoplasm', 'Phenotype', 'HP:0031495', (226, 243))	('mucinous cystic neoplasm', 'Disease', (247, 271))	('mucinous cystic neoplasm', 'Disease', 'MESH:D018297', (247, 271))	('cystic neoplasm', 'Phenotype', 'HP:0010576', (256, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('MEN1', 'Gene', '4221', (11, 15))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('RNF43', 'Gene', (328, 333))	('carcinoma', 'Disease', (115, 124))	('pancreatic neoplasm', 'Phenotype', 'HP:0002894', (53, 72))	('carcinoma', 'Disease', 'MESH:D002277', (134, 143))	('neoplasms', 'Phenotype', 'HP:0002664', (64, 73))	('papillary mucinous neoplasm', 'Disease', 'MESH:D000077779', (216, 243))	('pancreatic neoplasms', 'Disease', 'MESH:D010190', (53, 73))
53500	24293293	However, two of the six SMAD4 mutations occurred in pancreatoblastomas.	('SMAD4', 'Gene', (24, 29))	('SMAD4', 'Gene', '4089', (24, 29))	('pancreatoblastomas', 'Disease', 'MESH:C537162', (52, 70))	('pancreatoblastoma', 'Phenotype', 'HP:0100757', (52, 69))	('occurred', 'Reg', (40, 48))	('mutations', 'Var', (30, 39))	('pancreatoblastomas', 'Disease', (52, 70))
53504	24293293	Importantly, the types of mutations in some of these genes concurred with their previously described roles in tumorigenesis, such as mutations in the oncogenic hotspot (codon 600) in BRAF and inactivating mutations in the tumor suppressor gene RB1.	('tumor suppressor', 'biological_process', 'GO:0051726', ('222', '238'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('222', '238'))	('inactivating mutations', 'Var', (192, 214))	('codon 600', 'Var', (169, 178))	('RB1', 'Gene', (244, 247))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('RB1', 'Gene', '5925', (244, 247))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('mutations', 'Var', (26, 35))	('mutations', 'Var', (133, 142))	('tumor', 'Disease', (222, 227))	('BRAF', 'Gene', '673', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('BRAF', 'Gene', (183, 187))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
53514	24293293	Two of the three mixed acinar-ductal carcinomas harbored a CDKN2A homozygous deletion and two of the three contained a BRAF mutation, compared to the acinar cell carcinomas without ductal differentiation in which two of 18 harbored a CDKN2A homozygous deletion and one harbored a BRAF mutation.	('BRAF', 'Gene', '673', (119, 123))	('acinar-ductal carcinomas', 'Disease', 'MESH:D018267', (23, 47))	('BRAF', 'Gene', (119, 123))	('CDKN2A', 'Gene', (234, 240))	('CDKN2A', 'Gene', (59, 65))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (150, 172))	('harbored', 'Reg', (48, 56))	('acinar-ductal carcinomas', 'Disease', (23, 47))	('CDKN2A', 'Gene', '1029', (234, 240))	('CDKN2A', 'Gene', '1029', (59, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (30, 46))	('deletion', 'Var', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('BRAF', 'Gene', '673', (280, 284))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('BRAF', 'Gene', (280, 284))	('acinar cell carcinomas', 'Disease', (150, 172))	('mutation', 'Var', (124, 132))
53522	24293293	For example, in contrast to ductal adenocarcinomas which almost universally harbor KRAS gene mutations, none of the acinar cell carcinomas in this series had a KRAS mutation.	('KRAS', 'Gene', (83, 87))	('KRAS', 'Gene', '3845', (83, 87))	('mutations', 'Var', (93, 102))	('acinar cell carcinomas', 'Disease', (116, 138))	('ductal adenocarcinomas', 'Disease', (28, 50))	('KRAS', 'Gene', (160, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('KRAS', 'Gene', '3845', (160, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (116, 138))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('ductal adenocarcinomas', 'Disease', 'MESH:D044584', (28, 50))
53524	24293293	Acinar cell carcinomas harbor large numbers of chromosomal changes, ductal adenocarcinomas are characterized by SMAD4, TP53, KRAS and CDKN2A mutations, pancreatic neuroendocrine tumors by MEN-1, DAXX, ATRX and mTOR pathway gene mutations, solid-pseudopapillary neoplasms by CTNNB1 mutations, serous cystadenomas by VHL mutations, intraductal papillary mucinous neoplasms by GNAS, RNF43, TP53, SMAD4 and CDKN2A mutations, and mucinous cystic neoplasms by RNF43, TP53, SMAD4 and CDKN2A mutations.	('mTOR', 'Gene', (210, 214))	('TP53', 'Gene', (387, 391))	('KRAS', 'Gene', (125, 129))	('CDKN2A', 'Gene', '1029', (403, 409))	('VHL', 'Gene', (315, 318))	('RNF43', 'Gene', '54894', (380, 385))	('MEN-1', 'Gene', '4221', (188, 193))	('GNAS', 'Gene', (374, 378))	('mucinous neoplasm', 'Phenotype', 'HP:0031495', (352, 369))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (152, 184))	('neoplasm', 'Phenotype', 'HP:0002664', (441, 449))	('mucinous neoplasms', 'Phenotype', 'HP:0031495', (352, 370))	('cystic neoplasms', 'Phenotype', 'HP:0010576', (434, 450))	('mucinous cystic neoplasms', 'Disease', 'MESH:D018297', (425, 450))	('SMAD4', 'Gene', (467, 472))	('mutations', 'Var', (319, 328))	('TP53', 'Gene', '7157', (119, 123))	('RNF43', 'Gene', (454, 459))	('SMAD4', 'Gene', '4089', (112, 117))	('mTOR', 'Gene', '2475', (210, 214))	('neoplasms', 'Phenotype', 'HP:0002664', (361, 370))	('serous cystadenomas', 'Phenotype', 'HP:0012887', (292, 311))	('intraductal papillary mucinous neoplasms', 'Disease', (330, 370))	('GNAS', 'Gene', '2778', (374, 378))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('CTNNB1', 'Gene', (274, 280))	('TP53', 'Gene', '7157', (461, 465))	('DAXX', 'Gene', (195, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('neoplasms', 'Phenotype', 'HP:0002664', (441, 450))	('MEN-1', 'Gene', (188, 193))	('RNF43', 'Gene', (380, 385))	('VHL', 'Gene', '7428', (315, 318))	('pancreatic neuroendocrine tumors', 'Disease', (152, 184))	('ATRX', 'Gene', (201, 205))	('neoplasm', 'Phenotype', 'HP:0002664', (361, 369))	('DAXX', 'Gene', '1616', (195, 199))	('CDKN2A', 'Gene', (477, 483))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (163, 184))	('TP53', 'Gene', '7157', (387, 391))	('intraductal papillary mucinous neoplasms', 'Disease', 'MESH:D000077779', (330, 370))	('SMAD4', 'Gene', (393, 398))	('ATRX', 'Gene', '546', (201, 205))	('mucinous cystic neoplasms', 'Disease', (425, 450))	('mutations', 'Var', (141, 150))	('SMAD4', 'Gene', '4089', (467, 472))	('solid-pseudopapillary neoplasms', 'Disease', 'MESH:D018250', (239, 270))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('mutations', 'Var', (410, 419))	('CDKN2A', 'Gene', (134, 140))	('serous cystadenomas', 'Disease', (292, 311))	('serous cystadenomas', 'Disease', 'MESH:D018293', (292, 311))	('mutations', 'Var', (228, 237))	('Acinar cell carcinomas', 'Disease', 'MESH:D018267', (0, 22))	('ductal adenocarcinomas', 'Disease', 'MESH:D044584', (68, 90))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('TP53', 'Gene', (119, 123))	('CDKN2A', 'Gene', '1029', (477, 483))	('CDKN2A', 'Gene', (403, 409))	('ductal adenocarcinomas', 'Disease', (68, 90))	('Acinar cell carcinomas', 'Disease', (0, 22))	('SMAD4', 'Gene', (112, 117))	('neoplasm', 'Phenotype', 'HP:0002664', (261, 269))	('KRAS', 'Gene', '3845', (125, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('cystic neoplasm', 'Phenotype', 'HP:0010576', (434, 449))	('TP53', 'Gene', (461, 465))	('carcinomas', 'Phenotype', 'HP:0030731', (12, 22))	('SMAD4', 'Gene', '4089', (393, 398))	('CDKN2A', 'Gene', '1029', (134, 140))	('mutations', 'Var', (281, 290))	('CTNNB1', 'Gene', '1499', (274, 280))	('neoplasms', 'Phenotype', 'HP:0002664', (261, 270))	('RNF43', 'Gene', '54894', (454, 459))	('solid-pseudopapillary neoplasms', 'Disease', (239, 270))
53526	24293293	Through whole exome sequencing we also identified potentially therapeutically targetable mutations, such as those in genes coding for members of the Fanconi anemia pathway, in 43% of the carcinomas.	('Fanconi anemia', 'Disease', (149, 163))	('anemia', 'Phenotype', 'HP:0001903', (157, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('Fanconi anemia', 'Disease', 'MESH:D005199', (149, 163))	('carcinomas', 'Disease', 'MESH:D002277', (187, 197))	('mutations', 'Var', (89, 98))	('carcinomas', 'Disease', (187, 197))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (149, 163))
53527	24293293	These included mutations in BRCA2 (4%), PALB2 (4%), BAP1 (4%), ATM (4%), BRAF (13%) and JAK1 (17%).	('BRAF', 'Gene', '673', (73, 77))	('ATM', 'Gene', '472', (63, 66))	('JAK1', 'Gene', (88, 92))	('BAP1', 'Gene', '8314', (52, 56))	('BRCA2', 'Gene', '675', (28, 33))	('PALB2', 'Gene', '79728', (40, 45))	('mutations', 'Var', (15, 24))	('PALB2', 'Gene', (40, 45))	('JAK1', 'Gene', '3716', (88, 92))	('BAP1', 'Gene', (52, 56))	('JAK', 'molecular_function', 'GO:0004713', ('88', '91'))	('ATM', 'Gene', (63, 66))	('BRAF', 'Gene', (73, 77))	('BRCA2', 'Gene', (28, 33))
53528	24293293	Mutations in Fanconi anemia pathway genes such as BRCA1 and BRCA2 have also been reported previously in acinar cell carcinomas.	('BRCA1', 'Gene', (50, 55))	('Fanconi anemia', 'Disease', 'MESH:D005199', (13, 27))	('anemia', 'Phenotype', 'HP:0001903', (21, 27))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (104, 126))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (13, 27))	('BRCA2', 'Gene', (60, 65))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('Fanconi anemia', 'Disease', (13, 27))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('acinar cell carcinomas', 'Disease', (104, 126))	('BRCA1', 'Gene', '672', (50, 55))	('BRCA2', 'Gene', '675', (60, 65))	('reported', 'Reg', (81, 89))
53529	24293293	We and others have previously shown that ductal adenocarcinomas of the pancreas with inactivating mutations in genes coding for members of this pathway can be exquisitely sensitive to DNA cross-linking agents and to Poly (ADP-ribose) polymerase (PARP) inhibitors.	('adenocarcinomas of the pancreas', 'Phenotype', 'HP:0002894', (48, 79))	('sensitive', 'Reg', (171, 180))	('ductal adenocarcinomas of the pancreas', 'Disease', (41, 79))	('PARP', 'Gene', (246, 250))	('DNA', 'cellular_component', 'GO:0005574', ('184', '187'))	('Poly (ADP-ribose) polymerase', 'Gene', '142', (216, 244))	('PARP', 'Gene', '142', (246, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('Poly (ADP-ribose) polymerase', 'Gene', (216, 244))	('inactivating mutations', 'Var', (85, 107))	('ductal adenocarcinomas of the pancreas', 'Disease', 'MESH:D021441', (41, 79))
53530	24293293	Similarly, it has been suggested that ATM mutant neoplasms may be more sensitive to PARP inhibitors and inhibitors of protein kinase DNA-activated catalytic polypeptide (DNA-PKcs).	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))	('ATM', 'Gene', '472', (38, 41))	('mutant', 'Var', (42, 48))	('neoplasm', 'Phenotype', 'HP:0002664', (49, 57))	('sensitive', 'MPA', (71, 80))	('neoplasms', 'Disease', (49, 58))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('neoplasms', 'Disease', 'MESH:D009369', (49, 58))	('PARP', 'Gene', '142', (84, 88))	('ATM', 'Gene', (38, 41))	('neoplasms', 'Phenotype', 'HP:0002664', (49, 58))	('PARP', 'Gene', (84, 88))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
53531	24293293	In addition, targeted inhibitors for BRAF and JAK1 are currently in human clinical trials with promising results, and a BRAF inhibitor was recently approved by the United States Food and Drug Administration (FDA) for treatment of melanoma with the BRAF V600E mutation.	('human', 'Species', '9606', (68, 73))	('JAK1', 'Gene', (46, 50))	('V600E', 'Mutation', 'rs113488022', (253, 258))	('BRAF', 'Gene', '673', (37, 41))	('JAK1', 'Gene', '3716', (46, 50))	('BRAF', 'Gene', '673', (120, 124))	('JAK', 'molecular_function', 'GO:0004713', ('46', '49'))	('BRAF', 'Gene', (37, 41))	('V600E', 'Var', (253, 258))	('BRAF', 'Gene', (120, 124))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('melanoma', 'Disease', (230, 238))	('men', 'Species', '9606', (222, 225))	('BRAF', 'Gene', '673', (248, 252))	('melanoma', 'Disease', 'MESH:D008545', (230, 238))	('BRAF', 'Gene', (248, 252))
53532	24293293	While the sensitivity of acinar cell carcinomas with potentially targetable mutations has to first be established in the clinic, we can speculate that acinar cell carcinomas will be good candidates for a personalized approach to therapy based on the genetic changes in these patients' cancers.	('cancers', 'Disease', (285, 292))	('mutations', 'Var', (76, 85))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (25, 47))	('acinar cell carcinomas', 'Disease', 'MESH:D018267', (151, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('acinar cell carcinomas', 'Disease', (25, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('acinar cell carcinomas', 'Disease', (151, 173))	('patients', 'Species', '9606', (275, 283))	('cancers', 'Phenotype', 'HP:0002664', (285, 292))	('cancers', 'Disease', 'MESH:D009369', (285, 292))
53571	24571389	Searches were performed using the following settings: precursor ion m/z tolerance, +- 10 ppm; fragment ion m/z tolerance, +- 0.03 Da; two missed cleavages allowed; static modification, carbamidomethylation (+57.02146 Da, C) and TMT 6-plex (+219.163 Da) of lysines and protein N-termini; dynamic modifications: oxidation (+15.99492 Da, M) and deamidation (+0.98402 Da, N).	('+57.02146 Da', 'Var', (207, 219))	('+15.99492 Da', 'Var', (321, 333))	('protein', 'cellular_component', 'GO:0003675', ('268', '275'))	('oxidation', 'MPA', (310, 319))	('deamidation', 'MPA', (342, 353))	('TMT', 'molecular_function', 'GO:0018708', ('228', '231'))	('lysines', 'Chemical', 'MESH:D008239', (256, 263))	('+0.98402 Da', 'Var', (355, 366))	('+219.163 Da', 'Var', (240, 251))
53580	24571389	Previous reports have shown that abnormal fucosylation plays an important role in many pathological processes, such as pancreatic cancer and hepatocellular carcinoma (HCC).	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (141, 165))	('pancreatic cancer', 'Disease', (119, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('hepatocellular carcinoma', 'Disease', (141, 165))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (141, 165))	('fucosylation', 'Protein', (42, 54))	('role', 'Reg', (74, 78))	('fucosylation', 'biological_process', 'GO:0036065', ('42', '54'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (119, 136))	('abnormal', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('HCC', 'Phenotype', 'HP:0001402', (167, 170))
53589	24571389	Among populations with first-degree relatives with pancreatic cancer, p16 germline mutations, mismatch repair gene mutations, hereditary pancreatitis, or other genetic mutations, the prevalence increases dramatically.	('mutations', 'Var', (115, 124))	('mismatch repair', 'biological_process', 'GO:0006298', ('94', '109'))	('p16', 'Gene', '1029', (70, 73))	('mismatch repair gene', 'Gene', (94, 114))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('hereditary pancreatitis', 'Disease', (126, 149))	('pancreatic cancer', 'Disease', (51, 68))	('pancreatitis', 'Phenotype', 'HP:0001733', (137, 149))	('p16', 'Gene', (70, 73))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (51, 68))
53602	24569397	In the past, considerable efforts have been carried out to identify potential biomarkers that include aberrantly expressed genes, proteins, miRNA detectable through non-invasive techniques in cancerous tissue and body fluids.	('cancerous', 'Disease', 'MESH:D009369', (192, 201))	('cancerous tissue and body', 'Phenotype', 'HP:0002664', (192, 217))	('aberrantly', 'Var', (102, 112))	('proteins', 'Protein', (130, 138))	('cancerous', 'Disease', (192, 201))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
53603	24569397	In addition, mutations in few genes have also been identified to be associated with the progression of pancreatic cancer.	('associated', 'Reg', (68, 78))	('pancreatic cancer', 'Disease', (103, 120))	('pancreatic cancer', 'Disease', 'MESH:D010190', (103, 120))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (13, 22))
53605	24569397	Loss of gene expression due to methylation of promoter CpG island that is otherwise unmethylated in a normal cell has been the most widely investigated epigenetic event in cancer and thus has drawn significant attention as a biomarker candidate.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('gene expression', 'biological_process', 'GO:0010467', ('8', '23'))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('Loss', 'NegReg', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('methylation', 'Var', (31, 42))	('cancer', 'Disease', (172, 178))	('gene expression', 'MPA', (8, 23))
53642	24569397	Apart from being suitable biomarker for cancer detection, diagnosis and prognosis, DNA methylation of genes has also been realized to be an effective predictor of response to chemotherapeutic cancer drugs.	('DNA methylation', 'biological_process', 'GO:0006306', ('83', '98'))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('methylation', 'Var', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
53647	24569397	Hence, investigations into the cellular pathways associated with gene expression that get affected due to DNA methylation in cancer could open new avenues for therapeutic intervention.	('DNA methylation', 'biological_process', 'GO:0006306', ('106', '121'))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('gene expression', 'biological_process', 'GO:0010467', ('65', '80'))	('methylation', 'Var', (110, 121))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('DNA methylation', 'Var', (106, 121))
53687	23857605	Furthermore, knockdown of lamin B1 significantly attenuated the proliferation, invasion and tumorigenicity of pancreatic cancer cells.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (110, 127))	('attenuated', 'NegReg', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('pancreatic cancer', 'Disease', (110, 127))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('pancreatic cancer', 'Disease', 'MESH:D010190', (110, 127))	('lamin B1', 'Gene', (26, 34))	('tumor', 'Disease', (92, 97))	('invasion', 'CPA', (79, 87))	('knockdown', 'Var', (13, 22))
53701	23857605	Mutations of lamin genes, including lamin B1, will cause panoply of human diseases ("laminopathies").	('human', 'Species', '9606', (68, 73))	('lamin', 'Gene', (85, 90))	('lamin', 'Gene', (13, 18))	('lamin', 'Gene', '4000', (36, 41))	('panoply', 'Disease', (57, 64))	('lamin', 'Gene', '4000', (85, 90))	('lamin', 'Gene', '4000', (13, 18))	('Mutations', 'Var', (0, 9))	('cause', 'Reg', (51, 56))	('human diseases', 'Disease', (68, 82))	('lamin', 'Gene', (36, 41))
53705	23857605	For example, RNAi-mediated knockdown of lamin B1 in Hela cells arrests cell growth and causes apoptosis, and this finding is consistent with the notion that lamin B1 is essential for nuclear integrity, cell survival and normal development.	('knockdown', 'Var', (27, 36))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('cell growth', 'biological_process', 'GO:0016049', ('71', '82'))	('Hela cells', 'CellLine', 'CVCL:0030', (52, 62))	('cell growth', 'CPA', (71, 82))	('lamin B1', 'Gene', (40, 48))	('arrest', 'Disease', (63, 69))	('RNAi', 'biological_process', 'GO:0016246', ('13', '17'))	('causes', 'Reg', (87, 93))	('apoptosis', 'CPA', (94, 103))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))
53706	23857605	However, genetic knockout of lamin B1 in keratinocytes has no effect on cell proliferation or the development of skin and hair, and mouse embryonic stem cells apparently do not need any lamins for self-renewal and pluripotency.	('lamin', 'Gene', '4000', (29, 34))	('skin and hair', 'Disease', 'MESH:D012871', (113, 126))	('cell proliferation', 'biological_process', 'GO:0008283', ('72', '90'))	('pluripotency', 'Disease', (214, 226))	('cell proliferation', 'CPA', (72, 90))	('mouse', 'Species', '10090', (132, 137))	('lamin', 'Gene', (186, 191))	('pluripotency', 'Disease', 'None', (214, 226))	('lamin', 'Gene', (29, 34))	('lamin', 'Gene', '4000', (186, 191))	('genetic knockout', 'Var', (9, 25))
53719	23857605	Standard western blot was performed using 35 mug whole-cell protein lysates with primary antibodies against lamin B1 (sc-6216, Santa Cruz Biotechnology) or Sp1 (sc-59, Santa Cruz Biotechnology), and proper secondary antibodies (anti-rabbit IgG and anti-goat IgG, Santa Cruz Biotechnology).	('Sp', 'Chemical', 'MESH:C000604007', (156, 158))	('lamin B1', 'Protein', (108, 116))	('goat', 'Species', '9925', (253, 257))	('mug', 'molecular_function', 'GO:0043739', ('45', '48'))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('sc-6216', 'Var', (118, 125))	('Sp1', 'Gene', (156, 159))	('rabbit', 'Species', '9986', (233, 239))
53750	23857605	High lamin B1 staining was inversely correlated with the overall survival duration in Kaplan-Meier survival analysis; 60 patients with high lamin B1 expression had a median survival duration of only 9.75 months, whereas the 82 patients with low lamin B1 expression had a median survival duration of 12.4 months (P=0.007; Fig.	('high', 'Var', (135, 139))	('lamin B1', 'Gene', (140, 148))	('patients', 'Species', '9606', (121, 129))	('patients', 'Species', '9606', (227, 235))
53758	23857605	S5, knockdown of lamin B1 induced G1 arrest in both AsPC-1 cells and PANC-1 cells and this cell cycle arrest directly correlated with a significant suppression of the mRNA expression levels of Cyclin D1 and CDK4.	('mRNA expression levels', 'MPA', (167, 189))	('Cyclin D1', 'Gene', '595', (193, 202))	('Cyclin D1', 'Gene', (193, 202))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (91, 108))	('Cyclin', 'molecular_function', 'GO:0016538', ('193', '199'))	('arrest', 'Disease', (37, 43))	('knockdown', 'Var', (4, 13))	('arrest', 'Disease', (102, 108))	('AsPC-1', 'CellLine', 'CVCL:0152', (52, 58))	('CDK4', 'Gene', (207, 211))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('91', '108'))	('PANC-1', 'Gene', (69, 75))	('CDK', 'molecular_function', 'GO:0004693', ('207', '210'))	('arrest', 'Disease', 'MESH:D006323', (37, 43))	('suppression', 'NegReg', (148, 159))	('PANC-1', 'Gene', '104066', (69, 75))	('arrest', 'Disease', 'MESH:D006323', (102, 108))	('CDK4', 'Gene', '1019', (207, 211))	('lamin B1', 'Gene', (17, 25))
53761	23857605	Wound healing assay showed that silencing lamin B1 in AsPC-1 and PANC-1 cells significantly attenuated the migration and invasion ability of pancreatic cancer cells (P<0.05; Fig.	('PANC-1', 'Gene', (65, 71))	('lamin B1', 'Protein', (42, 50))	('pancreatic cancer', 'Disease', (141, 158))	('Wound healing', 'biological_process', 'GO:0042060', ('0', '13'))	('silencing', 'Var', (32, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (141, 158))	('AsPC-1', 'CellLine', 'CVCL:0152', (54, 60))	('invasion ability', 'CPA', (121, 137))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('attenuated', 'NegReg', (92, 102))	('PANC-1', 'Gene', '104066', (65, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (141, 158))
53762	23857605	Consistently, silencing lamin B1 significantly inhibited pancreatic tumor growth in vivo (Fig.	('silencing', 'Var', (14, 23))	('inhibited', 'NegReg', (47, 56))	('lamin B1', 'Protein', (24, 32))	('pancreatic tumor', 'Disease', (57, 73))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (57, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('pancreatic tumor', 'Disease', 'MESH:D010190', (57, 73))
53763	23857605	Immunohistochemical analysis validated the knockdown efficiency against lamin B1 in the xenograft tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('xenograft tumors', 'Disease', (88, 104))	('knockdown', 'Var', (43, 52))	('lamin B1', 'Protein', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('xenograft tumors', 'Disease', 'MESH:D009369', (88, 104))
53771	23857605	Furthermore, knockdown of Sp1 did not caused a drastic reduction of lamin B1 expression (Fig.	('expression', 'MPA', (77, 87))	('Sp', 'Chemical', 'MESH:C000604007', (26, 28))	('lamin', 'Protein', (68, 73))	('Sp1', 'Gene', (26, 29))	('knockdown', 'Var', (13, 22))
53774	23857605	Finally, knockdown of lamin B1 attenuated pancreatic cancer cell proliferation in vitro, while knockdown of Sp1 has little effect on pancreatic cancer growth in vitro (Fig.	('knockdown', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (42, 59))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (133, 150))	('lamin B1', 'Gene', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Sp', 'Chemical', 'MESH:C000604007', (108, 110))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (42, 59))	('pancreatic cancer', 'Disease', (133, 150))	('attenuated pancreatic cancer', 'Disease', (31, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (133, 150))	('attenuated pancreatic cancer', 'Disease', 'MESH:D010190', (31, 59))
53780	23857605	Third, knockdown of lamin B1 attenuated the growth and migration and invasion of pancreatic cancer in vitro and in animal models.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('attenuated', 'NegReg', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('lamin B1', 'Gene', (20, 28))	('knockdown', 'Var', (7, 16))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('pancreatic cancer', 'Disease', (81, 98))
53787	23857605	However, Sp1 knockdown does not drastically affect the growth of pancreatic cancer cells in vitro.	('Sp', 'Chemical', 'MESH:C000604007', (9, 11))	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('pancreatic cancer', 'Disease', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('Sp1', 'Gene', (9, 12))	('knockdown', 'Var', (13, 22))
53803	23857605	Because a modulation of "biomarker" expression can usually produce therapeutic effects, we further evaluated the biological functions of lamin B1 within pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (153, 170))	('modulation', 'Var', (10, 20))	('pancreatic cancer', 'Disease', (153, 170))	('pancreatic cancer', 'Disease', 'MESH:D010190', (153, 170))
53804	23857605	Our work showed that knockdown of lamin B1 significantly attenuated the proliferation, invasion and tumorigenesis of pancreatic cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('tumor', 'Disease', (100, 105))	('pancreatic cancer', 'Disease', (117, 134))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('invasion', 'CPA', (87, 95))	('lamin B1', 'Gene', (34, 42))	('knockdown', 'Var', (21, 30))	('attenuated', 'NegReg', (57, 67))
53810	23857605	Furthermore, Sp1 knockdown using siRNA has only marginal impacts on lamin B1 expression, whereas or mithramycin A, a commonly used Sp1-targeted drug did inhibited lamin B1 expression.	('expression', 'MPA', (77, 87))	('Sp', 'Chemical', 'MESH:C000604007', (13, 15))	('mithramycin A', 'Chemical', 'MESH:C066851', (100, 113))	('expression', 'MPA', (172, 182))	('lamin', 'Gene', (163, 168))	('lamin B1', 'Gene', (68, 76))	('knockdown', 'Var', (17, 26))	('Sp', 'Chemical', 'MESH:C000604007', (131, 133))	('inhibited', 'NegReg', (153, 162))
53916	24072676	Finally, PanIN3s, resulting from PanIN2 lesions are identified as papillary or micro-papillary structures characterized with high grade dysplasia and loss of nuclear polarity indicating development of pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (201, 218))	('PanIN2', 'Gene', (33, 39))	('pancreatic cancer', 'Disease', (201, 218))	('pancreatic cancer', 'Disease', 'MESH:D010190', (201, 218))	('dysplasia', 'Disease', (136, 145))	('loss', 'NegReg', (150, 154))	('dysplasia', 'Disease', 'MESH:D004476', (136, 145))	('nuclear polarity', 'CPA', (158, 174))	('lesions', 'Var', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
53927	24072676	Thus, the efficacy of the medium and high dose treatment groups were apparent whereby the ACS combination regimens reduced the transformation, and therefore progression, of low grade PanIN lesions to a higher grade variety, hence potentially arresting the onset of pancreatic carcinogenesis.	('ACS', 'molecular_function', 'GO:0003987', ('90', '93'))	('reduced', 'NegReg', (115, 122))	('transformation', 'MPA', (127, 141))	('pancreatic carcinogenesis', 'Disease', (265, 290))	('C', 'Chemical', 'MESH:D002244', (91, 92))	('ACS', 'molecular_function', 'GO:0043884', ('90', '93'))	('low grade', 'Var', (173, 182))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (265, 290))
53953	24072676	Recent results from our lab demonstrated that ACS combinations can induce apoptosis in MIA PaCa-2 and Panc-1 pancreatic cancer cells through activation of the ERK1/2 signaling system and inhibition of NF-kappaB pathway mechanisms.	('signaling', 'biological_process', 'GO:0023052', ('166', '175'))	('ACS', 'molecular_function', 'GO:0043884', ('46', '49'))	('pancreatic cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Panc-1', 'CellLine', 'CVCL:0480', (102, 108))	('ERK1/2', 'Gene', (159, 165))	('ERK1/2', 'Gene', '5595;5594', (159, 165))	('combinations', 'Var', (50, 62))	('apoptosis', 'CPA', (74, 83))	('inhibition', 'NegReg', (187, 197))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('ACS', 'molecular_function', 'GO:0003987', ('46', '49'))	('ACS combinations', 'Var', (46, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('C', 'Chemical', 'MESH:D002244', (47, 48))	('ERK1', 'molecular_function', 'GO:0004707', ('159', '163'))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (87, 97))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('activation', 'PosReg', (141, 151))	('NF-kappaB', 'Gene', (201, 210))	('C', 'Chemical', 'MESH:D002244', (93, 94))	('NF-kappaB', 'Gene', '4790', (201, 210))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('induce', 'PosReg', (67, 73))
53982	24072676	Additionally, defective apoptosis signaling is the underlying cause of failure to respond to the current treatment approaches for pancreatic cancer since cytotoxic therapeutic agents depend on induction of apoptosis in cancer cells in order to be effective.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('193', '215'))	('apoptosis signaling', 'biological_process', 'GO:0006915', ('24', '43'))	('defective', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('apoptosis', 'MPA', (24, 33))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (130, 147))	('cancer', 'Disease', (219, 225))	('pancreatic cancer', 'Disease', (130, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (130, 147))
53992	23316479	Multiple combinations of genetic alterations are known to occur in PDAC including mutational activation of KRAS, inactivation of p16/CDKN2A and SMAD4 (DPC4) and dysregulation of PTEN/PI3K/AKT signaling.	('activation', 'PosReg', (93, 103))	('PDAC', 'Disease', (67, 71))	('KRAS', 'Gene', '3845', (107, 111))	('CDKN2A', 'Gene', '1029', (133, 139))	('inactivation', 'NegReg', (113, 125))	('AKT', 'Gene', (188, 191))	('SMAD4', 'Gene', '4089', (144, 149))	('DPC4', 'Gene', (151, 155))	('KRAS', 'Gene', (107, 111))	('dysregulation', 'Var', (161, 174))	('p16', 'Gene', (129, 132))	('PI3K', 'molecular_function', 'GO:0016303', ('183', '187'))	('p16', 'Gene', '1029', (129, 132))	('mutational', 'Var', (82, 92))	('PDAC', 'Chemical', '-', (67, 71))	('PTEN', 'Gene', (178, 182))	('DPC4', 'Gene', '4089', (151, 155))	('PDAC', 'Phenotype', 'HP:0006725', (67, 71))	('AKT signaling', 'biological_process', 'GO:0043491', ('188', '201'))	('AKT', 'Gene', '207', (188, 191))	('PTEN', 'Gene', '5728', (178, 182))	('CDKN2A', 'Gene', (133, 139))	('SMAD4', 'Gene', (144, 149))
54004	23316479	Multiple combinations of genetic alterations are known to occur in PDAC including mutational activation of oncogenes like KRAS (>90% of PDACs), inactivation of tumor suppressor genes like TP53 (75-85%), p16/CDKN2A (40%), and SMAD4 (DPC4; 60%) and dysregulation of PTEN/PI3K/AKT signaling.	('activation', 'PosReg', (93, 103))	('PDAC', 'Disease', (67, 71))	('p16', 'Gene', (203, 206))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('DPC4', 'Gene', (232, 236))	('p16', 'Gene', '1029', (203, 206))	('KRAS', 'Gene', '3845', (122, 126))	('mutational', 'Var', (82, 92))	('AKT', 'Gene', (274, 277))	('PDAC', 'Chemical', '-', (67, 71))	('TP53', 'Gene', '7157', (188, 192))	('KRAS', 'Gene', (122, 126))	('DPC4', 'Gene', '4089', (232, 236))	('PI3K', 'molecular_function', 'GO:0016303', ('269', '273'))	('SMAD4', 'Gene', (225, 230))	('PTEN', 'Gene', (264, 268))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('160', '176'))	('PDAC', 'Phenotype', 'HP:0006725', (67, 71))	('CDKN2A', 'Gene', (207, 213))	('dysregulation', 'Var', (247, 260))	('tumor', 'Disease', (160, 165))	('PDAC', 'Chemical', '-', (136, 140))	('tumor suppressor', 'biological_process', 'GO:0051726', ('160', '176'))	('PTEN', 'Gene', '5728', (264, 268))	('CDKN2A', 'Gene', '1029', (207, 213))	('AKT', 'Gene', '207', (274, 277))	('PDAC', 'Phenotype', 'HP:0006725', (136, 140))	('inactivation', 'Var', (144, 156))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('SMAD4', 'Gene', '4089', (225, 230))	('AKT signaling', 'biological_process', 'GO:0043491', ('274', '287'))	('TP53', 'Gene', (188, 192))
54006	23316479	Alteration of this pathway has a prominent function in both the tumor cell and stromal cell compartments.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('Alteration', 'Var', (0, 10))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
54008	23316479	Through a functional TGF-beta signaling pathway and the presence of activating KRAS mutations, TGF-beta ligand stimulation promotes tumor cells to undergo epithelial-mesenchymal transition (EMT) and thus develop an aggressive and invasive phenotype.	('EMT', 'biological_process', 'GO:0001837', ('190', '193'))	('promotes', 'PosReg', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('activating', 'PosReg', (68, 78))	('TGF-beta', 'Gene', '7040', (95, 103))	('epithelial-mesenchymal transition', 'CPA', (155, 188))	('KRAS', 'Gene', '3845', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mutations', 'Var', (84, 93))	('TGF-beta', 'Gene', (95, 103))	('tumor', 'Disease', (132, 137))	('ligand', 'molecular_function', 'GO:0005488', ('104', '110'))	('develop', 'PosReg', (204, 211))	('TGF-beta', 'Gene', '7040', (21, 29))	('TGF-beta', 'Gene', (21, 29))	('KRAS', 'Gene', (79, 83))	('signaling pathway', 'biological_process', 'GO:0007165', ('30', '47'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('155', '188'))
54009	23316479	If aberrantly activated acts as a trigger of tumor progression and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('aberrantly activated', 'Var', (3, 23))	('tumor', 'Disease', (45, 50))	('metastasis', 'CPA', (67, 77))	('trigger', 'Reg', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
54011	23316479	It has been reported that repression of E-cadherin is associated with dedifferentiation, infiltrative growth, and high incidence of lymph node metastasis in pancreatic cancer, as well as various other malignancies.	('malignancies', 'Disease', (201, 213))	('infiltrative growth', 'CPA', (89, 108))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('E-cadherin', 'Gene', (40, 50))	('E-cadherin', 'Gene', '999', (40, 50))	('dedifferentiation', 'biological_process', 'GO:0043696', ('70', '87'))	('cadherin', 'molecular_function', 'GO:0008014', ('42', '50'))	('lymph node metastasis', 'Disease', (132, 153))	('repression', 'Var', (26, 36))	('metastasis in pancreatic cancer', 'Disease', (143, 174))	('lymph node metastasis', 'Disease', 'MESH:D009362', (132, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (157, 174))	('metastasis in pancreatic cancer', 'Disease', 'MESH:D009362', (143, 174))	('malignancies', 'Disease', 'MESH:D009369', (201, 213))	('dedifferentiation', 'CPA', (70, 87))	('associated', 'Reg', (54, 64))
54018	23316479	Cancer stem cells are defined by their immortality, their capacity to reproduce all derived cell phenotypes of a cancer and by biological and biochemical markers such as CD44, CD133, aldehyde, dehydrogenase, etc.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CD133', 'Gene', (176, 181))	('CD133', 'Gene', '8842', (176, 181))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', (113, 119))	('CD44', 'Var', (170, 174))
54029	23316479	We found an association between high-grade budding and aggressive clinicopathological features of the tumors, like advanced pT-stage and the presence of lymphatic invasion.	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('high-grade budding', 'Var', (32, 50))	('lymphatic invasion', 'CPA', (153, 171))	('budding', 'biological_process', 'GO:0007114', ('43', '50'))	('advanced', 'CPA', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
54035	23316479	In a breast cancer cell line down-regulation of cyclin A1 was shown to increase migration and decrease proliferation.	('cyclin A1', 'Gene', (48, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (5, 18))	('proliferation', 'CPA', (103, 116))	('migration', 'CPA', (80, 89))	('cyclin', 'molecular_function', 'GO:0016538', ('48', '54'))	('increase', 'PosReg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('down-regulation', 'Var', (29, 44))	('breast cancer', 'Disease', 'MESH:D001943', (5, 18))	('cyclin A1', 'Gene', '8900', (48, 57))	('regulation', 'biological_process', 'GO:0065007', ('34', '44'))	('breast cancer', 'Disease', (5, 18))	('decrease', 'NegReg', (94, 102))
54067	20367887	IKK, in turn, phosphorylates the IkappaBalpha protein, resulting in the ubiquitination and dissociation of IkappaBalpha from NF-kappaB complex, and eventually leading to the degradation of IkappaBalpha by the proteosome.	('leading to', 'Reg', (159, 169))	('IkappaBalpha', 'Gene', (189, 201))	('NF-kappaB', 'Gene', '18033', (125, 134))	('IkappaBalpha', 'Gene', (107, 119))	('IKK', 'Var', (0, 3))	('dissociation', 'MPA', (91, 103))	('ubiquitination', 'MPA', (72, 86))	('resulting in', 'Reg', (55, 67))	('IkappaBalpha', 'Gene', '18035', (189, 201))	('IkappaBalpha', 'Gene', '18035', (107, 119))	('NF-kappaB complex', 'cellular_component', 'GO:0071159', ('125', '142'))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('IkappaBalpha', 'Gene', (33, 45))	('IKK', 'molecular_function', 'GO:0008384', ('0', '3'))	('degradation', 'MPA', (174, 185))	('degradation', 'biological_process', 'GO:0009056', ('174', '185'))	('IkappaBalpha', 'Gene', '18035', (33, 45))	('NF-kappaB', 'Gene', (125, 134))
54140	20367887	Therefore, inhibition of NF-kappaB activation by pharmacologic approaches has become an attractive strategy for improving the anti-tumor activity of TNFalpha.	('NF-kappaB', 'Gene', '18033', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('improving', 'PosReg', (112, 121))	('TNFalpha', 'Gene', (149, 157))	('tumor', 'Disease', (131, 136))	('inhibition', 'Var', (11, 21))	('NF-kappaB', 'Gene', (25, 34))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('25', '45'))	('activation', 'PosReg', (35, 45))
54280	19774210	We have known that neither cetuximab nor panitumumab would provide any response benefit in KRAS mutant CRC.	('cetuximab', 'Chemical', 'MESH:D000068818', (27, 36))	('mutant', 'Var', (96, 102))	('panitumumab', 'Chemical', 'MESH:D000077544', (41, 52))	('KRAS', 'Gene', (91, 95))	('KRAS', 'Gene', '3845', (91, 95))
54423	19774210	Patients will be stratified to 'high risk' or 'low risk' based on microsatellite instability and loss of heterozygosity at 18q.	('loss', 'Var', (97, 101))	('Patients', 'Species', '9606', (0, 8))	('microsatellite instability', 'Var', (66, 92))
54508	19283083	However, 5-year-survival rates after PD with PV resection are significantly better after an R0 resection than an R1 or R2 resection.	('better', 'PosReg', (76, 82))	('R0 resection', 'Var', (92, 104))	('PD', 'Disease', 'MESH:D010300', (37, 39))
54568	33925979	Cancer cells can find ways to avoid the Ca2+-dependent apoptosis through modulation of Ca2+ levels inside the cell.	('Ca2', 'Gene', '760', (87, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('Ca2', 'Gene', '760', (40, 43))	('modulation', 'Var', (73, 83))	('Ca2', 'Gene', (87, 90))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('Ca2', 'Gene', (40, 43))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
54590	33925979	TRPM2 mutations have been associated with the survival time in patients with PDAC.	('TRPM2', 'Gene', '7226', (0, 5))	('TRPM2', 'Gene', (0, 5))	('PDAC', 'Disease', (77, 81))	('PDAC', 'Phenotype', 'HP:0006725', (77, 81))	('associated', 'Reg', (26, 36))	('patients', 'Species', '9606', (63, 71))	('PDAC', 'Chemical', '-', (77, 81))	('mutations', 'Var', (6, 15))
54596	33925979	Furthermore, SFMBT knockdown leads to higher levels of migration and invasion in prostate cancer cell lines.	('prostate cancer', 'Disease', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('knockdown', 'Var', (19, 28))	('migration', 'CPA', (55, 64))	('invasion', 'CPA', (69, 77))	('higher', 'PosReg', (38, 44))	('SFMBT', 'Gene', '51460', (13, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (81, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))	('SFMBT', 'Gene', (13, 18))
54607	33925979	The silencing of TRPM8 also leads to an increased proportion of cells in G0/G1 phases and a decrease in S and G2/M phases.	('decrease', 'NegReg', (92, 100))	('TRPM8', 'Gene', '79054', (17, 22))	('increased', 'PosReg', (40, 49))	('G0/G1 phases', 'CPA', (73, 85))	('silencing', 'Var', (4, 13))	('TRPM8', 'Gene', (17, 22))
54615	33925979	On the other hand, studies in PANC-1 cells showed that the silencing of TRPM8 stimulates cell migration and proliferation levels.	('TRPM8', 'Gene', (72, 77))	('stimulates', 'PosReg', (78, 88))	('PANC-1', 'CellLine', 'CVCL:0480', (30, 36))	('cell migration', 'biological_process', 'GO:0016477', ('89', '103'))	('cell migration', 'CPA', (89, 103))	('silencing', 'Var', (59, 68))	('TRPM8', 'Gene', '79054', (72, 77))
54618	33925979	TRPM8 targeting can also be used to enhance the effects of gemcitabine, a common drug used in chemotherapy, in vitro.	('gemcitabine', 'Chemical', 'MESH:C056507', (59, 70))	('targeting', 'Var', (6, 15))	('effects', 'MPA', (48, 55))	('TRPM8', 'Gene', '79054', (0, 5))	('TRPM8', 'Gene', (0, 5))	('enhance', 'PosReg', (36, 43))
54619	33925979	Combining the silencing of TRPM8 and gemcitabine treatment elicits a more pronounced inhibition of cell proliferation and migration in BXPC-3 and PANC-1 cell lines.	('silencing', 'Var', (14, 23))	('TRPM8', 'Gene', (27, 32))	('cell proliferation', 'CPA', (99, 117))	('PANC-1', 'CellLine', 'CVCL:0480', (146, 152))	('inhibition', 'NegReg', (85, 95))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('85', '117'))	('TRPM8', 'Gene', '79054', (27, 32))	('gemcitabine', 'Chemical', 'MESH:C056507', (37, 48))	('BXPC-3', 'CellLine', 'CVCL:0186', (135, 141))
54620	33925979	This might be explained by the down-regulation of multidrug resistance-related factors, P-gp, MRP-2, and LRP, that occur in response to TRPM8 silencing.	('silencing', 'Var', (142, 151))	('P-gp', 'Gene', (88, 92))	('LRP', 'Gene', '3921', (105, 108))	('TRPM8', 'Gene', '79054', (136, 141))	('MRP-2', 'Gene', '1244', (94, 99))	('MRP-2', 'Gene', (94, 99))	('TRPM8', 'Gene', (136, 141))	('down-regulation', 'NegReg', (31, 46))	('regulation', 'biological_process', 'GO:0065007', ('36', '46'))	('LRP', 'Gene', (105, 108))	('P-gp', 'Gene', '283871', (88, 92))
54641	33925979	demonstrated that the depletion of Zeb1 leads to reduced invasion, distant metastasis and colonization capabilities in KPC mice.	('invasion', 'CPA', (57, 65))	('distant metastasis', 'CPA', (67, 85))	('reduced', 'NegReg', (49, 56))	('depletion', 'Var', (22, 31))	('Zeb1', 'Gene', (35, 39))	('colonization capabilities', 'CPA', (90, 115))	('mice', 'Species', '10090', (123, 127))
54642	33925979	These mice possess a mutation in the Kras and Trp53 genes, which allows the study of PDAC in immunocompetent animals, while experiencing several features observed in human PDAC.	('PDAC', 'Chemical', '-', (85, 89))	('Kras', 'Gene', (37, 41))	('Kras', 'Gene', '16653', (37, 41))	('PDAC', 'Chemical', '-', (172, 176))	('PDAC', 'Phenotype', 'HP:0006725', (172, 176))	('human', 'Species', '9606', (166, 171))	('mice', 'Species', '10090', (6, 10))	('Trp53', 'Gene', (46, 51))	('mutation', 'Var', (21, 29))	('PDAC', 'Phenotype', 'HP:0006725', (85, 89))	('Trp53', 'Gene', '22059', (46, 51))
54656	33925979	TRPV4 is activated by Piezo-1 so that the use of TRPV4 receptor antagonists inhibits the sustained Ca2+ elevation.	('TRPV4', 'Gene', (49, 54))	('Ca2+ elevation', 'Phenotype', 'HP:0003072', (99, 113))	('Piezo-1', 'Gene', '9780', (22, 29))	('Piezo-1', 'Gene', (22, 29))	('inhibits', 'NegReg', (76, 84))	('Ca2', 'Gene', '760', (99, 102))	('Ca2', 'Gene', (99, 102))	('antagonists', 'Var', (64, 75))
54669	33925979	The silencing of TRPV6 in Capan-2 and SW1900 cells leads to decreased proliferation, increased apoptosis, lower levels of migration and invasion and cell cycle arrest.	('decreased', 'NegReg', (60, 69))	('lower', 'NegReg', (106, 111))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (149, 166))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('149', '166'))	('TRPV6', 'Gene', '55503', (17, 22))	('Capan-2', 'CellLine', 'CVCL:0026', (26, 33))	('apoptosis', 'CPA', (95, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('invasion', 'CPA', (136, 144))	('arrest', 'Disease', 'MESH:D006323', (160, 166))	('SW1900', 'CellLine', 'CVCL:R777', (38, 44))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('TRPV6', 'Gene', (17, 22))	('arrest', 'Disease', (160, 166))	('increased', 'PosReg', (85, 94))	('silencing', 'Var', (4, 13))
54677	33925979	Mutations on TRPML1 or TRPML3 can lead to several disorders such as Mucolipidosis type IV (TPLM1) or deafness and pigmentation defects (TPLM3).	('pigmentation defects', 'Phenotype', 'HP:0001000', (114, 134))	('pigmentation', 'biological_process', 'GO:0043473', ('114', '126'))	('pigmentation defects', 'Disease', 'MESH:D010859', (114, 134))	('Mucolipidosis type IV', 'Disease', 'MESH:D009081', (68, 89))	('TRPML3', 'Gene', (23, 29))	('deafness', 'Disease', 'MESH:D003638', (101, 109))	('Mucolipidosis type IV', 'Disease', (68, 89))	('TRPML3', 'Gene', '55283', (23, 29))	('lead to', 'Reg', (34, 41))	('Mutations', 'Var', (0, 9))	('deafness', 'Phenotype', 'HP:0000365', (101, 109))	('deafness', 'Disease', (101, 109))	('TRPML1', 'Gene', (13, 19))	('pigmentation defects', 'Disease', (114, 134))
54681	33925979	In a study with 80 PDAC patients, high levels of TRPML1 are associated with a short overall survival and relapse-free survival compared to the patients with lower levels of the channel.	('PDAC', 'Phenotype', 'HP:0006725', (19, 23))	('TRPML1', 'Gene', (49, 55))	('relapse-free survival', 'CPA', (105, 126))	('patients', 'Species', '9606', (143, 151))	('overall survival', 'CPA', (84, 100))	('PDAC', 'Chemical', '-', (19, 23))	('patients', 'Species', '9606', (24, 32))	('high levels', 'Var', (34, 45))
54693	33925979	Of these three, co-silencing of TRPC1 and NCX1 was able to inhibit TGF-beta induced cell motility.	('TGF-beta', 'Gene', '7039', (67, 75))	('cell motility', 'biological_process', 'GO:0048870', ('84', '97'))	('NCX1', 'Gene', '6546', (42, 46))	('TRPC1', 'Gene', (32, 37))	('co-silencing', 'Var', (16, 28))	('TGF-beta', 'Gene', (67, 75))	('inhibit', 'NegReg', (59, 66))	('cell motility', 'CPA', (84, 97))	('NCX1', 'Gene', (42, 46))
54694	33925979	Using primary stellate cells from mice, it was observed that the knock-out of TRPC1 leads to significantly lower levels of cell migration after pressure incubation.	('TRPC1', 'Gene', (78, 83))	('mice', 'Species', '10090', (34, 38))	('cell migration', 'CPA', (123, 137))	('lower', 'NegReg', (107, 112))	('knock-out', 'Var', (65, 74))	('cell migration', 'biological_process', 'GO:0016477', ('123', '137'))
54695	33925979	Furthermore, the loss of TRPC1 channels causes a reduced Ca2+ influx after pressure incubation.	('reduced', 'NegReg', (49, 56))	('Ca2', 'Gene', '760', (57, 60))	('TRPC1', 'Gene', (25, 30))	('Ca2', 'Gene', (57, 60))	('loss', 'Var', (17, 21))
54701	33925979	In primary murine pancreatic stellate cells, the knock-out of TRPC6 leads to impaired cell migration when the cells were exposed to a hypoxic environment.	('knock-out', 'Var', (49, 58))	('TRPC6', 'Gene', (62, 67))	('impaired', 'NegReg', (77, 85))	('cell migration', 'CPA', (86, 100))	('hypoxic', 'Disease', 'MESH:D000860', (134, 141))	('hypoxic', 'Disease', (134, 141))	('murine', 'Species', '10090', (11, 17))	('cell migration', 'biological_process', 'GO:0016477', ('86', '100'))
54716	33925979	One example of a possible targeted therapy in the silencing of TRPM8, which enhances the effects of gemcitabine in vitro, in pancreatic cancer cell lines.	('gemcitabine', 'Chemical', 'MESH:C056507', (100, 111))	('silencing', 'Var', (50, 59))	('effects of gemcitabine', 'MPA', (89, 111))	('pancreatic cancer', 'Disease', 'MESH:D010190', (125, 142))	('pancreatic cancer', 'Disease', (125, 142))	('TRPM8', 'Gene', '79054', (63, 68))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))	('TRPM8', 'Gene', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('enhances', 'PosReg', (76, 84))
54726	33925979	As mentioned above, this trial demonstrated that the use of SOR-C13 leads to reduced tumor size and CA19-9 marking.	('tumor', 'Disease', (85, 90))	('SOR', 'molecular_function', 'GO:0033755', ('60', '63'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('reduced', 'NegReg', (77, 84))	('CA19-9 marking', 'CPA', (100, 114))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('SOR', 'molecular_function', 'GO:0043826', ('60', '63'))	('SOR-C13', 'Var', (60, 67))
54734	33925979	Mice with TRPV1 knockout and TRPV1 antagonist experienced a significant attenuation in pain-related behaviors in comparison to wild-type animals.	('TRPV1', 'Gene', (10, 15))	('pain', 'Disease', 'MESH:D010146', (87, 91))	('pain', 'Disease', (87, 91))	('knockout', 'Var', (16, 24))	('Mice', 'Species', '10090', (0, 4))	('attenuation', 'NegReg', (72, 83))	('pain', 'Phenotype', 'HP:0012531', (87, 91))
54741	33925979	Several studies demonstrated that the knockdown of a TRP channel leads to the upregulation of other TRP channels in order to balance it.	('TRP', 'Protein', (100, 103))	('TRP', 'Gene', (53, 56))	('upregulation', 'PosReg', (78, 90))	('TRP', 'Chemical', '-', (53, 56))	('knockdown', 'Var', (38, 47))	('TRP', 'Chemical', '-', (100, 103))
54754	33328627	The levels of BAs were significantly higher in the PDAC + OJ group compared to the healthy control.	('PDAC', 'Chemical', '-', (51, 55))	('higher', 'PosReg', (37, 43))	('BAs', 'Chemical', 'MESH:D001647', (14, 17))	('PDAC + OJ', 'Var', (51, 60))	('levels of BAs', 'MPA', (4, 17))
54757	33328627	Silencing of MUC4 decreased BAs-induced carcinogenic processes in PDAC cells.	('carcinogenic', 'Disease', (40, 52))	('PDAC', 'Chemical', '-', (66, 70))	('decreased', 'NegReg', (18, 27))	('BAs', 'Chemical', 'MESH:D001647', (28, 31))	('Silencing', 'Var', (0, 9))	('carcinogenic', 'Disease', 'MESH:D063646', (40, 52))	('MUC4', 'Gene', (13, 17))
54778	33328627	In addition, we investigated the expression of MUC4 in human PC samples and identified a relation between the presence of OJ and increased expression of MUC4.	('presence', 'Var', (110, 118))	('human', 'Species', '9606', (55, 60))	('increased', 'PosReg', (129, 138))	('MUC4', 'Gene', (153, 157))	('PC', 'Gene', '5091', (61, 63))	('expression', 'MPA', (139, 149))
54861	33328627	2 min, m/z 498.0   125.2/108.3), TDCA (7.9 min, m/z 497.9   125.2/108.3), GCDA (8.8 min, m/z 448.2   75.6/330.5), GDCA (9.6 min, m/z 448.3   402.3/75.6), DCA-D4 (11.9 min, m/z 395.4   349.8/330.5) and GCDA-D4 (8.8 min, m/z 452.3   390.4/387.6).	('GCDA', 'Chemical', '-', (201, 205))	('GCDA', 'Chemical', '-', (74, 78))	('GDCA', 'Chemical', 'MESH:D006002', (114, 118))	('GCDA-D4', 'Chemical', '-', (201, 208))	('TDCA', 'Chemical', 'MESH:D013657', (33, 37))	('m/z 497.9', 'Var', (48, 57))	('DCA-D4', 'Chemical', '-', (154, 160))	('m/z 395.4', 'Var', (172, 181))
54871	33328627	In the case of PDAC + OJ a strong positive staining for vimentin was detected (Fig.	('PDAC + OJ', 'Var', (15, 24))	('vimentin', 'Protein', (56, 64))	('PDAC', 'Chemical', '-', (15, 19))	('vimentin', 'cellular_component', 'GO:0045099', ('56', '64'))	('vimentin', 'cellular_component', 'GO:0045098', ('56', '64'))
54936	33328627	The 4-year overall survival rate of the PDAC + OJ group was significantly lower than that of the PDAC group (p = 0.0191) (Fig.	('overall survival', 'CPA', (11, 27))	('PDAC + OJ', 'Var', (40, 49))	('PDAC', 'Chemical', '-', (97, 101))	('PDAC', 'Chemical', '-', (40, 44))	('lower', 'NegReg', (74, 79))	('rat', 'Species', '10116', (28, 31))
54938	33328627	The efficiency of MUC4 knockdown was confirmed by RT-PCR (Fig.	('PC', 'Gene', '5091', (53, 55))	('MUC4', 'Gene', (18, 22))	('knockdown', 'Var', (23, 32))
54939	33328627	We found that knockdown of MUC4 significantly increased cell death and decreased the rate of proliferation, adhesion, migration and colony forming in a time-dependent manner.	('cell death', 'biological_process', 'GO:0008219', ('56', '66'))	('MUC4', 'Gene', (27, 31))	('adhesion', 'CPA', (108, 116))	('death', 'Disease', (61, 66))	('increased', 'PosReg', (46, 55))	('death', 'Disease', 'MESH:D003643', (61, 66))	('colony forming', 'CPA', (132, 146))	('rat', 'Species', '10116', (85, 88))	('migration', 'CPA', (118, 127))	('knockdown', 'Var', (14, 23))	('decreased', 'NegReg', (71, 80))	('rat', 'Species', '10116', (100, 103))	('rat', 'Species', '10116', (121, 124))
54952	33328627	Moreover, the studies show that hydrophobic bile acids are mostly toxic to cells, by generating oxidative stress and DNA damage, while hydrophilic bile acids play a protective role.	('bile acids', 'Chemical', 'MESH:D001647', (147, 157))	('oxidative stress', 'Phenotype', 'HP:0025464', (96, 112))	('rat', 'Species', '10116', (89, 92))	('hydrophobic', 'Var', (32, 43))	('oxidative stress', 'MPA', (96, 112))	('bile acids', 'Chemical', 'MESH:D001647', (44, 54))	('generating', 'Reg', (85, 95))	('DNA damage', 'MPA', (117, 127))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))
54962	33328627	Since gene mutations are more frequent in the damaged DNA, this favours the tumour progression.	('gene mutations', 'Var', (6, 20))	('favours', 'PosReg', (64, 71))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('tumour', 'Disease', (76, 82))
54992	33328627	In order to clarify the role of MUC4 in the bile-induced cancer progression, we down-regulated MUC4 by siRNA transfection and found that MUC4 act as an oncogenic mucin.	('MUC4', 'Gene', (95, 99))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('mucin', 'Gene', '100508689', (162, 167))	('cancer', 'Disease', (57, 63))	('mucin', 'Gene', (162, 167))	('down-regulated', 'NegReg', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('MUC4', 'Var', (137, 141))
54993	33328627	The oncogenic potential of MUC4 is not surprising since silencing of MUC4 decreases the proliferation of many cancer cells.	('silencing', 'Var', (56, 65))	('cancer', 'Disease', (110, 116))	('rat', 'Species', '10116', (95, 98))	('MUC4', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('decreases', 'NegReg', (74, 83))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
54996	33328627	We have also demonstrated that inhibition of MUC4 expression significantly decreased the effect of TCDCA, one of the most effective BAs, indicating that the tumorigenic effect of bile is mediated by MUC4.	('MUC4', 'Protein', (45, 49))	('BAs', 'Chemical', 'MESH:D001647', (132, 135))	('effect', 'MPA', (89, 95))	('inhibition', 'Var', (31, 41))	('rat', 'Species', '10116', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('TCDCA', 'Chemical', 'MESH:D013655', (99, 104))	('tumorigenic', 'CPA', (157, 168))	('decreased', 'NegReg', (75, 84))
55050	33167508	The aberrantly glycosylated MUC1 expressed on malignant cells, called the tumor associated MUC1 or tMUC1 renders usually inaccessible MUC1 epitopes open to detection.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (74, 79))	('aberrantly', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
55056	33167508	MUC1-CT interacts with beta-catenin, stabilizes it and co-activates Wnt signaling.	('stabilizes', 'PosReg', (37, 47))	('MUC1-CT', 'Var', (0, 7))	('interacts', 'Interaction', (8, 17))	('Wnt signaling', 'Pathway', (68, 81))	('beta-catenin', 'Gene', (23, 35))	('co-activates', 'PosReg', (55, 67))	('beta-catenin', 'Gene', '1499', (23, 35))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))
55058	33167508	MUC1 also reduces pro-apoptotic signaling via the heat shock protein (HSP) 90, PI3K/Akt and Caspase-8 pathways.	('shock', 'Phenotype', 'HP:0031273', (55, 60))	('heat shock protein (HSP) 90', 'Gene', '3320', (50, 77))	('Akt', 'Gene', '207', (84, 87))	('reduces', 'NegReg', (10, 17))	('heat shock protein (HSP) 90', 'Gene', (50, 77))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('Caspase-8', 'Gene', '841', (92, 101))	('Akt', 'Gene', (84, 87))	('Caspase-8', 'Gene', (92, 101))	('MUC1', 'Var', (0, 4))	('PI3K', 'molecular_function', 'GO:0016303', ('79', '83'))	('pro-apoptotic signaling', 'MPA', (18, 41))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
55059	33167508	The hypoglycosylated tMUC1 has increased interaction with cell adhesion molecules ICAM-1 and E-selectin, both of which can improve cellular migration and vascular invasion.	('cell adhesion', 'biological_process', 'GO:0007155', ('58', '71'))	('interaction', 'Interaction', (41, 52))	('increased', 'PosReg', (31, 40))	('improve', 'PosReg', (123, 130))	('cellular migration', 'CPA', (131, 149))	('E-selectin', 'Gene', (93, 103))	('hypoglycosylated', 'Var', (4, 20))	('E-selectin', 'Gene', '6401', (93, 103))	('selectin', 'molecular_function', 'GO:0008337', ('95', '103'))	('tMUC1', 'Gene', (21, 26))	('ICAM-1', 'Gene', '3383', (82, 88))	('vascular invasion', 'CPA', (154, 171))	('selectin', 'molecular_function', 'GO:0030246', ('95', '103'))	('ICAM-1', 'Gene', (82, 88))
55065	33167508	Overexpression in multiple epithelial tumors, expression all over the surface of a tumor cell due to loss of apicobasal polarity in cancer cells, thus making it accessible to antibodies and tumor-specific aberrant glycosylation with truncated carbohydrate antigens Tn and TF in the VNTR region are features that make MUC1 an attractive target for immunotherapy.	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('loss', 'NegReg', (101, 105))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('glycosylation', 'biological_process', 'GO:0070085', ('214', '227'))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (205, 227))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Tn', 'Gene', '7123', (265, 267))	('apicobasal polarity', 'CPA', (109, 128))	('tumors', 'Disease', (38, 44))	('aberrant glycosylation', 'Var', (205, 227))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', (190, 195))	('glycosylation', 'Var', (214, 227))	('carbohydrate', 'Chemical', 'MESH:D002241', (243, 255))	('tumor', 'Disease', (38, 43))	('cancer', 'Disease', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
55081	33167508	In the preclinical studies, 131I- and 90Y-labeled PAM4, was shown to control pancreatic cancer with enhanced survival and clinical responses in pancreatic cancer patients.	('131I- and', 'Var', (28, 37))	('patients', 'Species', '9606', (162, 170))	('pancreatic cancer', 'Disease', (144, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('enhanced', 'PosReg', (100, 108))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (144, 161))	('control', 'PosReg', (69, 76))	('PAM4', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('pancreatic cancer', 'Disease', (77, 94))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))
55082	33167508	In the phase I clinical trial, 131I-PAM4 IgG and 99mTc-PAM4 Fab' showed the specific tumor localization in four out of five patients, therefore ensuring these are ideal candidates for further trials.	('tumor', 'Disease', (85, 90))	('Fab', 'Gene', '2187', (60, 63))	('localization', 'biological_process', 'GO:0051179', ('91', '103'))	('Fab', 'Gene', (60, 63))	('131I-PAM4 IgG', 'Var', (31, 44))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('patients', 'Species', '9606', (124, 132))
55084	33167508	In a phase I trial, it was shown that 90Y-Clivatuzumab tetraxetan was well tolerated with toxicity restricted to the bone marrow and manageable hematologic toxicity was seen at the maximal tolerated dose of 90Y.	('90Y-Clivatuzumab tetraxetan', 'Chemical', '-', (38, 65))	('90Y-Clivatuzumab', 'Var', (38, 54))	('toxicity', 'Disease', 'MESH:D064420', (90, 98))	('toxicity', 'Disease', (90, 98))	('toxicity', 'Disease', 'MESH:D064420', (156, 164))	('toxicity', 'Disease', (156, 164))
55087	33167508	Phase I/II trials with 80 participants are ongoing (NCT00603863) to test whether different doses of 90Y-hPAM4 in combination with gemcitabine are safe to give in patients with previously untreated pancreatic cancer.	('patients', 'Species', '9606', (162, 170))	('90Y-hPAM4', 'Var', (100, 109))	('participants', 'Species', '9606', (26, 38))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (197, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('pancreatic cancer', 'Disease', (197, 214))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('pancreatic cancer', 'Disease', 'MESH:D010190', (197, 214))	('gemcitabine', 'Chemical', 'MESH:C056507', (130, 141))
55094	33167508	TAB004 distinguishes between normal and tumor-associated forms of MUC1 solely based on the expression of hypo-glycosylated or aberrantly glycosylated MUC1.	('aberrantly glycosylated', 'Var', (126, 149))	('MUC1', 'Protein', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('hypo-glycosylated', 'Disease', 'MESH:D052456', (105, 122))	('tumor', 'Disease', (40, 45))	('hypo-glycosylated', 'Disease', (105, 122))	('MUC1', 'Gene', (66, 70))
55101	33167508	MUC1-014E showed sharp and specific staining of carcinoma cells, but no staining in fibroblasts, endothelial cells, and inflammatory cells.	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('MUC1-014E', 'Var', (0, 9))	('carcinoma', 'Disease', 'MESH:D009369', (48, 57))	('carcinoma', 'Disease', (48, 57))
55120	33167508	AR20.5 forms a complex with circulating MUC1 and/or transmembrane MUC1 on tumor cells.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('complex', 'Interaction', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('AR20.5', 'Var', (0, 6))	('tumor', 'Disease', (74, 79))	('transmembrane', 'cellular_component', 'GO:0044214', ('52', '65'))	('transmembrane', 'cellular_component', 'GO:0016021', ('52', '65'))
55133	33167508	Tumor improvement was shown in 35-60% of patients at different dosages of SAR566658.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SAR566658', 'Chemical', '-', (74, 83))	('SAR566658', 'Var', (74, 83))	('patients', 'Species', '9606', (41, 49))	('improvement', 'PosReg', (6, 17))
55135	33167508	Humanized C242 (HuC242 or Cantuzumab) has the CA242 epitope and reacts with a novel glycoform of MUC1 also known as CanAg glycoprotein (cancer antigen).	('Human', 'Species', '9606', (0, 5))	('C242', 'Var', (10, 14))	('CA242', 'Var', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('HuC242', 'Chemical', '-', (16, 22))	('Cantuzumab', 'Chemical', '-', (26, 36))	('reacts', 'Reg', (64, 70))	('CanAg', 'Chemical', '-', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
55140	33167508	Results showed that HuC242-DM1 is safe and well tolerated with effective antitumor activity.	('HuC242-DM1', 'Var', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('HuC242', 'Chemical', '-', (20, 26))	('DM1', 'Chemical', '-', (27, 30))	('tumor', 'Disease', (77, 82))
55154	33167508	MY.1E12 specifically reacts to T structure (ST) attached to Thr8.	('Thr8', 'Chemical', '-', (60, 64))	('MY.1E12', 'Var', (0, 7))	('reacts', 'Reg', (21, 27))
55172	33167508	Although reduction in tumor growth was limited, simultaneous administration of a combination of three bsAbs (M x 3, M x 28 and M x 2 bsAb) with peripheral blood mononuclear cells (PBMCs) or T-LAK cells in vitro showed higher cytotoxicity against MUC1-expressing bile duct carcinoma cells.	('M x 2 bsAb', 'Var', (127, 137))	('M x 28', 'Var', (116, 122))	('bile duct carcinoma', 'Disease', 'MESH:D001650', (262, 281))	('higher', 'PosReg', (218, 224))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (225, 237))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('bile duct carcinoma', 'Phenotype', 'HP:0030153', (262, 281))	('tumor', 'Disease', (22, 27))	('bile duct carcinoma', 'Disease', (262, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('cytotoxicity', 'Disease', (225, 237))
55184	33167508	This bsAb is currently under several phase II randomized clinical trials for advanced gastric, kidney, lung, breast, colorectal, pancreatic and liver cancers, but there is no further information available ([NCT03554395], [NCT03540199], [NCT03501056], [NCT03524261], [NCT03524274], [NCT03509298], and [NCT03484962]).	('[NCT03509298]', 'Var', (281, 294))	('N', 'Chemical', 'MESH:D009584', (252, 253))	('N', 'Chemical', 'MESH:D009584', (267, 268))	('[NCT03524261]', 'Var', (251, 264))	('N', 'Chemical', 'MESH:D009584', (282, 283))	('[NCT03501056]', 'Var', (236, 249))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('[NCT03554395]', 'Var', (206, 219))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('[NCT03484962]', 'Var', (300, 313))	('liver cancers', 'Phenotype', 'HP:0002896', (144, 157))	('[NCT03524274]', 'Var', (266, 279))	('pancreatic and liver cancers', 'Disease', 'MESH:D006528', (129, 157))	('N', 'Chemical', 'MESH:D009584', (207, 208))	('N', 'Chemical', 'MESH:D009584', (222, 223))	('liver cancer', 'Phenotype', 'HP:0002896', (144, 156))	('N', 'Chemical', 'MESH:D009584', (301, 302))	('N', 'Chemical', 'MESH:D009584', (237, 238))	('[NCT03540199]', 'Var', (221, 234))
55196	33167508	The high affinity for the glycopeptide and the lack of specific binding contacts of AR20.5 suggest that glycosylation of MUC1 stabilizes an extended bioactive conformation of the peptide that is recognized by the antibody.	('MUC1', 'Gene', (121, 125))	('extended bioactive conformation of the peptide', 'MPA', (140, 186))	('glycosylation', 'biological_process', 'GO:0070085', ('104', '117'))	('antibody', 'cellular_component', 'GO:0019814', ('213', '221'))	('binding', 'molecular_function', 'GO:0005488', ('64', '71'))	('antibody', 'molecular_function', 'GO:0003823', ('213', '221'))	('stabilizes', 'PosReg', (126, 136))	('glycopeptide', 'Chemical', 'MESH:D006020', (26, 38))	('antibody', 'cellular_component', 'GO:0042571', ('213', '221'))	('peptide', 'Chemical', 'MESH:D010455', (179, 186))	('glycosylation', 'Var', (104, 117))	('peptide', 'Chemical', 'MESH:D010455', (31, 38))	('antibody', 'cellular_component', 'GO:0019815', ('213', '221'))
55197	33167508	Evidence suggests that glycosylation of the peptide alters the conformational equilibrium of the antigen, and this allows the antibody to select the correct conformation.	('antibody', 'cellular_component', 'GO:0019815', ('126', '134'))	('peptide', 'Chemical', 'MESH:D010455', (44, 51))	('antibody', 'cellular_component', 'GO:0019814', ('126', '134'))	('glycosylation', 'biological_process', 'GO:0070085', ('23', '36'))	('alters', 'Reg', (52, 58))	('antibody', 'molecular_function', 'GO:0003823', ('126', '134'))	('glycosylation', 'Var', (23, 36))	('allows', 'Reg', (115, 121))	('conformational equilibrium of the antigen', 'MPA', (63, 104))	('antibody', 'cellular_component', 'GO:0042571', ('126', '134'))
55217	33167508	For example, some antibodies have been reported to show ADCC and ADCP, some others block anti-apoptotic mechanisms thus inducing cell death, also some antibodies reduce expression of pro-survival genes.	('reduce', 'NegReg', (162, 168))	('pro-survival', 'biological_process', 'GO:0043066', ('183', '195'))	('inducing', 'Reg', (120, 128))	('block', 'NegReg', (83, 88))	('pro-survival genes', 'Gene', (183, 201))	('anti-apoptotic', 'CPA', (89, 103))	('death', 'Disease', (134, 139))	('death', 'Disease', 'MESH:D003643', (134, 139))	('ADCC', 'biological_process', 'GO:0001788', ('56', '60'))	('cell death', 'biological_process', 'GO:0008219', ('129', '139'))	('ADCC', 'Disease', (56, 60))	('antibodies', 'Var', (151, 161))	('expression', 'MPA', (169, 179))
55224	33167508	However, it has been shown that high-MUC1 PDA cells are more sensitive toward the STAT-3 inhibitor Napabucasin.	('high-MUC1', 'Var', (32, 41))	('Napabucasin', 'Chemical', 'MESH:C000621033', (99, 110))	('STAT-3', 'Gene', (82, 88))	('STAT-3', 'Gene', '6774', (82, 88))
55289	32433600	Objective response (CR or PR) to preoperative mFOLFIRINOX was associated with better OS compared with the response of stable disease or progressive disease (median 26.2 months [95% CI, 22.7-29.8 months] vs 13.8 months [95% CI, 9.7-17.9 months], P = 0.046), although the relationship between response and PFS was not statistically significant (median 14.8 months [95% CI, 12.5-17.0 months] vs 9.8 months [95% CI, 6.7-12.9 months], P = 0.09; Supplementary Fig.	('stable disease', 'Disease', (118, 132))	('mFOLFIRINOX', 'Chemical', '-', (46, 57))	('better OS', 'Disease', (78, 87))	('mFOLFIRINOX', 'Var', (46, 57))	('stable disease', 'Disease', 'MESH:D060050', (118, 132))	('PR', 'Gene', '140738', (26, 28))	('progressive disease', 'Disease', 'MESH:D018450', (136, 155))	('progressive disease', 'Disease', (136, 155))
55315	32433600	Despite recent advances in neoadjuvant therapy using mFOLFIRINOX in BRPC, further improvements in its efficacy are needed considering that only two-thirds of patients undergo surgery and more than half of patients experience recurrence even after surgery less than 2 years postoperatively.	('mFOLFIRINOX', 'Chemical', '-', (53, 64))	('patients', 'Species', '9606', (205, 213))	('mFOLFIRINOX', 'Var', (53, 64))	('BRPC', 'Disease', (68, 72))	('patients', 'Species', '9606', (158, 166))
55342	32486098	Moreover, programs for the differentiation of monocytes and maturate macrophages are based on the significant epigenetic modifications (DNA methylation, histone modifications, miRNA.).	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('miR', 'Gene', '751557', (176, 179))	('DNA methylation', 'biological_process', 'GO:0006306', ('136', '151'))	('histone', 'MPA', (153, 160))	('DNA', 'Var', (136, 139))	('miR', 'Gene', (176, 179))
55351	32486098	PU.1 knockdown resulted in reduced alternative activation of macrophages that was associated with decreased expression of CCL22, while lipopolysaccharide (LPS) treatment resulted in up-regulation of PU.1 expression accompanied by increased level of CCL22 in murine BMDMs.	('reduced', 'NegReg', (27, 34))	('knockdown', 'Var', (5, 14))	('PU.1', 'Gene', (0, 4))	('PU.1', 'Gene', (199, 203))	('alternative activation of macrophages', 'CPA', (35, 72))	('level', 'MPA', (240, 245))	('CCL22', 'Gene', '20299', (249, 254))	('murine', 'Species', '10090', (258, 264))	('regulation', 'biological_process', 'GO:0065007', ('185', '195'))	('up-regulation', 'PosReg', (182, 195))	('CCL22', 'Gene', '20299', (122, 127))	('CCL', 'molecular_function', 'GO:0044101', ('249', '252'))	('increased', 'PosReg', (230, 239))	('expression', 'MPA', (204, 214))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (135, 153))	('CCL22', 'Gene', (249, 254))	('CCL', 'molecular_function', 'GO:0044101', ('122', '125'))	('CCL22', 'Gene', (122, 127))	('expression', 'MPA', (108, 118))	('decreased', 'NegReg', (98, 107))
55352	32486098	Thus, miR-181a induces macrophage polarization to M2 phenotype through suppression of the expression of PU.1, C/EBPalpha and KLF6 in human macrophages.	('induces', 'Reg', (15, 22))	('C/EBPalpha', 'Gene', '1050', (110, 120))	('KLF6', 'Gene', (125, 129))	('PU.1', 'Gene', (104, 108))	('suppression', 'NegReg', (71, 82))	('human', 'Species', '9606', (133, 138))	('miR-181a', 'Chemical', '-', (6, 14))	('expression', 'MPA', (90, 100))	('macrophage polarization', 'CPA', (23, 46))	('macrophage polarization', 'biological_process', 'GO:0042116', ('23', '46'))	('C/EBPalpha', 'Gene', (110, 120))	('miR-181a', 'Var', (6, 14))
55353	32486098	Thus, in a mouse model with functional PU.1 knockout in mature macrophages, the inhibition of inflammatory gene expression (COX-2, iNOS, TLR4) and inflammatory cytokine secretion (IL-6, MCP-1, IL-1beta, TNF-alpha), as well as significant decrease in systemic inflammation, was identified.	('TLR4', 'Gene', (137, 141))	('inflammation', 'biological_process', 'GO:0006954', ('259', '271'))	('inhibition', 'NegReg', (80, 90))	('cytokine secretion', 'biological_process', 'GO:0050663', ('160', '178'))	('knockout', 'Var', (44, 52))	('inflammation', 'Disease', 'MESH:D007249', (259, 271))	('IL-6', 'molecular_function', 'GO:0005138', ('180', '184'))	('MCP-1', 'Gene', '20296', (186, 191))	('COX-2', 'Gene', '17709', (124, 129))	('TLR4', 'Gene', '21898', (137, 141))	('PU.1', 'Gene', (39, 43))	('inflammation', 'Disease', (259, 271))	('iNOS', 'Gene', '18126', (131, 135))	('MCP-1', 'Gene', (186, 191))	('gene expression', 'biological_process', 'GO:0010467', ('107', '122'))	('COX-2', 'Gene', (124, 129))	('iNOS', 'Gene', (131, 135))	('decrease', 'NegReg', (238, 246))	('inflammatory', 'MPA', (94, 106))	('MCP', 'molecular_function', 'GO:0004298', ('186', '189'))	('IL-1', 'molecular_function', 'GO:0005149', ('193', '197'))	('mouse', 'Species', '10090', (11, 16))	('inflammatory cytokine secretion', 'MPA', (147, 178))
55371	32486098	Inhibition of the STAT6 pathway by using small interfering RNA or the pharmacologic inhibitor AS1517499 inhibited the differentiation of murine RAW264.7 macrophages into the M2 phenotype, as demonstrated by the reduction of ARG1 and CD206 expression.	('CD206', 'Gene', (233, 238))	('small interfering', 'Var', (41, 58))	('differentiation', 'CPA', (118, 133))	('reduction', 'NegReg', (211, 220))	('murine', 'Species', '10090', (137, 143))	('AS1517499', 'Chemical', 'MESH:C544923', (94, 103))	('RNA', 'cellular_component', 'GO:0005562', ('59', '62'))	('RAW264.7', 'CellLine', 'CVCL:0493', (144, 152))	('STAT6 pathway', 'Pathway', (18, 31))	('inhibited', 'NegReg', (104, 113))	('ARG1', 'Protein', (224, 228))
55372	32486098	Besides, AS1517499 significantly attenuated tumor growth and early liver metastasis in 4T1 mammary carcinoma mouse model.	('early liver metastasis', 'CPA', (61, 83))	('carcinoma', 'Disease', 'MESH:D009369', (99, 108))	('AS1517499', 'Var', (9, 18))	('attenuated tumor', 'Disease', (33, 49))	('attenuated tumor', 'Disease', 'MESH:C538265', (33, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('AS1517499', 'Chemical', 'MESH:C544923', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (91, 108))	('carcinoma', 'Disease', (99, 108))	('mouse', 'Species', '10090', (109, 114))
55379	32486098	In the tumor microenvironment, TAM-derived IL-10 inhibits IL-12 production associated with the lack of NF-kappaB activation promoting tumor survival, while blocking of IL-10 restores the IL-12 production in a mouse model of fibrosarcoma Tumor-promoting activation of NF-kappaB in macrophages was also demonstrated.	('IL-12', 'molecular_function', 'GO:0005143', ('58', '63'))	('fibrosarcoma Tumor', 'Disease', 'MESH:D005354', (224, 242))	('fibrosarcoma Tumor', 'Disease', (224, 242))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('IL-10', 'Gene', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('IL-12', 'molecular_function', 'GO:0005143', ('187', '192'))	('promoting', 'PosReg', (124, 133))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('Tumor', 'Phenotype', 'HP:0002664', (237, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('253', '276'))	('IL-10', 'molecular_function', 'GO:0005141', ('168', '173'))	('blocking', 'Var', (156, 164))	('IL-12 production', 'biological_process', 'GO:0032615', ('58', '74'))	('restores', 'PosReg', (174, 182))	('IL-12 production', 'biological_process', 'GO:0032615', ('187', '203'))	('IL-12 production', 'MPA', (58, 74))	('mouse', 'Species', '10090', (209, 214))	('tumor', 'Disease', (134, 139))	('TAM', 'Gene', (31, 34))	('tumor', 'Disease', (7, 12))	('inhibits', 'NegReg', (49, 57))	('IL-10', 'Gene', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('IL-10', 'molecular_function', 'GO:0005141', ('43', '48'))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('103', '123'))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (224, 236))	('TAM', 'Gene', '8205', (31, 34))
55394	32486098	Moreover, deletion of c-Myc in macrophages resulted in the reduced expression of pro-tumor genes (e.g., VEGF, MMP9, and HIF1a) in TAMs and reduced tumor development in a mouse model of melanoma.	('tumor', 'Disease', (85, 90))	('reduced', 'NegReg', (59, 66))	('MMP9', 'Gene', (110, 114))	('MMP9', 'molecular_function', 'GO:0004229', ('110', '114'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('reduced', 'NegReg', (139, 146))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('VEGF', 'Gene', (104, 108))	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('mouse', 'Species', '10090', (170, 175))	('c-Myc', 'Gene', (22, 27))	('HIF1a', 'Gene', '15251', (120, 125))	('TAMs', 'Chemical', '-', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('HIF1a', 'Gene', (120, 125))	('c-Myc', 'Gene', '4609', (22, 27))	('deletion', 'Var', (10, 18))	('expression', 'MPA', (67, 77))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))
55399	32486098	The knockdown of IRF1 in macrophages induces their pro-tumor activity regarding to hepatocellular carcinoma cell lines HepG2 and SMMC-7721, promoting proliferation and invasion of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('promoting', 'PosReg', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (83, 107))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (83, 107))	('IRF1', 'Gene', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('hepatocellular carcinoma', 'Disease', (83, 107))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', (55, 60))	('HepG2', 'CellLine', 'CVCL:0027', (119, 124))	('knockdown', 'Var', (4, 13))	('SMMC-7721', 'CellLine', 'CVCL:0534', (129, 138))	('proliferation', 'CPA', (150, 163))
55410	32486098	In human monocyte-derived macrophages IRF-7 knockdown by siRNA increased LPS-induced IL-10 production, indicating that IRF7 induction blocks early IL-10 response.	('IRF-7', 'Gene', '3665', (38, 43))	('IL-10', 'molecular_function', 'GO:0005141', ('85', '90'))	('increased', 'PosReg', (63, 72))	('LPS-induced IL-10 production', 'MPA', (73, 101))	('blocks', 'NegReg', (134, 140))	('increased LPS', 'Phenotype', 'HP:0003141', (63, 76))	('human', 'Species', '9606', (3, 8))	('IL-10', 'molecular_function', 'GO:0005141', ('147', '152'))	('IRF-7', 'Gene', (38, 43))	('knockdown', 'Var', (44, 53))	('IL-10 production', 'biological_process', 'GO:0032613', ('85', '101'))	('early IL-10 response', 'MPA', (141, 161))
55416	32486098	Furthermore, co-expression of IRF5 and IKKbeta (a kinase that phosphorylates and activates IRF5) mediates TAM polarization towards M1 phenotype, supressing tumor development in model systems of advanced-stage ovarian cancer, metastatic melanoma, and glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (250, 262))	('melanoma', 'Disease', 'MESH:D008545', (236, 244))	('tumor', 'Disease', (156, 161))	('IKKbeta', 'Gene', (39, 46))	('glioblastoma', 'Disease', (250, 262))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('glioblastoma', 'Phenotype', 'HP:0012174', (250, 262))	('co-expression', 'Var', (13, 26))	('IRF5', 'Gene', '27056', (30, 34))	('ovarian cancer', 'Phenotype', 'HP:0100615', (209, 223))	('TAM', 'Gene', (106, 109))	('advanced-stage ovarian cancer', 'Disease', (194, 223))	('IRF5', 'Gene', (30, 34))	('IKKbeta', 'Gene', '12675', (39, 46))	('advanced-stage ovarian cancer', 'Phenotype', 'HP:0008209', (194, 223))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('melanoma', 'Disease', (236, 244))	('TAM', 'Gene', '8205', (106, 109))	('supressing', 'NegReg', (145, 155))	('IRF5', 'Gene', '27056', (91, 95))	('IRF5', 'Gene', (91, 95))	('advanced-stage ovarian cancer', 'Disease', 'MESH:D020178', (194, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
55419	32486098	Inhibition of IRF8 in macrophages reduces expression of inflammatory mediators associated with M1 macrophage (IL-1b, IL-6, iNOS, and TNF-alpha) and delayed wound healing in vivo.	('reduces', 'NegReg', (34, 41))	('wound healing', 'biological_process', 'GO:0042060', ('156', '169'))	('IL-1', 'molecular_function', 'GO:0005149', ('110', '114'))	('expression of inflammatory', 'MPA', (42, 68))	('wound healing', 'CPA', (156, 169))	('IL-6', 'molecular_function', 'GO:0005138', ('117', '121'))	('delayed', 'NegReg', (148, 155))	('Inhibition', 'Var', (0, 10))	('delayed wound healing', 'Phenotype', 'HP:0001058', (148, 169))	('reduces expression of inflammatory mediators', 'Phenotype', 'HP:0012648', (34, 78))	('iNOS', 'Gene', '18126', (123, 127))	('IRF8', 'Gene', (14, 18))	('iNOS', 'Gene', (123, 127))
55421	32486098	High levels of IRF8 expression is associated with prolonged DFS in renal cell carcinoma patients.	('associated', 'Reg', (34, 44))	('patients', 'Species', '9606', (88, 96))	('IRF8', 'Gene', (15, 19))	('High levels', 'Var', (0, 11))	('prolonged DFS in renal cell carcinoma', 'Disease', (50, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (67, 87))	('prolonged DFS in renal cell carcinoma', 'Disease', 'MESH:C538614', (50, 87))
55439	32486098	LPS-stimulated peritoneal macrophages derived from macrophage-specific dominant-negative MafB transgenic mice showed increased expression of IL-6 and TNF-a.	('transgenic', 'Var', (94, 104))	('TNF-a', 'Gene', (150, 155))	('MafB', 'Gene', (89, 93))	('transgenic mice', 'Species', '10090', (94, 109))	('increased', 'PosReg', (117, 126))	('expression', 'MPA', (127, 137))	('increased expression of IL-6', 'Phenotype', 'HP:0030783', (117, 145))	('TNF-a', 'Gene', '21926', (150, 155))	('IL-6', 'molecular_function', 'GO:0005138', ('141', '145'))	('IL-6', 'Gene', (141, 145))
55441	32486098	Besides, strong expression of MafB was identified by immunostaining analysis in CD204+ and CD68+ TAMs on stage 3 of human lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Disease', (122, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('CD204', 'Gene', '4481', (80, 85))	('TAMs', 'Chemical', '-', (97, 101))	('CD68+', 'Var', (91, 96))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('MafB', 'Gene', (30, 34))	('CD204', 'Gene', (80, 85))	('human', 'Species', '9606', (116, 121))
55445	32486098	Deletion of c-Maf in macrophages resulted in reduced tumor size and enhanced antitumor T cell immunity in vivo.	('enhanced', 'PosReg', (68, 76))	('reduced', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('enhanced antitumor T cell immunity', 'Phenotype', 'HP:0031402', (68, 102))	('c-Maf', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (81, 86))	('Deletion', 'Var', (0, 8))
55452	32486098	TFEB knockdown in EO771 or LLC-derived C57BL/6 mice resulting in enhanced angiogenesis, tumor growth and reduced infiltration of CD8+ T cells.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('knockdown', 'Var', (5, 14))	('angiogenesis', 'CPA', (74, 86))	('enhanced', 'PosReg', (65, 73))	('angiogenesis', 'biological_process', 'GO:0001525', ('74', '86'))	('TFEB', 'Gene', '21425', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('reduced', 'NegReg', (105, 112))	('TFEB', 'Gene', (0, 4))	('infiltration of CD8+ T cells', 'CPA', (113, 141))	('tumor', 'Disease', (88, 93))	('mice', 'Species', '10090', (47, 51))	('LLC', 'cellular_component', 'GO:0038045', ('27', '30'))
55458	32486098	Deletion of KLF4 in murine myeloid cells resulted in suppression of expression of M2 markers (ArRG1, CD206, IL-10, TGF-beta1, and Chil3) and reduction of HCC growth.	('TGF-beta1', 'Gene', '21803', (115, 124))	('IL-10', 'molecular_function', 'GO:0005141', ('108', '113'))	('Chil3', 'Gene', (130, 135))	('CD206', 'Gene', (101, 106))	('expression', 'MPA', (68, 78))	('KLF4', 'Gene', '16600', (12, 16))	('suppression', 'NegReg', (53, 64))	('TGF-beta1', 'Gene', (115, 124))	('Chil3', 'Gene', '12655', (130, 135))	('murine', 'Species', '10090', (20, 26))	('HCC', 'Phenotype', 'HP:0001402', (154, 157))	('HCC growth', 'CPA', (154, 164))	('KLF4', 'Gene', (12, 16))	('ArRG1', 'Gene', (94, 99))	('reduction', 'NegReg', (141, 150))	('Deletion', 'Var', (0, 8))
55470	32486098	In cancer, DNA methylation is critical for the suppression of the expression of tumor suppressor genes while loss of DNA methylation leads to the overexpression of oncogenes.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('DNA methylation', 'biological_process', 'GO:0006306', ('117', '132'))	('overexpression', 'PosReg', (146, 160))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('DNA methylation', 'biological_process', 'GO:0006306', ('11', '26'))	('oncogenes', 'MPA', (164, 173))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('DNA', 'Gene', (117, 120))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('expression', 'MPA', (66, 76))	('loss', 'Var', (109, 113))	('tumor', 'Disease', (80, 85))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('cancer', 'Disease', (3, 9))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('suppression', 'NegReg', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
55472	32486098	DNMT3b knockdown promotes macrophage polarization to alternatively activated M2 phenotype in RAW264.7 cells.	('macrophage polarization', 'biological_process', 'GO:0042116', ('26', '49'))	('promotes', 'PosReg', (17, 25))	('DNMT3b', 'Gene', (0, 6))	('macrophage polarization', 'CPA', (26, 49))	('DNMT3b', 'Gene', '13436', (0, 6))	('RAW264.7', 'CellLine', 'CVCL:0493', (93, 101))	('knockdown', 'Var', (7, 16))
55476	32486098	In type 2 diabetic mice, decrease in the ability of macrophages to support wound healing was associated with microRNA let-7d-3p, which was up-regulated by DNMT1 resulting in the differentiation of cells toward the M1 phenotype.	('differentiation', 'CPA', (178, 193))	('microRNA', 'Var', (109, 117))	('diabetic', 'Disease', 'MESH:D003920', (10, 18))	('decrease', 'NegReg', (25, 33))	('up-regulated', 'PosReg', (139, 151))	('diabetic', 'Disease', (10, 18))	('wound healing', 'biological_process', 'GO:0042060', ('75', '88'))	('mice', 'Species', '10090', (19, 23))
55477	32486098	However, the effect of LPS in BMDMs during M1 activation is also associated with a significant reduction in the expression of DNMT 1, 3a and 3b, and a significant increase in the expression of TET2 and TET3 (Table 2, Figure 1).	('expression', 'MPA', (112, 122))	('expression', 'MPA', (179, 189))	('increase', 'PosReg', (163, 171))	('TET2', 'Gene', (193, 197))	('TET3', 'Gene', '194388', (202, 206))	('DNMT 1', 'Gene', (126, 132))	('TET3', 'Gene', (202, 206))	('TET2', 'Gene', '214133', (193, 197))	('reduction', 'NegReg', (95, 104))	('LPS', 'Var', (23, 26))
55479	32486098	Recently, the combination of mass spectrometry and single molecular imaging demonstrated that LPS induces global changes in DNA methylation of the genome of murine macrophages.	('changes', 'Reg', (113, 120))	('changes in DNA methylation', 'biological_process', 'GO:0044728', ('113', '139'))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('LPS', 'Var', (94, 97))	('murine', 'Species', '10090', (157, 163))	('DNA methylation', 'MPA', (124, 139))
55491	32486098	Moreover, di- or tri-methylation of histone H3 in lysine-4 and -79 is associated with gene activation, while the methyl group (H3K9me2/3 and H3K27me3) relates to transcriptional repression.	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('histone H3', 'Gene', '260423', (36, 46))	('H3K9me2/3', 'Var', (127, 136))	('histone H3', 'Gene', (36, 46))	('lysine', 'Chemical', 'MESH:D008239', (50, 56))	('gene activation', 'MPA', (86, 101))	('di-', 'Var', (10, 13))	('tri-methylation', 'Var', (17, 32))	('H3K27me3', 'Var', (141, 149))
55499	32486098	Most of the data indicates the involvement of histone modification in TAMs in the formation of immunosuppressive M2-like phenotype in tumors (Table 2).	('histone', 'Var', (46, 53))	('tumors', 'Disease', (134, 140))	('TAMs', 'Gene', (70, 74))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('TAMs', 'Chemical', '-', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('formation', 'biological_process', 'GO:0009058', ('82', '91'))	('involvement', 'Reg', (31, 42))	('histone modification', 'biological_process', 'GO:0016570', ('46', '66'))
55503	32486098	When combining JQ1 with a PI3K inhibitor, or using the double PI3K/BRD4 inhibitor SF2523 (previously reported as a strong inhibitor of tumor growth and metastasis in various cancer models), tumor growth was suppressed in syngenic and spontaneous mouse cancer models.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('BRD4', 'Gene', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('mouse', 'Species', '10090', (246, 251))	('suppressed', 'NegReg', (207, 217))	('JQ1', 'Var', (15, 18))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (252, 258))	('PI3K', 'molecular_function', 'GO:0016303', ('26', '30'))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', (190, 195))	('BRD4', 'Gene', '57261', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('PI3K', 'molecular_function', 'GO:0016303', ('62', '66'))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('cancer', 'Disease', 'MESH:D009369', (174, 180))
55515	32486098	A similar result was obtained for murine models of lung and pancreatic cancer where inhibition of HDAC had an antitumor effect by acting through the mechanisms of regulation of nitride oxide (NO) production in TAMs.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('lung', 'Disease', (51, 55))	('TAMs', 'Chemical', '-', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('nitride oxide', 'Chemical', '-', (177, 190))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('murine', 'Species', '10090', (34, 40))	('tumor', 'Disease', (114, 119))	('HDAC', 'Gene', (98, 102))	('pancreatic cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('regulation', 'biological_process', 'GO:0065007', ('163', '173'))	('HDAC', 'Gene', '9734', (98, 102))	('inhibition', 'Var', (84, 94))
55526	32486098	Moreover, knockdown of miR-146a promoted polarization of macrophages into M1-like phenotype and decreased polarization to M2-like phenotype.	('promoted', 'PosReg', (32, 40))	('polarization', 'MPA', (106, 118))	('polarization', 'CPA', (41, 53))	('miR-146a', 'Gene', (23, 31))	('miR-146a', 'Gene', '387164', (23, 31))	('decreased', 'NegReg', (96, 105))	('knockdown', 'Var', (10, 19))
55531	32486098	In addition, microRNA-19-a-3p inhibits tumor progression by downregulation of human fos-related antigen 1 (FRA-1) gene (acting as a pro-oncogene by supporting the invasion and progression of breast tumors) and the FRA/STAT3 signaling pathway in RAW264.7 cells.	('FRA/STAT3 signaling pathway', 'Pathway', (214, 241))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('progression', 'CPA', (176, 187))	('breast tumor', 'Phenotype', 'HP:0100013', (191, 203))	('invasion', 'CPA', (163, 171))	('supporting', 'PosReg', (148, 158))	('breast tumors', 'Disease', 'MESH:D001943', (191, 204))	('breast tumors', 'Disease', (191, 204))	('FRA-1', 'Gene', (107, 112))	('breast tumors', 'Phenotype', 'HP:0100013', (191, 204))	('human', 'Species', '9606', (78, 83))	('microRNA-19-a-3p', 'Var', (13, 29))	('inhibits', 'NegReg', (30, 38))	('downregulation', 'NegReg', (60, 74))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (198, 203))	('fos-related antigen 1', 'Gene', (84, 105))	('RAW264.7', 'CellLine', 'CVCL:0493', (245, 253))	('FRA-1', 'Gene', '8061', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('fos-related antigen 1', 'Gene', '8061', (84, 105))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('signaling pathway', 'biological_process', 'GO:0007165', ('224', '241'))
55549	32486098	PKM2 was found to activate the LPS-induced pro-inflammatory phenotype of M1 macrophages in murine model via the production of HIF-1alpha, IL-1beta and other HIF-1alpha-dependent genes as well as to promote inflammasome activation by modulating eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) phosphorylation in macrophages.	('phosphorylation', 'biological_process', 'GO:0016310', ('312', '327'))	('phosphorylation', 'MPA', (312, 327))	('IL-1', 'molecular_function', 'GO:0005149', ('138', '142'))	('promote', 'PosReg', (198, 205))	('translation initiation', 'biological_process', 'GO:0006413', ('255', '277'))	('inflammasome activation', 'MPA', (206, 229))	('modulating', 'Reg', (233, 243))	('murine', 'Species', '10090', (91, 97))	('activate', 'PosReg', (18, 26))	('eukaryotic translation initiation factor 2 alpha kinase 2', 'Gene', '19106', (244, 301))	('EIF2AK2', 'Gene', (303, 310))	('LPS-induced', 'Gene', (31, 42))	('EIF2AK2', 'Gene', '19106', (303, 310))	('IL-1beta', 'Gene', (138, 146))	('EIF2', 'cellular_component', 'GO:0005850', ('303', '307'))	('pro-inflammatory phenotype', 'MPA', (43, 69))	('HIF-1alpha', 'Gene', (126, 136))	('PKM2', 'Var', (0, 4))
55552	32486098	Moreover, combined deletion of two forms of pyruvate dehydrogenase kinase PDK2 and PDK4 in myeloid cells prevents M1 polarization and correlates with the improved mitochondrial respiration in mouse models.	('PDK2', 'Gene', '18604', (74, 78))	('improved', 'PosReg', (154, 162))	('prevents', 'NegReg', (105, 113))	('PDK2', 'Gene', (74, 78))	('PDK4', 'Gene', '27273', (83, 87))	('mouse', 'Species', '10090', (192, 197))	('deletion', 'Var', (19, 27))	('PDK4', 'Gene', (83, 87))	('mitochondrial respiration', 'MPA', (163, 188))	('PDK4', 'molecular_function', 'GO:0004740', ('83', '87'))	('respiration', 'biological_process', 'GO:0007585', ('177', '188'))	('PDK2', 'molecular_function', 'GO:0004740', ('74', '78'))	('M1 polarization', 'CPA', (114, 129))	('pyruvate', 'Chemical', 'MESH:D019289', (44, 52))	('respiration', 'biological_process', 'GO:0045333', ('177', '188'))
55558	32486098	Inhibition of histone acetylase p300 as well as knockdown of Raptor, a main subunit of the mTORC1 complex, reduced induction of Akt-dependent M2 genes.	('Raptor', 'Gene', (61, 67))	('Akt-dependent M2 genes', 'Gene', (128, 150))	('mTORC1', 'Gene', (91, 97))	('Raptor', 'Gene', '74370', (61, 67))	('reduced', 'NegReg', (107, 114))	('p300', 'Gene', '328572', (32, 36))	('mTORC1', 'cellular_component', 'GO:0031931', ('91', '97'))	('p300', 'Gene', (32, 36))	('induction', 'MPA', (115, 124))	('mTORC1', 'Gene', '382056', (91, 97))	('knockdown', 'Var', (48, 57))
55562	32486098	Deletion of Rictor, a subunit of mTORC2 complex, diminished the expression of a number of M2-specific genes (CD301, RELMalpha, ARG1, Chil3 (Ym1), IL-10, LIPA, CD36, FABP4, PPARG, and PPARGC1B) and glucose uptake in IL-4-stimulated macrophages.	('PPARG', 'Gene', (172, 177))	('IL-10', 'molecular_function', 'GO:0005141', ('146', '151'))	('Ym1', 'Gene', (140, 143))	('glucose', 'Chemical', 'MESH:D005947', (197, 204))	('IL-4', 'molecular_function', 'GO:0005136', ('215', '219'))	('CD36', 'Species', '42374', (159, 163))	('LIPA', 'molecular_function', 'GO:0016992', ('153', '157'))	('glucose uptake', 'biological_process', 'GO:0046323', ('197', '211'))	('FABP4', 'Gene', (165, 170))	('mTORC2', 'Gene', '74343', (33, 39))	('Ym1', 'Gene', '12655', (140, 143))	('ARG1', 'Gene', (127, 131))	('mTORC2', 'cellular_component', 'GO:0031932', ('33', '39'))	('diminished', 'NegReg', (49, 59))	('Deletion', 'Var', (0, 8))	('expression', 'MPA', (64, 74))	('Rictor', 'Gene', (12, 18))	('LIPA', 'Gene', (153, 157))	('glucose uptake', 'CPA', (197, 211))	('CD301', 'Gene', (109, 114))	('PPARGC1B', 'Gene', (183, 191))	('Chil3', 'Gene', (133, 138))	('Chil3', 'Gene', '12655', (133, 138))	('CD36', 'MPA', (159, 163))	('mTORC2', 'Gene', (33, 39))
55564	32486098	In an in vivo mouse model of melanoma, loss of the mTORC2 in TAMs diminished M2 activation and suppressed tumor growth.	('mTORC2', 'Gene', '74343', (51, 57))	('suppressed', 'NegReg', (95, 105))	('TAMs', 'Chemical', '-', (61, 65))	('mouse', 'Species', '10090', (14, 19))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('activation', 'MPA', (80, 90))	('diminished', 'NegReg', (66, 76))	('mTORC2', 'cellular_component', 'GO:0031932', ('51', '57'))	('loss', 'Var', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mTORC2', 'Gene', (51, 57))	('tumor', 'Disease', (106, 111))
55583	32486098	Furthermore, elevated CD36 expression is substantial for the up-regulation of gene expression defining for IL-4-induced macrophages (CD206, CD301, PD-L2 and RELMalphain).	('CD36', 'Species', '42374', (22, 26))	('CD36', 'Protein', (22, 26))	('elevated', 'PosReg', (13, 21))	('expression', 'MPA', (27, 37))	('CD301', 'Var', (140, 145))	('CD206', 'Var', (133, 138))	('up-regulation', 'PosReg', (61, 74))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('64', '93'))	('IL-4', 'molecular_function', 'GO:0005136', ('107', '111'))
55586	32486098	Additionally, in vivo delivery of CpG oligodeoxynucleotide, a Toll-like receptor 9 agonist, to tumor-bearing mice with pancreatic ductal adenocarcinoma (PDAC) cells resulted in the suppression of tumor growth in pancreatic cancer models enhancing the anti-tumor activity of F4/80+ TAMs through the induction of phagocytosis of tumor cells.	('pancreatic cancer', 'Disease', 'MESH:D010190', (212, 229))	('tumor', 'Disease', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('CpG oligodeoxynucleotide', 'Var', (34, 58))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('F4/80', 'Gene', '13733', (274, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('pancreatic cancer', 'Disease', (212, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('Toll-like receptor 9', 'Gene', (62, 82))	('enhancing', 'PosReg', (237, 246))	('tumor', 'Disease', (327, 332))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (119, 151))	('F4/80', 'Gene', (274, 279))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (38, 58))	('tumor', 'Disease', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('suppression', 'NegReg', (181, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (212, 229))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('pancreatic ductal adenocarcinoma', 'Disease', (119, 151))	('PDAC', 'Chemical', '-', (153, 157))	('Toll-like receptor 9', 'Gene', '81897', (62, 82))	('tumor', 'Disease', (95, 100))	('TAMs', 'Chemical', '-', (281, 285))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('PDAC', 'Phenotype', 'HP:0006725', (153, 157))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (119, 151))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('phagocytosis', 'biological_process', 'GO:0006909', ('311', '323'))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('mice', 'Species', '10090', (109, 113))
55604	32486098	Analysis of TAMs from MMTV-PyMT mice and BMDMs stimulated by tumor extract from MMTV-PyMT mice revealed the significant increase in HK2, enolase 1 (ENO1), and 6-phosphofructokinase (PFKL), a key mediators of aerobic glycolysis (Table 4).	('MMTV-PyMT', 'Var', (80, 89))	('TAMs', 'Chemical', '-', (12, 16))	('ENO1', 'Gene', (148, 152))	('enolase 1', 'Gene', '13806', (137, 146))	('MMTV', 'Species', '11757', (80, 84))	('HK2', 'Protein', (132, 135))	('6-phosphofructokinase', 'MPA', (159, 180))	('ENO1', 'Gene', '13806', (148, 152))	('PFKL', 'Gene', (182, 186))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mice', 'Species', '10090', (90, 94))	('enolase 1', 'Gene', (137, 146))	('mice', 'Species', '10090', (32, 36))	('PFKL', 'Gene', '18641', (182, 186))	('MMTV', 'Species', '11757', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('increase', 'PosReg', (120, 128))	('tumor', 'Disease', (61, 66))
55606	32486098	For example, in human breast cancer tissues the positive correlation between CD68+ TAM infiltration and glycolytic enzyme expression GLUT1, GLUT3 and HK2 in cancer cells was demonstrated by immunostaining.	('HK2', 'molecular_function', 'GO:0008256', ('150', '153'))	('GLUT3', 'Gene', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('glycolytic enzyme', 'Gene', '3098', (104, 121))	('GLUT1', 'Protein', (133, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('TAM', 'Gene', (83, 86))	('HK2', 'Gene', (150, 153))	('CD68+', 'Var', (77, 82))	('human', 'Species', '9606', (16, 21))	('TAM', 'Gene', '8205', (83, 86))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('cancer', 'Disease', (29, 35))	('glycolytic enzyme', 'Gene', (104, 121))	('breast cancer', 'Disease', (22, 35))	('GLUT3', 'Gene', '6515', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
55619	32486098	Inhibition of mTORC1 by REDD1 resulted in the shift of the macrophage phenotype towards the immunosuppressive and pro-angiogenic phenotype that was due to the inhibition of glucose uptake and glycolysis and enhancing glucose availability for endothelial cells.	('mTORC1', 'Gene', (14, 20))	('glucose uptake', 'MPA', (173, 187))	('glucose', 'Chemical', 'MESH:D005947', (173, 180))	('REDD1', 'Gene', (24, 29))	('glucose availability for endothelial cells', 'MPA', (217, 259))	('glycolysis', 'biological_process', 'GO:0006096', ('192', '202'))	('mTORC1', 'Gene', '382056', (14, 20))	('REDD1', 'Gene', '74747', (24, 29))	('glycolysis', 'MPA', (192, 202))	('Inhibition', 'Var', (0, 10))	('glucose', 'Chemical', 'MESH:D005947', (217, 224))	('mTORC1', 'cellular_component', 'GO:0031931', ('14', '20'))	('glucose uptake', 'biological_process', 'GO:0046323', ('173', '187'))	('enhancing', 'PosReg', (207, 216))	('shift', 'Reg', (46, 51))	('inhibition', 'NegReg', (159, 169))
55620	32486098	REDD1 deletion in TAMs from murine LLC tumor promotes tumor vessel normalization and inhibits metastasis, providing evidence about the link between TAM metabolism in hypoxia and tumor vessel morphogenesis.	('REDD1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('TAM', 'Gene', (148, 151))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('LLC', 'cellular_component', 'GO:0038045', ('35', '38'))	('TAM', 'Gene', '8205', (148, 151))	('tumor', 'Disease', (178, 183))	('metastasis', 'CPA', (94, 104))	('REDD1', 'Gene', '74747', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('deletion', 'Var', (6, 14))	('murine', 'Species', '10090', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('hypoxia', 'Disease', (166, 173))	('LLC tumor promotes tumor', 'Disease', 'MESH:D009369', (35, 59))	('inhibits', 'NegReg', (85, 93))	('TAM', 'Gene', (18, 21))	('metabolism', 'biological_process', 'GO:0008152', ('152', '162'))	('tumor', 'Disease', (39, 44))	('TAM', 'Gene', '8205', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('hypoxia', 'Disease', 'MESH:D000860', (166, 173))	('LLC tumor promotes tumor', 'Disease', (35, 59))	('morphogenesis', 'biological_process', 'GO:0009653', ('191', '204'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('TAMs', 'Chemical', '-', (18, 22))	('tumor', 'Disease', (54, 59))
55621	32486098	In an in vitro model of TAMs where human blood monocytes were stimulated with the conditioned medium of human melanoma cells (MV3), TAMs expressed M2 specific markers (CD206 and CD163), however they were metabolically distinct from typical M2 and had metabolic features of M1-like macrophages.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('CD206', 'Var', (168, 173))	('CD163', 'Var', (178, 183))	('TAMs', 'Chemical', '-', (24, 28))	('human', 'Species', '9606', (35, 40))	('TAMs', 'Chemical', '-', (132, 136))	('human', 'Species', '9606', (104, 109))
55625	32486098	Immunohistochemical analysis (IHC) of tumors of patients with thyroid cancer (TC) also validated the increase in glycolytic enzymes and lactate receptor (GBR18, PFKFB3, PKM2) in TAMs.	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('thyroid cancer', 'Disease', 'MESH:D013964', (62, 76))	('glycolytic enzyme', 'Gene', (113, 130))	('lactate receptor', 'MPA', (136, 152))	('PKM2', 'Var', (169, 173))	('thyroid cancer', 'Phenotype', 'HP:0002890', (62, 76))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('PFKFB3', 'Gene', (161, 167))	('increase', 'PosReg', (101, 109))	('TC', 'Phenotype', 'HP:0002890', (78, 80))	('GBR18', 'Gene', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('thyroid cancer', 'Disease', (62, 76))	('glycolytic enzyme', 'Gene', '3098', (113, 130))	('lactate', 'Chemical', 'MESH:D019344', (136, 143))	('TAMs', 'Chemical', '-', (178, 182))	('patients', 'Species', '9606', (48, 56))
55630	32486098	Interestingly, in breast cancer tissue TAMs expressing CD206 are located in well-nourished perivascular regions, whereas macrophages produced high levels of ARG1 located within hypoxic regions, far from the vasculature.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('CD206', 'Var', (55, 60))	('breast cancer', 'Disease', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('perivascular regions', 'Phenotype', 'HP:0012520', (91, 111))	('TAMs', 'Chemical', '-', (39, 43))
55638	32486098	However, the depletion of HMGB1 with shRNA in mice with B16 melanoma cells-derived tumor significantly reduced tumor growth and the amount of TAMs.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('HMGB1', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('reduced', 'NegReg', (103, 110))	('tumor', 'Disease', (83, 88))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('depletion', 'Var', (13, 22))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('tumor', 'Disease', (111, 116))	('TAMs', 'Chemical', '-', (142, 146))	('amount of TAMs', 'MPA', (132, 146))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
55639	32486098	The significant influence of hypoxia was shown in macrophages differentiated in vitro from human peripheral blood or BMDMs isolated from mice bearing deletions in the HIF-1alpha or HIF-2alpha genes.	('deletions', 'Var', (150, 159))	('hypoxia', 'Disease', (29, 36))	('hypoxia', 'Disease', 'MESH:D000860', (29, 36))	('HIF-2alpha', 'Gene', '13819', (181, 191))	('HIF-1alpha', 'Gene', (167, 177))	('HIF-2alpha', 'Gene', (181, 191))	('mice', 'Species', '10090', (137, 141))	('human', 'Species', '9606', (91, 96))
55643	32486098	LPS was found to activate HIF-1alpha in murine AHA-1 macrophage cells under hypoxic conditions in vitro.	('murine', 'Species', '10090', (40, 46))	('LPS', 'Var', (0, 3))	('activate', 'PosReg', (17, 25))	('HIF-1alpha', 'Protein', (26, 36))
55644	32486098	LPS induced transcriptional activity, but not protein expression and DNA binding activities of HIF-1alpha in macrophages by a ROS-dependent pathway.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('DNA binding', 'molecular_function', 'GO:0003677', ('69', '80'))	('ROS', 'Chemical', 'MESH:D017382', (126, 129))	('LPS', 'Var', (0, 3))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('transcriptional activity', 'MPA', (12, 36))	('HIF-1alpha', 'Gene', (95, 105))
55655	32486098	In patients with glioma, IHC analysis revealed the positive correlation between HIF-1alpha expression, periostin (POSTN) expression, and the infiltration of TAMs (CD11b+) and M2 type TAMs (CD206+) in tumor sections.	('expression', 'MPA', (121, 131))	('positive', 'PosReg', (51, 59))	('POSTN', 'Gene', (114, 119))	('TAMs', 'Chemical', '-', (157, 161))	('tumor', 'Disease', (200, 205))	('glioma', 'Disease', (17, 23))	('POSTN', 'Gene', '10631', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('CD206+', 'Var', (189, 195))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('periostin', 'Gene', (103, 112))	('patients', 'Species', '9606', (3, 11))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('HIF-1alpha', 'Gene', (80, 90))	('TAMs', 'Chemical', '-', (183, 187))	('CD11b', 'Gene', '3684', (163, 168))	('periostin', 'Gene', '10631', (103, 112))	('CD11b', 'Gene', (163, 168))
55667	32486098	However, inhibition of DGAT, an enzyme responsible for the formation of lipid droplets in myeloid cells, prevented oleate-induced immunosuppressive M2 phenotype in murine BMDMs and human monocyte-derived macrophages.	('human', 'Species', '9606', (181, 186))	('DGAT', 'Gene', '13350', (23, 27))	('oleate-induced immunosuppressive M2 phenotype', 'MPA', (115, 160))	('oleate', 'Chemical', 'MESH:D019301', (115, 121))	('prevented', 'NegReg', (105, 114))	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('DGAT', 'Gene', (23, 27))	('lipid', 'Chemical', 'MESH:D008055', (72, 77))	('murine', 'Species', '10090', (164, 170))	('inhibition', 'Var', (9, 19))
55668	32486098	Besides, mTOR inhibition in myeloid cells eliminated specific lipid droplet-dependent mitochondrial respiration in M2-like macrophages.	('mTOR', 'Gene', (9, 13))	('lipid', 'Chemical', 'MESH:D008055', (62, 67))	('eliminated', 'NegReg', (42, 52))	('respiration', 'biological_process', 'GO:0007585', ('100', '111'))	('lipid droplet', 'cellular_component', 'GO:0005811', ('62', '75'))	('inhibition', 'Var', (14, 24))	('respiration', 'biological_process', 'GO:0045333', ('100', '111'))
55682	32486098	Moreover, deletion of GS in macrophages promotes vascular normalization, accumulation of cytotoxic T cells, and metastasis inhibition and skews TAMs toward the M1-like phenotype in mice implanted with Lewis lung carcinoma (LLC) cells.	('GS', 'Gene', '14645', (22, 24))	('mice', 'Species', '10090', (181, 185))	('vascular normalization', 'CPA', (49, 71))	('metastasis inhibition', 'CPA', (112, 133))	('TAMs', 'Chemical', '-', (144, 148))	('accumulation', 'PosReg', (73, 85))	('Lewis lung carcinoma', 'Disease', (201, 221))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (201, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('LLC', 'cellular_component', 'GO:0038045', ('223', '226'))	('deletion', 'Var', (10, 18))	('promotes', 'PosReg', (40, 48))
55683	32486098	Deletion of GS in macrophages leads to the reduced expression of M2-specific markers (ARG1, CD206, CCL17, and CCL22) and upregulation of M1 marker MHC class II.	('upregulation', 'PosReg', (121, 133))	('ARG1', 'Gene', (86, 90))	('CCL', 'molecular_function', 'GO:0044101', ('110', '113'))	('CCL17', 'Gene', '20295', (99, 104))	('Deletion', 'Var', (0, 8))	('CCL', 'molecular_function', 'GO:0044101', ('99', '102'))	('expression', 'MPA', (51, 61))	('CD206', 'Gene', (92, 97))	('CCL17', 'Gene', (99, 104))	('CCL22', 'Gene', '20299', (110, 115))	('reduced', 'NegReg', (43, 50))	('GS', 'Gene', '14645', (12, 14))	('CCL22', 'Gene', (110, 115))
55696	32486098	Close interplay of transcriptional factors and epigenetic enzymes is responsible for the activation of pro- or anti-tumor programs, and is utilized by cancer cells to give instructions to macrophages to support tumor progression.	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('epigenetic enzymes', 'Var', (47, 65))	('pro-', 'CPA', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Disease', (151, 157))	('activation', 'PosReg', (89, 99))	('tumor', 'Disease', (211, 216))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (116, 121))
55716	32423123	Conclusion: RDC was independently associated with better prognosis after NACT in patients with BRPC or LAPC.	('patients', 'Species', '9606', (81, 89))	('RDC', 'Var', (12, 15))	('BRPC', 'Disease', (95, 99))	('LAPC', 'Disease', (103, 107))	('better', 'PosReg', (50, 56))
55722	32423123	Although the optimal NACT regimen has not yet been determined, a recent meta-analysis found that FOLFIRINOX-based NACT yielded better oncologic outcomes than gemcitabine-based NACT, despite the former having greater toxicity.	('gemcitabine', 'Chemical', 'MESH:C056507', (158, 169))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (97, 107))	('toxicity', 'Disease', 'MESH:D064420', (216, 224))	('FOLFIRINOX-based', 'Var', (97, 113))	('toxicity', 'Disease', (216, 224))	('oncologic outcomes', 'CPA', (134, 152))	('better', 'PosReg', (127, 133))	('men', 'Species', '9606', (30, 33))
55757	32423123	The patients with RDC < 0 showed higher nodal stage than RDC >= 0 group (p = 0.037).	('nodal stage', 'CPA', (40, 51))	('higher', 'PosReg', (33, 39))	('patients', 'Species', '9606', (4, 12))	('RDC < 0', 'Var', (18, 25))
55761	32423123	Neither the 62 patients with CA19-9 < 37 U/mL nor the 26 patients with CA 19-9 >1000 U/mL before NACT showed significant improvements in OS and RFS during NACT.	('CA19-9', 'Var', (29, 35))	('patients', 'Species', '9606', (15, 23))	('CA 19-9', 'Chemical', 'MESH:C086528', (71, 78))	('patients', 'Species', '9606', (57, 65))	('men', 'Species', '9606', (128, 131))	('CA19-9', 'Chemical', 'MESH:C086528', (29, 35))	('RFS', 'MPA', (144, 147))
55762	32423123	However, the 133 patients with CA 19-9 37-1000 U/mL before NACT showed better OS (hazard ratio [HR]: 0.262; 95% confidence interval [CI]: 0.092-0.748; p = 0.012) and RFS (HR: 0.290; 95% CI: 0.134-0.628; p = 0.002) after NACT.	('CA 19-9 37-1000 U/mL', 'Var', (31, 51))	('RFS', 'MPA', (166, 169))	('patients', 'Species', '9606', (17, 25))	('CA 19-9', 'Chemical', 'MESH:C086528', (31, 38))	('better', 'PosReg', (71, 77))
55772	32423123	However, elevated CA 19-9 has also been associated with other gastrointestinal tumors, as well as with biliary tract inflammation.	('inflammation', 'Disease', (117, 129))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (62, 85))	('elevated', 'Var', (9, 17))	('gastrointestinal tumors', 'Disease', (62, 85))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (62, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('CA 19-9', 'Chemical', 'MESH:C086528', (18, 25))	('CA 19-9', 'Protein', (18, 25))	('inflammation', 'biological_process', 'GO:0006954', ('117', '129'))	('associated', 'Reg', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('inflammation', 'Disease', 'MESH:D007249', (117, 129))
55774	32423123	CA 19-9 concentration after NACT may be a biologic marker in patients with BRPC and LAPC because normalized or reduced CA 19-9 concentration after NACT has been reported to be an important prognostic marker of better OS and RFS.	('LAPC', 'Disease', (84, 88))	('CA 19-9 concentration', 'MPA', (119, 140))	('normalized', 'Var', (97, 107))	('patients', 'Species', '9606', (61, 69))	('CA 19-9', 'Chemical', 'MESH:C086528', (119, 126))	('RFS', 'Disease', (224, 227))	('reduced', 'NegReg', (111, 118))	('CA 19-9', 'Chemical', 'MESH:C086528', (0, 7))	('BRPC', 'Disease', (75, 79))	('better OS', 'Disease', (210, 219))
55776	32423123	Although normalization of CA19-9 after NACT was found to be more prognostic of survival outcomes than reduced CA 19-9, that study included patients with CA 19-9 >1000 U/mL, with this subgroup showing higher CA19-9 and a lower normalization rate after NACT than patients with CA19-9 <1000 U/mL.	('patients', 'Species', '9606', (261, 269))	('>1000 U/mL', 'Var', (161, 171))	('patients', 'Species', '9606', (139, 147))	('CA19-9', 'MPA', (207, 213))	('CA19-9', 'Chemical', 'MESH:C086528', (275, 281))	('CA19-9', 'Chemical', 'MESH:C086528', (207, 213))	('lower', 'NegReg', (220, 225))	('normalization rate', 'MPA', (226, 244))	('CA19-9', 'Chemical', 'MESH:C086528', (26, 32))	('CA 19-9', 'Chemical', 'MESH:C086528', (110, 117))	('CA 19-9', 'Chemical', 'MESH:C086528', (153, 160))	('higher', 'PosReg', (200, 206))
55781	32423123	In the present study, only 14% of patients with high CA 19-9 before NACT achieved normalization after NACT, with survival outcomes being poorer than in patients with CA19-9 <1000 U/mL before NACT, although the differences were not statistically significant.	('CA 19-9', 'Chemical', 'MESH:C086528', (53, 60))	('poorer', 'NegReg', (137, 143))	('normalization', 'MPA', (82, 95))	('CA19-9', 'Chemical', 'MESH:C086528', (166, 172))	('patients', 'Species', '9606', (34, 42))	('CA 19-9', 'Gene', (53, 60))	('high', 'Var', (48, 52))	('patients', 'Species', '9606', (152, 160))
55788	32423123	The present study also found that the change of CA 19-9 was unable to predict the need for resection of adjacent vessels, R0 resection, or tumor regression grade.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('CA 19-9', 'Gene', (48, 55))	('change', 'Var', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('CA 19-9', 'Chemical', 'MESH:C086528', (48, 55))
55802	32429474	Therefore, aberrant TGFbeta signaling and EMT are linked to promoting PDAC aggressiveness.	('PDAC', 'Phenotype', 'HP:0006725', (70, 74))	('aggressiveness', 'Phenotype', 'HP:0000718', (75, 89))	('EMT', 'CPA', (42, 45))	('EMT', 'biological_process', 'GO:0001837', ('42', '45'))	('aberrant', 'Var', (11, 19))	('TGFbeta', 'Protein', (20, 27))	('signaling', 'biological_process', 'GO:0023052', ('28', '37'))	('aggressiveness', 'Disease', 'MESH:D001523', (75, 89))	('aggressiveness', 'Disease', (75, 89))	('promoting', 'PosReg', (60, 69))	('PDAC', 'Disease', (70, 74))
55813	32429474	Nab-paclitaxel also represents an alternative in association with gemcitabine in metastatic PDAC patients, with a median overall survival of 8.5 months (hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.62, 0.83; p < 0.001).	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('PDAC', 'Phenotype', 'HP:0006725', (92, 96))	('gemcitabine', 'Chemical', 'MESH:C056507', (66, 77))	('Nab-paclitaxel', 'Var', (0, 14))	('Nab', 'Chemical', '-', (0, 3))	('metastatic PDAC', 'Disease', (81, 96))	('patients', 'Species', '9606', (97, 105))
55814	32429474	The POLO clinical trial (Pancreas Cancer Olaparib Ongoing) evaluated the efficacy of maintenance therapy with olaparib, a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, in patients with germline BRCA mutation and metastatic pancreatic cancer.	('BRCA', 'Gene', (212, 216))	('pancreatic cancer', 'Disease', (241, 258))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('germline', 'Var', (203, 211))	('pancreatic cancer', 'Disease', 'MESH:D010190', (241, 258))	('Pancreas Cancer', 'Disease', (25, 40))	('mutation', 'Var', (217, 225))	('olaparib', 'Chemical', 'MESH:C531550', (110, 118))	('Olaparib', 'Chemical', 'MESH:C531550', (41, 49))	('adenosine', 'Chemical', 'MESH:D000241', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('Pancreas Cancer', 'Phenotype', 'HP:0002894', (25, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (241, 258))	('patients', 'Species', '9606', (189, 197))	('Pancreas Cancer', 'Disease', 'MESH:D010190', (25, 40))
55816	32429474	Genomic analyses of PDAC revealed a large panel of molecular alterations particularly affecting Kirsten rat sarcoma viral oncogene (KRAS), tumor protein P53 (TP53), Mothers Against Decapentaplegic Homolog 4 (SMAD4), and cyclin-dependent kinase inhibitor 2A (CDKN2A) genes.	('kinase inhibitor', 'biological_process', 'GO:0033673', ('237', '253'))	('Mothers Against Decapentaplegic Homolog 4', 'Gene', (165, 206))	('sarcoma', 'Disease', (108, 115))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '25163', (220, 256))	('tumor protein P53', 'Gene', '24842', (139, 156))	('Mothers Against Decapentaplegic Homolog 4', 'Gene', '50554', (165, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('220', '253'))	('alterations', 'Var', (61, 72))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (220, 256))	('CDKN2A', 'Gene', (258, 264))	('affecting', 'Reg', (86, 95))	('PDAC', 'Phenotype', 'HP:0006725', (20, 24))	('sarcoma', 'Disease', 'MESH:D012509', (108, 115))	('tumor protein P53', 'Gene', (139, 156))
55869	32429474	However, in PDAC alterations of TGFbeta signaling through the mutation of genes involved in the pathway (e.g., SMAD4, SMAD3, TbetaR-I, TbetaR-II, ACVR1B, and ACVR2A), this role is present in 47% of cases, highlighting that TGFbeta can sometimes acts as a tumor promoter.	('SMAD4', 'Gene', (111, 116))	('ACVR2A', 'Gene', '92', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('ACVR2A', 'Gene', (158, 164))	('TbetaR-II', 'Gene', '7048', (135, 144))	('alterations', 'Var', (17, 28))	('tumor', 'Disease', (255, 260))	('PDAC', 'Phenotype', 'HP:0006725', (12, 16))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('SMAD3', 'Gene', '4088', (118, 123))	('ACVR1B', 'Gene', '91', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('TbetaR-II', 'Gene', (135, 144))	('TbetaR-I', 'Gene', '7046', (135, 143))	('TbetaR-I', 'Gene', (135, 143))	('ACVR1B', 'Gene', (146, 152))	('mutation', 'Var', (62, 70))	('TbetaR-I', 'Gene', '7046', (125, 133))	('TbetaR-I', 'Gene', (125, 133))	('SMAD3', 'Gene', (118, 123))
55871	32429474	A high level of TGFbeta signaling in PDAC was associated with poor prognosis despite its clear tumor-suppressive effect.	('PDAC', 'Phenotype', 'HP:0006725', (37, 41))	('high', 'Var', (2, 6))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('TGFbeta signaling', 'MPA', (16, 33))	('tumor', 'Disease', (95, 100))	('signaling', 'biological_process', 'GO:0023052', ('24', '33'))
55890	32429474	KRAS is activated by mutation in almost 90% of cases, TP53 is inactivated in 50%-75% of cases, and CDK2NA is inactivated in about 30% of patients with PDAC.	('activated', 'PosReg', (8, 17))	('patients', 'Species', '9606', (137, 145))	('mutation', 'Var', (21, 29))	('CDK2', 'Gene', '1017', (99, 103))	('PDAC', 'Disease', (151, 155))	('PDAC', 'Phenotype', 'HP:0006725', (151, 155))	('CDK', 'molecular_function', 'GO:0004693', ('99', '102'))	('CDK2', 'Gene', (99, 103))
55891	32429474	SMAD4 was firstly identified as a tumor suppressor gene that is inactivated in 60% of PDAC cases due to homozygous deletion or mutation.	('tumor', 'Disease', (34, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('mutation', 'Var', (127, 135))	('SMAD4', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PDAC', 'Phenotype', 'HP:0006725', (86, 90))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))
55892	32429474	Alterations of the SMAD4 gene occur in late stages when the carcinoma is histologically recognizable.	('carcinoma', 'Disease', (60, 69))	('SMAD4', 'Gene', (19, 24))	('carcinoma', 'Disease', 'MESH:D009369', (60, 69))	('Alterations', 'Var', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))
55893	32429474	In pancreatic cancers, homozygous deletion of SMAD4 is found in approximately 30% of cases, inactivation is found in 20% of cases, and allelic loss of chromosome 18q is found in almost 90% of cases.	('found', 'Reg', (55, 60))	('homozygous deletion', 'Var', (23, 42))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (3, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('inactivation', 'MPA', (92, 104))	('pancreatic cancers', 'Disease', 'MESH:D010190', (3, 21))	('pancreatic cancers', 'Disease', (3, 21))	('chromosome', 'cellular_component', 'GO:0005694', ('151', '161'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('SMAD4', 'Gene', (46, 51))
55894	32429474	Notably, two SMAD4 missense mutations (Pro130Ser and Asn351His) were found to increase SMAD4 phosphorylation by GSK3 and lead to protein degradation.	('Asn351His', 'Var', (53, 62))	('Pro130Ser', 'Var', (39, 48))	('phosphorylation', 'biological_process', 'GO:0016310', ('93', '108'))	('Ser', 'cellular_component', 'GO:0005790', ('45', '48'))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('increase', 'PosReg', (78, 86))	('SMAD4', 'Gene', (13, 18))	('lead to', 'Reg', (121, 128))	('protein degradation', 'biological_process', 'GO:0030163', ('129', '148'))	('GSK', 'molecular_function', 'GO:0050321', ('112', '115'))	('phosphorylation', 'MPA', (93, 108))	('protein degradation', 'MPA', (129, 148))	('Pro130Ser', 'Mutation', 'p.P130S', (39, 48))	('SMAD4', 'Protein', (87, 92))	('Asn351His', 'Mutation', 'p.N351H', (53, 62))
55895	32429474	Loss of SMAD4 inhibits the tumor suppressor effects of TGFbeta without affecting tumor response, promoting a more aggressive phenotype.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('SMAD4', 'Gene', (8, 13))	('inhibits', 'NegReg', (14, 22))	('tumor', 'Disease', (27, 32))	('promoting', 'PosReg', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor suppressor', 'biological_process', 'GO:0051726', ('27', '43'))	('TGFbeta', 'Gene', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('Loss', 'Var', (0, 4))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('27', '43'))	('tumor', 'Disease', (81, 86))
55896	32429474	In another study using SMAD4 silencing, SMAD4 was required in TGFbeta-induced cell-cycle arrest and migration.	('arrest', 'Disease', (89, 95))	('migration', 'CPA', (100, 109))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('78', '95'))	('silencing', 'Var', (29, 38))	('TGFbeta-induced', 'Gene', (62, 77))	('arrest', 'Disease', 'MESH:D006323', (89, 95))
55898	32429474	SMAD4 deficiency in PDAC cells induces E-cadherin expression and is associated with an ineffectiveness of TGFbeta to induce EMT.	('induces', 'PosReg', (31, 38))	('E-cadherin', 'Gene', (39, 49))	('E-cadherin', 'Gene', '999', (39, 49))	('cadherin', 'molecular_function', 'GO:0008014', ('41', '49'))	('SMAD4', 'Gene', (0, 5))	('deficiency', 'Var', (6, 16))	('EMT', 'biological_process', 'GO:0001837', ('124', '127'))	('PDAC', 'Phenotype', 'HP:0006725', (20, 24))	('expression', 'MPA', (50, 60))
55901	32429474	SMAD4 can suppress JNK activation; therefore, in the case of SMAD4 deletion, JNK activity is subsequently enhanced and can be required in the EMT response.	('EMT', 'biological_process', 'GO:0001837', ('142', '145'))	('enhanced', 'PosReg', (106, 114))	('JNK', 'Gene', (77, 80))	('JNK', 'Gene', (19, 22))	('deletion', 'Var', (67, 75))	('SMAD4', 'Gene', (61, 66))	('JNK', 'molecular_function', 'GO:0004705', ('77', '80'))	('JNK', 'molecular_function', 'GO:0004705', ('19', '22'))	('JNK', 'Gene', '5599', (77, 80))	('JNK', 'Gene', '5599', (19, 22))
55909	32429474	It was found that SMAD4 gene inactivation, by intragenic mutation or homozygous deletion, leads to poor prognosis for patients with surgically resected pancreatic adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('mutation', 'Var', (57, 65))	('poor', 'NegReg', (99, 103))	('pancreatic adenocarcinoma', 'Disease', (152, 177))	('inactivation', 'NegReg', (29, 41))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (152, 177))	('SMAD4', 'Gene', (18, 23))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (152, 177))	('patients', 'Species', '9606', (118, 126))
55912	32429474	Recently, an analysis of publicly available datasets from The Cancer Genome Atlas (TGCA) indicated that PDAC patients with a deleted SMAD4 gene had poorer DFS; however, SMAD4 alterations did not predict the OS.	('SMAD4', 'Gene', (133, 138))	('patients', 'Species', '9606', (109, 117))	('Cancer', 'Disease', (62, 68))	('deleted', 'Var', (125, 132))	('poorer', 'NegReg', (148, 154))	('Cancer', 'Disease', 'MESH:D009369', (62, 68))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('PDAC', 'Phenotype', 'HP:0006725', (104, 108))	('DFS', 'MPA', (155, 158))
55919	32429474	Synthetic lethality-based screening methodologies identified two compounds (UA62001 and UA62784) to selectively target SMAD4-negative cells.	('UA62001', 'Chemical', '-', (76, 83))	('UA62784', 'Chemical', 'MESH:C535156', (88, 95))	('UA62001', 'Var', (76, 83))	('UA62784', 'Var', (88, 95))
55920	32429474	In SMAD4-negative pancreatic cancer cells treated with the compound UA62001, the cell cycle was interrupted in synthesis (S) and Gap 2 (G2) - mitotic (M) phases, whereas UA62784 activated CDK1 and induced mitotic cell-cycle arrest and apoptosis.	('UA62001', 'Chemical', '-', (68, 75))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (18, 35))	('cell cycle', 'CPA', (81, 91))	('UA62784', 'Var', (170, 177))	('apoptosis', 'CPA', (235, 244))	('arrest', 'Disease', 'MESH:D006323', (224, 230))	('activated', 'PosReg', (178, 187))	('UA62001', 'Var', (68, 75))	('synthesis', 'biological_process', 'GO:0009058', ('111', '120'))	('mitotic cell-cycle arrest', 'biological_process', 'GO:0071850', ('205', '230'))	('CDK', 'molecular_function', 'GO:0004693', ('188', '191'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (18, 35))	('cell cycle', 'biological_process', 'GO:0007049', ('81', '91'))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('UA62784', 'Chemical', 'MESH:C535156', (170, 177))	('CDK1', 'Gene', (188, 192))	('pancreatic cancer', 'Disease', (18, 35))	('arrest', 'Disease', (224, 230))	('CDK1', 'Gene', '983', (188, 192))	('apoptosis', 'biological_process', 'GO:0097194', ('235', '244'))	('apoptosis', 'biological_process', 'GO:0006915', ('235', '244'))
55923	32429474	SMAD4 deficiency can enhance the glycolytic capacity of cancer cells with upregulation of glucose transporter expression contributing to aerobic glycolysis, which is the main metabolic pathway in PDAC.	('enhance', 'PosReg', (21, 28))	('glucose', 'Chemical', 'MESH:D005947', (90, 97))	('glycolysis', 'biological_process', 'GO:0006096', ('145', '155'))	('glucose transporter expression contributing', 'MPA', (90, 133))	('SMAD4', 'Gene', (0, 5))	('upregulation', 'PosReg', (74, 86))	('deficiency', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('PDAC', 'Phenotype', 'HP:0006725', (196, 200))	('aerobic glycolysis', 'MPA', (137, 155))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('glycolytic capacity', 'MPA', (33, 52))
55924	32429474	PDAC harboring mutant SMAD4 exhibited a high metabolic tumor burden.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('SMAD4', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('mutant', 'Var', (15, 21))
55928	32429474	Different studies used a microarray-based strategy and identified miR-301a-3p, miR-483-3p, and miR-421 to target SMAD4 in PDAC.	('miR-421', 'Gene', (95, 102))	('target', 'Reg', (106, 112))	('miR-483-3p', 'Var', (79, 89))	('PDAC', 'Disease', (122, 126))	('SMAD4', 'Gene', (113, 118))	('miR-301a-3p', 'Var', (66, 77))	('miR-421', 'Gene', '693122', (95, 102))	('PDAC', 'Phenotype', 'HP:0006725', (122, 126))
55929	32429474	SMAD4 mutations can interfere with its regulation associated with the Wnt/GSK3 and Erk pathways.	('Erk', 'Gene', (83, 86))	('Erk', 'Gene', '5594', (83, 86))	('SMAD4', 'Gene', (0, 5))	('interfere', 'NegReg', (20, 29))	('regulation', 'MPA', (39, 49))	('GSK', 'molecular_function', 'GO:0050321', ('74', '77'))	('regulation', 'biological_process', 'GO:0065007', ('39', '49'))	('Erk', 'molecular_function', 'GO:0004707', ('83', '86'))	('mutations', 'Var', (6, 15))
55930	32429474	The authors demonstrated that GSK3 inhibition reactivated TGFbeta signaling in SMAD4 mutated cells in colon cancer.	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('TGFbeta signaling', 'MPA', (58, 75))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('reactivated', 'PosReg', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colon cancer', 'Disease', 'MESH:D015179', (102, 114))	('mutated', 'Var', (85, 92))	('colon cancer', 'Disease', (102, 114))	('GSK', 'molecular_function', 'GO:0050321', ('30', '33'))	('GSK3', 'Protein', (30, 34))	('inhibition', 'NegReg', (35, 45))
55934	32429474	Inactivation of SMAD4 leads to a modification in TGFbeta responses, promoting non-canonical TGFbeta signaling which is linked to pro-tumorigenic responses.	('modification', 'Reg', (33, 45))	('SMAD4', 'Gene', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('non-canonical TGFbeta', 'MPA', (78, 99))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('promoting', 'PosReg', (68, 77))	('Inactivation', 'Var', (0, 12))
55938	32226532	A miR-146a-5p/TRAF6/NF-kB p65 axis regulates pancreatic cancer chemoresistance: functional validation and clinical significance Background: Dysregulated microRNA (miRNA) expression in cancer can act as a key factor that modifies biological processes, including chemoresistance.	('cancer', 'Disease', (184, 190))	('chemoresistance', 'CPA', (261, 276))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', (56, 62))	('miR', 'Gene', (163, 166))	('miR', 'Gene', '220972', (2, 5))	('p65', 'Gene', (26, 29))	('pancreatic cancer', 'Disease', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('modifies', 'Reg', (220, 228))	('regulates', 'Reg', (35, 44))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('miR', 'Gene', (2, 5))	('p65', 'Gene', '5970', (26, 29))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('TRAF6', 'Gene', '7189', (14, 19))	('Dysregulated', 'Var', (140, 152))	('miR', 'Gene', '220972', (163, 166))	('TRAF6', 'Gene', (14, 19))
55942	32226532	Bioinformatics analysis, luciferase reporter assays, and chromatin immunoprecipitation assays were used to confirm tumor necrosis factor receptor-associated factor 6 (TRAF6) as a direct target of miR-146a-5p and to explore the potential transcription factor binding and regulation by miR-146a-5p.	('TRAF6', 'Gene', '7189', (167, 172))	('tumor necrosis factor receptor-associated factor 6', 'Gene', '7189', (115, 165))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('miR-146a-5p', 'Chemical', '-', (196, 207))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('237', '265'))	('transcription', 'biological_process', 'GO:0006351', ('237', '250'))	('tumor necrosis factor receptor-associated factor 6', 'Gene', (115, 165))	('necrosis', 'biological_process', 'GO:0070265', ('121', '129'))	('necrosis', 'biological_process', 'GO:0008219', ('121', '129'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('115', '136'))	('necrosis', 'biological_process', 'GO:0019835', ('121', '129'))	('regulation', 'biological_process', 'GO:0065007', ('270', '280'))	('necrosis', 'biological_process', 'GO:0008220', ('121', '129'))	('TRAF6', 'Gene', (167, 172))	('miR-146a-5p', 'Var', (196, 207))	('necrosis', 'biological_process', 'GO:0001906', ('121', '129'))	('chromatin', 'cellular_component', 'GO:0000785', ('57', '66'))	('miR-146a-5p', 'Chemical', '-', (284, 295))
55943	32226532	Results: MiR-146a-5p expression was significantly decreased in PDAC tissues compared with adjacent normal tissues, and miR-146a-5p expression correlated with prognosis in PDAC patients.	('patients', 'Species', '9606', (176, 184))	('miR-146a-5p', 'Chemical', '-', (119, 130))	('MiR-146a', 'Gene', (9, 17))	('PDAC', 'Chemical', '-', (63, 67))	('MiR-146a', 'Gene', '406938', (9, 17))	('correlated', 'Reg', (142, 152))	('PDAC', 'Disease', (171, 175))	('expression', 'MPA', (21, 31))	('PDAC', 'Phenotype', 'HP:0006725', (171, 175))	('decreased', 'NegReg', (50, 59))	('miR-146a-5p', 'Var', (119, 130))	('PDAC', 'Disease', (63, 67))	('PDAC', 'Phenotype', 'HP:0006725', (63, 67))	('PDAC', 'Chemical', '-', (171, 175))
55944	32226532	Functional studies indicated that miR-146a-5p suppressed PDAC cell proliferation and sensitized PDAC cells to GEM chemotherapy by targeting the 3'-untranslated region (3'-UTR) of TRAF6.	('sensitized', 'Reg', (85, 95))	('miR-146a-5p', 'Chemical', '-', (34, 45))	('TRAF6', 'Gene', '7189', (179, 184))	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('GEM chemotherapy', 'CPA', (110, 126))	('PDAC', 'Chemical', '-', (96, 100))	('targeting', 'Reg', (130, 139))	('GEM', 'Chemical', 'MESH:C056507', (110, 113))	('PDAC', 'Phenotype', 'HP:0006725', (57, 61))	('rat', 'Species', '10116', (74, 77))	('PDAC cell proliferation', 'CPA', (57, 80))	('miR-146a-5p', 'Var', (34, 45))	('PDAC', 'Phenotype', 'HP:0006725', (96, 100))	('PDAC', 'Chemical', '-', (57, 61))	('TRAF6', 'Gene', (179, 184))	('suppressed', 'NegReg', (46, 56))
55949	32226532	The molecular mechanisms underlying chemoresistance in different types of cancer include drug inactivation and target alteration, epithelial-mesenchymal transition, DNA damage repair, cell death inhibition, inherent cell heterogeneity, and epigenetic effects.	('cell death', 'biological_process', 'GO:0008219', ('184', '194'))	('epithelial-mesenchymal transition', 'CPA', (130, 163))	('cell death inhibition', 'CPA', (184, 205))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('130', '163'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('drug inactivation', 'Var', (89, 106))	('cancer', 'Disease', (74, 80))	('rat', 'Species', '10116', (122, 125))	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))	('epigenetic effects', 'Var', (240, 258))	('alteration', 'Var', (118, 128))
55958	32226532	Studies have demonstrated that crosstalk of NF-kappaB with other regulators, such as SOCS3, TRIM31, ITCH, and TNIP1, leads to GEM resistance.	('GEM', 'Chemical', 'MESH:C056507', (126, 129))	('crosstalk', 'Var', (31, 40))	('TNIP1', 'Gene', (110, 115))	('NF-kappaB', 'Gene', '4790', (44, 53))	('ITCH', 'Gene', '83737', (100, 104))	('TRIM31', 'Gene', '11074', (92, 98))	('ITCH', 'Phenotype', 'HP:0000989', (100, 104))	('SOCS3', 'Gene', (85, 90))	('TRIM31', 'Gene', (92, 98))	('SOCS3', 'Gene', '9021', (85, 90))	('leads to', 'Reg', (117, 125))	('TNIP1', 'Gene', '10318', (110, 115))	('NF-kappaB', 'Gene', (44, 53))	('ITCH', 'Gene', (100, 104))	('rat', 'Species', '10116', (20, 23))	('GEM resistance', 'CPA', (126, 140))
55962	32226532	Herein, we confirmed that TRAF6 is a direct target of miR-146a-5p and is also upregulated in PDAC-GR cells.	('upregulated', 'PosReg', (78, 89))	('PDAC', 'Chemical', '-', (93, 97))	('miR-146a-5p', 'Var', (54, 65))	('miR-146a-5p', 'Chemical', '-', (54, 65))	('TRAF6', 'Gene', (26, 31))	('PDAC', 'Phenotype', 'HP:0006725', (93, 97))	('TRAF6', 'Gene', '7189', (26, 31))
55963	32226532	Next, we demonstrated that miR-146a-5p regulates the carcinogenesis and chemoresistance of PDAC cells by repressing TRAF6 expression in vitro and in vivo.	('carcinogenesis', 'Disease', 'MESH:D063646', (53, 67))	('regulates', 'Reg', (39, 48))	('PDAC', 'Chemical', '-', (91, 95))	('expression', 'MPA', (122, 132))	('carcinogenesis', 'Disease', (53, 67))	('rat', 'Species', '10116', (16, 19))	('miR-146a-5p', 'Chemical', '-', (27, 38))	('repressing', 'PosReg', (105, 115))	('PDAC', 'Phenotype', 'HP:0006725', (91, 95))	('TRAF6', 'Gene', (116, 121))	('miR-146a-5p', 'Var', (27, 38))	('chemoresistance', 'CPA', (72, 87))	('TRAF6', 'Gene', '7189', (116, 121))
55996	32226532	From the time of the formation of palpable tumors, miR-146a-5p agomir and agomir NC (RiboBio, Guangzhou, China) were injected into the tumor at multiple sites twice per week.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('miR-146a-5p', 'Chemical', '-', (51, 62))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('formation', 'biological_process', 'GO:0009058', ('21', '30'))	('tumors', 'Disease', (43, 49))	('tumor', 'Disease', (43, 48))	('tumors', 'Disease', 'MESH:D009369', (43, 49))	('miR-146a-5p', 'Var', (51, 62))
56005	32226532	Spearman correlation analysis was used to determine the association of miR-146a-5p expression with TRAF6 expression.	('miR-146a-5p', 'Var', (71, 82))	('association', 'Interaction', (56, 67))	('miR-146a-5p', 'Chemical', '-', (71, 82))	('expression', 'MPA', (105, 115))	('TRAF6', 'Gene', (99, 104))	('TRAF6', 'Gene', '7189', (99, 104))
56012	32226532	Moreover, to determine the clinical significance of miR-146a-5p in PDAC, we assessed its expression in a cohort comprising 93 pairs of PDAC tumors and matched adjacent normal tissues.	('PDAC', 'Disease', (135, 139))	('miR-146a-5p', 'Var', (52, 63))	('PDAC', 'Phenotype', 'HP:0006725', (135, 139))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('PDAC', 'Phenotype', 'HP:0006725', (67, 71))	('PDAC', 'Disease', (67, 71))	('miR-146a-5p', 'Chemical', '-', (52, 63))	('PDAC', 'Chemical', '-', (135, 139))	('PDAC', 'Chemical', '-', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
56021	32226532	We observed that the IC50 values of GEM were remarkably reduced in PDAC cells transfected with the miR-146a-5p mimic, suggesting that miR-146a-5p enhanced the cytotoxicity of GEM (Figure 2D-E).	('cytotoxicity', 'Disease', 'MESH:D064420', (159, 171))	('miR-146a-5p', 'Chemical', '-', (134, 145))	('PDAC', 'Phenotype', 'HP:0006725', (67, 71))	('miR-146a-5p', 'Var', (134, 145))	('GEM', 'Chemical', 'MESH:C056507', (36, 39))	('cytotoxicity', 'Disease', (159, 171))	('enhanced', 'PosReg', (146, 154))	('PDAC', 'Chemical', '-', (67, 71))	('miR-146a-5p', 'Chemical', '-', (99, 110))	('GEM', 'Chemical', 'MESH:C056507', (175, 178))
56024	32226532	After treatment with GEM for 48 h, similar results were obtained, showing that the GEM-induced apoptosis rate greatly increased in miR-146a-5p-mimic cells, whereas downregulation of miR-146a-5p inhibited apoptosis after GEM treatment (Figure 2F-I).	('miR-146a-5p-mimic', 'Var', (131, 148))	('inhibited', 'NegReg', (194, 203))	('rat', 'Species', '10116', (105, 108))	('miR-146a-5p', 'Chemical', '-', (182, 193))	('GEM', 'Chemical', 'MESH:C056507', (83, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('increased', 'PosReg', (118, 127))	('apoptosis rate', 'CPA', (95, 109))	('downregulation', 'NegReg', (164, 178))	('apoptosis', 'biological_process', 'GO:0097194', ('204', '213'))	('apoptosis', 'biological_process', 'GO:0006915', ('204', '213'))	('miR-146a-5p', 'Chemical', '-', (131, 142))	('GEM', 'Chemical', 'MESH:C056507', (21, 24))	('GEM', 'Chemical', 'MESH:C056507', (220, 223))	('apoptosis', 'CPA', (204, 213))
56025	32226532	Taken together, these results indicate that miR-146a-5p not only inhibits cell proliferation but also enhances the cytotoxicity of GEM.	('cell proliferation', 'CPA', (74, 92))	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))	('inhibits', 'NegReg', (65, 73))	('cytotoxicity', 'Disease', 'MESH:D064420', (115, 127))	('GEM', 'Chemical', 'MESH:C056507', (131, 134))	('enhances', 'PosReg', (102, 110))	('miR-146a-5p', 'Var', (44, 55))	('cytotoxicity', 'Disease', (115, 127))	('rat', 'Species', '10116', (86, 89))	('miR-146a-5p', 'Chemical', '-', (44, 55))
56026	32226532	To further confirm whether miR-146a-5p correlated with GEM resistance in vivo, we established PDAC xenograft models.	('GEM', 'Chemical', 'MESH:C056507', (55, 58))	('correlated', 'Reg', (39, 49))	('miR-146a-5p', 'Chemical', '-', (27, 38))	('PDAC', 'Chemical', '-', (94, 98))	('GEM resistance', 'CPA', (55, 69))	('miR-146a-5p', 'Var', (27, 38))	('PDAC', 'Phenotype', 'HP:0006725', (94, 98))
56027	32226532	When transplanted mice presented palpable xenografted tumors, they were treated with miR-146a-5p and GEM twice per week (Figure 3A).	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('GEM', 'Chemical', 'MESH:C056507', (101, 104))	('mice', 'Species', '10090', (18, 22))	('miR-146a-5p', 'Var', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('miR-146a-5p', 'Chemical', '-', (85, 96))	('tumors', 'Disease', (54, 60))
56028	32226532	The expression level of miR-146a-5p in xenograft tumor tissues treated with miR-146a-5p agomir was increased compared with that in tissues treated with negative control (NC) agomir (Figure 3B).	('expression level', 'MPA', (4, 20))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('miR-146a-5p', 'Chemical', '-', (24, 35))	('tumor', 'Disease', (49, 54))	('miR-146a-5p', 'Chemical', '-', (76, 87))	('increased', 'PosReg', (99, 108))	('miR-146a-5p agomir', 'Var', (76, 94))
56029	32226532	As shown in Figure 3C-E and Figure S2A-C, in the absence of GEM treatment, the tumor sizes and weights were significantly lower in the miR-146a-5p agomir-treated group than in the NC agomir group.	('lower', 'NegReg', (122, 127))	('tumor', 'Disease', (79, 84))	('miR-146a-5p', 'Var', (135, 146))	('GEM', 'Chemical', 'MESH:C056507', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('miR-146a-5p', 'Chemical', '-', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
56030	32226532	Moreover, the tumor sizes and weights were further reduced in the miR-146a-5p agomir with GEM treatment group.	('tumor', 'Disease', (14, 19))	('reduced', 'NegReg', (51, 58))	('GEM', 'Chemical', 'MESH:C056507', (90, 93))	('miR-146a-5p', 'Chemical', '-', (66, 77))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('miR-146a-5p', 'Var', (66, 77))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
56031	32226532	Subsequent IHC examination of the expression levels of the proliferation marker Ki-67 demonstrated that cell proliferation was inhibited and apoptosis was significantly increased in the miR-146a-5p agomir group with GEM treatment (Figure 3F-G and Figure 2SD-E).	('apoptosis', 'biological_process', 'GO:0097194', ('141', '150'))	('GEM', 'Chemical', 'MESH:C056507', (216, 219))	('miR-146a-5p', 'Var', (186, 197))	('apoptosis', 'biological_process', 'GO:0006915', ('141', '150'))	('increased', 'PosReg', (169, 178))	('rat', 'Species', '10116', (66, 69))	('cell proliferation', 'biological_process', 'GO:0008283', ('104', '122'))	('cell proliferation', 'CPA', (104, 122))	('inhibited', 'NegReg', (127, 136))	('rat', 'Species', '10116', (116, 119))	('miR-146a-5p', 'Chemical', '-', (186, 197))	('apoptosis', 'CPA', (141, 150))	('rat', 'Species', '10116', (93, 96))
56032	32226532	Collectively, these results demonstrated that miR-146a-5p could inhibit tumor growth and sensitize PDAC cells to GEM treatment.	('PDAC', 'Chemical', '-', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('miR-146a-5p', 'Var', (46, 57))	('GEM treatment', 'CPA', (113, 126))	('PDAC', 'Phenotype', 'HP:0006725', (99, 103))	('inhibit', 'NegReg', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('sensitize', 'Reg', (89, 98))	('GEM', 'Chemical', 'MESH:C056507', (113, 116))	('miR-146a-5p', 'Chemical', '-', (46, 57))	('rat', 'Species', '10116', (35, 38))	('PDAC cells', 'CPA', (99, 109))
56033	32226532	We next investigated the mechanism by which miR-146a-5p regulates cell proliferation and GEM resistance in PDAC cells.	('GEM resistance', 'CPA', (89, 103))	('cell proliferation', 'CPA', (66, 84))	('PDAC', 'Chemical', '-', (107, 111))	('miR-146a-5p', 'Var', (44, 55))	('rat', 'Species', '10116', (78, 81))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('regulates', 'Reg', (56, 65))	('GEM', 'Chemical', 'MESH:C056507', (89, 92))	('PDAC', 'Phenotype', 'HP:0006725', (107, 111))	('miR-146a-5p', 'Chemical', '-', (44, 55))
56036	32226532	The results showed that TRAF6 expression was reduced in cells treated with the miR-146a-5p mimic and increased in cells treated with the miR-146a-5p inhibitor (Figure 4B-D).	('miR-146a-5p', 'Chemical', '-', (137, 148))	('expression', 'MPA', (30, 40))	('reduced', 'NegReg', (45, 52))	('TRAF6', 'Gene', '7189', (24, 29))	('increased', 'PosReg', (101, 110))	('miR-146a-5p', 'Chemical', '-', (79, 90))	('miR-146a-5p mimic', 'Var', (79, 96))	('TRAF6', 'Gene', (24, 29))
56037	32226532	To further investigate the significance of the interaction between miR-146a-5p and TRAF6, a dual-luciferase reporter assay was performed.	('miR-146a-5p', 'Chemical', '-', (67, 78))	('miR-146a-5p', 'Var', (67, 78))	('TRAF6', 'Gene', (83, 88))	('TRAF6', 'Gene', '7189', (83, 88))
56038	32226532	Then, the predicted miR-146a-5p binding site on the 3'-UTR of wild-type TRAF6 (WT, 5'-GAGGCCGG-3') was mutated (MU, 5'-CACCCGCC-3'), and the full-length 3'-UTR was cloned into a luciferase reporter vector (Figure 4E).	('mutated', 'Var', (103, 110))	('TRAF6', 'Gene', (72, 77))	('miR-146a-5p', 'Gene', (20, 31))	('TRAF6', 'Gene', '7189', (72, 77))	('miR-146a-5p', 'Chemical', '-', (20, 31))	('binding', 'molecular_function', 'GO:0005488', ('32', '39'))	('binding', 'Interaction', (32, 39))
56039	32226532	After the vector containing the mutant 3'-UTR was transfected into PANC-1 and SW1990 cells, the inhibitory effect of miR-146a-5p on the luciferase activity was decreased (Figure 4F), confirming that miR-146a-5p can directly bind to TRAF6 and suppress its expression.	('miR-146a-5p', 'Var', (199, 210))	('luciferase activity', 'molecular_function', 'GO:0045289', ('136', '155'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('136', '155'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('136', '155'))	('inhibitory effect', 'MPA', (96, 113))	('suppress', 'NegReg', (242, 250))	('luciferase activity', 'molecular_function', 'GO:0050397', ('136', '155'))	('miR-146a-5p', 'Chemical', '-', (117, 128))	('expression', 'MPA', (255, 265))	('miR-146a-5p', 'Chemical', '-', (199, 210))	('luciferase', 'Enzyme', (136, 146))	('mutant', 'Var', (32, 38))	('TRAF6', 'Gene', (232, 237))	('TRAF6', 'Gene', '7189', (232, 237))	('decreased', 'NegReg', (160, 169))	('luciferase activity', 'molecular_function', 'GO:0047077', ('136', '155'))	('activity', 'MPA', (147, 155))	('bind', 'Interaction', (224, 228))
56046	32226532	qPCR and Western blotting analyses confirmed TRAF6 knockdown and overexpression, respectively (Figure 5A-D).	('TRAF6', 'Gene', (45, 50))	('TRAF6', 'Gene', '7189', (45, 50))	('overexpression', 'PosReg', (65, 79))	('knockdown', 'Var', (51, 60))
56047	32226532	Silencing TRAF6 dramatically decreased the IC50 values of GEM and increased its cytotoxic effect in PDAC cells, whereas TRAF6 overexpression increased the IC50 value (Figure 5E-F).	('TRAF6', 'Gene', '7189', (120, 125))	('PDAC', 'Phenotype', 'HP:0006725', (100, 104))	('IC50 values', 'MPA', (43, 54))	('increased', 'PosReg', (66, 75))	('TRAF6', 'Gene', '7189', (10, 15))	('PDAC', 'Chemical', '-', (100, 104))	('GEM', 'MPA', (58, 61))	('decreased', 'NegReg', (29, 38))	('cytotoxic effect', 'CPA', (80, 96))	('TRAF6', 'Gene', (120, 125))	('Silencing', 'Var', (0, 9))	('TRAF6', 'Gene', (10, 15))	('GEM', 'Chemical', 'MESH:C056507', (58, 61))
56049	32226532	In addition, to further verify whether TRAF6 mediates the effect of miR-146a-5p on GEM chemoresistance, we cotransfected both the miR-146a-5p mimic and TRAF6 overexpression vector into PDAC cells.	('miR-146a-5p', 'Chemical', '-', (68, 79))	('PDAC', 'Chemical', '-', (185, 189))	('TRAF6', 'Gene', (152, 157))	('TRAF6', 'Gene', '7189', (152, 157))	('GEM', 'Chemical', 'MESH:C056507', (83, 86))	('miR-146a-5p', 'Var', (130, 141))	('TRAF6', 'Gene', (39, 44))	('TRAF6', 'Gene', '7189', (39, 44))	('PDAC', 'Phenotype', 'HP:0006725', (185, 189))	('miR-146a-5p', 'Chemical', '-', (130, 141))
56051	32226532	Therefore, these results demonstrate that miR-146a-5p could sensitize PDAC cells to the chemotherapeutic efficacy of GEM by directly targeting TRAF6.	('PDAC', 'Phenotype', 'HP:0006725', (70, 74))	('TRAF6', 'Gene', (143, 148))	('targeting', 'Reg', (133, 142))	('TRAF6', 'Gene', '7189', (143, 148))	('rat', 'Species', '10116', (32, 35))	('GEM', 'Chemical', 'MESH:C056507', (117, 120))	('miR-146a-5p', 'Chemical', '-', (42, 53))	('PDAC', 'Chemical', '-', (70, 74))	('sensitize', 'Reg', (60, 69))	('miR-146a-5p', 'Var', (42, 53))
56055	32226532	Hence, we hypothesized that miR-146a-5p regulated the TRAF6/NF-kappaB p65/P-gp axis during the process of acquired GEM resistance in PDAC cells.	('miR-146a-5p', 'Var', (28, 39))	('PDAC', 'Phenotype', 'HP:0006725', (133, 137))	('TRAF6', 'Gene', '7189', (54, 59))	('miR-146a-5p', 'Chemical', '-', (28, 39))	('GEM', 'Chemical', 'MESH:C056507', (115, 118))	('regulated', 'Reg', (40, 49))	('NF-kappaB p65', 'Gene', (60, 73))	('TRAF6', 'Gene', (54, 59))	('PDAC', 'Chemical', '-', (133, 137))	('NF-kappaB p65', 'Gene', '5970', (60, 73))
56056	32226532	As determined in Figure 6A, miR-146a-5p overexpression decreased the NF-kappaB p65 and P-gp expression levels, whereas the levels of these proteins were markedly increased in cells upon miR-146a-5p inhibition.	('NF-kappaB p65', 'Gene', (69, 82))	('increased', 'PosReg', (162, 171))	('miR-146a-5p', 'Var', (186, 197))	('NF-kappaB p65', 'Gene', '5970', (69, 82))	('P-gp expression levels', 'MPA', (87, 109))	('miR-146a-5p', 'Chemical', '-', (28, 39))	('decreased', 'NegReg', (55, 64))	('miR-146a-5p', 'Chemical', '-', (186, 197))
56057	32226532	Similarly, TRAF6 knockdown downregulated the expression levels of NF-kappaB p65 and P-gp (Figure 6B).	('expression levels', 'MPA', (45, 62))	('NF-kappaB p65', 'Gene', (66, 79))	('TRAF6', 'Gene', '7189', (11, 16))	('NF-kappaB p65', 'Gene', '5970', (66, 79))	('downregulated', 'NegReg', (27, 40))	('TRAF6', 'Gene', (11, 16))	('knockdown', 'Var', (17, 26))	('P-gp', 'MPA', (84, 88))
56058	32226532	In addition, the increased levels of these proteins by miR-146a-5p overexpression could be ameliorated by upregulation of TRAF6 (Figure 6C).	('increased', 'PosReg', (17, 26))	('miR-146a-5p', 'Var', (55, 66))	('rat', 'Species', '10116', (97, 100))	('levels of these proteins', 'MPA', (27, 51))	('miR-146a-5p', 'Chemical', '-', (55, 66))	('TRAF6', 'Gene', (122, 127))	('upregulation', 'PosReg', (106, 118))	('TRAF6', 'Gene', '7189', (122, 127))
56060	32226532	The results revealed that the levels of these proteins were decreased in the miR-146a-5p agomir group compared with those in the NC agomir group (Figure 6D-E).	('levels of these proteins', 'MPA', (30, 54))	('decreased', 'NegReg', (60, 69))	('miR-146a-5p', 'Chemical', '-', (77, 88))	('miR-146a-5p', 'Var', (77, 88))
56062	32226532	These results indicate that miR-146a-5p regulates GEM resistance through the TRAF6/NF-kappaB p65/P-gp axis in PDAC cells.	('NF-kappaB p65', 'Gene', (83, 96))	('regulates', 'Reg', (40, 49))	('miR-146a-5p', 'Var', (28, 39))	('PDAC', 'Chemical', '-', (110, 114))	('NF-kappaB p65', 'Gene', '5970', (83, 96))	('miR-146a-5p', 'Chemical', '-', (28, 39))	('GEM', 'Chemical', 'MESH:C056507', (50, 53))	('GEM resistance', 'MPA', (50, 64))	('PDAC', 'Phenotype', 'HP:0006725', (110, 114))	('TRAF6', 'Gene', (77, 82))	('TRAF6', 'Gene', '7189', (77, 82))
56066	32226532	After performing a series of experiments, we found that miR-146a-5p was downregulated in GR cells and that miR-146a-5p inhibited PDAC cell proliferation and resistance to GEM in vitro and in vivo.	('PDAC', 'Chemical', '-', (129, 133))	('miR-146a-5p', 'Var', (107, 118))	('rat', 'Species', '10116', (146, 149))	('PDAC', 'Phenotype', 'HP:0006725', (129, 133))	('inhibited', 'NegReg', (119, 128))	('cell proliferation', 'biological_process', 'GO:0008283', ('134', '152'))	('miR-146a-5p', 'Chemical', '-', (56, 67))	('PDAC cell proliferation', 'CPA', (129, 152))	('miR-146a-5p', 'Chemical', '-', (107, 118))	('downregulated', 'NegReg', (72, 85))	('GEM', 'Chemical', 'MESH:C056507', (171, 174))	('resistance to GEM', 'CPA', (157, 174))
56067	32226532	In addition, we also demonstrated that decreased miR-146a-5p expression is significantly associated with poor prognosis in PDAC patients.	('miR-146a-5p', 'Var', (49, 60))	('PDAC', 'Disease', (123, 127))	('PDAC', 'Phenotype', 'HP:0006725', (123, 127))	('miR-146a-5p', 'Chemical', '-', (49, 60))	('decreased', 'NegReg', (39, 48))	('patients', 'Species', '9606', (128, 136))	('rat', 'Species', '10116', (28, 31))	('PDAC', 'Chemical', '-', (123, 127))
56072	32226532	Moreover, recent studies have suggested that miR-146a-5p also exerts either a positive or negative effect on drug resistance.	('miR-146a-5p', 'Chemical', '-', (45, 56))	('drug resistance', 'biological_process', 'GO:0042493', ('109', '124'))	('drug resistance', 'MPA', (109, 124))	('drug resistance', 'biological_process', 'GO:0009315', ('109', '124'))	('negative', 'NegReg', (90, 98))	('drug resistance', 'Phenotype', 'HP:0020174', (109, 124))	('miR-146a-5p', 'Var', (45, 56))
56077	32226532	found in a rat model of chronic refractory epilepsy that silencing miR-146a can improve drug resistance by regulating the HMGB1/TLR4/NF-kappaB/P-gp axis.	('miR-146a', 'Gene', (67, 75))	('epilepsy', 'Disease', (43, 51))	('HMGB1', 'Gene', (122, 127))	('drug resistance', 'biological_process', 'GO:0009315', ('88', '103'))	('drug resistance', 'biological_process', 'GO:0042493', ('88', '103'))	('NF-kappaB', 'Gene', (133, 142))	('TLR4', 'Gene', (128, 132))	('drug resistance', 'MPA', (88, 103))	('silencing', 'Var', (57, 66))	('regulating', 'Reg', (107, 117))	('HMGB1', 'Gene', '25459', (122, 127))	('rat', 'Species', '10116', (11, 14))	('epilepsy', 'Disease', 'MESH:D004827', (43, 51))	('epilepsy', 'Phenotype', 'HP:0001250', (43, 51))	('improve', 'PosReg', (80, 87))	('TLR4', 'Gene', '29260', (128, 132))	('drug resistance', 'Phenotype', 'HP:0020174', (88, 103))	('NF-kappaB', 'Gene', '4790', (133, 142))
56078	32226532	Increasing evidence suggests that miR-146a-5p, which binds to various downstream targets including IRAK1, EGFR, NOTCH1/2, SOX2/5 and CHOP, plays a role in many biological processes.	('miR-146a-5p', 'Chemical', '-', (34, 45))	('SOX2/5', 'Gene', '11166;6657;6660', (122, 128))	('CHOP', 'Gene', '1649', (133, 137))	('SOX2/5', 'Gene', (122, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('106', '110'))	('NOTCH1/2', 'Gene', '4851;4853', (112, 120))	('plays', 'Reg', (139, 144))	('CHOP', 'Gene', (133, 137))	('NOTCH1/2', 'Gene', (112, 120))	('miR-146a-5p', 'Var', (34, 45))	('binds', 'Interaction', (53, 58))	('role', 'Reg', (147, 151))	('IRAK1', 'Gene', '3654', (99, 104))	('EGFR', 'Gene', '1956', (106, 110))	('IRAK1', 'Gene', (99, 104))	('EGFR', 'Gene', (106, 110))
56080	32226532	Here, we identified TRAF6 as a potential target of miR-146a-5p through bioinformatics analysis.	('TRAF6', 'Gene', '7189', (20, 25))	('TRAF6', 'Gene', (20, 25))	('miR-146a-5p', 'Chemical', '-', (51, 62))	('miR-146a-5p', 'Var', (51, 62))
56083	32226532	P-gp, also known as multidrug resistance 1 (MDR1), plays an important role in the efflux of many drugs, including GEM, and enhanced chemoresistance, the latter of which is regulated by activation of the NF-kappaB signaling pathway.	('enhanced', 'PosReg', (123, 131))	('MDR1', 'Gene', (44, 48))	('multidrug resistance 1', 'Gene', '5243', (20, 42))	('signaling pathway', 'biological_process', 'GO:0007165', ('213', '230'))	('efflux', 'biological_process', 'GO:0140115', ('82', '88'))	('drug resistance', 'Phenotype', 'HP:0020174', (25, 40))	('chemoresistance', 'CPA', (132, 147))	('efflux', 'biological_process', 'GO:0140352', ('82', '88'))	('multidrug resistance 1', 'Gene', (20, 42))	('efflux', 'MPA', (82, 88))	('GEM', 'Chemical', 'MESH:C056507', (114, 117))	('NF-kappaB', 'Gene', '4790', (203, 212))	('MDR1', 'Gene', '5243', (44, 48))	('NF-kappaB', 'Gene', (203, 212))	('P-gp', 'Var', (0, 4))	('MDR', 'molecular_function', 'GO:0004745', ('44', '47'))
56085	32226532	Several studies have examined the impact of regulatory proteins on miR-146a-5p expression in cancer cells.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('miR-146a-5p', 'Var', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('miR-146a-5p', 'Chemical', '-', (67, 78))
56088	32226532	Furthermore, epigenetic mechanisms, including DNA CpG methylation, histone acetylation, and histone methylation, contribute to the dysregulation of miR-146a expression in cancer.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('dysregulation', 'MPA', (131, 144))	('histone methylation', 'MPA', (92, 111))	('expression', 'MPA', (157, 167))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('methylation', 'Var', (54, 65))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('histone acetylation', 'MPA', (67, 86))	('histone methylation', 'biological_process', 'GO:0016571', ('92', '111'))	('miR-146a', 'Gene', (148, 156))	('histone acetylation', 'biological_process', 'GO:0016573', ('67', '86'))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
56089	32226532	reported that DNA methylation at CpG sites in promoter regions contributes to decreased miR-146a expression in NSCLC cells.	('NSCLC', 'Disease', (111, 116))	('DNA methylation', 'biological_process', 'GO:0006306', ('14', '29'))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('methylation', 'Var', (18, 29))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('decreased', 'NegReg', (78, 87))	('expression', 'MPA', (97, 107))	('miR-146a', 'Gene', (88, 96))
56092	32226532	We found that miR-146a-5p dysregulation in PDAC tissues were correlated with OS of patients.	('dysregulation', 'Var', (26, 39))	('PDAC', 'Phenotype', 'HP:0006725', (43, 47))	('miR-146a-5p', 'Gene', (14, 25))	('miR-146a-5p', 'Chemical', '-', (14, 25))	('correlated', 'Reg', (61, 71))	('OS', 'Chemical', '-', (77, 79))	('patients', 'Species', '9606', (83, 91))	('PDAC', 'Chemical', '-', (43, 47))
56093	32226532	Moreover, our data indicate that miR-146a-5p expression is a potential biomarker for chemotherapy selection in patients with PDAC who receive GEM-based or fluoropyrimidine-based chemotherapy.	('GEM', 'Chemical', 'MESH:C056507', (142, 145))	('PDAC', 'Chemical', '-', (125, 129))	('miR-146a-5p', 'Var', (33, 44))	('PDAC', 'Phenotype', 'HP:0006725', (125, 129))	('fluoropyrimidine', 'Chemical', '-', (155, 171))	('PDAC', 'Disease', (125, 129))	('miR-146a-5p', 'Chemical', '-', (33, 44))	('patients', 'Species', '9606', (111, 119))
56094	32226532	Similarly, NSCLC patients with increased serum levels of miR-146a had a better response to chemotherapy and experienced better OS than patients with lower levels, as reported previously by Wu et al..	('NSCLC', 'Disease', (11, 16))	('patients', 'Species', '9606', (135, 143))	('increased', 'PosReg', (31, 40))	('NSCLC', 'Disease', 'MESH:D002289', (11, 16))	('better', 'PosReg', (72, 78))	('serum', 'MPA', (41, 46))	('OS', 'Chemical', '-', (127, 129))	('patients', 'Species', '9606', (17, 25))	('miR-146a', 'Var', (57, 65))	('response', 'CPA', (79, 87))
56095	32226532	Hence, additional studies are required to confirm that miR-146a-5p expression is a potential biomarker for chemotherapy selection in patients with PDAC.	('miR-146a-5p', 'Var', (55, 66))	('PDAC', 'Chemical', '-', (147, 151))	('patients', 'Species', '9606', (133, 141))	('PDAC', 'Disease', (147, 151))	('miR-146a-5p', 'Chemical', '-', (55, 66))	('PDAC', 'Phenotype', 'HP:0006725', (147, 151))
56096	32226532	Taken together, the data from our study provide a new understanding of miR-146a-5p in PDAC cell growth and GEM resistance through the regulation of TRAF6/NF-kappaB signaling, which may represent a novel regulatory mechanism for PDAC.	('PDAC', 'Phenotype', 'HP:0006725', (228, 232))	('miR-146a-5p', 'Var', (71, 82))	('TRAF6', 'Gene', (148, 153))	('NF-kappaB', 'Gene', '4790', (154, 163))	('GEM', 'Chemical', 'MESH:C056507', (107, 110))	('cell growth', 'biological_process', 'GO:0016049', ('91', '102'))	('GEM resistance', 'CPA', (107, 121))	('NF-kappaB', 'Gene', (154, 163))	('TRAF6', 'Gene', '7189', (148, 153))	('PDAC', 'Chemical', '-', (86, 90))	('regulation', 'biological_process', 'GO:0065007', ('134', '144'))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))	('PDAC', 'Chemical', '-', (228, 232))	('miR-146a-5p', 'Chemical', '-', (71, 82))	('PDAC', 'Disease', (86, 90))	('PDAC', 'Phenotype', 'HP:0006725', (86, 90))	('regulation', 'Reg', (134, 144))
56098	32226532	Furthermore, the expression levels of miR-146a-5p may have prognostic significance and act as a vital predictive biomarker for clinical chemotherapy selection in PDAC patients.	('miR-146a-5p', 'Chemical', '-', (38, 49))	('expression levels', 'MPA', (17, 34))	('PDAC', 'Chemical', '-', (162, 166))	('patients', 'Species', '9606', (167, 175))	('miR-146a-5p', 'Var', (38, 49))	('PDAC', 'Disease', (162, 166))	('PDAC', 'Phenotype', 'HP:0006725', (162, 166))
56100	31263025	Oncogenic Kras induces Nix-mediated mitophagy to promote pancreatic cancer Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive.	('mitophagy', 'biological_process', 'GO:0000423', ('36', '45'))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('KRAS', 'Gene', (86, 90))	('Kras', 'Gene', (10, 14))	('promote', 'PosReg', (49, 56))	('Nix', 'Gene', (23, 26))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (57, 74))	('found', 'Reg', (105, 110))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (134, 166))	('pancreatic ductal adenocarcinoma', 'Disease', (134, 166))	('KRAS', 'Gene', '3845', (221, 225))	('Nix', 'Gene', '665', (23, 26))	('pancreatic cancer', 'Disease', 'MESH:D010190', (57, 74))	('PDAC', 'Chemical', '-', (168, 172))	('KRAS', 'Gene', (221, 225))	('KRAS', 'Gene', '3845', (86, 90))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (134, 166))	('mitophagy', 'biological_process', 'GO:0000422', ('36', '45'))	('mutations', 'Var', (91, 100))	('PDAC', 'Phenotype', 'HP:0006725', (168, 172))	('Kras', 'Gene', '3845', (10, 14))	('pancreatic cancer', 'Disease', (57, 74))
56102	31263025	We show that oncogenic KRAS induces BNIP3L/NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity.	('mitophagy', 'biological_process', 'GO:0000422', ('74', '83'))	('BNIP3L', 'Gene', (36, 42))	('BNIP3L', 'Gene', '665', (36, 42))	('glucose', 'Chemical', 'MESH:D005947', (107, 114))	('glucose flux to the mitochondria', 'MPA', (107, 139))	('mitophagy', 'biological_process', 'GO:0000423', ('74', '83'))	('oncogenic', 'Var', (13, 22))	('redox capacity', 'MPA', (153, 167))	('KRAS', 'Gene', (23, 27))	('induces', 'Reg', (28, 35))	('mitochondria', 'cellular_component', 'GO:0005739', ('127', '139'))	('enhances', 'PosReg', (144, 152))	('restricts', 'NegReg', (97, 106))	('KRAS', 'Gene', '3845', (23, 27))	('red', 'Chemical', '-', (153, 156))	('mitophagy program', 'CPA', (74, 91))
56103	31263025	Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions.	('restores', 'PosReg', (12, 20))	('NADPH', 'Gene', '1666', (78, 83))	('functional mitochondria', 'MPA', (21, 44))	('red', 'Chemical', '-', (84, 87))	('glucose', 'Chemical', 'MESH:D005947', (131, 138))	('proliferation', 'CPA', (114, 127))	('decreasing', 'NegReg', (103, 113))	('increasing', 'PosReg', (55, 65))	('demands', 'MPA', (66, 73))	('Loss', 'Var', (0, 4))	('NADPH', 'Gene', (78, 83))	('Nix', 'Gene', (8, 11))	('mitochondria', 'cellular_component', 'GO:0005739', ('32', '44'))
56104	31263025	Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC.	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('progression', 'CPA', (29, 40))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('murine', 'Species', '10090', (89, 95))	('PDAC', 'Chemical', '-', (111, 115))	('Nix', 'Gene', (0, 3))	('survival', 'MPA', (75, 83))	('deletion', 'Var', (4, 12))	('improves', 'PosReg', (66, 74))	('delays', 'NegReg', (22, 28))	('pancreatic cancer', 'Disease', (44, 61))	('PDAC', 'Phenotype', 'HP:0006725', (111, 115))
56105	31263025	While conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and PanIN lesions progress to PDAC.	('PDAC', 'Chemical', '-', (216, 220))	('normalizes', 'MPA', (127, 137))	('increased', 'PosReg', (142, 151))	('progress', 'Reg', (204, 212))	('lesions', 'Var', (196, 203))	('PDAC', 'Disease', (216, 220))	('PDAC', 'Phenotype', 'HP:0006725', (216, 220))	('ablation', 'Var', (22, 30))	('mitochondrial content', 'MPA', (94, 115))	('mitochondrial clearance programs', 'MPA', (152, 184))	('mitochondria', 'cellular_component', 'GO:0005739', ('80', '92'))	('mitochondria', 'MPA', (80, 92))	('accumulation', 'PosReg', (64, 76))
56108	31263025	The most prevalent type, pancreatic ductal adenocarcinoma (PDAC), is characterized by near-universal mutational activation of KRAS.	('KRAS', 'Gene', '3845', (126, 130))	('PDAC', 'Chemical', '-', (59, 63))	('mutational', 'Var', (101, 111))	('PDAC', 'Phenotype', 'HP:0006725', (59, 63))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (25, 57))	('pancreatic ductal adenocarcinoma', 'Disease', (25, 57))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (25, 57))	('KRAS', 'Gene', (126, 130))
56109	31263025	Oncogenic KRAS can promote proliferation under the nutrient-limiting conditions found in tumors by altering both the uptake of nutrients from the environment and the expression and activity of metabolic enzymes.	('activity', 'MPA', (181, 189))	('tumors', 'Disease', (89, 95))	('KRAS', 'Gene', '3845', (10, 14))	('promote', 'PosReg', (19, 26))	('uptake of nutrients from the environment', 'MPA', (117, 157))	('altering', 'Reg', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('uptake', 'biological_process', 'GO:0098739', ('117', '123'))	('proliferation', 'CPA', (27, 40))	('uptake', 'biological_process', 'GO:0098657', ('117', '123'))	('metabolic enzymes', 'Enzyme', (193, 210))	('iron', 'Chemical', 'MESH:D007501', (149, 153))	('expression', 'MPA', (166, 176))	('Oncogenic', 'Var', (0, 9))	('KRAS', 'Gene', (10, 14))
56111	31263025	In these studies, pharmacological inhibition and/or genetic ablation of general autophagy and lysosomal programs led to the accumulation of defective mitochondria and consequent metabolic insufficiencies.	('lysosomal programs', 'CPA', (94, 112))	('metabolic insufficiencies', 'Disease', (178, 203))	('accumulation', 'PosReg', (124, 136))	('metabolic insufficiencies', 'Disease', 'MESH:D000309', (178, 203))	('genetic ablation', 'Var', (52, 68))	('autophagy', 'biological_process', 'GO:0016236', ('80', '89'))	('mitochondria', 'cellular_component', 'GO:0005739', ('150', '162'))	('defective mitochondria', 'Disease', (140, 162))	('defective mitochondria', 'Disease', 'MESH:C565498', (140, 162))	('autophagy', 'biological_process', 'GO:0006914', ('80', '89'))
56112	31263025	Additionally, cells surviving loss of oncogenic Kras expression in an inducible model of pancreatic cancer had increased mitochondrial content and exhibited increased sensitivity to mitochondrial inhibitors.	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('increased mitochondrial content', 'Phenotype', 'HP:0040014', (111, 142))	('increased', 'PosReg', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('oncogenic', 'Var', (38, 47))	('mitochondrial content', 'MPA', (121, 142))	('Kras', 'Gene', (48, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('increased', 'PosReg', (157, 166))	('loss', 'NegReg', (30, 34))	('pancreatic cancer', 'Disease', (89, 106))	('sensitivity to mitochondrial inhibitors', 'MPA', (167, 206))
56114	31263025	We previously reported that KrasG12D activated the Nfe2l2/Nrf2 antioxidant pathway to lower cytoplasmic reactive oxygen species (ROS), promoting cell proliferation and the initiation of early lung and pancreatic cancers.	('pancreatic cancers', 'Disease', (201, 219))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (201, 218))	('cell proliferation', 'biological_process', 'GO:0008283', ('145', '163'))	('KrasG12D', 'Var', (28, 36))	('pancreatic cancers', 'Disease', 'MESH:D010190', (201, 219))	('Nrf2', 'Gene', '4780', (58, 62))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('promoting', 'PosReg', (135, 144))	('early lung', 'Disease', (186, 196))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (201, 219))	('cell proliferation', 'CPA', (145, 163))	('Nrf2', 'Gene', (58, 62))	('Nfe2l2', 'Gene', '4780', (51, 57))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (104, 127))	('ROS', 'Chemical', 'MESH:D017382', (129, 132))	('Nfe2l2', 'Gene', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
56115	31263025	As part of these findings, we observed a KrasG12D-dependent reduction in mitochondrial ROS levels but did not further interrogate the mitochondrial response to oncogenic Kras.	('red', 'Chemical', '-', (60, 63))	('mitochondrial ROS levels', 'MPA', (73, 97))	('ROS', 'Chemical', 'MESH:D017382', (87, 90))	('reduction', 'NegReg', (60, 69))	('KrasG12D-dependent', 'Var', (41, 59))
56117	31263025	Cells were cultured in low glucose medium (0.5 mM and 2mM glucose for 2D cells and organoids, respectively), because these limited conditions select for the emergence and outgrowth of cells harboring Kras mutations in vitro and are a closer approximation than normal commercial media for the nutrient environment of PDAC in vivo.	('glucose', 'Chemical', 'MESH:D005947', (27, 34))	('PDAC', 'Chemical', '-', (316, 320))	('mutations', 'Var', (205, 214))	('outgrowth', 'CPA', (171, 180))	('iron', 'Chemical', 'MESH:D007501', (304, 308))	('glucose', 'Chemical', 'MESH:D005947', (58, 65))	('PDAC', 'Phenotype', 'HP:0006725', (316, 320))	('red', 'Chemical', '-', (16, 19))	('Kras', 'Gene', (200, 204))
56118	31263025	Consistent with our published work, we found that KrasG12D decreased both cytoplasmic and mitochondrial ROS levels, indicated by diminished DCF-DA and MitoSox Red fluorescent intensity, respectively, in MEFs (Fig 1A).	('mitochondrial ROS levels', 'MPA', (90, 114))	('decreased', 'NegReg', (59, 68))	('MitoSox Red fluorescent intensity', 'MPA', (151, 184))	('diminished', 'NegReg', (129, 139))	('ROS', 'Chemical', 'MESH:D017382', (104, 107))	('DCF-DA', 'MPA', (140, 146))	('KrasG12D', 'Var', (50, 58))	('MitoSox Red', 'Chemical', 'MESH:C000597839', (151, 162))	('DCF-DA', 'Chemical', 'MESH:C029569', (140, 146))
56119	31263025	While levels of cytoplasmic ROS in Kras-mutant MEFs remained at Kras-wild type (WT) levels in the absence of Nrf2, the reduction in mitochondrial ROS persisted, suggesting that the effects of mutant Kras on mitochondrial ROS are independent of the Nrf2 program (Fig S1A).	('red', 'Chemical', '-', (119, 122))	('mutant', 'Var', (192, 198))	('Nrf2', 'Gene', (109, 113))	('Kras-mutant', 'Gene', (35, 46))	('ROS', 'Chemical', 'MESH:D017382', (28, 31))	('Nrf2', 'Gene', '4780', (248, 252))	('Nrf2', 'Gene', '4780', (109, 113))	('ROS', 'Chemical', 'MESH:D017382', (221, 224))	('ROS', 'Chemical', 'MESH:D017382', (146, 149))	('Nrf2', 'Gene', (248, 252))	('reduction', 'NegReg', (119, 128))	('mitochondrial ROS', 'MPA', (132, 149))
56120	31263025	Alongside diminished mitochondrial ROS, the expression of mutant Kras in MEFs and organoids also led to decreased mitochondrial mass and total mitochondrial membrane potential per cell (Fig 1A-B), suggesting a reduced mitochondrial network.	('mutant', 'Var', (58, 64))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('143', '165'))	('reduced', 'NegReg', (210, 217))	('ROS', 'Chemical', 'MESH:D017382', (35, 38))	('mitochondrial', 'MPA', (114, 127))	('red', 'Chemical', '-', (210, 213))	('decreased', 'NegReg', (104, 113))	('decreased mitochondrial mass', 'Phenotype', 'HP:0040013', (104, 132))	('Kras', 'Gene', (65, 69))	('mitochondrial ROS', 'MPA', (21, 38))	('diminished', 'NegReg', (10, 20))	('mitochondrial network', 'CPA', (218, 239))
56122	31263025	Determination of the ratio of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA), an alternative method of evaluating mitochondrial content, also showed a decreased ratio in KrasG12D MEFs compared to Kras-WT MEFs, further indicating a suppression of mitochondrial content (Fig S1D).	('mtDNA', 'cellular_component', 'GO:0000262', ('49', '54'))	('mitochondrial content', 'MPA', (247, 268))	('KrasG12D MEFs', 'Var', (171, 184))	('decreased', 'NegReg', (152, 161))	('suppression', 'NegReg', (232, 243))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('30', '47'))	('red', 'Chemical', '-', (190, 193))
56123	31263025	To study the effects of loss of mutant Kras on this mitochondrial phenotype, we crossed mice harboring an excisable endogenous mutant Kras allele (FRT-LSL-KrasG12V-FRT, Fig S1E) with mice harboring LSL-Trp53R172H/+, Pdx1-Cre and Rosa26-FlpOERT2 alleles to generate an autochthonous "FPC" mouse model of PDAC in which we could delete mutant Kras using tamoxifen.	('mutant', 'Var', (333, 339))	('mouse', 'Species', '10090', (288, 293))	('Pdx1-Cre', 'Gene', (216, 224))	('Rosa26', 'Gene', '14910', (229, 235))	('PDAC', 'Chemical', '-', (303, 307))	('Trp53', 'Gene', (202, 207))	('Pdx1-Cre', 'Gene', '18609', (216, 224))	('FPC', 'cellular_component', 'GO:1990900', ('282', '285'))	('Kras', 'Gene', (340, 344))	('mice', 'Species', '10090', (183, 187))	('Trp53', 'Gene', '7157', (202, 207))	('Rosa26', 'Gene', (229, 235))	('PDAC', 'Phenotype', 'HP:0006725', (303, 307))	('mice', 'Species', '10090', (88, 92))
56124	31263025	Cell lines derived from tumors arising in FPC mice were cultured with 4-OH-tamoxifen (4OHT) for 96 hours, which led to excision of the mutant Kras allele (Fig S1F).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('red', 'Chemical', '-', (61, 64))	('excision', 'MPA', (119, 127))	('4-OH-tamoxifen', 'Chemical', '-', (70, 84))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('4OHT', 'Chemical', '-', (86, 90))	('mutant', 'Var', (135, 141))	('FPC', 'cellular_component', 'GO:1990900', ('42', '45'))	('mice', 'Species', '10090', (46, 50))	('Kras', 'Gene', (142, 146))
56126	31263025	Moreover, in the setting of KRAS-mutant human PDAC cell lines (Suit2 and FA6), siRNA-mediated knockdown of KRAS similarly led to an increase in mitochondrial mass as measured by flow cytometry, electron microscopy, and mtDNA/nDNA ratio (Fig 1F, Fig S2 A-G).	('mitochondrial mass', 'MPA', (144, 162))	('mtDNA', 'cellular_component', 'GO:0000262', ('219', '224'))	('KRAS', 'Gene', (28, 32))	('knockdown', 'Var', (94, 103))	('KRAS', 'Gene', (107, 111))	('red', 'Chemical', '-', (171, 174))	('KRAS', 'Gene', '3845', (28, 32))	('increase', 'PosReg', (132, 140))	('PDAC', 'Phenotype', 'HP:0006725', (46, 50))	('KRAS', 'Gene', '3845', (107, 111))	('PDAC', 'Chemical', '-', (46, 50))	('human', 'Species', '9606', (40, 45))	('mtDNA/nDNA ratio', 'MPA', (219, 235))
56128	31263025	Consistent with this prediction, we did not observe significant changes in the expression of key transcription factors involved in mitochondrial biogenesis including Pgc1a, Nrf1 and Tfam following activation of mutant Kras, suggesting that a decrease in biogenesis was not the primary explanation for decreased mitochondrial mass (Fig S3 A-B).	('Tfam', 'Gene', (182, 186))	('biogenesis', 'MPA', (254, 264))	('Tfam', 'Gene', '7019', (182, 186))	('red', 'Chemical', '-', (22, 25))	('Kras', 'Gene', (218, 222))	('transcription', 'biological_process', 'GO:0006351', ('97', '110'))	('Nrf1', 'Gene', (173, 177))	('Pgc1a', 'Gene', '10891', (166, 171))	('Pgc1a', 'Gene', (166, 171))	('mutant', 'Var', (211, 217))	('mitochondrial mass', 'MPA', (311, 329))	('decreased mitochondrial mass', 'Phenotype', 'HP:0040013', (301, 329))	('Nrf1', 'Gene', '4899', (173, 177))	('decrease', 'NegReg', (242, 250))
56129	31263025	In this setting, expression of KrasG12D resulted in increased mRNA expression of the mitophagy mediator BCL2/adenovirus E1B 19-kDa-interacting protein 3-like (Bnip3l/Nix) but not of other mediators of mitophagy such as p62/Sqstm1, Pink1, or Park2 (Fig S3C).	('KrasG12D', 'Var', (31, 39))	('mitophagy', 'biological_process', 'GO:0000422', ('85', '94'))	('increased', 'PosReg', (52, 61))	('Sqstm1', 'Gene', (223, 229))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('mitophagy', 'biological_process', 'GO:0000423', ('201', '210'))	('mitophagy', 'biological_process', 'GO:0000423', ('85', '94'))	('Sqstm1', 'Gene', '8878', (223, 229))	('BCL2', 'molecular_function', 'GO:0015283', ('104', '108'))	('Bnip3l', 'Gene', '665', (159, 165))	('Bnip3l', 'Gene', (159, 165))	('mRNA expression', 'MPA', (62, 77))	('BCL2/adenovirus E1B 19-kDa-interacting protein 3-like', 'Gene', '665;596', (104, 157))	('mitophagy', 'biological_process', 'GO:0000422', ('201', '210'))
56130	31263025	In organoids, we found that activation of mutant Kras also led to an increase in Nix protein and a trend towards increased Nix mRNA level, with a concurrent increase in levels of lipidated LC3 (LC3-II), a marker of active autophagy (Fig 2B, S3D).	('autophagy', 'biological_process', 'GO:0016236', ('222', '231'))	('mutant', 'Var', (42, 48))	('increase', 'PosReg', (69, 77))	('LC3', 'Gene', '84557', (189, 192))	('LC3', 'Gene', (189, 192))	('levels', 'MPA', (169, 175))	('autophagy', 'biological_process', 'GO:0006914', ('222', '231'))	('Nix protein', 'MPA', (81, 92))	('LC3-II', 'Gene', '84557', (194, 200))	('Kras', 'Gene', (49, 53))	('increased', 'PosReg', (113, 122))	('LC3', 'Gene', '84557', (194, 197))	('LC3-II', 'Gene', (194, 200))	('increase', 'PosReg', (157, 165))	('LC3', 'Gene', (194, 197))	('Nix mRNA level', 'MPA', (123, 137))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
56138	31263025	Excision of mutant Kras led to a reduction in Nix mRNA levels and protein in FPC organoids and 2D cells, respectively (Fig 2F, S3F), demonstrating that sustained Kras signaling is required to maintain Nix levels in Kras-mutant cells.	('signaling', 'biological_process', 'GO:0023052', ('167', '176'))	('red', 'Chemical', '-', (33, 36))	('Kras', 'Gene', (19, 23))	('reduction', 'NegReg', (33, 42))	('red', 'Chemical', '-', (185, 188))	('FPC', 'cellular_component', 'GO:1990900', ('77', '80'))	('mutant', 'Var', (12, 18))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
56145	31263025	These changes were also recapitulated in both MEFs and FA6 cells treated with the MEK inhibitor AZD6244 (Fig S4 C-D) as well as in FA6 cells treated with siRNA against MAP2K2/MEK2 (Fig 3E), confirming that MAPK signaling is important for maintaining both Nix and the mitophagy program.	('MAP2K2', 'Gene', '5605', (168, 174))	('MEK2', 'Gene', '5605', (175, 179))	('MAPK', 'molecular_function', 'GO:0004707', ('206', '210'))	('MEK', 'Gene', (175, 178))	('MEK', 'Gene', '5609', (82, 85))	('MAPK', 'Gene', (206, 210))	('MEK2', 'Gene', (175, 179))	('MEK', 'Gene', '5609', (175, 178))	('MEK2', 'molecular_function', 'GO:0004708', ('175', '179'))	('mitophagy', 'biological_process', 'GO:0000423', ('267', '276'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('206', '220'))	('MAPK', 'Gene', '26413', (206, 210))	('mitophagy', 'biological_process', 'GO:0000422', ('267', '276'))	('MAP2K2', 'Gene', (168, 174))	('AZD6244', 'Var', (96, 103))	('AZD6244', 'Chemical', 'MESH:C517975', (96, 103))	('MEK', 'Gene', (82, 85))	('MAP2K', 'molecular_function', 'GO:0004708', ('168', '173'))
56152	31263025	In such a model, mitophagy would divert glucose away from the tricarboxylic acid (TCA) cycle and allow for its greater utilization in aerobic glycolysis and other anabolic pathways.	('utilization', 'MPA', (119, 130))	('mitophagy', 'biological_process', 'GO:0000423', ('17', '26'))	('glucose', 'MPA', (40, 47))	('TCA', 'Chemical', 'MESH:D014233', (82, 85))	('glucose', 'Chemical', 'MESH:D005947', (40, 47))	('aerobic glycolysis', 'MPA', (134, 152))	('divert', 'NegReg', (33, 39))	('greater', 'PosReg', (111, 118))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (62, 80))	('TCA) cycle', 'biological_process', 'GO:0006099', ('82', '92'))	('mitophagy', 'biological_process', 'GO:0000422', ('17', '26'))	('mitophagy', 'Var', (17, 26))	('glycolysis', 'biological_process', 'GO:0006096', ('142', '152'))
56154	31263025	Since it has been shown that KRAS mutations provide a growth advantage to cells cultured in glucose-limited medium, we investigated whether the KRAS-NIX mitophagy program might support increased proliferation in these conditions.	('red', 'Chemical', '-', (85, 88))	('KRAS', 'Gene', '3845', (144, 148))	('growth', 'MPA', (54, 60))	('KRAS', 'Gene', (29, 33))	('glucose', 'Chemical', 'MESH:D005947', (92, 99))	('mitophagy', 'biological_process', 'GO:0000423', ('153', '162'))	('KRAS', 'Gene', '3845', (29, 33))	('KRAS', 'Gene', (144, 148))	('mutations', 'Var', (34, 43))	('mitophagy', 'biological_process', 'GO:0000422', ('153', '162'))
56156	31263025	This proliferative defect following Nix loss was even more profound in KrasG12D-expressing MEFs and occurred even in high glucose conditions (Fig S4G).	('high glucose', 'Phenotype', 'HP:0003074', (117, 129))	('proliferative', 'CPA', (5, 18))	('KrasG12D-expressing', 'Var', (71, 90))	('Nix', 'MPA', (36, 39))	('red', 'Chemical', '-', (105, 108))	('glucose', 'Chemical', 'MESH:D005947', (122, 129))
56157	31263025	Oncogenic RAS has been previously reported to engage a p62-dependent autophagy program that is required for pancreatic cancer progression.	('Oncogenic RAS', 'Var', (0, 13))	('autophagy program', 'CPA', (69, 86))	('autophagy', 'biological_process', 'GO:0016236', ('69', '78'))	('red', 'Chemical', '-', (100, 103))	('pancreatic cancer', 'Disease', (108, 125))	('autophagy', 'biological_process', 'GO:0006914', ('69', '78'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))
56158	31263025	This requirement for p62 in RAS mutant cells may reflect both its central function in selective autophagy/mitophagy programs and subsequent maintenance of a pool of functional mitochondria as well as its function in promoting Nrf2 anti-oxidant signaling through interactions with Keap1.	('mitophagy', 'biological_process', 'GO:0000422', ('106', '115'))	('Keap1', 'Gene', '9817', (280, 285))	('selective autophagy', 'biological_process', 'GO:0061912', ('86', '105'))	('autophagy/mitophagy', 'CPA', (96, 115))	('mitophagy', 'biological_process', 'GO:0000423', ('106', '115'))	('signaling', 'biological_process', 'GO:0023052', ('244', '253'))	('Nrf2', 'Gene', (226, 230))	('RAS', 'Gene', (28, 31))	('mutant', 'Var', (32, 38))	('interactions', 'Interaction', (262, 274))	('mitochondria', 'cellular_component', 'GO:0005739', ('176', '188'))	('pool of functional mitochondria', 'MPA', (157, 188))	('promoting', 'PosReg', (216, 225))	('Keap1', 'Gene', (280, 285))	('Nrf2', 'Gene', '4780', (226, 230))
56160	31263025	To assess whether mitochondria restored by the loss of Nix in Kras-mutant cells were functional, we measured the oxygen consumption rate (OCR) following constitutive knockdown of Nix in mouse tumor (mT) organoids, KrasG12D-expressing MEFs, and human PDAC cells.	('tumor', 'Disease', (192, 197))	('oxygen', 'Chemical', 'MESH:D010100', (113, 119))	('human', 'Species', '9606', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('oxygen consumption rate', 'MPA', (113, 136))	('PDAC', 'Phenotype', 'HP:0006725', (250, 254))	('mouse', 'Species', '10090', (186, 191))	('mitochondria', 'cellular_component', 'GO:0005739', ('18', '30'))	('loss', 'Var', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('red', 'Chemical', '-', (105, 108))	('PDAC', 'Chemical', '-', (250, 254))	('red', 'Chemical', '-', (36, 39))
56161	31263025	In organoids, shRNA-mediated knockdown of Nix led to increased basal respiration and a greater maximal respiratory rate in response to the mitochondrial uncoupler FCCP, suggesting that restored mitochondria in organoids are indeed functional (Fig 4A).	('FCCP', 'Chemical', 'MESH:D002259', (163, 167))	('basal respiration', 'MPA', (63, 80))	('knockdown', 'Var', (29, 38))	('respiration', 'biological_process', 'GO:0045333', ('69', '80'))	('greater', 'PosReg', (87, 94))	('maximal respiratory rate', 'MPA', (95, 119))	('mitochondria', 'cellular_component', 'GO:0005739', ('194', '206'))	('increased', 'PosReg', (53, 62))	('response to the mitochondrial uncoupler FCCP', 'MPA', (123, 167))	('Nix', 'Gene', (42, 45))	('respiration', 'biological_process', 'GO:0007585', ('69', '80'))	('red', 'Chemical', '-', (190, 193))
56163	31263025	Similarly, we found that although mitochondrial ROS per cell increased after NIX knockdown in vitro (Fig 1A and 3D), the mitochondrial ROS per mitochondrial mass ratio did not increase as would be expected if the mitochondria were damaged (Figure 4E).	('mitochondria', 'cellular_component', 'GO:0005739', ('213', '225'))	('mitochondrial ROS', 'MPA', (34, 51))	('ROS', 'Chemical', 'MESH:D017382', (48, 51))	('knockdown', 'Var', (81, 90))	('increased', 'PosReg', (61, 70))	('mitochondrial ROS per mitochondrial mass ratio', 'MPA', (121, 167))	('ROS', 'Chemical', 'MESH:D017382', (135, 138))
56165	31263025	As expected, acute treatment with mitoPQ increased the mitochondrial ROS/mass ratio compared to control treated cells (Figure S5B).	('red', 'Chemical', '-', (89, 92))	('increased', 'PosReg', (41, 50))	('ROS', 'Chemical', 'MESH:D017382', (69, 72))	('mitoPQ', 'Var', (34, 40))	('mitoPQ', 'Chemical', '-', (34, 40))	('mitochondrial ROS/mass ratio', 'MPA', (55, 83))
56169	31263025	Consistent with this hypothesis, we observed smaller steady state pools of the TCA cycle intermediates succinate and malate in KrasG12D MEFs compared with WT MEFs, with a restoration of these pools to WT levels in KrasG12D MEFs treated with Nix siRNA (Fig 4G).	('succinate', 'Chemical', 'MESH:D019802', (103, 112))	('pools', 'MPA', (66, 71))	('smaller', 'NegReg', (45, 52))	('TCA cycle', 'biological_process', 'GO:0006099', ('79', '88'))	('TCA', 'Chemical', 'MESH:D014233', (79, 82))	('malate', 'MPA', (117, 123))	('malate', 'Chemical', 'MESH:C030298', (117, 123))	('red', 'Chemical', '-', (146, 149))	('TCA cycle intermediates succinate', 'MPA', (79, 112))	('KrasG12D', 'Var', (127, 135))
56170	31263025	In agreement with this observation, siRNA-mediated NIX depletion in both FA6 and Suit2 cells led to greater accumulation of 13C6-glucose-derived label in TCA cycle intermediates, especially citrate and malate, following a 45 minute incubation with 2mM 13C6-glucose, with comparable labeling of glycolytic pools of glucose 6 phosphate (G6P), dihydroxyacetone phosphate/glyceraldehyde-3-phosphate (DHAP/G3P), and pyruvate (Fig 4H, S5C-E).	('13C6-glucose-derived label', 'MPA', (124, 150))	('13C6-glucose', 'Chemical', '-', (252, 264))	('TCA', 'Enzyme', (154, 157))	('TCA', 'Chemical', 'MESH:D014233', (154, 157))	('glucose', 'Chemical', 'MESH:D005947', (314, 321))	('13C6-glucose', 'Chemical', '-', (124, 136))	('pyruvate', 'Chemical', 'MESH:D019289', (411, 419))	('TCA cycle', 'biological_process', 'GO:0006099', ('154', '163'))	('citrate', 'Chemical', 'MESH:D019343', (190, 197))	('glucose', 'Chemical', 'MESH:D005947', (129, 136))	('malate', 'MPA', (202, 208))	('citrate', 'MPA', (190, 197))	('malate', 'Chemical', 'MESH:C030298', (202, 208))	('pyruvate', 'MPA', (411, 419))	('greater accumulation', 'PosReg', (100, 120))	('depletion', 'Var', (55, 64))	('glucose', 'Chemical', 'MESH:D005947', (257, 264))
56173	31263025	Both constitutive knockdown of Nix in mT8 organoids and its inducible knockdown in mT5 organoids led to a significant increase in the accumulation of labeled isotopologues of TCA cycle intermediates in shNix organoids compared with controls (Fig S5G-I).	('knockdown', 'Var', (18, 27))	('TCA cycle', 'biological_process', 'GO:0006099', ('175', '184'))	('knockdown', 'Var', (70, 79))	('increase', 'PosReg', (118, 126))	('TCA', 'Chemical', 'MESH:D014233', (175, 178))	('TCA cycle', 'Enzyme', (175, 184))	('mT8 organoids', 'Chemical', '-', (38, 51))	('accumulation of labeled isotopologues', 'MPA', (134, 171))	('red', 'Chemical', '-', (223, 226))	('mT5', 'Gene', '69814', (83, 86))	('mT5', 'Gene', (83, 86))
56175	31263025	These findings demonstrate that suppression of mitochondrial content in KrasG12D -expressing cells facilitates reduced cycling of glucose-derived carbon within mitochondria and its greater relative conversion to lactate.	('mitochondrial content', 'MPA', (47, 68))	('greater', 'PosReg', (181, 188))	('mitochondria', 'cellular_component', 'GO:0005739', ('160', '172'))	('conversion', 'MPA', (198, 208))	('KrasG12D', 'Var', (72, 80))	('glucose', 'Chemical', 'MESH:D005947', (130, 137))	('reduced', 'NegReg', (111, 118))	('suppression', 'NegReg', (32, 43))	('lactate', 'Chemical', 'MESH:D019344', (212, 219))	('red', 'Chemical', '-', (111, 114))	('carbon', 'Chemical', 'MESH:D002244', (146, 152))
56183	31263025	This finding generalized to both Suit2 cells and organoids wherein NIX depletion resulted in reduced steady-state NADPH/NADP+ ratios in each system (Fig 4L/M).	('NADP+', 'Chemical', 'MESH:D009249', (120, 125))	('reduced', 'NegReg', (93, 100))	('4L/M', 'Var', (153, 157))	('red', 'Chemical', '-', (93, 96))	('4L/M', 'SUBSTITUTION', 'None', (153, 157))	('NIX', 'Var', (67, 70))	('NADPH', 'Gene', (114, 119))	('NADPH', 'Gene', '1666', (114, 119))
56196	31263025	As long as mitochondria are functional, the subsequent oxidation of this citrate then regenerates NADPH in the mitochondria.	('NADPH', 'Gene', '1666', (98, 103))	('citrate', 'Chemical', 'MESH:D019343', (73, 80))	('mitochondria', 'cellular_component', 'GO:0005739', ('111', '123'))	('mitochondria', 'cellular_component', 'GO:0005739', ('11', '23'))	('oxidation', 'Var', (55, 64))	('NADPH', 'Gene', (98, 103))
56203	31263025	To determine whether the Nix-mediated mitochondrial and metabolic alterations observed in vitro influence the development of pancreatic cancer, we conditionally deleted Nix in the pancreata of KC and KPC mice using a floxed Nix allele.	('deleted', 'Var', (161, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (125, 142))	('pancreatic cancer', 'Disease', (125, 142))	('mice', 'Species', '10090', (204, 208))	('influence', 'Reg', (96, 105))	('Nix', 'Gene', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))
56206	31263025	Despite Nix deletion, PanIN-1 lesions in KCNixDelta/Delta mice had similar levels of Ki67 and p-Erk expression compared to controls (Fig S7B), suggesting that loss of Nix did not initially impair the proliferative effects of oncogenic Kras signaling.	('deletion', 'Var', (12, 20))	('Ki67', 'Gene', '17345', (85, 89))	('KCNixDelta', 'Disease', (41, 51))	('red', 'Chemical', '-', (116, 119))	('signaling', 'biological_process', 'GO:0023052', ('240', '249'))	('proliferative effects', 'CPA', (200, 221))	('Ki67', 'Gene', (85, 89))	('loss', 'Var', (159, 163))	('impair', 'NegReg', (189, 195))	('mice', 'Species', '10090', (58, 62))	('Erk', 'Gene', '26413', (96, 99))	('Erk', 'molecular_function', 'GO:0004707', ('96', '99'))	('PanIN-1', 'Gene', (22, 29))	('Nix', 'Gene', (8, 11))	('KCNixDelta', 'Disease', 'None', (41, 51))	('Erk', 'Gene', (96, 99))
56208	31263025	Indeed, although all KC mice examined harbored PanIN-2 and PanIN-3 lesions, most KCNixDelta/Delta mice still exhibited only low-grade PanIN-1A and PanIN-1B lesions (Fig 5C-D).	('mice', 'Species', '10090', (24, 28))	('PanIN-3', 'Gene', (59, 66))	('KCNixDelta', 'Disease', 'None', (81, 91))	('PanIN-1B lesions', 'Disease', 'MESH:D002607', (147, 163))	('PanIN-1B lesions', 'Disease', (147, 163))	('red', 'Chemical', '-', (43, 46))	('lesions', 'Var', (67, 74))	('KCNixDelta', 'Disease', (81, 91))	('mice', 'Species', '10090', (98, 102))	('PanIN-2', 'Gene', (47, 54))
56209	31263025	Extending these observations to the aggressive KPC genetically engineered mouse model of PDAC, the pancreata of KPCNixFL/FL (KPCNixDelta/Delta) mice sacrificed at 4 months of age had mostly low-grade PanIN-1A and PanIN-1B lesions, with only 1 mouse (out of 5 mice analyzed) harboring a solitary cystic papillary neoplasm (CPN), and no mice harboring PDAC within the cohort (Fig 5E-F).	('KPCNixDelta', 'Disease', (125, 136))	('cystic papillary neoplasm', 'Disease', 'MESH:D002291', (295, 320))	('mice', 'Species', '10090', (259, 263))	('PanIN-1B lesions', 'Disease', (213, 229))	('neoplasm', 'Phenotype', 'HP:0002664', (312, 320))	('cystic papillary neoplasm', 'Disease', (295, 320))	('PanIN-1B lesions', 'Disease', 'MESH:D002607', (213, 229))	('PanIN-1A', 'Gene', (200, 208))	('KPCNixFL/FL', 'Var', (112, 123))	('mouse', 'Species', '10090', (74, 79))	('red', 'Chemical', '-', (70, 73))	('KPCNixDelta', 'Disease', 'None', (125, 136))	('mouse', 'Species', '10090', (243, 248))	('PDAC', 'Chemical', '-', (350, 354))	('PDAC', 'Chemical', '-', (89, 93))	('mice', 'Species', '10090', (335, 339))	('mice', 'Species', '10090', (144, 148))	('PDAC', 'Phenotype', 'HP:0006725', (350, 354))	('PDAC', 'Phenotype', 'HP:0006725', (89, 93))
56214	31263025	We followed a cohort of mice to humane endpoint and found that Nix ablation in the KPC model led to a significant extension of median survival from 21.86 weeks to 34.86 weeks in KPCNixDelta/Deltamice, although KPCNixDelta/Delta mice eventually all succumbed to malignant disease (Fig 6C).	('malignant disease', 'Disease', 'None', (261, 278))	('mice', 'Species', '10090', (228, 232))	('mice', 'Species', '10090', (195, 199))	('KPCNixDelta', 'Disease', (178, 189))	('mice', 'Species', '10090', (24, 28))	('ablation', 'Var', (67, 75))	('succumbed', 'Reg', (248, 257))	('KPCNixDelta', 'Disease', 'None', (178, 189))	('KPCNixDelta', 'Disease', (210, 221))	('KPCNixDelta', 'Disease', 'None', (210, 221))	('human', 'Species', '9606', (32, 37))	('malignant disease', 'Disease', (261, 278))	('median survival', 'CPA', (127, 142))	('extension', 'PosReg', (114, 123))
56217	31263025	This observation was recapitulated in organoids derived from KPC and KPCNixDelta/Delta mice grown in low glucose medium, wherein mitochondrial content in the groups was not significantly different:confirming a selective pressure to maintain mitochondrial content suppression in Kras-mutant cells (Fig S8B-C).	('mitochondrial content', 'MPA', (241, 262))	('mice', 'Species', '10090', (87, 91))	('Kras-mutant', 'Gene', (278, 289))	('Kras-mutant', 'Var', (278, 289))	('glucose', 'Chemical', 'MESH:D005947', (105, 112))	('KPCNixDelta', 'Disease', (69, 80))	('suppression', 'NegReg', (263, 274))	('KPCNixDelta', 'Disease', 'None', (69, 80))
56220	31263025	Additionally, when Suit2 and FA-6 cells were grown in low glucose media in hypoxic (1% O2) culture conditions, knockdown of Nix led to induction of Bnip3 and loss of the proliferation defect seen in normoxic low glucose conditions (Fig S8D-E).	('O2', 'Chemical', '-', (87, 89))	('hypoxic', 'Disease', 'MESH:D000860', (75, 82))	('knockdown', 'Var', (111, 120))	('Bnip3', 'Gene', (148, 153))	('FA-6', 'CellLine', 'CVCL:4034', (29, 33))	('loss of the proliferation defect', 'Disease', (158, 190))	('normoxic low glucose conditions', 'Disease', (199, 230))	('normoxic low glucose conditions', 'Disease', 'MESH:D018149', (199, 230))	('induction', 'Reg', (135, 144))	('Nix', 'Gene', (124, 127))	('glucose', 'Chemical', 'MESH:D005947', (58, 65))	('glucose', 'Chemical', 'MESH:D005947', (212, 219))	('hypoxic', 'Disease', (75, 82))	('loss of the proliferation defect', 'Disease', 'MESH:D065703', (158, 190))
56223	31263025	Collectively, our results demonstrate that Nix promotes the progression of KrasG12D-driven PanIN to PDAC and nominate the Nix pathway as a new dependency in PDAC.	('KrasG12D-driven', 'Var', (75, 90))	('PanIN', 'Disease', (91, 96))	('promotes', 'PosReg', (47, 55))	('PDAC', 'Chemical', '-', (100, 104))	('PDAC', 'Phenotype', 'HP:0006725', (157, 161))	('PDAC', 'Disease', (100, 104))	('PDAC', 'Phenotype', 'HP:0006725', (100, 104))	('PDAC', 'Chemical', '-', (157, 161))
56225	31263025	We find that oncogenic Kras induces Nix expression and suppression of mitochondrial content in a MAPK pathway-dependent fashion.	('suppression', 'NegReg', (55, 66))	('mitochondrial content', 'MPA', (70, 91))	('Nix expression', 'MPA', (36, 50))	('MAPK', 'Gene', (97, 101))	('MAPK', 'Gene', '26413', (97, 101))	('Kras', 'Var', (23, 27))	('MAPK', 'molecular_function', 'GO:0004707', ('97', '101'))
56226	31263025	Loss of Nix led to a shift toward oxidative glucose metabolism, with a compensatory increase in flux through the oxidative arm of the PPP and reductive carboxylation of glutamine:pathways that regenerate NADPH and can facilitate its shuttling into mitochondria.	('shuttling into mitochondria', 'MPA', (233, 260))	('glutamine', 'Chemical', 'MESH:D005973', (169, 178))	('oxidative glucose metabolism', 'MPA', (34, 62))	('NADPH', 'Gene', '1666', (204, 209))	('mitochondria', 'cellular_component', 'GO:0005739', ('248', '260'))	('glucose', 'Chemical', 'MESH:D005947', (44, 51))	('red', 'Chemical', '-', (142, 145))	('increase', 'PosReg', (84, 92))	('facilitate', 'PosReg', (218, 228))	('glucose metabolism', 'biological_process', 'GO:0006006', ('44', '62'))	('NADPH', 'Gene', (204, 209))	('Loss', 'Var', (0, 4))	('Nix', 'Gene', (8, 11))	('flux', 'MPA', (96, 100))
56233	31263025	Similarly, deletion of Bnip3 in breast cancer cells leads to upregulation of glycolysis and promotes tumor progression.	('breast cancer', 'Disease', (32, 45))	('promotes', 'PosReg', (92, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('glycolysis', 'MPA', (77, 87))	('upregulation', 'PosReg', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Bnip3', 'Gene', (23, 28))	('deletion', 'Var', (11, 19))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('upregulation of glycolysis', 'biological_process', 'GO:0045821', ('61', '87'))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
56237	31263025	In the KC and KPC mouse models, the role of Nix is pro-tumorigenic as Nix ablation significantly delays tumor progression and extends survival.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ablation', 'Var', (74, 82))	('mouse', 'Species', '10090', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('survival', 'CPA', (134, 142))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Disease', (55, 60))	('delays', 'NegReg', (97, 103))	('extends', 'PosReg', (126, 133))
56244	31263025	We found that loss of Nix restores functional mitochondria to pancreatic cancer cells, leading to increased respiratory capacity in these cells and a reduced ability of resultant PanIN lesions to progress to cancer in vivo.	('cancer', 'Disease', (208, 214))	('pancreatic cancer', 'Disease', 'MESH:D010190', (62, 79))	('progress', 'CPA', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('PanIN', 'Gene', (179, 184))	('cancer', 'Disease', (73, 79))	('red', 'Chemical', '-', (150, 153))	('loss', 'Var', (14, 18))	('respiratory capacity', 'MPA', (108, 128))	('pancreatic cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('functional mitochondria', 'MPA', (35, 58))	('lesions', 'Var', (185, 192))	('increased', 'PosReg', (98, 107))	('reduced', 'NegReg', (150, 157))	('mitochondria', 'cellular_component', 'GO:0005739', ('46', '58'))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('restores', 'PosReg', (26, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (62, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))
56272	31263025	MEK inhibitor experiments used AZD6244 at a concentration of 5 muM for 24hrs.	('AZD6244', 'Chemical', 'MESH:C517975', (31, 38))	('muM', 'Gene', '56925', (63, 66))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('muM', 'Gene', (63, 66))	('AZD6244', 'Var', (31, 38))
56284	31263025	The following Dharmafect siRNA targets were used: Non-targeting control (cat # D-001810-10-05) Human KRAS (cat # L-005069-00-0005) Human NIX / BNIP3L (cat # L-005069-00-0005) Human MAP2K2 / MEK2 (cat # L-003573-00-0005) Human p62 / SQSTM1 (cat # L-010230-00-0005) Mouse Nix / Bnip3l (cat # L-058953-00-0005) MEFs were infected with adenoviral control or CRE at least 72 hours prior to transfection with siRNA.	('Human', 'Species', '9606', (175, 180))	('KRAS', 'Gene', (101, 105))	('SQSTM1', 'Gene', '8878', (232, 238))	('MEK2', 'Gene', (190, 194))	('MEK2', 'Gene', '5605', (190, 194))	('Human', 'Species', '9606', (95, 100))	('MAP2K', 'molecular_function', 'GO:0004708', ('181', '186'))	('BNIP3L', 'Gene', (143, 149))	('cat', 'molecular_function', 'GO:0004096', ('196', '199'))	('cat # L-058953-00-0005', 'Var', (284, 306))	('MAP2K2', 'Gene', (181, 187))	('cat', 'molecular_function', 'GO:0004096', ('284', '287'))	('Human', 'Species', '9606', (220, 225))	('cat', 'molecular_function', 'GO:0004096', ('240', '243'))	('Human', 'Species', '9606', (131, 136))	('cat', 'molecular_function', 'GO:0004096', ('107', '110'))	('Mouse', 'Species', '10090', (264, 269))	('MEK2', 'molecular_function', 'GO:0004708', ('190', '194'))	('SQSTM1', 'Gene', (232, 238))	('BNIP3L', 'Gene', '665', (143, 149))	('KRAS', 'Gene', '3845', (101, 105))	('cat', 'molecular_function', 'GO:0004096', ('73', '76'))	('cat', 'molecular_function', 'GO:0004096', ('151', '154'))	('Bnip3l', 'Gene', (276, 282))	('MAP2K2', 'Gene', '5605', (181, 187))	('Bnip3l', 'Gene', '665', (276, 282))
56301	31263025	To determine the mitochondria volume fraction of MEFs, human cancer cell lines and organoids, at least 20 randomly obtained images per sample were taken at a direct magnification of 6500X (2D cell lines) or 11000x or higher (organoids).	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('human', 'Species', '9606', (55, 60))	('cancer', 'Disease', (61, 67))	('11000x', 'Var', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mitochondria', 'cellular_component', 'GO:0005739', ('17', '29'))
56358	30866585	In the recent Japan Pancreatic Cancer Registry analyzed by the Japan Pancreas Society (JPS), it was reported that the 5-year survival rate of cases <10 mm was 80.4%, and that of cases with stage 0 PC, comprising high-grade pancreatic intraepithelial neoplasia/carcinoma in situ (PCIS) was 85.8%.	('pancreatic intraepithelial neoplasia/carcinoma', 'Disease', 'MESH:D019048', (223, 269))	('PC', 'Phenotype', 'HP:0002894', (197, 199))	('Pancreatic Cancer', 'Disease', (20, 37))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (234, 259))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (20, 37))	('neoplasia', 'Phenotype', 'HP:0002664', (250, 259))	('<10 mm', 'Var', (148, 154))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (260, 277))	('PC', 'Phenotype', 'HP:0002894', (279, 281))	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (20, 37))	('pancreatic intraepithelial neoplasia/carcinoma', 'Disease', (223, 269))
56379	30866585	Additionally, there were PCIS cases with intraductal spread into the MPD and branch duct, and mismatch of PCIS and MPD stenosis.	('PD', 'Disease', 'MESH:D010300', (116, 118))	('MPD stenosis', 'Disease', (115, 127))	('PCIS', 'Disease', (25, 29))	('MPD stenosis', 'Disease', 'MESH:D003251', (115, 127))	('PC', 'Phenotype', 'HP:0002894', (106, 108))	('PD', 'Disease', 'MESH:D010300', (70, 72))	('mismatch', 'Var', (94, 102))	('PC', 'Phenotype', 'HP:0002894', (25, 27))
56432	30852389	Overall, data suggest that NO is a key player associated with resistance to radiation and metastasis of pancreatic cancer; and inhibition of NOS demonstrates therapeutic potential as observed in the animal model by specifically targeting the metastatic cells that harbor stem-like features and are potentially responsible for relapse.	('metastasis of pancreatic cancer', 'Disease', 'MESH:D009362', (90, 121))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('targeting', 'Reg', (228, 237))	('metastasis of pancreatic cancer', 'Disease', (90, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('inhibition', 'Var', (127, 137))	('metastatic cells', 'CPA', (242, 258))	('NOS', 'Gene', (141, 144))
56444	30852389	Recent studies showed that C-ion RT led to favorable outcomes both as a stand-alone therapy as well as in combination with gemcitabine, a chemotherapeutic used for pancreatic cancer.	('pancreatic cancer', 'Disease', (164, 181))	('C', 'Chemical', 'MESH:D002244', (27, 28))	('gemcitabine', 'Chemical', 'MESH:C056507', (123, 134))	('pancreatic cancer', 'Disease', 'MESH:D010190', (164, 181))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (164, 181))	('C-ion', 'Var', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
56460	30852389	Our results convincingly establish that inhibition of NO production is a viable therapeutic option to improve efficacy of C-ion RT.	('NO production', 'MPA', (54, 67))	('C', 'Chemical', 'MESH:D002244', (122, 123))	('inhibition', 'Var', (40, 50))	('efficacy', 'MPA', (110, 118))
56519	30852389	While there were no observable differences in sensitivity of INV or WCC towards X-ray radiation, C-ion radiation induced a dose dependent decrease in survival of both WCC and INV, with INV showing significantly higher resistance to C-ion radiation compared to WCC (Fig.	('C', 'Chemical', 'MESH:D002244', (262, 263))	('C', 'Chemical', 'MESH:D002244', (168, 169))	('C', 'Chemical', 'MESH:D002244', (261, 262))	('C', 'Chemical', 'MESH:D002244', (97, 98))	('C', 'Chemical', 'MESH:D002244', (69, 70))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('survival', 'CPA', (150, 158))	('higher', 'PosReg', (211, 217))	('resistance', 'MPA', (218, 228))	('C-ion radiation', 'Var', (97, 112))	('WCC', 'Chemical', '-', (260, 263))	('C', 'Chemical', 'MESH:D002244', (232, 233))	('WCC', 'Chemical', '-', (68, 71))	('WCC', 'Chemical', '-', (167, 170))	('C', 'Chemical', 'MESH:D002244', (169, 170))	('decrease', 'NegReg', (138, 146))
56522	30852389	Thus, the use of focused irradiation for pancreatic cancer treatment may leave behind the recalcitrant cells with the INV phenotype which may subsequently lead to metastatic disease and relapse.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('relapse', 'CPA', (186, 193))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (41, 58))	('leave', 'Reg', (73, 78))	('lead to', 'Reg', (155, 162))	('focused', 'Var', (17, 24))	('pancreatic cancer', 'Disease', (41, 58))	('metastatic disease', 'CPA', (163, 181))	('pancreatic cancer', 'Disease', 'MESH:D010190', (41, 58))
56524	30852389	L-NMMA was also effective at decreasing the invasiveness of non-irradiated PANC-1 cells thereby indicating an involvement of NO in determining invasiveness of PANC-1 cells.	('decreasing', 'NegReg', (29, 39))	('PANC-1', 'CellLine', 'CVCL:0480', (159, 165))	('invasiveness', 'CPA', (44, 56))	('PANC-1', 'CellLine', 'CVCL:0480', (75, 81))	('PANC-1', 'Gene', (75, 81))	('L-NMMA', 'Chemical', 'MESH:D019323', (0, 6))	('L-NMMA', 'Var', (0, 6))
56527	30852389	The effect of NO can be dramatically different depending on their concentration, and low flux NO is known to activate soluble guanylyl cyclase (sGC) pathway.	('activate', 'PosReg', (109, 117))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('low', 'Var', (85, 88))	('soluble', 'cellular_component', 'GO:0005625', ('118', '125'))
56544	30852389	Using NO donors, such as DETA/NO, we can establish the specific concentration of NO and map the signaling pathways regulated at different NO levels; DETA/NO generates approximately a steady state NO flux in the nM range for the corresponding uM concentration of exogenous NO (ie., 1000 times lower flux).	('NO flux in the', 'MPA', (196, 210))	('signaling', 'biological_process', 'GO:0023052', ('96', '105'))	('DETA/NO', 'Chemical', '-', (25, 32))	('DETA/NO', 'Var', (149, 156))	('DETA/NO', 'Chemical', '-', (149, 156))
56559	30852389	Furthermore, the number of DAF-positive INV cells drastically decreased with l-NAME treatment (Supplemental Fig.	('l-NAME treatment', 'Var', (77, 93))	('l-NAME', 'Chemical', 'MESH:D019331', (77, 83))	('decreased', 'NegReg', (62, 71))
56563	30852389	Thus, l-NAME may enhance the therapeutic benefits afforded by C-ion RT by multiple mechanisms.	('therapeutic benefits', 'MPA', (29, 49))	('C', 'Chemical', 'MESH:D002244', (62, 63))	('enhance', 'PosReg', (17, 24))	('l-NAME', 'Var', (6, 12))	('l-NAME', 'Chemical', 'MESH:D019331', (6, 12))
56579	30852389	4E), and the higher ability of spheroid formation observed in INV was slightly but significantly reduced with l-NAME (Fig.	('spheroid formation', 'CPA', (31, 49))	('formation', 'biological_process', 'GO:0009058', ('40', '49'))	('reduced', 'NegReg', (97, 104))	('l-NAME', 'Chemical', 'MESH:D019331', (110, 116))	('l-NAME', 'Var', (110, 116))
56582	30852389	NOS2 is also known to activate MEK-ERK and PI3K-AKT pathways, which can induce CSC related genes.	('ERK', 'molecular_function', 'GO:0004707', ('35', '38'))	('PI3', 'Gene', '5266', (43, 46))	('AKT', 'Gene', (48, 51))	('MEK', 'Gene', (31, 34))	('C', 'Chemical', 'MESH:D002244', (79, 80))	('MEK', 'Gene', '5609', (31, 34))	('PI3K', 'molecular_function', 'GO:0016303', ('43', '47'))	('induce', 'PosReg', (72, 78))	('PI3', 'Gene', (43, 46))	('C', 'Chemical', 'MESH:D002244', (81, 82))	('NOS2', 'Var', (0, 4))	('activate', 'PosReg', (22, 30))	('ERK', 'Gene', '5594', (35, 38))	('AKT', 'Gene', '207', (48, 51))	('ERK', 'Gene', (35, 38))	('CSC', 'Disease', (79, 82))
56584	30852389	We have previously reported that PI3K-AKT pathway was activated in PANC-1 INV compared to WCC, and PI3K inhibitors, LY294002 or Wortmannin, reduced PANC-1 invasion by over 40%.	('PANC-1', 'CellLine', 'CVCL:0480', (148, 154))	('INV', 'Var', (74, 77))	('PI3K', 'molecular_function', 'GO:0016303', ('99', '103'))	('PANC-1', 'CellLine', 'CVCL:0480', (67, 73))	('PI3', 'Gene', (99, 102))	('PI3', 'Gene', '5266', (33, 36))	('AKT', 'Gene', (38, 41))	('LY294002', 'Chemical', 'MESH:C085911', (116, 124))	('reduced', 'NegReg', (140, 147))	('PANC-1 invasion', 'CPA', (148, 163))	('PI3', 'Gene', (33, 36))	('PANC-1', 'Gene', (67, 73))	('WCC', 'Chemical', '-', (90, 93))	('AKT', 'Gene', '207', (38, 41))	('activated', 'PosReg', (54, 63))	('PI3', 'Gene', '5266', (99, 102))	('Wortmannin', 'Chemical', 'MESH:D000077191', (128, 138))	('LY294002', 'Var', (116, 124))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))
56586	30852389	Inhibition of MEK-ERK pathway reduced PANC-1 invasion by 39% or 74%, respectively in the presence of 0.5 nM or 10 nM U0126, while 1 nM or 10 nM ERK inhibitor 1 blocked invasion by 40% or 48%, respectively (Fig.	('ERK', 'Gene', (18, 21))	('blocked', 'NegReg', (160, 167))	('U0126', 'Chemical', 'MESH:C113580', (117, 122))	('ERK', 'molecular_function', 'GO:0004707', ('144', '147'))	('ERK', 'molecular_function', 'GO:0004707', ('18', '21'))	('MEK', 'Gene', (14, 17))	('PANC-1', 'Protein', (38, 44))	('MEK', 'Gene', '5609', (14, 17))	('U0126', 'Var', (117, 122))	('reduced', 'NegReg', (30, 37))	('ERK', 'Gene', '5594', (144, 147))	('ERK', 'Gene', '5594', (18, 21))	('PANC-1', 'CellLine', 'CVCL:0480', (38, 44))	('ERK', 'Gene', (144, 147))
56607	30852389	These higher number of metastatic colonies in INV group were dramatically suppressed to 5.4 +- 4.2 colonies in the presence of l-NAME (Fig.	('metastatic colonies', 'CPA', (23, 42))	('l-NAME', 'Chemical', 'MESH:D019331', (127, 133))	('l-NAME', 'Var', (127, 133))	('suppressed', 'NegReg', (74, 84))
56609	30852389	Histometric analysis of H&E-stained mouse liver sections confirmed that INV did have higher ability to metastasize specially to liver in our model, and l-NAME was effective in reducing this metastatic ability (Fig.	('to metastasize', 'CPA', (100, 114))	('l-NAME', 'Chemical', 'MESH:D019331', (152, 158))	('mouse', 'Species', '10090', (36, 41))	('and', 'Var', (148, 151))
56623	30852389	The mesenchymal nature of INVS is further confirmed by the reduced E-cadherin expression observed in INV compared to WCC.	('reduced', 'NegReg', (59, 66))	('expression', 'MPA', (78, 88))	('INVS', 'Gene', '27130', (26, 30))	('E-cadherin', 'Gene', (67, 77))	('E-cadherin', 'Gene', '999', (67, 77))	('INVS', 'Gene', (26, 30))	('cadherin', 'molecular_function', 'GO:0008014', ('69', '77'))	('WCC', 'Chemical', '-', (117, 120))	('INV', 'Var', (101, 104))
56629	30852389	Concomitantly, l-NAME suppressed invasion, whereas 1400W or ODQ only slightly reduced invasiveness.	('suppressed', 'NegReg', (22, 32))	('l-NAME', 'Chemical', 'MESH:D019331', (15, 21))	('invasion', 'CPA', (33, 41))	('ODQ', 'Chemical', '-', (60, 63))	('1400W', 'Chemical', 'MESH:C496401', (51, 56))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('l-NAME', 'Var', (15, 21))
56633	30852389	Low flux of NO that NOS1 or NOS3 produces is known to activate sGC pathway, and it appears that cGMP has a powerful role in the aggressive phenotype of certain cancers.	('NOS3', 'Var', (28, 32))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('C', 'Chemical', 'MESH:D002244', (65, 66))	('cancers', 'Disease', (160, 167))	('sGC pathway', 'Pathway', (63, 74))	('cGMP', 'Chemical', 'MESH:D006152', (96, 100))	('cGMP', 'Protein', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('activate', 'PosReg', (54, 62))
56635	30852389	Overall, our data showed that NOS2 and NOS1 and/or NOS3 together induce metastatic and CSC property of INV, and hence, NO plays important roles in several steps of metastasis leading to higher in vivo metastatic ability of INV cells compared to WCC in NSG mice.	('CSC property', 'CPA', (87, 99))	('WCC', 'Chemical', '-', (245, 248))	('mice', 'Species', '10090', (256, 260))	('C', 'Chemical', 'MESH:D002244', (87, 88))	('NOS2', 'Var', (30, 34))	('C', 'Chemical', 'MESH:D002244', (246, 247))	('induce', 'PosReg', (65, 71))	('higher', 'PosReg', (186, 192))	('NOS1', 'Gene', (39, 43))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('NOS3', 'Gene', (51, 55))	('C', 'Chemical', 'MESH:D002244', (247, 248))
56637	30852389	In the case of WCC bearing mice, l-NAME enhanced their metastasis (data not shown), indicating that blocking NO production in WCC may activate other signaling pathways or activate other cell populations that do not produce NO, which enhances metastasis.	('activate', 'PosReg', (171, 179))	('signaling', 'biological_process', 'GO:0023052', ('149', '158'))	('metastasis', 'CPA', (55, 65))	('activate', 'PosReg', (134, 142))	('WCC', 'Chemical', '-', (15, 18))	('mice', 'Species', '10090', (27, 31))	('metastasis', 'CPA', (242, 252))	('WCC', 'Chemical', '-', (126, 129))	('blocking NO', 'Var', (100, 111))	('enhances', 'PosReg', (233, 241))	('signaling pathways', 'Pathway', (149, 167))	('l-NAME', 'Var', (33, 39))	('enhanced', 'PosReg', (40, 48))	('l-NAME', 'Chemical', 'MESH:D019331', (33, 39))
56642	30852389	In a previous study, we used 31 cancer cell lines to examine whether C-ion radiation affects cancer cell invasiveness and found that C-ion radiation was effective to reduce invasion of many cell lines, but PANC-1 was the exception.	('cancer', 'Disease', (93, 99))	('invasion', 'CPA', (173, 181))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('C', 'Chemical', 'MESH:D002244', (69, 70))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PANC-1', 'CellLine', 'CVCL:0480', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer cell invasiveness', 'Disease', 'MESH:D009362', (93, 117))	('C', 'Chemical', 'MESH:D002244', (133, 134))	('cancer cell invasiveness', 'Disease', (93, 117))	('C', 'Chemical', 'MESH:D002244', (209, 210))	('reduce', 'NegReg', (166, 172))	('C-ion radiation', 'Var', (133, 148))
56665	30699894	Inactivating mutations of the STK11/LKB1 gene regulating cell growth, proliferation and DNA damage response are causative for PJS.	('causative', 'Reg', (112, 121))	('STK11', 'Gene', (30, 35))	('DNA damage response', 'biological_process', 'GO:0006974', ('88', '107'))	('STK11', 'Gene', '6794', (30, 35))	('Inactivating mutations', 'Var', (0, 22))	('PJS', 'Gene', '6794', (126, 129))	('cell growth', 'biological_process', 'GO:0016049', ('57', '68'))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('STK11', 'molecular_function', 'GO:0033868', ('30', '35'))	('LKB1', 'Gene', (36, 40))	('PJS', 'Gene', (126, 129))	('LKB1', 'Gene', '6794', (36, 40))
56668	30699894	Hearle et al., reported that 297 of 419 (70.9%) cases with PJS harbored STK11/LKB1 mutation, and cumulative risks of any cancer and PC were 85% and 11%, respectively, at 70 years of age.	('LKB1', 'Gene', '6794', (78, 82))	('PC', 'Phenotype', 'HP:0002894', (132, 134))	('LKB1', 'Gene', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('STK11', 'Gene', (72, 77))	('mutation', 'Var', (83, 91))	('PJS', 'Gene', '6794', (59, 62))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('STK11', 'molecular_function', 'GO:0033868', ('72', '77'))	('STK11', 'Gene', '6794', (72, 77))	('cancer', 'Disease', (121, 127))	('PJS', 'Gene', (59, 62))
56669	30699894	Here, the cumulative risk of any cancer was not significantly different between the cases with STK11/LKB1 mutation and those without the mutation (p = 0.43).	('STK11', 'molecular_function', 'GO:0033868', ('95', '100'))	('STK11', 'Gene', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', (33, 39))	('mutation', 'Var', (106, 114))	('STK11', 'Gene', '6794', (95, 100))	('LKB1', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('LKB1', 'Gene', '6794', (101, 105))
56670	30699894	In an analysis of a series of 240 PJS patients harboring STK11 mutation, cumulative PC risk was 8% at 60 years of age.	('STK11', 'Gene', (57, 62))	('PC', 'Phenotype', 'HP:0002894', (84, 86))	('STK11', 'Gene', '6794', (57, 62))	('PJS', 'Gene', '6794', (34, 37))	('mutation', 'Var', (63, 71))	('PJS', 'Gene', (34, 37))	('patients', 'Species', '9606', (38, 46))	('STK11', 'molecular_function', 'GO:0033868', ('57', '62'))
56674	30699894	Activating mutations in PRSS1 encoding the cationic trypsinogen related to trypsin activation, and inactivating mutations in SPINK1 inhibiting trypsin are causative for this syndrome.	('Activating', 'PosReg', (0, 10))	('PRSS1', 'Gene', '5644', (24, 29))	('SPINK1', 'Gene', (125, 131))	('PRSS1', 'Gene', (24, 29))	('SPINK1', 'Gene', '6690', (125, 131))	('inactivating mutations', 'Var', (99, 121))	('trypsin', 'MPA', (143, 150))
56677	30699894	According to a recent study of 217 PRSS1 mutation carriers, R122H and N29I variants were detected in 83.9% and 11.5% of the cases, respectively, and cumulative PC risk was 7.2% at 70 years of age.	('R122H', 'Mutation', 'rs111033565', (60, 65))	('PRSS1', 'Gene', '5644', (35, 40))	('PC', 'Phenotype', 'HP:0002894', (160, 162))	('N29I', 'Var', (70, 74))	('R122H', 'Var', (60, 65))	('PRSS1', 'Gene', (35, 40))	('N29I', 'Mutation', 'rs111033566', (70, 74))	('detected', 'Reg', (89, 97))
56680	30699894	detected PRSS1 mutation in 80.5% of the cases (34% R122H variant; 27% R122C; 12% N29I; 7% E79K).	('N29I', 'Mutation', 'rs111033566', (81, 85))	('E79K', 'Var', (90, 94))	('N29I', 'Var', (81, 85))	('R122C', 'Mutation', 'rs111033568', (70, 75))	('R122H', 'Mutation', 'rs111033565', (51, 56))	('PRSS1', 'Gene', '5644', (9, 14))	('E79K', 'Mutation', 'rs111033564', (90, 94))	('PRSS1', 'Gene', (9, 14))	('R122C', 'Var', (70, 75))
56681	30699894	also conducted a genomic analysis of a cohort of 200 French HP cases, and detected PRSS1 mutation in 68% (53% R122H variant; 8% N29I) and SPINK1 mutation in 13% of the cases.	('PRSS1', 'Gene', '5644', (83, 88))	('SPINK1', 'Gene', (138, 144))	('mutation', 'Var', (89, 97))	('PRSS1', 'Gene', (83, 88))	('R122H', 'Mutation', 'rs111033565', (110, 115))	('SPINK1', 'Gene', '6690', (138, 144))	('N29I', 'Mutation', 'rs111033566', (128, 132))
56682	30699894	A Japanese survey of 271 patients in 100 HP families showed a PRSS1 mutation prevalence of 41.1% and a SPINK1 mutation prevalence of 35.6%.	('PRSS1', 'Gene', '5644', (62, 67))	('SPINK1', 'Gene', (103, 109))	('mutation', 'Var', (68, 76))	('SPINK1', 'Gene', '6690', (103, 109))	('PRSS1', 'Gene', (62, 67))	('patients', 'Species', '9606', (25, 33))
56687	30699894	Inactivating mutations in CDKN2A (p16) inducing G1/G2 cell cycle arrest are causative for this syndrome.	('CDKN2A', 'Gene', (26, 32))	('p16', 'Gene', (34, 37))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('CDKN2A', 'Gene', '1029', (26, 32))	('Inactivating mutations', 'Var', (0, 22))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('54', '71'))	('G1/G2 cell cycle arrest', 'CPA', (48, 71))	('p16', 'Gene', '1029', (34, 37))	('inducing', 'Reg', (39, 47))
56689	30699894	showed that cumulative PC risk in FAMMM families harboring CDKN2A mutation was 17% at 75 years of age.	('FAMMM', 'Gene', (34, 39))	('PC', 'Phenotype', 'HP:0002894', (23, 25))	('mutation', 'Var', (66, 74))	('CDKN2A', 'Gene', (59, 65))	('FAMMM', 'Gene', '1243', (34, 39))	('CDKN2A', 'Gene', '1029', (59, 65))
56690	30699894	reported that relative PC risk in families with CDKN2A mutation was 13.1-22 and 46.6, respectively.	('CDKN2A', 'Gene', '1029', (48, 54))	('CDKN2A', 'Gene', (48, 54))	('PC', 'Phenotype', 'HP:0002894', (23, 25))	('mutation', 'Var', (55, 63))
56692	30699894	monitored 77 germline CDKN2A mutation carriers with magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP), and detected 7 (9.1%) resectable PC cases, concluding that further studies are warranted.	('mutation', 'Var', (29, 37))	('CDKN2A', 'Gene', (22, 28))	('CDKN2A', 'Gene', '1029', (22, 28))	('PC', 'Phenotype', 'HP:0002894', (173, 175))
56699	30699894	LS is also termed hereditary nonpolyposis colorectal cancer, and is genetically characterized by the presence of inactivating mutations in MMR genes (MLH1, MSH2, MSH6 and PMS2) and EPCAM.	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (18, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('MSH6', 'Gene', (162, 166))	('MMR', 'biological_process', 'GO:0006298', ('139', '142'))	('MSH2', 'Gene', '4436', (156, 160))	('PMS2', 'Gene', '5395', (171, 175))	('MLH1', 'Gene', '4292', (150, 154))	('EPCAM', 'Gene', (181, 186))	('MLH1', 'Gene', (150, 154))	('hereditary nonpolyposis colorectal cancer', 'Disease', (18, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('MSH6', 'Gene', '2956', (162, 166))	('MSH2', 'Gene', (156, 160))	('PC', 'Phenotype', 'HP:0002894', (182, 184))	('inactivating mutations', 'Var', (113, 135))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (18, 59))	('EPCAM', 'Gene', '4072', (181, 186))	('PMS2', 'Gene', (171, 175))
56701	30699894	The revised Bethesda Guidelines (RBG) for identifying MMR gene mutation carriers categorize PC as one of the LS-associated neoplasms, along with other types of malignancies such as endometrial, small intestinal or ureter/renal pelvic cancers.	('neoplasms', 'Disease', 'MESH:D009369', (123, 132))	('MMR gene', 'Gene', (54, 62))	('neoplasms', 'Disease', (123, 132))	('malignancies', 'Disease', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('PC', 'Phenotype', 'HP:0002894', (92, 94))	('MMR', 'biological_process', 'GO:0006298', ('54', '57'))	('mutation', 'Var', (63, 71))	('neoplasms', 'Phenotype', 'HP:0002664', (123, 132))	('small intestinal', 'Disease', (194, 210))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('ureter/renal pelvic cancers', 'Disease', 'MESH:D014516', (214, 241))	('ureter/renal pelvic cancers', 'Disease', (214, 241))	('malignancies', 'Disease', 'MESH:D009369', (160, 172))	('endometrial', 'Disease', (181, 192))	('neoplasm', 'Phenotype', 'HP:0002664', (123, 131))
56703	30699894	A recent prospective observational study of 3119 MMR-mutation carriers found that relative cumulative PC risk was 7.8 (95% CI: 3.3-12.3) in MLH1 mutation carriers at 75 years of age, although MSH2, MSH6 or PMS2 carriers did not show increased risk.	('MSH6', 'Gene', '2956', (198, 202))	('PMS2', 'Gene', (206, 210))	('MSH2', 'Gene', (192, 196))	('MSH2', 'Gene', '4436', (192, 196))	('MLH1', 'Gene', '4292', (140, 144))	('MSH6', 'Gene', (198, 202))	('PMS2', 'Gene', '5395', (206, 210))	('MLH1', 'Gene', (140, 144))	('PC', 'Phenotype', 'HP:0002894', (102, 104))	('MMR', 'biological_process', 'GO:0006298', ('49', '52'))	('mutation', 'Var', (145, 153))
56705	30699894	We detected PMS2 mutation in only one case (0.3% of all 304 cases).	('PMS2', 'Gene', (12, 16))	('mutation', 'Var', (17, 25))	('PMS2', 'Gene', '5395', (12, 16))
56706	30699894	exhaustively conducted immunohistochemistry (IHC), microsatellite instability (MSI) testing and germline DNA sequencing in a series of 833 PC patients, and identified 7 (0.8%) MMR mutation carriers, including 5 cases meeting RBG criteria.	('MMR', 'Gene', (176, 179))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('MMR', 'biological_process', 'GO:0006298', ('176', '179'))	('patients', 'Species', '9606', (142, 150))	('mutation', 'Var', (180, 188))	('PC', 'Phenotype', 'HP:0002894', (139, 141))
56709	30699894	HBOC is genetically caused by inactivating mutations in BRCA1/BRCA2, which are involved in the homologous recombination repair (HRR) pathway.	('HBOC', 'Disease', 'MESH:D061325', (0, 4))	('BRCA1', 'Gene', '672', (56, 61))	('BRCA2', 'Gene', '675', (62, 67))	('homologous recombination', 'biological_process', 'GO:0035825', ('95', '119'))	('BRCA1', 'Gene', (56, 61))	('HRR', 'biological_process', 'GO:0000724', ('128', '131'))	('HBOC', 'Disease', (0, 4))	('caused by', 'Reg', (20, 29))	('inactivating mutations', 'Var', (30, 52))	('BRCA2', 'Gene', (62, 67))
56710	30699894	While BRCA2 mutation is widely accepted as a PC risk factor, the data for BRCA1 mutation are conflicting.	('BRCA2', 'Gene', '675', (6, 11))	('PC', 'Phenotype', 'HP:0002894', (45, 47))	('BRCA1', 'Gene', '672', (74, 79))	('mutation', 'Var', (12, 20))	('BRCA2', 'Gene', (6, 11))	('BRCA1', 'Gene', (74, 79))
56711	30699894	prospectively identified 8 PC cases from 3942 BRCA1 and 1147 BRCA2 mutation carriers, and reported that the relative PC risk compared with the general population was 2.6 (95% CI: 1.0-5.3) in BRCA1 carriers and 2.1 (95% CI: 0.4-7.0) in BRCA2 carriers.	('BRCA1', 'Gene', (191, 196))	('mutation', 'Var', (67, 75))	('BRCA1', 'Gene', '672', (46, 51))	('BRCA2', 'Gene', (235, 240))	('PC', 'Phenotype', 'HP:0002894', (27, 29))	('BRCA2', 'Gene', (61, 66))	('PC', 'Phenotype', 'HP:0002894', (117, 119))	('BRCA1', 'Gene', (46, 51))	('BRCA2', 'Gene', '675', (235, 240))	('BRCA1', 'Gene', '672', (191, 196))	('BRCA2', 'Gene', '675', (61, 66))
56712	30699894	According to a study of 613 BRCA1 and 459 BRCA2 mutation carriers, relative PC risk for BRCA2 mutation carriers was 21.7 (95% CI: 13.1-34.0), whereas BRCA1 mutation did not significantly increase the risk.	('BRCA1', 'Gene', '672', (28, 33))	('BRCA1', 'Gene', (150, 155))	('BRCA2', 'Gene', '675', (42, 47))	('BRCA1', 'Gene', (28, 33))	('BRCA2', 'Gene', (88, 93))	('mutation', 'Var', (48, 56))	('BRCA2', 'Gene', '675', (88, 93))	('BRCA1', 'Gene', '672', (150, 155))	('PC', 'Phenotype', 'HP:0002894', (76, 78))	('BRCA2', 'Gene', (42, 47))	('mutation', 'Var', (94, 102))
56719	30699894	identified germline BRCA2 mutation in 5 of 29 (17.2%) FPC patients, including 3 cases harboring 6174delT frameshift variant.	('BRCA2', 'Gene', '675', (20, 25))	('FPC', 'cellular_component', 'GO:1990900', ('54', '57'))	('6174delT', 'Mutation', 'rs786204278', (96, 104))	('mutation', 'Var', (26, 34))	('BRCA2', 'Gene', (20, 25))	('patients', 'Species', '9606', (58, 66))	('FPC', 'Disease', (54, 57))	('PC', 'Phenotype', 'HP:0002894', (55, 57))
56720	30699894	also identified a germline BRCA2 frameshift variant in 3 of a cohort of 26 (11.5%) FPC patients.	('BRCA2', 'Gene', '675', (27, 32))	('PC', 'Phenotype', 'HP:0002894', (84, 86))	('frameshift', 'Var', (33, 43))	('FPC', 'Disease', (83, 86))	('FPC', 'cellular_component', 'GO:1990900', ('83', '86'))	('BRCA2', 'Gene', (27, 32))	('patients', 'Species', '9606', (87, 95))
56721	30699894	It is known that BRCA2 mutation prevalence differs among ethnic groups, and is especially high in Ashkenazi Jews.	('high', 'Reg', (90, 94))	('BRCA2', 'Gene', (17, 22))	('BRCA2', 'Gene', '675', (17, 22))	('mutation', 'Var', (23, 31))
56722	30699894	Germline mutation analysis of 5,318 Jewish subjects detected BRCA2 6174delT variant in 1.2%, as well as BRCA1 185delAG or 5382insC variant in 1.2%.	('5382insC', 'Var', (122, 130))	('185delAG', 'DELETION', 'None', (110, 118))	('BRCA2', 'Gene', '675', (61, 66))	('BRCA1', 'Gene', '672', (104, 109))	('6174delT', 'Var', (67, 75))	('185delAG', 'Var', (110, 118))	('BRCA2', 'Gene', (61, 66))	('BRCA1', 'Gene', (104, 109))	('6174delT', 'Mutation', 'rs786204278', (67, 75))	('5382insC', 'INSERTION', 'None', (122, 130))
56724	30699894	Indeed, germline BRCA1 mutation analysis of 66 PC patients with 2 or more affected relatives detected no mutated cases.	('BRCA1', 'Gene', '672', (17, 22))	('patients', 'Species', '9606', (50, 58))	('mutation', 'Var', (23, 31))	('BRCA1', 'Gene', (17, 22))	('PC', 'Phenotype', 'HP:0002894', (47, 49))
56725	30699894	discovered a PALB2 frameshift variant (c.172_175 delTTGT) in one FPC patient by examining whole-exome sequencing data, and identified PALB2 truncation mutation leading to a stop codon in 3 of 96 (3.1%) FPC cases, in comparison with no mutation in the control cohort of 1,084.	('c.172_175 delTTGT', 'Var', (39, 56))	('FPC', 'Disease', (202, 205))	('PALB2', 'Gene', (134, 139))	('PALB2', 'Gene', '79728', (134, 139))	('PALB2', 'Gene', '79728', (13, 18))	('FPC', 'cellular_component', 'GO:1990900', ('202', '205'))	('PC', 'Phenotype', 'HP:0002894', (203, 205))	('c.172_175 delTTGT', 'Mutation', 'rs180177143', (39, 56))	('PALB2', 'Gene', (13, 18))	('patient', 'Species', '9606', (69, 76))	('PC', 'Phenotype', 'HP:0002894', (66, 68))	('stop codon', 'MPA', (173, 183))	('FPC', 'cellular_component', 'GO:1990900', ('65', '68'))
56726	30699894	Interestingly, the locations of mutations found in this study were different from those previously reported in familial breast cancer or Fanconi anemia.	('Fanconi anemia', 'Disease', 'MESH:D005199', (137, 151))	('familial breast cancer', 'Disease', 'MESH:D001943', (111, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('familial breast cancer', 'Disease', (111, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('anemia', 'Phenotype', 'HP:0001903', (145, 151))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (137, 151))	('mutations', 'Var', (32, 41))	('Fanconi anemia', 'Disease', (137, 151))
56727	30699894	also sequenced the 13 exons of the PALB2 gene for 81 FPC families, and identified truncating mutation leading to a stop codon in 3 (3.7%) cases.	('FPC', 'cellular_component', 'GO:1990900', ('53', '56'))	('PC', 'Phenotype', 'HP:0002894', (54, 56))	('truncating mutation', 'Var', (82, 101))	('stop codon', 'MPA', (115, 125))	('PALB2', 'Gene', (35, 40))	('PALB2', 'Gene', '79728', (35, 40))
56728	30699894	discovered heterozygous ATM nonsense variants (c. 8266A>T; c.170G>A) in 2 FPC kindreds from whole-genome or whole-exome sequencing data, and validated deleterious ATM mutations in 4 of 166 (2.4%) FPC probands in comparison with no mutation in a control cohort.	('c.170G>A', 'Mutation', 'rs587779818', (59, 67))	('ATM', 'Gene', '472', (24, 27))	('PC', 'Phenotype', 'HP:0002894', (197, 199))	('PC', 'Phenotype', 'HP:0002894', (75, 77))	('8266A>T', 'SUBSTITUTION', 'None', (50, 57))	('FPC', 'Disease', (196, 199))	('ATM', 'Gene', '472', (163, 166))	('FPC', 'cellular_component', 'GO:1990900', ('74', '77'))	('mutations', 'Var', (167, 176))	('c.170G>A', 'Var', (59, 67))	('8266A>T', 'Var', (50, 57))	('ATM', 'Gene', (24, 27))	('ATM', 'Gene', (163, 166))	('FPC', 'cellular_component', 'GO:1990900', ('196', '199'))
56734	30699894	detected 1100delC variant of CHEK2 in 2.9% of German FPC families, and Lener et al.	('FPC', 'cellular_component', 'GO:1990900', ('53', '56'))	('PC', 'Phenotype', 'HP:0002894', (54, 56))	('CHEK2', 'Gene', '11200', (29, 34))	('CHEK2', 'Gene', (29, 34))	('1100delC', 'Var', (9, 17))	('1100delC', 'Mutation', 'rs555607708', (9, 17))
56735	30699894	linked mutations in Fanconi anemia genes (FANCC and FANCG) with young onset PC.	('Fanconi anemia', 'Disease', 'MESH:D005199', (20, 34))	('FANCG', 'Gene', (52, 57))	('FANCG', 'Gene', '2189', (52, 57))	('anemia', 'Phenotype', 'HP:0001903', (28, 34))	('FANCC', 'Gene', '2176', (42, 47))	('Fanconi anemia', 'Disease', (20, 34))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (20, 34))	('FANCC', 'Gene', (42, 47))	('PC', 'Phenotype', 'HP:0002894', (76, 78))	('mutations', 'Var', (7, 16))
56738	30699894	According to a germline mutation analysis of four genes (BRCA1, BRCA2, PALB2 and CDKN2A) in 727 affected cases including 521 FPC, the percentage of cases harboring the above gene mutations was higher in FPC probands than in non-FPC probands (8.0% vs. 3.5%) (odds ratio: 2.4, 95% CI: 1.1-5.4).	('BRCA1', 'Gene', (57, 62))	('BRCA2', 'Gene', '675', (64, 69))	('PC', 'Phenotype', 'HP:0002894', (204, 206))	('FPC', 'cellular_component', 'GO:1990900', ('125', '128'))	('PALB2', 'Gene', (71, 76))	('PC', 'Phenotype', 'HP:0002894', (229, 231))	('PALB2', 'Gene', '79728', (71, 76))	('FPC', 'Disease', (203, 206))	('CDKN2A', 'Gene', (81, 87))	('FPC', 'cellular_component', 'GO:1990900', ('203', '206'))	('PC', 'Phenotype', 'HP:0002894', (126, 128))	('FPC', 'cellular_component', 'GO:1990900', ('228', '231'))	('CDKN2A', 'Gene', '1029', (81, 87))	('BRCA2', 'Gene', (64, 69))	('BRCA1', 'Gene', '672', (57, 62))	('mutations', 'Var', (179, 188))	('higher', 'PosReg', (193, 199))
56741	30699894	also conducted germline analysis of 25 cancer susceptibility genes for 303 PC patients including an FPC cohort in the Mayo Clinic Familial Pancreatic Cancer Registry, and reported that 12.9% of 186 FPC cases and 9.4% of 117 non-FPC cases harbored some mutations.	('patients', 'Species', '9606', (78, 86))	('PC', 'Phenotype', 'HP:0002894', (199, 201))	('harbored', 'Reg', (238, 246))	('FPC', 'Disease', (198, 201))	('Familial Pancreatic Cancer', 'Disease', (130, 156))	('cancer', 'Disease', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('FPC', 'cellular_component', 'GO:1990900', ('198', '201'))	('FPC', 'cellular_component', 'GO:1990900', ('100', '103'))	('PC', 'Phenotype', 'HP:0002894', (229, 231))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (139, 156))	('Cancer', 'Phenotype', 'HP:0002664', (150, 156))	('mutations', 'Var', (252, 261))	('PC', 'Phenotype', 'HP:0002894', (101, 103))	('PC', 'Phenotype', 'HP:0002894', (75, 77))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('FPC', 'cellular_component', 'GO:1990900', ('228', '231'))	('Mayo', 'Species', '162683', (118, 122))	('Familial Pancreatic Cancer', 'Disease', 'MESH:D010190', (130, 156))
56744	30699894	In this study, deleterious mutations were detected in 8 of 54 (14.5%) cases, including 3 (5.6%) BRCA2 mutation, 2 (3.7%) PALB2 mutation, 2 (3.7%) ATM mutation and 1 (1.9%) MLH1 mutation.	('ATM', 'Gene', (146, 149))	('PALB2', 'Gene', (121, 126))	('mutation', 'Var', (102, 110))	('mutation', 'Var', (127, 135))	('BRCA2', 'Gene', '675', (96, 101))	('ATM', 'Gene', '472', (146, 149))	('MLH1', 'Gene', '4292', (172, 176))	('MLH1', 'Gene', (172, 176))	('PALB2', 'Gene', '79728', (121, 126))	('BRCA2', 'Gene', (96, 101))	('detected', 'Reg', (42, 50))
56745	30699894	Germline mutations in cancer susceptibility genes are also found in cases without definite family history or association with hereditary syndromes.	('Germline mutations', 'Var', (0, 18))	('hereditary syndromes', 'Disease', (126, 146))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('found', 'Reg', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('hereditary syndromes', 'Disease', 'MESH:D009386', (126, 146))
56746	30699894	conducted germline analysis of 22 cancer susceptibility genes for 96 PC cases without preselection based on family history, and detected deleterious mutations in 13.5% of the cases, including 9.4% for four genes (BRCA1, BRCA2, ATM, and MSH6).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('MSH6', 'Gene', '2956', (236, 240))	('mutations', 'Var', (149, 158))	('BRCA1', 'Gene', (213, 218))	('BRCA2', 'Gene', '675', (220, 225))	('ATM', 'Gene', '472', (227, 230))	('ATM', 'Gene', (227, 230))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('MSH6', 'Gene', (236, 240))	('cancer', 'Disease', (34, 40))	('BRCA2', 'Gene', (220, 225))	('BRCA1', 'Gene', '672', (213, 218))	('PC', 'Phenotype', 'HP:0002894', (69, 71))
56747	30699894	conducted targeted sequencing of 24 hereditary cancer susceptibility genes in a series of 289 resected PC, and detected mutations in 9.7% of the cases including 7.3% for HRR genes and 1.0% for MMR genes.	('HRR', 'biological_process', 'GO:0000724', ('170', '173'))	('MMR genes', 'Gene', (193, 202))	('MMR', 'biological_process', 'GO:0006298', ('193', '196'))	('HRR genes', 'Gene', (170, 179))	('mutations', 'Var', (120, 129))	('hereditary cancer', 'Disease', 'MESH:D009369', (36, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('PC', 'Phenotype', 'HP:0002894', (103, 105))	('hereditary cancer', 'Disease', (36, 53))
56748	30699894	recently compared genomic data of 3,030 affected cases and a normal cohort, and found that 5.5% of the affected cases harbored mutation in 6 genes associated with increased PC risk (CDKN2A, TP53, MLH1, BRCA1, BRCA2, and ATM).	('BRCA2', 'Gene', '675', (209, 214))	('BRCA1', 'Gene', '672', (202, 207))	('PC', 'Phenotype', 'HP:0002894', (173, 175))	('mutation', 'Var', (127, 135))	('MLH1', 'Gene', '4292', (196, 200))	('MLH1', 'Gene', (196, 200))	('BRCA1', 'Gene', (202, 207))	('TP53', 'Gene', '7157', (190, 194))	('ATM', 'Gene', (220, 223))	('TP53', 'Gene', (190, 194))	('CDKN2A', 'Gene', (182, 188))	('BRCA2', 'Gene', (209, 214))	('CDKN2A', 'Gene', '1029', (182, 188))	('ATM', 'Gene', '472', (220, 223))
56749	30699894	In the latest germline analysis of 298 unselected PC patients, 23 (7.7%) patients harbored deleterious mutations in PC susceptibility genes.	('harbored', 'Reg', (82, 90))	('mutations', 'Var', (103, 112))	('PC', 'Phenotype', 'HP:0002894', (50, 52))	('patients', 'Species', '9606', (53, 61))	('PC', 'Phenotype', 'HP:0002894', (116, 118))	('patients', 'Species', '9606', (73, 81))
56750	30699894	In this study, 6 of 23 (26.1%) mutated cases actually did not fulfill prescribed genetic testing criteria for hereditary cancer syndrome or FPC, and 12 of the 23 (52.2%) mutated cases would not have been checked according to the criteria.	('FPC', 'Disease', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('FPC', 'cellular_component', 'GO:1990900', ('140', '143'))	('hereditary cancer syndrome', 'Disease', (110, 136))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (110, 136))	('PC', 'Phenotype', 'HP:0002894', (141, 143))	('mutated', 'Var', (31, 38))
56751	30699894	The expert consensus practice recommendations formulated in the International Symposium of Inherited Diseases of the Pancreas in 2007 describe potential subjects for surveillance as follows: (1) individuals with PJS or hereditary pancreatitis; (2) BRCA1, BRCA2 or CDKN2A mutation carriers with at least one affected first- or second-degree relative; (3) individuals with three or more affected first-degree, second-degree or third-degree relatives; and (4) individuals with two affected relatives including at least one FDR.	('BRCA1', 'Gene', '672', (248, 253))	('CDKN2A', 'Gene', '1029', (264, 270))	('hereditary pancreatitis', 'Disease', (219, 242))	('BRCA1', 'Gene', (248, 253))	('BRCA2', 'Gene', '675', (255, 260))	('mutation', 'Var', (271, 279))	('PJS', 'Gene', '6794', (212, 215))	('hereditary pancreatitis', 'Disease', 'MESH:C537262', (219, 242))	('pancreatitis', 'Phenotype', 'HP:0001733', (230, 242))	('PJS', 'Gene', (212, 215))	('CDKN2A', 'Gene', (264, 270))	('BRCA2', 'Gene', (255, 260))
56754	30699894	selected 134 relatives with two affected FDRs, 80 relatives with at least three affected FDRs, 178 unaffected CDKN2A mutation carriers and 19 unaffected BRCA2/PALB2 mutation carriers from three cohorts in Europe, and prospectively monitored them as high-risk individuals using MRI (i.e., magnetic resonance cholangiopancreatography) or EUS.	('CDKN2A', 'Gene', (110, 116))	('BRCA2', 'Gene', (153, 158))	('CDKN2A', 'Gene', '1029', (110, 116))	('BRCA2', 'Gene', '675', (153, 158))	('mutation', 'Var', (117, 125))	('PALB2', 'Gene', '79728', (159, 164))	('PALB2', 'Gene', (159, 164))
56755	30699894	Among CDKN2A mutation carriers, 13 (7.3%) cases developed PC, and the clinical outcomes were favorable (75% resection rate and 24% 5-year overall survival (OS) rate).	('PC', 'Phenotype', 'HP:0002894', (58, 60))	('mutation', 'Var', (13, 21))	('developed', 'Reg', (48, 57))	('CDKN2A', 'Gene', (6, 12))	('CDKN2A', 'Gene', '1029', (6, 12))
56759	30699894	reviewed clinical outcomes in a series of 71 PC patients harboring BRCA1/BRCA2 mutation, and reported that stage 3/4 patients receiving a platinum regimen had significantly longer OS than those receiving a non-platinum regimen (median OS: 22 months vs. 9 months).	('platinum', 'Chemical', 'MESH:D010984', (138, 146))	('BRCA2', 'Gene', (73, 78))	('BRCA2', 'Gene', '675', (73, 78))	('BRCA1', 'Gene', '672', (67, 72))	('mutation', 'Var', (79, 87))	('platinum', 'Chemical', 'MESH:D010984', (210, 218))	('patients', 'Species', '9606', (117, 125))	('PC', 'Phenotype', 'HP:0002894', (45, 47))	('patients', 'Species', '9606', (48, 56))	('BRCA1', 'Gene', (67, 72))
56761	30699894	According to a retrospective review of 36 metastatic PC patients receiving the leucovorin calcium, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) regimen, cases harboring mutations in DNA damage repair (DDR) genes (BRCA1, BRCA2, PALB2, MSH2 and FANCF) had marginally longer OS than those without the mutations (median OS: 14 months vs. 5 months), and multivariate analysis showed a significant association between DDR gene mutation status and longer OS.	('patients', 'Species', '9606', (56, 64))	('BRCA1', 'Gene', (236, 241))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (142, 153))	('FANCF', 'Gene', '2188', (266, 271))	('mutations', 'Var', (192, 201))	('leucovorin calcium', 'Chemical', 'MESH:D002955', (79, 97))	('BRCA2', 'Gene', '675', (243, 248))	('irinotecan hydrochloride', 'Chemical', 'MESH:D000077146', (113, 137))	('PC', 'Phenotype', 'HP:0002894', (53, 55))	('FANCF', 'Gene', (266, 271))	('PALB2', 'Gene', (250, 255))	('MSH2', 'Gene', (257, 261))	('DNA', 'cellular_component', 'GO:0005574', ('205', '208'))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (155, 165))	('PALB2', 'Gene', '79728', (250, 255))	('MSH2', 'Gene', '4436', (257, 261))	('fluorouracil', 'Chemical', 'MESH:D005472', (99, 111))	('BRCA2', 'Gene', (243, 248))	('BRCA1', 'Gene', '672', (236, 241))
56768	30699894	DSBs are usually restored by the HRR pathway, whereas BRCA protein deficiency deriving from inactivating BRCA1/BRCA2 mutation inhibits this pathway and finally induces cell death.	('BRCA protein deficiency', 'Disease', 'MESH:D011488', (54, 77))	('BRCA1', 'Gene', (105, 110))	('inhibits', 'NegReg', (126, 134))	('BRCA2', 'Gene', (111, 116))	('BRCA1', 'Gene', '672', (105, 110))	('BRCA2', 'Gene', '675', (111, 116))	('cell death', 'CPA', (168, 178))	('inactivating', 'Var', (92, 104))	('HRR', 'biological_process', 'GO:0000724', ('33', '36'))	('HRR pathway', 'Pathway', (33, 44))	('DSBs', 'Chemical', '-', (0, 4))	('BRCA protein deficiency', 'Disease', (54, 77))	('mutation', 'Var', (117, 125))	('cell death', 'biological_process', 'GO:0008219', ('168', '178'))	('induces', 'Reg', (160, 167))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
56770	30699894	performed a phase II trial of rucaparib (RUCAPANC trial) for 19 patients with locally advanced/metastatic PC harboring BRCA1/BRCA2 mutation, and reported an ORR of 21.1% and disease control rate of 31.6%.	('BRCA2', 'Gene', (125, 130))	('RUCAPANC', 'Chemical', '-', (41, 49))	('locally advanced/metastatic PC', 'Disease', (78, 108))	('BRCA1', 'Gene', (119, 124))	('patients', 'Species', '9606', (64, 72))	('BRCA2', 'Gene', '675', (125, 130))	('rucaparib', 'Chemical', 'MESH:C531549', (30, 39))	('PC', 'Phenotype', 'HP:0002894', (106, 108))	('BRCA1', 'Gene', '672', (119, 124))	('mutation', 'Var', (131, 139))
56771	30699894	According to another phase II trial of veliparib for 16 PC patients with BRCA1/BRCA2 mutation, no patient achieved a response, and the median OS and PFS were only 3.1 months and 1.7 months, respectively.	('BRCA2', 'Gene', '675', (79, 84))	('veliparib', 'Chemical', 'MESH:C521013', (39, 48))	('patient', 'Species', '9606', (98, 105))	('patient', 'Species', '9606', (59, 66))	('BRCA1', 'Gene', '672', (73, 78))	('mutation', 'Var', (85, 93))	('patients', 'Species', '9606', (59, 67))	('BRCA2', 'Gene', (79, 84))	('BRCA1', 'Gene', (73, 78))	('PC', 'Phenotype', 'HP:0002894', (56, 58))
56774	30699894	Out of two PC cases that achieved a partial response in this trial, one case harbored BRCA2 mutation and the other, PALB2 mutation.	('BRCA2', 'Gene', (86, 91))	('harbored', 'Reg', (77, 85))	('mutation', 'Var', (92, 100))	('PALB2', 'Gene', '79728', (116, 121))	('BRCA2', 'Gene', '675', (86, 91))	('PALB2', 'Gene', (116, 121))	('PC', 'Phenotype', 'HP:0002894', (11, 13))
56776	30699894	Firstly, a phase II trial of rucaparib for locally advanced/metastatic PC cases harboring BRCA1, BRCA2 or PALB2 mutation is in progress in the Abramson Cancer Center of the University of Pennsylvania, where the clinical efficacy of rucaparib maintenance therapy is being assessed following a platinum-based induction regimen of at least 16 weeks (NCT03140670).	('Cancer', 'Phenotype', 'HP:0002664', (152, 158))	('BRCA2', 'Gene', (97, 102))	('rucaparib', 'Chemical', 'MESH:C531549', (232, 241))	('mutation', 'Var', (112, 120))	('Abramson Cancer', 'Disease', (143, 158))	('BRCA1', 'Gene', '672', (90, 95))	('PC', 'Phenotype', 'HP:0002894', (71, 73))	('BRCA2', 'Gene', '675', (97, 102))	('PALB2', 'Gene', '79728', (106, 111))	('Abramson Cancer', 'Disease', 'MESH:D009369', (143, 158))	('PALB2', 'Gene', (106, 111))	('BRCA1', 'Gene', (90, 95))	('platinum', 'Chemical', 'MESH:D010984', (292, 300))	('rucaparib', 'Chemical', 'MESH:C531549', (29, 38))
56777	30699894	In a phase III trial of olaparib (POLO trial), metastatic PC patients with germline BRCA1/BRCA2 mutation who do not experience disease progression after a platinum-based regimen for 16 weeks or more are randomized to olaparib 300 mg twice daily or placebo (NCT02184195).	('BRCA2', 'Gene', (90, 95))	('olaparib', 'Chemical', 'MESH:C531550', (24, 32))	('patients', 'Species', '9606', (61, 69))	('BRCA1', 'Gene', '672', (84, 89))	('metastatic PC', 'Disease', (47, 60))	('mutation', 'Var', (96, 104))	('BRCA2', 'Gene', '675', (90, 95))	('olaparib', 'Chemical', 'MESH:C531550', (217, 225))	('BRCA1', 'Gene', (84, 89))	('PC', 'Phenotype', 'HP:0002894', (58, 60))	('platinum', 'Chemical', 'MESH:D010984', (155, 163))
56779	30699894	conducted a phase I trial of GEM/CDDP plus veliparib for 17 patients with untreated advanced PC, including 9 cases harboring germline BRCA1/BRCA2 mutation, and reported an ORR of 77.8% and median OS of 23.3 months in BRCA-mutated cases.	('BRCA', 'Gene', '672', (134, 138))	('BRCA', 'Gene', '672', (140, 144))	('PC', 'Phenotype', 'HP:0002894', (93, 95))	('BRCA1', 'Gene', (134, 139))	('BRCA', 'Gene', '672', (217, 221))	('veliparib', 'Chemical', 'MESH:C521013', (43, 52))	('BRCA', 'Gene', (134, 138))	('BRCA', 'Gene', (140, 144))	('patients', 'Species', '9606', (60, 68))	('CDDP', 'Chemical', '-', (33, 37))	('BRCA', 'Gene', (217, 221))	('BRCA2', 'Gene', (140, 145))	('GEM', 'Chemical', 'MESH:C056507', (29, 32))	('BRCA1', 'Gene', '672', (134, 139))	('mutation', 'Var', (146, 154))	('BRCA2', 'Gene', '675', (140, 145))
56792	30699894	immunohistochemically identified 4 MMR-deficient cases from a cohort of 385 sporadic PC patients, and showed that all 4 patients harbored somatic mutations in MLH1 or MSH2 without germline mutation.	('harbored', 'Reg', (129, 137))	('MSH2', 'Gene', (167, 171))	('MSH2', 'Gene', '4436', (167, 171))	('mutations', 'Var', (146, 155))	('MMR', 'biological_process', 'GO:0006298', ('35', '38'))	('PC', 'Phenotype', 'HP:0002894', (85, 87))	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (120, 128))	('MLH1', 'Gene', '4292', (159, 163))	('MLH1', 'Gene', (159, 163))
56891	29394913	Interestingly, both low TIMP-1 levels and absence of cachexia were independently beneficial for survival (Fig.	('cachexia', 'Phenotype', 'HP:0004326', (53, 61))	('survival', 'CPA', (96, 104))	('cachexia', 'Disease', (53, 61))	('cachexia', 'Disease', 'MESH:D002100', (53, 61))	('beneficial', 'PosReg', (81, 91))	('low', 'Var', (20, 23))	('TIMP-1 levels', 'MPA', (24, 37))
56929	28854931	We also observed that oncosuppressor mutated cells would show an increased uptake of cancer-derived exosomes and we suggested that oncosuppressor genes might protect the integrity of the cell genome by blocking integration of cancer-derived exosomes.	('increased', 'PosReg', (65, 74))	('blocking', 'NegReg', (202, 210))	('uptake', 'MPA', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('uptake', 'biological_process', 'GO:0098739', ('75', '81'))	('cancer', 'Disease', (85, 91))	('integration', 'MPA', (211, 222))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('uptake', 'biological_process', 'GO:0098657', ('75', '81'))	('mutated', 'Var', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
56930	28854931	In the present study, we tested the hypothesis that cancer patients' sera-derived exosomes might be responsible for the malignant transformation of target cells and that oncosuppressor mutation would promote their increased uptake.	('uptake', 'biological_process', 'GO:0098739', ('224', '230'))	('sera', 'molecular_function', 'GO:0004617', ('69', '73'))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutation', 'Var', (185, 193))	('increased', 'PosReg', (214, 223))	('tested', 'Reg', (25, 31))	('patients', 'Species', '9606', (59, 67))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('uptake', 'MPA', (224, 230))	('malignant transformation', 'CPA', (120, 144))	('promote', 'PosReg', (200, 207))	('uptake', 'biological_process', 'GO:0098657', ('224', '230'))
56938	28854931	Oncosuppressor mutation promoted the de novo expression, on the plasma membrane of target cells, of receptors, responsible for the increased uptake of cancer-derived exosomes.	('mutation', 'Var', (15, 23))	('Oncosuppressor', 'Gene', (0, 14))	('increased', 'PosReg', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('uptake', 'biological_process', 'GO:0098657', ('141', '147'))	('cancer', 'Disease', (151, 157))	('promoted', 'PosReg', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('uptake', 'biological_process', 'GO:0098739', ('141', '147'))	('uptake', 'MPA', (141, 147))	('plasma membrane', 'cellular_component', 'GO:0005886', ('64', '79'))
56951	28854931	Following our observation that cells carrying oncosuppressor mutations, display a significantly increased uptake of cancer-derived exosomes, we suggested that cancer-derived exosomes might carry the oncogenic information through the blood and be responsible for the malignant transformation of the target cells.	('cancer', 'Disease', (159, 165))	('increased', 'PosReg', (96, 105))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('mutations', 'Var', (61, 70))	('uptake', 'biological_process', 'GO:0098657', ('106', '112'))	('uptake', 'MPA', (106, 112))	('uptake', 'biological_process', 'GO:0098739', ('106', '112'))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
56957	28854931	Oncosuppressor mutation promoted the de novo expression of receptors, on the plasma membrane of target cells, responsible for the increased uptake of cancer-derived exosomes.	('mutation', 'Var', (15, 23))	('Oncosuppressor', 'Gene', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('expression', 'MPA', (45, 55))	('uptake', 'MPA', (140, 146))	('promoted', 'PosReg', (24, 32))	('uptake', 'biological_process', 'GO:0098739', ('140', '146'))	('increased', 'PosReg', (130, 139))	('plasma membrane', 'cellular_component', 'GO:0005886', ('77', '92'))	('uptake', 'biological_process', 'GO:0098657', ('140', '146'))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
57029	28854931	This observation confirms our hypothesis that oncosuppressor gene mutations might induce expression of proteins on the membrane that would allow cancer exosomes to enter the cell, deliver their cargo and damage the genome.	('cancer', 'Disease', (145, 151))	('mutations', 'Var', (66, 75))	('induce', 'Reg', (82, 88))	('expression', 'MPA', (89, 99))	('proteins', 'Protein', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('damage', 'Reg', (204, 210))	('genome', 'MPA', (215, 221))	('cargo', 'molecular_function', 'GO:0140355', ('194', '199'))	('oncosuppressor gene', 'Gene', (46, 65))	('membrane', 'cellular_component', 'GO:0016020', ('119', '127'))	('cargo', 'MPA', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('allow', 'Reg', (139, 144))	('deliver', 'MPA', (180, 187))
57033	28854931	Taken together these data show that cancer exosomes express proteins, which enable them to interact with receptors, de novo expressed on the membrane of BRCA1 mutated fibroblasts.	('mutated', 'Var', (159, 166))	('membrane', 'cellular_component', 'GO:0016020', ('141', '149'))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('interact', 'Interaction', (91, 99))	('BRCA1', 'Gene', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
57035	28854931	To determine if the de novo expressed cell receptors after oncosuppressor mutation (Additional file 3: Table S3) and the newly identified cancer exosome ligands (Additional file 6: Table S6) played a role in the increased cancer exosomes uptake, displayed by BRCA1-KO fibroblasts, we used a panel of pharmacological antagonists.	('mutation', 'Var', (74, 82))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('uptake', 'biological_process', 'GO:0098739', ('238', '244'))	('cancer', 'Disease', (222, 228))	('uptake', 'biological_process', 'GO:0098657', ('238', '244'))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('exosome', 'cellular_component', 'GO:0070062', ('145', '152'))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('increased', 'PosReg', (212, 221))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
57073	28854931	In order to confirm this view, we sought to verify if the mutation of the BRCA1 oncosuppressor would trigger some membrane changes, which would lead to an active uptake of cancer exosomes as opposed to passive penetration and selective membrane fusion.	('uptake', 'biological_process', 'GO:0098657', ('162', '168'))	('membrane changes', 'MPA', (114, 130))	('uptake', 'biological_process', 'GO:0098739', ('162', '168'))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('membrane', 'cellular_component', 'GO:0016020', ('236', '244'))	('mutation', 'Var', (58, 66))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('lead to', 'Reg', (144, 151))	('membrane', 'cellular_component', 'GO:0016020', ('114', '122'))	('cancer', 'Disease', (172, 178))	('BRCA1', 'Gene', (74, 79))	('membrane fusion', 'biological_process', 'GO:0061025', ('236', '251'))	('trigger', 'Reg', (101, 108))
57074	28854931	The discovery that the knock-out of the oncosuppressor BRCA1 is associated with the de novo expression of proteins already associated with metastasis and aggressiveness such as dynamin, integrins, galectin and EPCAM is intriguing.	('galectin', 'molecular_function', 'GO:0001577', ('197', '205'))	('EPCAM', 'Gene', '4072', (210, 215))	('aggressiveness', 'Disease', (154, 168))	('dynamin', 'Protein', (177, 184))	('knock-out', 'Var', (23, 32))	('aggressiveness', 'Phenotype', 'HP:0000718', (154, 168))	('BRCA1', 'Gene', (55, 60))	('EPCAM', 'Gene', (210, 215))	('aggressiveness', 'Disease', 'MESH:D001523', (154, 168))	('expression', 'MPA', (92, 102))	('proteins', 'Protein', (106, 114))
57076	28854931	In the model that we hypothesized instead, these proteins enable the active uptake of cancer exosomes and their antagonistic blockage would inhibit the malignant transformation at distance and therefore the metastatic event.	('blockage', 'Var', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('inhibit', 'NegReg', (140, 147))	('malignant transformation at distance', 'CPA', (152, 188))	('metastatic event', 'CPA', (207, 223))	('active uptake', 'MPA', (69, 82))	('uptake', 'biological_process', 'GO:0098657', ('76', '82'))	('uptake', 'biological_process', 'GO:0098739', ('76', '82'))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('enable', 'PosReg', (58, 64))	('cancer', 'Disease', (86, 92))
57079	28854931	As a matter of fact, carcinogenesis is not a sudden process and it requires accumulation of several mutations that cause a normal cell to become first metaplastic, then anaplastic and eventually dysplastic.	('dysplastic', 'Disease', (195, 205))	('mutations', 'Var', (100, 109))	('dysplastic', 'Disease', 'MESH:D004416', (195, 205))	('carcinogenesis', 'Disease', 'MESH:D063646', (21, 35))	('carcinogenesis', 'Disease', (21, 35))
57082	28854931	might cause mutations that would favor the uptake of circulating cancer exosomes in cells located in distant organs with their subsequent malignant transformation.	('malignant transformation', 'CPA', (138, 162))	('uptake', 'MPA', (43, 49))	('cause', 'Reg', (6, 11))	('mutations', 'Var', (12, 21))	('favor', 'PosReg', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('uptake', 'biological_process', 'GO:0098657', ('43', '49'))	('uptake', 'biological_process', 'GO:0098739', ('43', '49'))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
57097	28161904	In in vitro experiments, knockdown of cofilin-1 significantly decreased chemotaxis in PDAC cell lines.	('chemotaxis in PDAC cell lines', 'CPA', (72, 101))	('cofilin-1', 'Gene', (38, 47))	('decreased', 'NegReg', (62, 71))	('PDAC', 'Chemical', '-', (86, 90))	('chemotaxis', 'biological_process', 'GO:0006935', ('72', '82'))	('knockdown', 'Var', (25, 34))
57130	28161904	After siRNA transfection, cells were incubated for 24 h and then harvested for the cell proliferation assay.	('transfection', 'Var', (12, 24))	('cell proliferation', 'biological_process', 'GO:0008283', ('83', '101'))	('rat', 'Species', '10116', (95, 98))	('siRNA', 'Gene', (6, 11))
57189	28161904	They suggested that PD-ECGF expression in PDAC enhances tumor invasion and/or metastasis through its angiogenic properties.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('PDAC', 'Chemical', '-', (42, 46))	('tumor', 'Disease', (56, 61))	('enhances', 'PosReg', (47, 55))	('PD-ECGF', 'Gene', '1890', (20, 27))	('expression', 'Var', (28, 38))	('angiogenic properties', 'CPA', (101, 122))	('metastasis', 'CPA', (78, 88))	('PD-ECGF', 'Gene', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
57193	28161904	Many of these reports describe the positive correlation between cofilin expression and invasion and metastases of tumor cells because cofilin activation is essential for the formation of stable invadopods, which are used during the migration of invasive tumor cells, linking cofilin to tumor cell invasion.21  In line with previous findings, we have shown that cofilin-1 expression is associated with high incidence of hematogenous metastases of PDAC patients after curative surgery.	('metastases', 'Disease', (100, 110))	('cofilin', 'Gene', '1072', (275, 282))	('cofilin', 'Gene', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('metastases', 'Disease', 'MESH:D009362', (432, 442))	('associated with', 'Reg', (385, 400))	('expression', 'Var', (371, 381))	('metastases', 'Disease', (432, 442))	('rat', 'Species', '10116', (468, 471))	('cofilin', 'Gene', '1072', (361, 368))	('cofilin', 'Gene', (275, 282))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('PDAC', 'Chemical', '-', (446, 450))	('tumor', 'Disease', (254, 259))	('metastases of tumor', 'Disease', 'MESH:D009362', (100, 119))	('tumor', 'Disease', (286, 291))	('formation', 'biological_process', 'GO:0009058', ('174', '183'))	('rat', 'Species', '10116', (235, 238))	('metastases of tumor', 'Disease', (100, 119))	('invasive tumor', 'Disease', (245, 259))	('cofilin', 'Gene', '1072', (64, 71))	('cofilin', 'Gene', '1072', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('cofilin', 'Gene', (361, 368))	('hematogenous', 'Disease', (419, 431))	('metastases', 'Disease', 'MESH:D009362', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('invasive tumor', 'Disease', 'MESH:D009369', (245, 259))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('cofilin', 'Gene', (134, 141))	('patients', 'Species', '9606', (451, 459))
57210	28388884	Inhibition of Six1 affects tumour invasion and the expression of cancer stem cell markers in pancreatic cancer Epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSC) contribute to tumour progression and metastasis.	('Epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('111', '147'))	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('Epithelial-to-mesenchymal transition', 'CPA', (111, 147))	('Six1', 'Gene', '6495', (14, 18))	('pancreatic cancer', 'Disease', 'MESH:D010190', (93, 110))	('tumour', 'Disease', 'MESH:D009369', (196, 202))	('expression', 'MPA', (51, 61))	('tumour', 'Disease', (196, 202))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', (65, 71))	('pancreatic cancer', 'Disease', (93, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (158, 164))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('metastasis', 'CPA', (219, 229))	('tumour', 'Disease', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('affects', 'Reg', (19, 26))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (93, 110))	('EMT', 'biological_process', 'GO:0001837', ('149', '152'))	('Six1', 'Gene', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('contribute', 'Reg', (182, 192))
57223	28388884	Therefore, targeting Six1 might be a novel therapeutic approach in patients with pancreatic cancer.	('Six1', 'Gene', (21, 25))	('patients', 'Species', '9606', (67, 75))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (81, 98))	('targeting', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (81, 98))	('pancreatic cancer', 'Disease', (81, 98))	('Six1', 'Gene', '6495', (21, 25))
57300	28388884	Inhibition of Six1 reduced migration in Panc1 cells by 37% (p = 0.008) and in BxPc3 cells by 24.2% (p = 0.031) (Fig.	('migration', 'CPA', (27, 36))	('Six1', 'Gene', (14, 18))	('BxPc3', 'CellLine', 'CVCL:0186', (78, 83))	('Six1', 'Gene', '6495', (14, 18))	('Panc1', 'CellLine', 'CVCL:0480', (40, 45))	('Inhibition', 'Var', (0, 10))	('reduced', 'NegReg', (19, 26))
57306	28388884	At time of euthanasia, the average tumour volume was 124.13 mm3 (+-46.59) in the Panc1shctrl group and 50.22 mm3 (+-29.76) in Panc1shSix1 (p = 0.0008).	('Panc1shSix1', 'Gene', (126, 137))	('Panc1', 'CellLine', 'CVCL:0480', (81, 86))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('Panc1shctrl', 'Var', (81, 92))	('Panc1shSix1', 'Gene', '6495', (126, 137))	('Panc1', 'CellLine', 'CVCL:0480', (126, 131))	('tumour', 'Disease', (35, 41))
57308	28388884	As expected, tumours from the Panc1shctrl group showed a higher expression of Six1 than tumours from the Panc1shSix1 group (Fig.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('Panc1shSix1', 'Gene', '6495', (105, 116))	('Panc1', 'CellLine', 'CVCL:0480', (105, 110))	('tumours', 'Disease', (88, 95))	('Panc1shSix1', 'Gene', (105, 116))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('Six1', 'Gene', (112, 116))	('expression', 'MPA', (64, 74))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('tumours', 'Disease', (13, 20))	('Panc1', 'CellLine', 'CVCL:0480', (30, 35))	('Six1', 'Gene', (78, 82))	('Six1', 'Gene', '6495', (112, 116))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('higher', 'PosReg', (57, 63))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('Panc1shctrl', 'Var', (30, 41))	('Six1', 'Gene', '6495', (78, 82))
57309	28388884	Interestingly, in the tumour specimens of the Panc1shctrl group, we observed an increased expression of Six1 at the invasive edge where EMT plays an important role for tumour invasion.	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('Six1', 'Gene', '6495', (104, 108))	('Panc1', 'CellLine', 'CVCL:0480', (46, 51))	('EMT', 'biological_process', 'GO:0001837', ('136', '139'))	('tumour', 'Disease', (22, 28))	('Six1', 'Gene', (104, 108))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('increased', 'PosReg', (80, 89))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('Panc1shctrl', 'Var', (46, 57))	('expression', 'MPA', (90, 100))	('tumour', 'Disease', (168, 174))
57311	28388884	Four out of five control tumours were CD44+/CD24+ whereas all Six1-downregulated tumours lost that phenotype and were CD44-/CD24+ (Fig.	('CD44-/CD24+', 'Var', (118, 129))	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('lost', 'NegReg', (89, 93))	('Six1', 'Gene', '6495', (62, 66))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('CD44+/CD24+', 'Var', (38, 49))	('Six1', 'Gene', (62, 66))	('tumours', 'Disease', 'MESH:D009369', (81, 88))	('tumours', 'Disease', (81, 88))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('tumours', 'Disease', (25, 32))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
57340	28388884	It remains speculative but our data may indicate that inhibition of Six1 may affect the EMT-MET axis by regulating both mesenchymal and epithelial genes.	('inhibition', 'Var', (54, 64))	('EMT-MET axis', 'CPA', (88, 100))	('affect', 'Reg', (77, 83))	('EMT', 'biological_process', 'GO:0001837', ('88', '91'))	('regulating', 'Reg', (104, 114))	('Six1', 'Gene', '6495', (68, 72))	('Six1', 'Gene', (68, 72))
57347	28388884	had identified CD24+/CD44+/ESA+ cells as pancreatic cancer stem cells.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('CD24+/CD44+/ESA+ cells', 'Var', (15, 37))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (41, 58))	('pancreatic cancer', 'Disease', (41, 58))	('pancreatic cancer', 'Disease', 'MESH:D010190', (41, 58))
57348	28388884	In our experiment, control tumours displayed a significantly stronger expression CD24+/CD44+ cells than tumours with down-regulation of Six1.	('Six1', 'Gene', '6495', (136, 140))	('regulation', 'biological_process', 'GO:0065007', ('122', '132'))	('stronger', 'PosReg', (61, 69))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumours', 'Disease', (104, 111))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('Six1', 'Gene', (136, 140))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('tumours', 'Disease', (27, 34))	('tumours', 'Disease', 'MESH:D009369', (104, 111))	('CD24+/CD44+ cells', 'Var', (81, 98))
57352	28388884	Furthermore, we show that inhibition of Six1 leads to decreased cell motility in Panc1 and BxPc3 cells.	('inhibition', 'Var', (26, 36))	('BxPc3', 'CellLine', 'CVCL:0186', (91, 96))	('Panc1', 'CellLine', 'CVCL:0480', (81, 86))	('Six1', 'Gene', '6495', (40, 44))	('Six1', 'Gene', (40, 44))	('decreased', 'NegReg', (54, 63))	('cell motility', 'biological_process', 'GO:0048870', ('64', '77'))	('cell motility', 'CPA', (64, 77))
57358	28388884	Therefore, targeting Six1 might be a novel promising therapeutic approach in patients with pancreatic cancer.	('Six1', 'Gene', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('patients', 'Species', '9606', (77, 85))	('targeting', 'Var', (11, 20))	('pancreatic cancer', 'Disease', (91, 108))	('Six1', 'Gene', '6495', (21, 25))
57360	27751347	Noninvasive Assessment of Losartan-Induced Increase in Functional Microvasculature and Drug Delivery in Pancreatic Ductal Adenocarcinoma1 PURPOSE: Losartan, an angiotensin II receptor blocker, can reduce desmoplasia and enhance drug delivery and efficacy through improving interstitial transport and vascular perfusion in pancreatic ductal adenocarcinoma (PDAC) models in mice.	('vascular perfusion', 'MPA', (300, 318))	('PDAC', 'Chemical', '-', (356, 360))	('drug delivery', 'MPA', (228, 241))	('pancreatic ductal adenocarcinoma', 'Disease', (322, 354))	('PDAC', 'Phenotype', 'HP:0006725', (356, 360))	('desmoplasia', 'Disease', 'None', (204, 215))	('SE', 'Disease', 'None', (143, 145))	('reduce', 'NegReg', (197, 203))	('enhance', 'PosReg', (220, 227))	('desmoplasia', 'Disease', (204, 215))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (322, 354))	('Losartan', 'Chemical', 'MESH:D019808', (26, 34))	('transport', 'biological_process', 'GO:0006810', ('286', '295'))	('Losartan', 'Var', (147, 155))	('improving', 'PosReg', (263, 272))	('efficacy', 'MPA', (246, 254))	('mice', 'Species', '10090', (372, 376))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (322, 354))	('interstitial transport', 'MPA', (273, 295))	('Losartan', 'Chemical', 'MESH:D019808', (147, 155))	('Functional Microvasculature and Drug Delivery in Pancreatic Ductal Adenocarcinoma1', 'Disease', 'MESH:D021441', (55, 137))
57375	27751347	In a transgenic mice model of PDAC, PEGPH20, a recombinant enzyme which degrades hyaluronan, reduced the hyaluronan content and enhanced vascular perfusion and the efficacy of gemcitabine.	('hyaluronan content', 'MPA', (105, 123))	('PDAC', 'Chemical', '-', (30, 34))	('PEGPH20', 'Var', (36, 43))	('efficacy', 'CPA', (164, 172))	('reduced', 'NegReg', (93, 100))	('hyaluronan', 'Protein', (81, 91))	('transgenic mice', 'Species', '10090', (5, 20))	('PDAC', 'Phenotype', 'HP:0006725', (30, 34))	('enhanced', 'PosReg', (128, 136))	('vascular perfusion', 'CPA', (137, 155))	('gemcitabine', 'Chemical', 'MESH:C056507', (176, 187))	('hyaluronan', 'Chemical', 'MESH:D006820', (105, 115))	('hyaluronan', 'Chemical', 'MESH:D006820', (81, 91))
57389	27751347	We determined the relationship of the steady-state shifts DeltaR2 and DeltaR2* in the transverse relaxation rates 1/T2 and 1/T2* caused by injection of long circulating MNPs by modeling the fBV (~DeltaR2*), VSI (~DeltaR2*/DeltaR2)n, and vessel density index (VDI) [DeltaR2/(DeltaR2*)n].	('DeltaR2', 'DELETION', 'None', (213, 220))	('DeltaR2', 'DELETION', 'None', (274, 281))	('DeltaR2', 'DELETION', 'None', (58, 65))	('DeltaR2', 'DELETION', 'None', (222, 229))	('DeltaR2', 'Var', (274, 281))	('DeltaR2', 'Var', (213, 220))	('DeltaR2', 'Var', (222, 229))	('DeltaR2', 'Var', (58, 65))	('DeltaR2', 'Var', (70, 77))	('DeltaR2', 'DELETION', 'None', (196, 203))	('DeltaR2', 'Var', (196, 203))	('DeltaR2', 'DELETION', 'None', (265, 272))	('DeltaR2', 'DELETION', 'None', (70, 77))	('DeltaR2', 'Var', (265, 272))	('T2 and 1', 'Gene', '21331;17082', (116, 124))
57418	27751347	This was also replicated in the histogram analysis (Figure 2G), and when performing the quantitative ROI analysis, the VDI was significantly higher (P < .05) in control- (0.15 +- 0.06) than losartan- (0.04 +- 0.01) treated animals.	('VDI', 'MPA', (119, 122))	('losartan', 'Chemical', 'MESH:D019808', (190, 198))	('0.15', 'Var', (171, 175))	('higher', 'PosReg', (141, 147))
57435	27751347	In other studies, the genetic deletion of AT1R and high doses of ARBs or losartan significantly reduced the tumor microvessel density.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('AT1R', 'Gene', '11610', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('AT1R', 'Gene', (42, 46))	('tumor', 'Disease', (108, 113))	('genetic deletion', 'Var', (22, 38))	('losartan', 'Chemical', 'MESH:D019808', (73, 81))	('reduced', 'NegReg', (96, 103))
57460	26876216	Furthermore, activation of HGF/Met signaling increased the expression and transcriptional activity of FOXM1, and the cross-talk between FOXM1 and HGF/Met signaling promoted PDA growth and resistance to Met inhibition.	('PDA growth', 'CPA', (173, 183))	('increased', 'PosReg', (45, 54))	('resistance', 'CPA', (188, 198))	('PDA', 'Chemical', '-', (173, 176))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('expression', 'Species', '29278', (59, 69))	('promoted', 'PosReg', (164, 172))	('expression', 'MPA', (59, 69))	('FOXM1', 'Gene', (102, 107))	('FOXM1', 'Gene', (136, 141))	('PDA', 'Phenotype', 'HP:0006725', (173, 176))	('transcriptional activity', 'MPA', (74, 98))	('cross-talk', 'Var', (117, 127))
57466	26876216	Binding of Met with its ligand hepatocyte growth factor (HGF) leads to dimerization and phosphorylation at two tyrosine residues (Tyr1234 and Tyr1235) close to or within the catalytic pocket of Met.	('Tyr1235', 'Var', (142, 149))	('phosphorylation', 'MPA', (88, 103))	('Tyr1235', 'Chemical', '-', (142, 149))	('phosphorylation', 'biological_process', 'GO:0016310', ('88', '103'))	('tyrosine', 'Chemical', 'MESH:D014443', (111, 119))	('Tyr1234', 'Var', (130, 137))	('leads to', 'Reg', (62, 70))	('dimerization', 'MPA', (71, 83))	('Tyr1234', 'Chemical', '-', (130, 137))	('Binding', 'Interaction', (0, 7))	('ligand', 'molecular_function', 'GO:0005488', ('24', '30'))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('31', '55'))
57467	26876216	Furthermore, Met could associate and form dimerization with receptor originated from Nantes (RON), and RON ligand macrophage stimulating protein (MSP) induced a transphosphorylation of MetTyr1234/Tyr12354.	('associate', 'Interaction', (23, 32))	('ligand', 'molecular_function', 'GO:0005488', ('107', '113'))	('transphosphorylation', 'MPA', (161, 181))	('Tyr12354', 'Chemical', '-', (196, 204))	('MetTyr1234/Tyr12354', 'Var', (185, 204))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('MetTyr1234', 'Chemical', '-', (185, 195))	('form dimerization', 'MPA', (37, 54))
57471	26876216	Furthermore, PDA cells overexpressing Met are resistant to treatment with gemcitabine and radiation.	('gemcitabine', 'Chemical', 'MESH:C056507', (74, 85))	('PDA', 'Phenotype', 'HP:0006725', (13, 16))	('resistant', 'MPA', (46, 55))	('PDA', 'Chemical', '-', (13, 16))	('Met', 'Var', (38, 41))
57477	26876216	Recently, we have reported that FOXM1 transactivates lactate dehydrogenase A and promotes the Warburg effect and PDA progression.	('PDA', 'Phenotype', 'HP:0006725', (113, 116))	('Warburg effect', 'CPA', (94, 108))	('promotes', 'PosReg', (81, 89))	('FOXM1', 'Gene', (32, 37))	('PDA', 'Chemical', '-', (113, 116))	('lactate', 'Enzyme', (53, 60))	('transactivates', 'Var', (38, 52))	('PDA progression', 'CPA', (113, 128))
57492	26876216	Further statistical analysis revealed that the expression of Met was significantly correlated with that of FOXM1 in the TMA (r=0.293, P<0.001) (Fig.	('FOXM1', 'Gene', (107, 112))	('correlated', 'Reg', (83, 93))	('TMA', 'Chemical', '-', (120, 123))	('Met', 'Var', (61, 64))	('expression', 'Species', '29278', (47, 57))	('expression', 'MPA', (47, 57))
57497	26876216	Overexpression of FOXM1 increased the MET promoter activity, whereas knockdown of FOXM1 decreased the MET promoter activity of both pLuc-Met-1259 and pLuc-Met-1069 reporters.	('MET promoter activity', 'MPA', (102, 123))	('expression', 'Species', '29278', (4, 14))	('MET promoter activity', 'MPA', (38, 59))	('FOXM1', 'Gene', (82, 87))	('decreased', 'NegReg', (88, 97))	('FOXM1', 'Gene', (18, 23))	('knockdown', 'Var', (69, 78))	('increased', 'PosReg', (24, 33))
57500	26876216	Met is autophosphorylated at Tyr1234 and Tyr1235 when binds with HGF, leading to activation of a series of intracellular downstream signaling events, including RAS/ERK, PI3K/AKT, and STAT signaling.	('intracellular', 'cellular_component', 'GO:0005622', ('107', '120'))	('RAS/ERK', 'Pathway', (160, 167))	('Tyr1234', 'Var', (29, 36))	('STAT', 'MPA', (183, 187))	('ERK', 'molecular_function', 'GO:0004707', ('164', '167'))	('PI3K/AKT', 'Pathway', (169, 177))	('HGF', 'Protein', (65, 68))	('activation', 'PosReg', (81, 91))	('Tyr1234', 'Chemical', '-', (29, 36))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('signaling', 'biological_process', 'GO:0023052', ('188', '197'))	('binds', 'Interaction', (54, 59))	('Tyr1235', 'Var', (41, 48))	('Tyr1235', 'Chemical', '-', (41, 48))	('PI3K', 'molecular_function', 'GO:0016303', ('169', '173'))
57503	26876216	3D and 3E, knockdown of FOXM1 expression in FG cells led to decreased HGF-dependent phosphorylation of Met at Y1234 and Y1235 and its downstream transducers, including ERK1/2 at T202 and Y204, AKT at S473, and STAT3 at Y705.	('AKT', 'Pathway', (193, 196))	('STAT3', 'Gene', '6774', (210, 215))	('Y1235', 'Var', (120, 125))	('decreased', 'NegReg', (60, 69))	('Met at Y1234', 'Var', (103, 115))	('STAT3', 'Gene', (210, 215))	('HGF-dependent phosphorylation', 'MPA', (70, 99))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('ERK1', 'molecular_function', 'GO:0004707', ('168', '172'))	('Y204', 'Var', (187, 191))	('FOXM1', 'Gene', (24, 29))	('expression', 'Species', '29278', (30, 40))
57507	26876216	Furthermore, activation of HGF/Met signaling elevated the expression of FOXM1 downstream target genes, such as cyclin D1, cyclin B1, and c-Myc, whereas PHA-665752 suppressed the expression of FOXM1 downstream target genes (Fig.	('FOXM1', 'Gene', (72, 77))	('cyclin', 'MPA', (122, 128))	('expression', 'Species', '29278', (178, 188))	('expression', 'Species', '29278', (58, 68))	('expression', 'MPA', (58, 68))	('c-Myc', 'MPA', (137, 142))	('PHA-665752', 'Var', (152, 162))	('expression', 'MPA', (178, 188))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('elevated', 'PosReg', (45, 53))	('FOXM1', 'Gene', (192, 197))	('cyclin', 'molecular_function', 'GO:0016538', ('111', '117'))	('suppressed', 'NegReg', (163, 173))	('cyclin D1', 'MPA', (111, 120))	('cyclin', 'molecular_function', 'GO:0016538', ('122', '128'))
57508	26876216	We next sought to determine which of the HGF/Met downstream signaling pathways played key roles in regulation of FOXM1 transcriptional activity by using ERK1/2 inhibitor FR180204, AKT inhibitor GSK690693, and STAT3 inhibitor S3I-201.	('ERK1', 'molecular_function', 'GO:0004707', ('153', '157'))	('GSK', 'molecular_function', 'GO:0050321', ('194', '197'))	('S3I-201', 'Chemical', 'MESH:C520337', (225, 232))	('FR180204', 'Var', (170, 178))	('GSK690693', 'Chemical', 'MESH:C528328', (194, 203))	('STAT3', 'Gene', '6774', (209, 214))	('FOXM1', 'Gene', (113, 118))	('FR180204', 'Chemical', 'MESH:C505241', (170, 178))	('STAT3', 'Gene', (209, 214))	('regulation', 'biological_process', 'GO:0065007', ('99', '109'))	('signaling', 'biological_process', 'GO:0023052', ('60', '69'))
57514	26876216	Conversely, FOXM1 knockdown markedly decreased Met expression and inhibited tumor growth (Supplementary Fig.	('knockdown', 'Var', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('FOXM1', 'Gene', (12, 17))	('expression', 'Species', '29278', (51, 61))	('Met expression', 'MPA', (47, 61))	('inhibited', 'NegReg', (66, 75))	('decreased', 'NegReg', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
57516	26876216	PHA-665752 is an ATP-competitive small-molecule inhibitor of Met that selectively inhibits the receptor kinase domain, disrupting the HGF/Met signaling pathway.	('disrupting', 'NegReg', (119, 129))	('receptor kinase domain', 'Pathway', (95, 117))	('ATP', 'Chemical', 'MESH:D000255', (17, 20))	('HGF/Met signaling pathway', 'Pathway', (134, 159))	('Met signaling pathway', 'biological_process', 'GO:0048012', ('138', '159'))	('inhibits', 'NegReg', (82, 90))	('PHA-665752', 'Var', (0, 10))
57520	26876216	Also, the PHA-665752-resistant cells had higher levels of FOXM1 and Met expression than the parental cells did (Fig.	('levels', 'MPA', (48, 54))	('PHA-665752-resistant', 'Var', (10, 30))	('expression', 'Species', '29278', (72, 82))	('higher', 'PosReg', (41, 47))	('Met expression', 'MPA', (68, 82))	('FOXM1', 'Gene', (58, 63))
57521	26876216	S10A and S10B).	('S10B', 'SUBSTITUTION', 'None', (9, 13))	('S10A', 'SUBSTITUTION', 'None', (0, 4))	('S10B', 'Var', (9, 13))	('S10A', 'Var', (0, 4))
57524	26876216	S10C, S10D, S10E and S10F).	('S10D', 'Var', (6, 10))	('S10F', 'Var', (21, 25))	('S10F', 'Mutation', 'p.S10F', (21, 25))	('S10E', 'Mutation', 'p.S10E', (12, 16))	('S10D', 'Mutation', 'p.S10D', (6, 10))	('S10E', 'Var', (12, 16))	('S10C', 'Mutation', 'p.S10C', (0, 4))
57526	26876216	Conversely, knockdown of FOXM1 expression in PANC-1-R and FG-R cells led to less resistance to PHA-665752 than the control siRNA groups (IC50, 1.36 versus 0.56 [P<0.001] and 1.45 versus 0.56 [P=0.006], respectively) (Fig.	('less', 'NegReg', (76, 80))	('resistance to PHA-665752', 'MPA', (81, 105))	('expression', 'Species', '29278', (31, 41))	('knockdown', 'Var', (12, 21))	('PANC-1-R', 'CellLine', 'CVCL:0480', (45, 53))	('FOXM1', 'Gene', (25, 30))
57529	26876216	We finally sought to determine whether inhibition of FOXM1 expression is an effective strategy of reversing resistance of PDA cells to Met inhibition.	('resistance', 'MPA', (108, 118))	('inhibition', 'Var', (39, 49))	('PDA', 'Phenotype', 'HP:0006725', (122, 125))	('FOXM1', 'Gene', (53, 58))	('expression', 'Species', '29278', (59, 69))	('PDA', 'Chemical', '-', (122, 125))
57543	26876216	Conversely, both FOXM1 knockdown and blockade of Met signaling downregulated FOXM1 expression, and decreased the activation of Met and its downstream signaling.	('decreased', 'NegReg', (99, 108))	('activation', 'MPA', (113, 123))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('blockade', 'Var', (37, 45))	('Met', 'MPA', (127, 130))	('knockdown', 'Var', (23, 32))	('FOXM1', 'Gene', (77, 82))	('downregulated', 'NegReg', (63, 76))	('expression', 'Species', '29278', (83, 93))	('expression', 'MPA', (83, 93))	('downstream signaling', 'MPA', (139, 159))	('signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('FOXM1', 'Gene', (17, 22))
57554	26876216	In the present study, we showed that PDA cells resistant to the Met inhibitor PHA-665752 had higher levels of FOXM1 and Met expression than the control cells and that FOXM1 overexpression resulted in increased resistance to PHA-665752, whereas knockdown of FOXM1 expression led to reduced resistance to it.	('higher', 'PosReg', (93, 99))	('PDA', 'Phenotype', 'HP:0006725', (37, 40))	('overexpression', 'PosReg', (173, 187))	('PHA-665752', 'Var', (224, 234))	('levels', 'MPA', (100, 106))	('increased', 'PosReg', (200, 209))	('expression', 'Species', '29278', (124, 134))	('PDA', 'Chemical', '-', (37, 40))	('FOXM1', 'Gene', (167, 172))	('expression', 'Species', '29278', (263, 273))	('expression', 'Species', '29278', (177, 187))	('Met expression', 'MPA', (120, 134))	('FOXM1', 'MPA', (110, 115))	('resistance', 'MPA', (210, 220))
57559	26876216	Therefore, we have not only identified a novel molecular mechanism underlying aberrant activation of HGF/Met and FOXM1 in PDA cells, but also have revealed that the combine use of both inhibitors for FOXM1 and HGF/Met signaling is a promising therapeutic strategy for PDA.	('activation', 'PosReg', (87, 97))	('PDA', 'Chemical', '-', (268, 271))	('PDA', 'Phenotype', 'HP:0006725', (122, 125))	('FOXM1', 'Gene', (200, 205))	('inhibitors', 'Var', (185, 195))	('PDA', 'Phenotype', 'HP:0006725', (268, 271))	('signaling', 'biological_process', 'GO:0023052', ('218', '227'))	('HGF/Met', 'Gene', (101, 108))	('FOXM1', 'Gene', (113, 118))	('PDA', 'Chemical', '-', (122, 125))	('PDA', 'Disease', (268, 271))
57561	26876216	The Met tyrosine kinase inhibitor PHA-665752, ERK1/2 inhibitor FR180204, AKT kinase inhibitor GSK690693, STAT3 inhibitor S3I-201, Met ligand HGF, and FOXM1 inhibitor thiostrepton (TST) were obtained from Sigma-Aldrich.	('ERK1', 'molecular_function', 'GO:0004707', ('46', '50'))	('GSK690693', 'Chemical', 'MESH:C528328', (94, 103))	('tyrosine', 'Chemical', 'MESH:D014443', (8, 16))	('FR180204', 'Chemical', 'MESH:C505241', (63, 71))	('STAT3', 'Gene', '6774', (105, 110))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('77', '93'))	('S3I-201', 'Chemical', 'MESH:C520337', (121, 128))	('ERK1/2', 'Gene', (46, 52))	('ligand', 'molecular_function', 'GO:0005488', ('134', '140'))	('PHA-665752', 'Var', (34, 44))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('17', '33'))	('STAT3', 'Gene', (105, 110))	('thiostrepton', 'Chemical', 'MESH:D013883', (166, 178))	('GSK', 'molecular_function', 'GO:0050321', ('94', '97'))
57563	26876216	The concentration of PHA-665752 was progressively increased once every 2 weeks in 0.5-muM increments up to a final concentration of 2.5 muM.	('muM', 'Gene', '56925', (86, 89))	('muM', 'Gene', (136, 139))	('muM', 'Gene', (86, 89))	('PHA-665752', 'Var', (21, 31))	('muM', 'Gene', '56925', (136, 139))
57577	26876216	PDA cells were transfected with Met promoter reporters, siFOXM1, or an expression plasmid or transfected with pFOXM1, pLuc-cyclin B1 and a FOXM1-dependent luciferase reporter (6X-FOXM1-Luc), which was described previously, and treated with HGF or PHA-665752 and HGF with FR180204, GSK690693, or S3I-201.	('cyclin', 'molecular_function', 'GO:0016538', ('123', '129'))	('FR180204', 'Chemical', 'MESH:C505241', (271, 279))	('GSK', 'molecular_function', 'GO:0050321', ('281', '284'))	('S3I-201', 'Chemical', 'MESH:C520337', (295, 302))	('PDA', 'Phenotype', 'HP:0006725', (0, 3))	('GSK690693', 'Var', (281, 290))	('FR180204', 'Var', (271, 279))	('GSK690693', 'Chemical', 'MESH:C528328', (281, 290))	('PDA', 'Chemical', '-', (0, 3))	('expression', 'Species', '29278', (71, 81))
57609	26969625	Previous studies have observed that miR-21 dysregulates in many cancers and acts as a key factor mediating the growth, development, and progression of tumors, which is expected to be a novel predictor and target.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('miR-21', 'Gene', '406991', (36, 42))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('dysregulates', 'Var', (43, 55))	('miR-21', 'Gene', (36, 42))	('mediating', 'Reg', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
57630	26969625	In patients receiving adjuvant chemotherapy, high expression of miR-21 is also associated with poor prognosis (HR = 2.37, 95 % CI 1.88-3.00, P < 0.001), Fig.	('patients', 'Species', '9606', (3, 11))	('miR-21', 'Gene', '406991', (64, 70))	('high expression', 'Var', (45, 60))	('miR-21', 'Gene', (64, 70))
57648	26969625	Aberrant expression of PTEN was associated with the development and progression of multiple tumors.	('Aberrant expression', 'Var', (0, 19))	('multiple tumors', 'Disease', (83, 98))	('multiple tumors', 'Disease', 'MESH:D009369', (83, 98))	('PTEN', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('PTEN', 'Gene', '5728', (23, 27))	('associated with', 'Reg', (32, 47))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
57649	26969625	found that inhibition of miR-21 in cultured HCC cells increased the expression of PTEN.	('miR-21', 'Gene', (25, 31))	('expression', 'MPA', (68, 78))	('increased', 'PosReg', (54, 63))	('inhibition', 'Var', (11, 21))	('miR-21', 'Gene', '406991', (25, 31))	('PTEN', 'Gene', (82, 86))	('PTEN', 'Gene', '5728', (82, 86))
57658	26969625	More importantly, miR-21 expression is likely to be correlated with chemoresistance as growing evidence suggests that aberrant miR-21 expression strongly cripples the response to the chemotherapy.	('miR-21', 'Gene', (127, 133))	('miR-21', 'Gene', '406991', (18, 24))	('cripples', 'NegReg', (154, 162))	('response to the chemotherapy', 'CPA', (167, 195))	('miR-21', 'Gene', (18, 24))	('aberrant', 'Var', (118, 126))	('miR-21', 'Gene', '406991', (127, 133))
57661	26969625	Meanwhile, antisense inhibition of miR-21 induced the reduction of cancer cell proliferation, invasion, and chemoresistance against gemcitabine and 5-fluorouracil.	('invasion', 'CPA', (94, 102))	('chemoresistance', 'CPA', (108, 123))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (148, 162))	('reduction of cancer', 'Disease', 'MESH:D009369', (54, 73))	('reduction of cancer', 'Disease', (54, 73))	('miR-21', 'Gene', (35, 41))	('gemcitabine', 'Chemical', 'MESH:C056507', (132, 143))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('antisense inhibition', 'Var', (11, 31))	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))	('miR-21', 'Gene', '406991', (35, 41))
57665	26969625	Additionally, ectopic expression of FasL significantly abrogated the miR-21-induced chemoresistance.	('abrogated', 'NegReg', (55, 64))	('chemoresistance', 'CPA', (84, 99))	('miR-21', 'Gene', (69, 75))	('FasL', 'Gene', '356', (36, 40))	('FasL', 'Gene', (36, 40))	('ectopic expression', 'Var', (14, 32))	('miR-21', 'Gene', '406991', (69, 75))
57666	26969625	These evidences may also partially explain that high expression of miR-21 predicts poor prognosis.	('miR-21', 'Gene', '406991', (67, 73))	('miR-21', 'Gene', (67, 73))	('expression', 'MPA', (53, 63))	('high', 'Var', (48, 52))	('poor prognosis', 'CPA', (83, 97))
57674	26259033	We found evidence of 465 somatic LINE-1 insertions in 20 PDAC genomes absent from corresponding normal samples.	('PDAC', 'Chemical', '-', (57, 61))	('insertions', 'Var', (40, 50))	('PDAC', 'Phenotype', 'HP:0006725', (57, 61))	('somatic LINE-1', 'Gene', (25, 39))
57679	26259033	Somatically acquired mutations are central to the development of PDAC.	('PDAC', 'Disease', (65, 69))	('PDAC', 'Phenotype', 'HP:0006725', (65, 69))	('PDAC', 'Chemical', '-', (65, 69))	('mutations', 'Var', (21, 30))
57680	26259033	Most mutations occur while the neoplasm is localized to the pancreas, before metastasis .	('neoplasm', 'Phenotype', 'HP:0002664', (31, 39))	('neoplasm', 'Disease', 'MESH:D009369', (31, 39))	('mutations', 'Var', (5, 14))	('occur', 'Reg', (15, 20))	('neoplasm', 'Disease', (31, 39))
57689	26259033	After subtracting the known germline variants, significant read pile-ups (peaks) from normal tissue TIP-seq indicated novel constitutional L1Hs insertions.	('pile-ups', 'Disease', 'MESH:D000067251', (64, 72))	('L1Hs', 'Gene', (139, 143))	('insertions', 'Var', (144, 154))	('constitutional L1Hs', 'Gene', (124, 143))	('pile', 'Phenotype', 'HP:0032551', (64, 68))	('pile-ups', 'Disease', (64, 72))
57696	26259033	LINE-1 ORF1p expression level scored by immunohistochemistry correlated with numbers of somatically acquired LINE-1 insertions albeit not to statistical significance (p=0.07).	('insertions', 'Var', (116, 126))	('expression', 'MPA', (13, 23))	('LINE-1', 'Gene', (109, 115))	('ORF1p', 'Gene', '55354', (7, 12))	('ORF1p', 'Gene', (7, 12))
57697	26259033	Survival after diagnosis was inversely correlated with somatically acquired LINE-1 insertions found in the primary tumor and with LINE-1 ORF1p immunoreactivity (p=0.025 and p=0.03, respectively)(Fig.	('inversely', 'NegReg', (29, 38))	('LINE-1', 'Gene', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('primary tumor', 'Disease', (107, 120))	('ORF1p', 'Gene', '55354', (137, 142))	('primary tumor', 'Disease', 'MESH:D009369', (107, 120))	('ORF1p', 'Gene', (137, 142))	('insertions', 'Var', (83, 93))
57699	26259033	We found evidence for 51 and 63 somatic LINE-1 insertions in these PDAC mimics.	('PDAC', 'Chemical', '-', (67, 71))	('PDAC', 'Phenotype', 'HP:0006725', (67, 71))	('insertions', 'Var', (47, 57))	('somatic LINE-1', 'Gene', (32, 46))
57704	26259033	We expect insertions shared between primary and metastatic samples of a case arose in the progenitor lineage of the primary tumor.	('primary tumor', 'Disease', 'MESH:D009369', (116, 129))	('primary tumor', 'Disease', (116, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('insertions', 'Var', (10, 20))
57717	26259033	To test for concordance between acquired single nucleotide changes and LINE-1 insertions, we compared proportions of shared (i.e., primary and metastasis) and 'metastasis- only' alterations in a PDAC case.	('alterations', 'Var', (178, 189))	('PDAC', 'Phenotype', 'HP:0006725', (195, 199))	('PDAC', 'Chemical', '-', (195, 199))	('single nucleotide changes', 'Var', (41, 66))
57720	26259033	Together, these data indicate that LINE-1 insertions are not commonly canonical 'driver' mutations, and that any one insertion is likely dispensable for tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('LINE-1', 'Gene', (35, 41))	('insertions', 'Var', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	("'driver", 'PosReg', (80, 87))
57735	26259033	Tumors with many insertions may have acquired these in series of breaches or even in isolated catastrophic episodes that can be likened to chromothripsis in cancer genomes .	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('insertions', 'Var', (17, 27))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('chromothripsis', 'Disease', (139, 153))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('chromothripsis', 'Disease', 'MESH:D000072837', (139, 153))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', (157, 163))
57736	26259033	Although many LINE-1 insertions can occur in metastatic progenitor lineages, they appear dispensable for PDAC.	('PDAC', 'Disease', (105, 109))	('PDAC', 'Phenotype', 'HP:0006725', (105, 109))	('LINE-1', 'Gene', (14, 20))	('insertions', 'Var', (21, 31))	('PDAC', 'Chemical', '-', (105, 109))
57781	26597727	Pancreatic cancer stem cells (PCSC) were identified in 2007, when several groups demonstrated the presence of CD24, CD44, epithelial specific antigen (ESA) triple positive markers or CD133 positive cells had the ability to initiate tumor formation in animals at very low numbers.	('CD133', 'Var', (183, 188))	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('formation', 'biological_process', 'GO:0009058', ('238', '247'))	('CD44', 'Gene', '960', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('CD44', 'Gene', (116, 120))	('CD24', 'Gene', '100133941', (110, 114))	('tumor', 'Disease', (232, 237))	('CD24', 'Gene', (110, 114))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
57817	26597727	Consistent with the in vitro surrogate experiments, CD133+ cells from both CSM and 12 T groups formed tumors in mice where as CD133- cells did not (Fig.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('CD133+', 'Var', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('mice', 'Species', '10090', (112, 116))
57848	26597727	Our earlier results show that treatment with Minnelide is able to significantly reduce the CD133+ population in the spontaneous KPC (KrasG12D,Trp53 R172H,Pdx-1-Cre) murine model tumors and in human patient tumor derived xenografts.	('CD133+', 'MPA', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('Trp53', 'Gene', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (178, 183))	('human', 'Species', '9606', (192, 197))	('murine', 'Species', '10090', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('R172H', 'Var', (148, 153))	('patient', 'Species', '9606', (198, 205))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('R172H', 'SUBSTITUTION', 'None', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumors', 'Disease', (178, 184))	('tumor', 'Disease', (206, 211))	('Trp53', 'Gene', '22059', (142, 147))	('Minnelide', 'Chemical', 'MESH:C579022', (45, 54))	('reduce', 'NegReg', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
57860	26597727	As seen in cancer stem cells isolated from tumor xenografts, the 12 T cells showed similar enrichment of surface markers CD24/CD44/ESA and CD133.	('CD133', 'Var', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('CD44', 'Gene', '960', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('CD44', 'Gene', (126, 130))	('cancer', 'Disease', (11, 17))	('tumor', 'Disease', (43, 48))	('CD24', 'Gene', '100133941', (121, 125))	('CD24', 'Gene', (121, 125))
57881	26597727	Cells were washed once in PBS and gently scraped into 15 mL centrifuge tubes, washed in PBS prior to staining and stained with the following directly conjugated monoclonal antibodies in the presence of FcR blocking reagent (Miltenyi Biotech): anti-mouse CD133-PE (Miltenyi Biotech), anti-mouse CD44-FITC (BD Biosciences), ESA-APC (BD Bioscience) and CD24-PE (BD Biosciences, USA).	('mouse', 'Species', '10090', (288, 293))	('PBS', 'Chemical', 'MESH:D007854', (26, 29))	('CD44', 'Gene', '960', (294, 298))	('PBS', 'Chemical', 'MESH:D007854', (88, 91))	('mouse', 'Species', '10090', (248, 253))	('CD44', 'Gene', (294, 298))	('CD24', 'Gene', '100133941', (350, 354))	('CD24', 'Gene', (350, 354))	('ESA-APC', 'Disease', (322, 329))	('APC', 'cellular_component', 'GO:0005680', ('326', '329'))	('anti-mouse CD133-PE', 'Var', (243, 262))
57886	26597727	Either 1000 or 10,000 cells (CSM, 12 T sorted for CD133+ or CD133-) were injected subcutaneously into the right and left flank of age and gender matched C57BL/6 mice (Jackson Laboratories).	('CD133+', 'Var', (50, 56))	('mice', 'Species', '10090', (161, 165))	('Jackson Laboratories', 'Disease', 'MESH:D007757', (167, 187))	('CD133-', 'Var', (60, 66))	('Jackson Laboratories', 'Disease', (167, 187))
57929	26539408	Abnormally large collagen deposition is the most well-documented ECM alteration in many tumor types, and collagen deposition has been causally linked to an increase in mammary tumor and metastasis incidence.	('linked', 'Reg', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('increase', 'PosReg', (156, 164))	('metastasis', 'CPA', (186, 196))	('tumor', 'Disease', (176, 181))	('collagen', 'molecular_function', 'GO:0005202', ('105', '113'))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Abnormally', 'Var', (0, 10))	('collagen', 'molecular_function', 'GO:0005202', ('17', '25'))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
57933	26539408	First, the production of the glycosaminoglycan HA has been demonstrated to induce EMT in both normal and transformed epithelial cells in vitro [reviewed in Ref.	('glycosaminoglycan', 'Protein', (29, 46))	('EMT', 'biological_process', 'GO:0001837', ('82', '85'))	('EMT', 'CPA', (82, 85))	('production', 'Var', (11, 21))	('induce', 'PosReg', (75, 81))	('HA', 'Chemical', 'MESH:D006820', (47, 49))
57935	26539408	However, overproduction of HA is not in itself enough to create an invasive phenotype, on its own it actually decreases cell motility and tumorigenesis.	('cell motility', 'biological_process', 'GO:0048870', ('120', '133'))	('cell motility', 'CPA', (120, 133))	('tumor', 'Disease', (138, 143))	('HA', 'Chemical', 'MESH:D006820', (27, 29))	('decreases', 'NegReg', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('overproduction', 'Var', (9, 23))
57936	26539408	However, if the general turnover of HA is increased due to high levels of both HA synthases and hyaluronidases, i.e., increased levels of LMW-HA, then this leads to an increase in cell motility in vitro.	('increased', 'PosReg', (42, 51))	('increase', 'PosReg', (168, 176))	('cell motility', 'biological_process', 'GO:0048870', ('180', '193'))	('levels', 'MPA', (128, 134))	('LMW-HA', 'Var', (138, 144))	('HA', 'Chemical', 'MESH:D006820', (79, 81))	('increased', 'PosReg', (118, 127))	('HA', 'Chemical', 'MESH:D006820', (142, 144))	('cell motility in vitro', 'CPA', (180, 202))	('HA', 'Chemical', 'MESH:D006820', (36, 38))
57946	26539408	Furthermore, LMW-HA is also angiogenic, so the production of LMW-HA fragments in the tumor microenvironment can thus compromise the tumor vessel integrity and promote angiogenesis, making it easier for cancer cells to intravasate and continue the metastatic process.	('tumor', 'Disease', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('promote', 'PosReg', (159, 166))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('fragments', 'Var', (68, 77))	('angiogenesis', 'biological_process', 'GO:0001525', ('167', '179'))	('angiogenesis', 'CPA', (167, 179))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('compromise', 'NegReg', (117, 127))	('LMW-HA', 'Gene', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('metastatic process', 'CPA', (247, 265))	('HA', 'Chemical', 'MESH:D006820', (17, 19))	('HA', 'Chemical', 'MESH:D006820', (65, 67))	('easier', 'PosReg', (191, 197))	('cancer', 'Disease', (202, 208))
57949	26539408	Recently, it has been reported that inhibition of collagen synthesis in human MDA-MB231 breast cancer xenografts leads to a decrease in local invasion into the surrounding adipose tissue and to a decrease in metastasis to both the draining lymph nodes and lungs.	('collagen', 'molecular_function', 'GO:0005202', ('50', '58'))	('inhibition', 'Var', (36, 46))	('decrease', 'NegReg', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('collagen synthesis', 'biological_process', 'GO:0032964', ('50', '68'))	('local invasion into the surrounding adipose tissue', 'CPA', (136, 186))	('collagen synthesis', 'MPA', (50, 68))	('human', 'Species', '9606', (72, 77))	('MDA-MB231 breast cancer', 'Disease', 'MESH:D001943', (78, 101))	('metastasis to', 'CPA', (208, 221))	('decrease', 'NegReg', (124, 132))	('MDA-MB231 breast cancer', 'Disease', (78, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
57963	26539408	A further mediator of cell motility is tenascin C. By binding to either integrin alphavbeta1 or alphavbeta6, recombinant tenascin C induced a change in the morphology of the breast cancer cell line MCF-7 to a more mesenchymal phenotype (Figure 2).	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('cell motility', 'biological_process', 'GO:0048870', ('22', '35'))	('binding', 'molecular_function', 'GO:0005488', ('54', '61'))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('tenascin C', 'cellular_component', 'GO:0090733', ('39', '49'))	('morphology', 'CPA', (156, 166))	('change', 'Reg', (142, 148))	('alphavbeta6', 'Var', (96, 107))	('more mesenchymal phenotype', 'CPA', (209, 235))	('MCF-7', 'CellLine', 'CVCL:0031', (198, 203))	('tenascin C', 'cellular_component', 'GO:0090733', ('121', '131'))	('binding', 'Interaction', (54, 61))
57964	26539408	were able to diminish the invasive potential of a metastatic breast cancer cell line by knocking down tenascin C expression.	('expression', 'MPA', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('tenascin C', 'cellular_component', 'GO:0090733', ('102', '112'))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('diminish', 'NegReg', (13, 21))	('knocking', 'Var', (88, 96))	('tenascin', 'Protein', (102, 110))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
57985	26539408	The importance of cancer cell interaction with HA on endothelial cells in the process of extravasation is backed by a recent in vivo study, which showed that knockdown of the HA receptor CD44 in MDA-MB-231 breast cancer cells drastically decreased the number of experimental metastases in an intracardiac dissemination model.	('metastases', 'Disease', (275, 285))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (195, 205))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('CD44', 'Gene', (187, 191))	('HA', 'Chemical', 'MESH:D006820', (175, 177))	('metastases', 'Disease', 'MESH:D009362', (275, 285))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('breast cancer', 'Disease', (206, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('knockdown', 'Var', (158, 167))	('decreased', 'NegReg', (238, 247))	('cancer', 'Disease', (213, 219))	('CD44', 'Gene', '960', (187, 191))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('HA', 'Chemical', 'MESH:D006820', (47, 49))
57988	26539408	recently showed that the levels of circulating LMW-HA in the blood is an important factor for melanoma cell adhesion to endothelial cells.	('HA', 'Chemical', 'MESH:D006820', (51, 53))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('adhesion', 'CPA', (108, 116))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('LMW-HA', 'Var', (47, 53))	('cell adhesion', 'biological_process', 'GO:0007155', ('103', '116'))
57990	26539408	Strikingly, elevated LMW-HA in serum also prevented spontaneous lung and lymph node metastasis of orthotopically implanted human MDA-MB-231 and mouse 4T1 breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (129, 139))	('LMW-HA', 'Var', (21, 27))	('mouse', 'Species', '10090', (144, 149))	('HA', 'Chemical', 'MESH:D006820', (25, 27))	('breast cancer', 'Disease', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('human', 'Species', '9606', (123, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('prevented', 'NegReg', (42, 51))
57992	26539408	Blocking HARE or saturating it with HA can prevent direct binding of cancer cells to HARE+ cells through their HA-rich pericellular matrix and simultaneously the elevated blood levels of HA, created by lack of HARE-mediated clearance, might also saturate CD44 on the cancer cells, preventing them from utilizing this previously demonstrated important factor for extravasation.	('lack', 'NegReg', (202, 206))	('HARE', 'Gene', '55576', (210, 214))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('HARE', 'Gene', (85, 89))	('CD44', 'Gene', '960', (255, 259))	('HARE', 'Gene', (210, 214))	('HA', 'Chemical', 'MESH:D006820', (111, 113))	('CD44', 'Gene', (255, 259))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('extravasation', 'MPA', (362, 375))	('HA', 'Chemical', 'MESH:D006820', (85, 87))	('binding', 'Interaction', (58, 65))	('binding', 'molecular_function', 'GO:0005488', ('58', '65'))	('HARE', 'Gene', '55576', (9, 13))	('preventing', 'NegReg', (281, 291))	('blood levels', 'MPA', (171, 183))	('HA', 'Chemical', 'MESH:D006820', (187, 189))	('HA', 'Chemical', 'MESH:D006820', (36, 38))	('HARE', 'Gene', (9, 13))	('cancer', 'Disease', (267, 273))	('HA', 'Chemical', 'MESH:D006820', (210, 212))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Disease', (69, 75))	('prevent', 'NegReg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('HA', 'Chemical', 'MESH:D006820', (9, 11))	('saturate', 'Var', (246, 254))	('HARE', 'Gene', '55576', (85, 89))
57996	26539408	Lysyl oxidase, LOXL2, or LOXL4 expression in the primary breast tumor leads to pre-metastatic deposition of collagen I in the lungs of mice (Figure 4), favoring the formation of metastases in the lungs.	('metastases', 'Disease', 'MESH:D009362', (178, 188))	('Lysyl oxidase', 'Gene', (0, 13))	('formation', 'CPA', (165, 174))	('collagen', 'molecular_function', 'GO:0005202', ('108', '116'))	('formation', 'biological_process', 'GO:0009058', ('165', '174'))	('LOXL4', 'Gene', '67573', (25, 30))	('breast tumor', 'Phenotype', 'HP:0100013', (57, 69))	('favoring', 'PosReg', (152, 160))	('LOXL2', 'Var', (15, 20))	('mice', 'Species', '10090', (135, 139))	('LOXL4', 'Gene', (25, 30))	('metastases', 'Disease', (178, 188))	('breast tumor', 'Disease', 'MESH:D001943', (57, 69))	('pre-metastatic', 'MPA', (79, 93))	('pre', 'molecular_function', 'GO:0003904', ('79', '82'))	('Lysyl oxidase', 'Gene', '16948', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('breast tumor', 'Disease', (57, 69))
57997	26539408	Furthermore, LOX-mediated cross-linking of collagen I increases the fibrotic response in lungs and livers of mice and helps form a favorable metastatic niche in these organs.	('collagen', 'molecular_function', 'GO:0005202', ('43', '51'))	('LOX-mediated', 'Var', (13, 25))	('collagen I', 'Protein', (43, 53))	('increases', 'PosReg', (54, 63))	('fibrotic response', 'CPA', (68, 85))	('helps', 'PosReg', (118, 123))	('mice', 'Species', '10090', (109, 113))
58005	26539408	By combining the breast cancer model with periostin null mice, the authors could reveal that stromal periostin supports the survival and proliferation of cancer stem cells (CSCs, CD90+, and CD24+) through the activation of WNT signaling (Figure 4).	('CD24', 'Gene', '100133941', (190, 194))	('CD24', 'Gene', (190, 194))	('mice', 'Species', '10090', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('CD90+', 'Var', (179, 184))	('WNT signaling', 'Pathway', (223, 236))	('signaling', 'biological_process', 'GO:0023052', ('227', '236'))	('breast cancer', 'Disease', (17, 30))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('survival', 'CPA', (124, 132))	('supports', 'PosReg', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('proliferation', 'CPA', (137, 150))
58011	26539408	The tenascin C knockdown resulted in a 90% inhibition of lung colonization in either experimental or spontaneous lung metastases of these cells.	('knockdown', 'Var', (15, 24))	('inhibition', 'NegReg', (43, 53))	('lung colonization', 'CPA', (57, 74))	('lung metastases', 'Disease', (113, 128))	('tenascin C', 'cellular_component', 'GO:0090733', ('4', '14'))	('lung metastases', 'Disease', 'MESH:D009362', (113, 128))	('tenascin C', 'Gene', (4, 14))
58013	26539408	used an inducible knockdown model narrowing down the time frame for the dependency on tumor-derived tenascin C. Interestingly, depriving the breast cancer cells of tenascin C only affected the outgrowth of metastases when they reached a certain size.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tenascin C', 'cellular_component', 'GO:0090733', ('164', '174'))	('metastases', 'Disease', 'MESH:D009362', (206, 216))	('tumor', 'Disease', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tenascin C', 'cellular_component', 'GO:0090733', ('100', '110'))	('depriving', 'Var', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('metastases', 'Disease', (206, 216))	('affected', 'Reg', (180, 188))
58014	26539408	In pancreatic cancer, ectopic tenascin C expression in RIP-Taq2 mice significantly increased the establishment of micrometastases, whereas a tenascin C knockout reduced tumor cell engraftment in the lungs.	('reduced', 'NegReg', (161, 168))	('pancreatic cancer', 'Disease', (3, 20))	('increased', 'PosReg', (83, 92))	('ectopic', 'Var', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('RIP', 'Gene', '110628', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mice', 'Species', '10090', (64, 68))	('metastases', 'Disease', (119, 129))	('tenascin C', 'Gene', (30, 40))	('tumor', 'Disease', (169, 174))	('tenascin C', 'cellular_component', 'GO:0090733', ('30', '40'))	('tenascin C', 'cellular_component', 'GO:0090733', ('141', '151'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('RIP', 'Gene', (55, 58))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
58018	26539408	Extravasated MDA-MB-231 cells with a knockdown of prolyl-4-hydroxylases, an enzyme essential for correct collagen biosynthesis, were able to survive but formed smaller lung metastases than their wild-type counterparts.	('smaller lung', 'Phenotype', 'HP:0002089', (160, 172))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (13, 23))	('knockdown', 'Var', (37, 46))	('collagen', 'molecular_function', 'GO:0005202', ('105', '113'))	('prolyl-4-hydroxylases', 'Gene', (50, 71))	('lung metastases', 'Disease', 'MESH:D009362', (168, 183))	('smaller', 'NegReg', (160, 167))	('collagen biosynthesis', 'biological_process', 'GO:0032964', ('105', '126'))	('lung metastases', 'Disease', (168, 183))
58021	26539408	LOX-mediated cross-linking of collagen IV recruits CD11b+ BMDC to the metastatic niche in the lungs, and these CD11b+ cells further remodel the ECM into a favorable home for extravasating cancer cells, e.g., by laying down the proteoglycan versican (Figure 5).	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('CD11b+', 'Var', (111, 117))	('proteoglycan', 'molecular_function', 'GO:0005203', ('227', '239'))	('collagen', 'molecular_function', 'GO:0005202', ('30', '38'))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('remodel', 'Reg', (132, 139))
58022	26539408	Inhibiting versican production by CD11b+ BDMCs radically decreased the burden of lung metastases in a mouse model of spontaneous breast cancer, specifically preventing the progression from micrometastases to macrometastases.	('breast cancer', 'Disease', (129, 142))	('metastases', 'Disease', (86, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('metastases', 'Disease', (194, 204))	('metastases', 'Disease', 'MESH:D009362', (86, 96))	('Inhibiting', 'NegReg', (0, 10))	('mouse', 'Species', '10090', (102, 107))	('lung metastases', 'Disease', (81, 96))	('CD11b+ BDMCs', 'Var', (34, 46))	('lung metastases', 'Disease', 'MESH:D009362', (81, 96))	('metastases', 'Disease', 'MESH:D009362', (194, 204))	('metastases', 'Disease', (213, 223))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('preventing', 'NegReg', (157, 167))	('decreased', 'NegReg', (57, 66))	('metastases', 'Disease', 'MESH:D009362', (213, 223))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
58033	26539408	revealed an inverse time course of the role of tumor-endogenous and stromal tenascin C. While an induced knockdown of the protein diminished metastatic engraftment in the beginning, tumor cells induced myofibroblasts to produce tenascin C when the tumors reached a certain size, compensating the loss of the matricellular protein.	('diminished', 'NegReg', (130, 140))	('tenascin C', 'cellular_component', 'GO:0090733', ('228', '238'))	('tumors', 'Disease', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tenascin C', 'cellular_component', 'GO:0090733', ('76', '86'))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('tumor', 'Disease', (248, 253))	('metastatic engraftment', 'CPA', (141, 163))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('knockdown', 'Var', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', (182, 187))	('protein', 'cellular_component', 'GO:0003675', ('322', '329'))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
58036	26539408	Although having its main function in creating a metastatic niche and inducing WNT and NOTCH signaling pathways, tenascin C depletion did not correlate with a reduction of stem cell characteristics of the breast cancer cells in this study.	('inducing', 'Reg', (69, 77))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('tenascin C', 'cellular_component', 'GO:0090733', ('112', '122'))	('depletion', 'Var', (123, 132))	('reduction', 'NegReg', (158, 167))	('breast cancer', 'Disease', 'MESH:D001943', (204, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('breast cancer', 'Disease', (204, 217))	('stem cell characteristics of', 'CPA', (171, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (204, 217))
58050	26539408	Although hyaluronidase treatment of cancers produces LMW-HA fragments, which can increase angiogenesis and disrupt vessel integrity, PEGPH20 treatment of experimental pancreatic cancer in combination with chemotherapy increased overall survival and decreased the metastatic incidence.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('PEG', 'Gene', (133, 136))	('increase', 'PosReg', (81, 89))	('angiogenesis', 'CPA', (90, 102))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (167, 184))	('increased', 'PosReg', (218, 227))	('overall survival', 'CPA', (228, 244))	('disrupt', 'NegReg', (107, 114))	('LMW-HA', 'Var', (53, 59))	('metastatic incidence', 'CPA', (263, 283))	('vessel integrity', 'MPA', (115, 131))	('HA', 'Chemical', 'MESH:D006820', (57, 59))	('PEG', 'Gene', '5047', (133, 136))	('pancreatic cancer', 'Disease', 'MESH:D010190', (167, 184))	('angiogenesis', 'biological_process', 'GO:0001525', ('90', '102'))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('decreased', 'NegReg', (249, 258))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('pancreatic cancer', 'Disease', (167, 184))
58051	26539408	It is conceivable that by stripping cancer cells of their pericellular matrix, the hyaluronidase treatment is sensitizing any extravasating cancer cells to immune cell lysis, in this way counteracting the effect of restoring tumor vessel function.	('extravasating', 'MPA', (126, 139))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('cancer', 'Disease', (36, 42))	('stripping', 'Var', (26, 35))	('cancer', 'Disease', (140, 146))	('tumor', 'Disease', (225, 230))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('lysis', 'biological_process', 'GO:0019835', ('168', '173'))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
58058	26539408	Several in vivo studies have reported promising inhibition of tumor growth and metastasis formation upon treatment with 4-MU [reviewed in Ref.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('4-MU', 'Chemical', 'MESH:D006923', (120, 124))	('tumor', 'Disease', (62, 67))	('formation', 'biological_process', 'GO:0009058', ('90', '99'))	('4-MU [', 'Var', (120, 126))	('inhibition', 'NegReg', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
58070	26539408	However, sHA fragments of a similar size correlate to increased lymphatic invasion and development of lymph node metastasis in colorectal cancer patients, suggesting that small sHA may promote tumor progression.	('patients', 'Species', '9606', (145, 153))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('increased', 'PosReg', (54, 63))	('colorectal cancer', 'Disease', (127, 144))	('sHA', 'Chemical', '-', (177, 180))	('sHA', 'Chemical', '-', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('promote', 'PosReg', (185, 192))	('development of lymph node metastasis', 'CPA', (87, 123))	('lymphatic invasion', 'CPA', (64, 82))	('small', 'Var', (171, 176))
58100	26539408	CP4H catalyzes the conversion of proline to hydroxyproline, facilitating the assembly of three procollagen proteins into a procollagen triple helix.	('assembly', 'MPA', (77, 85))	('hydroxyproline', 'Chemical', 'MESH:D006909', (44, 58))	('CP4H', 'Chemical', '-', (0, 4))	('proline', 'Chemical', 'MESH:D011392', (51, 58))	('CP4H', 'Var', (0, 4))	('proline', 'Chemical', 'MESH:D011392', (33, 40))
58101	26539408	Recent studies in preclinical breast cancer models have shown that inhibition of CP4H either completely prevents or dramatically decreases spontaneous metastasis to the lungs.	('inhibition', 'Var', (67, 77))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('breast cancer', 'Disease', (30, 43))	('spontaneous metastasis to the lungs', 'CPA', (139, 174))	('CP4H', 'Protein', (81, 85))	('CP4H', 'Chemical', '-', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('decreases', 'NegReg', (129, 138))
58107	26539408	In particular, combination treatment with gold-standard therapeutics seems to be a promising strategy, as targeting the macromolecules facilitates the delivery and efficacy of the standard treatment and inhibits protumorigenic signaling of the ECM itself.	('inhibits', 'NegReg', (203, 211))	('targeting', 'Var', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('signaling', 'biological_process', 'GO:0023052', ('227', '236'))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('delivery', 'MPA', (151, 159))	('tumor', 'Disease', (215, 220))	('efficacy', 'MPA', (164, 172))	('facilitates', 'PosReg', (135, 146))	('mole', 'Phenotype', 'HP:0003764', (125, 129))
58120	25137017	Functionally, cell proliferation was significantly attenuated following TTK knockdown, whereas apoptosis and necrosis rates were significantly increased.	('increased', 'PosReg', (143, 152))	('TTK', 'molecular_function', 'GO:0050321', ('72', '75'))	('knockdown', 'Var', (76, 85))	('TTK', 'Gene', (72, 75))	('apoptosis', 'CPA', (95, 104))	('cell proliferation', 'CPA', (14, 32))	('attenuated', 'NegReg', (51, 61))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('cell proliferation', 'biological_process', 'GO:0008283', ('14', '32'))	('necrosis', 'biological_process', 'GO:0070265', ('109', '117'))	('necrosis', 'Disease', (109, 117))	('TTK', 'Gene', '7272', (72, 75))	('necrosis', 'biological_process', 'GO:0008219', ('109', '117'))	('necrosis', 'biological_process', 'GO:0019835', ('109', '117'))	('necrosis', 'biological_process', 'GO:0008220', ('109', '117'))	('necrosis', 'Disease', 'MESH:D009336', (109, 117))	('necrosis', 'biological_process', 'GO:0001906', ('109', '117'))
58122	25137017	Interestingly, immortalised normal pancreatic hTERT-HPNE cells were not affected by loss of TTK function.	('pancreatic', 'Disease', (35, 45))	('hTERT-HPNE', 'CellLine', 'CVCL:C466', (46, 56))	('TTK', 'molecular_function', 'GO:0050321', ('92', '95'))	('TTK', 'Gene', (92, 95))	('loss', 'Var', (84, 88))	('TTK', 'Gene', '7272', (92, 95))	('pancreatic', 'Disease', 'MESH:D010195', (35, 45))
58123	25137017	Mechanistically, these effects in cancer cells were associated with increased formation of micronuclei, suggesting that loss of TTK function in pancreatic cancer cells results in chromosomal instability and mitotic catastrophe.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mitotic catastrophe', 'CPA', (207, 226))	('pancreatic cancer', 'Disease', (144, 161))	('TTK', 'molecular_function', 'GO:0050321', ('128', '131'))	('TTK', 'Gene', '7272', (128, 131))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (144, 161))	('increased formation of micronuclei', 'Phenotype', 'HP:0040012', (68, 102))	('results in', 'Reg', (168, 178))	('TTK', 'Gene', (128, 131))	('cancer', 'Disease', (155, 161))	('formation', 'biological_process', 'GO:0009058', ('78', '87'))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('207', '226'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (144, 161))	('chromosomal instability', 'Phenotype', 'HP:0040012', (179, 202))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('chromosomal instability', 'CPA', (179, 202))	('cancer', 'Disease', (34, 40))	('loss', 'Var', (120, 124))
58158	25137017	Membranes were blocked in 5% non fat dry milk in TBST (10 mM Tris-HCl, pH 7.6, 100 mM NaCl, 0.1% Tween 20) for 2-4 h at room temperature and then probed with appropriate primary and secondary antibodies (anti-Phospho-Chk1 (Ser345): Cell Signaling, Boston, MA, USA; cat# 2341; anti-Phospho-Histone H2A.x (Ser139): Cell Signaling, cat# 9718; anti-Cyclin B1: Cell Signaling, cat# 4135; anti-Mps1 (TTK): Millipore; cat# 05-682; anti-PARP: Cell Signaling, cat# 9532 and; anti-Caspase-3: Cell Signaling, cat# 9664 and 9665).	('Cyclin B1', 'Gene', '891', (345, 354))	('Caspase-3', 'Gene', (471, 480))	('Signaling', 'biological_process', 'GO:0023052', ('361', '370'))	('TTK', 'molecular_function', 'GO:0050321', ('394', '397'))	('Ser', 'cellular_component', 'GO:0005790', ('304', '307'))	('cat#', 'Var', (329, 333))	('cat', 'molecular_function', 'GO:0004096', ('329', '332'))	('Cyclin', 'molecular_function', 'GO:0016538', ('345', '351'))	('cat', 'molecular_function', 'GO:0004096', ('498', '501'))	('Signaling', 'biological_process', 'GO:0023052', ('318', '327'))	('cat# 4135', 'Var', (372, 381))	('cat# 9664', 'Var', (498, 507))	('cat', 'molecular_function', 'GO:0004096', ('265', '268'))	('cat', 'molecular_function', 'GO:0004096', ('411', '414'))	('PARP', 'Gene', '1302', (429, 433))	('TTK', 'Gene', '7272', (394, 397))	('Signaling', 'biological_process', 'GO:0023052', ('440', '449'))	('Chk1', 'Gene', (217, 221))	('Caspase-3', 'Gene', '836', (471, 480))	('cat# 9532', 'Var', (451, 460))	('Chk1', 'Gene', '1111', (217, 221))	('Ser', 'cellular_component', 'GO:0005790', ('223', '226'))	('TTK', 'Gene', (394, 397))	('PARP', 'Gene', (429, 433))	('Mps1', 'Gene', '7272', (388, 392))	('Signaling', 'biological_process', 'GO:0023052', ('237', '246'))	('Mps1', 'Gene', (388, 392))	('Cyclin B1', 'Gene', (345, 354))	('cat', 'molecular_function', 'GO:0004096', ('372', '375'))	('HCl', 'Chemical', '-', (66, 69))	('NaCl', 'Chemical', 'MESH:D012965', (86, 90))	('cat', 'molecular_function', 'GO:0004096', ('451', '454'))	('Signaling', 'biological_process', 'GO:0023052', ('487', '496'))
58196	25137017	In all three cell lines tested, TTK knockdown by the three independent siRNAs led to a significant reduction in proliferation rates compared with cells treated with non-silencing control siRNA (Figure 2B), with the exception of si3 in Panc1 cells, where the proliferation was also lower but did not reach statistical significance.	('TTK', 'molecular_function', 'GO:0050321', ('32', '35'))	('Panc1', 'CellLine', 'CVCL:0480', (235, 240))	('TTK', 'Gene', (32, 35))	('knockdown', 'Var', (36, 45))	('reduction', 'NegReg', (99, 108))	('proliferation rates', 'CPA', (112, 131))	('TTK', 'Gene', '7272', (32, 35))
58197	25137017	These results were confirmed in MTT assays, where knockdown of TTK expression with any of the three independent siRNAs in any of the three pancreatic cancer cell lines led to statistically highly significant decrease in the viability of the cells as compared with controls (Figure 2C).	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('TTK', 'Gene', (63, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (139, 156))	('viability of the cells', 'CPA', (224, 246))	('knockdown', 'Var', (50, 59))	('TTK', 'Gene', '7272', (63, 66))	('pancreatic cancer', 'Disease', (139, 156))	('pancreatic cancer', 'Disease', 'MESH:D010190', (139, 156))	('decrease', 'NegReg', (208, 216))	('MTT', 'Chemical', 'MESH:C070243', (32, 35))
58199	25137017	Long-term survival studied using the PaTu-8988T cell line demonstrated that efficient and sustained growth inhibition persisted over a period of 7 days following TTK knockdown, thus providing no indication of compensatory mechanisms that would allow cells to successfully escape growth inhibition (Figure 2D).	('knockdown', 'Var', (166, 175))	('PaTu-8988T', 'CellLine', 'CVCL:1847', (37, 47))	('TTK', 'Gene', (162, 165))	('TTK', 'Gene', '7272', (162, 165))	('TTK', 'molecular_function', 'GO:0050321', ('162', '165'))	('growth inhibition', 'CPA', (100, 117))
58203	25137017	Flow cytometric cell cycle analyses of PaTu-8988T cells revealed only a modest influence of TTK knockdown on the relative distribution of cells across different phases of the cell cycle, thus producing no indication of induction of a cell cycle arrest following loss of TTK function (Figure 4A).	('knockdown', 'Var', (96, 105))	('cell cycle', 'biological_process', 'GO:0007049', ('16', '26'))	('PaTu-8988T', 'CellLine', 'CVCL:1847', (39, 49))	('TTK', 'Gene', '7272', (270, 273))	('TTK', 'molecular_function', 'GO:0050321', ('92', '95'))	('TTK', 'molecular_function', 'GO:0050321', ('270', '273'))	('TTK', 'Gene', (270, 273))	('arrest', 'Disease', 'MESH:D006323', (245, 251))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('234', '251'))	('cell cycle', 'biological_process', 'GO:0007049', ('175', '185'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (234, 251))	('TTK', 'Gene', (92, 95))	('arrest', 'Disease', (245, 251))	('TTK', 'Gene', '7272', (92, 95))
58205	25137017	Phosphorylation of the ATR/p53 targets H2AX and Chk1 was not changed, and Cyclin B1 levels were not systematically altered in TTK knockdown cells (Figure 4B), indicating that mitotic exit and cell cycle progression were not attenuated following TTK knockdown.	('mitotic exit', 'biological_process', 'GO:0010458', ('175', '187'))	('Cyclin B1', 'Gene', '891', (74, 83))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('cell cycle', 'biological_process', 'GO:0007049', ('192', '202'))	('ATR', 'Gene', (23, 26))	('mitotic exit', 'CPA', (175, 187))	('TTK', 'molecular_function', 'GO:0050321', ('126', '129'))	('knockdown', 'Var', (130, 139))	('TTK', 'Gene', '7272', (245, 248))	('Cyclin', 'molecular_function', 'GO:0016538', ('74', '80'))	('TTK', 'Gene', '7272', (126, 129))	('TTK', 'molecular_function', 'GO:0050321', ('245', '248'))	('H2AX', 'Gene', (39, 43))	('p53', 'Gene', '7157', (27, 30))	('cell cycle progression', 'CPA', (192, 214))	('ATR', 'Gene', '545', (23, 26))	('H2AX', 'Gene', '3014', (39, 43))	('TTK', 'Gene', (245, 248))	('Phosphorylation', 'MPA', (0, 15))	('Chk1', 'Gene', (48, 52))	('Cyclin B1', 'Gene', (74, 83))	('Chk1', 'Gene', '1111', (48, 52))	('p53', 'Gene', (27, 30))	('TTK', 'Gene', (126, 129))
58217	25137017	The SAC thus serves as a safeguard against chromosome missegregation and subsequent aneuploidy.	('chromosome missegregation', 'Var', (43, 68))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('aneuploidy', 'Disease', (84, 94))	('SAC', 'biological_process', 'GO:0071173', ('4', '7'))	('aneuploidy', 'Disease', 'MESH:D000782', (84, 94))	('SAC', 'cellular_component', 'GO:0035003', ('4', '7'))
58218	25137017	In an apparent contradiction to its role as a checkpoint protein, TTK has been shown to be overexpressed in breast cancer and other solid cancers, and RNAi-mediated or pharmacological inhibition of TTK function efficiently attenuated growth of a variety of cancer cell lines.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('inhibition', 'Var', (184, 194))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('overexpressed', 'PosReg', (91, 104))	('TTK', 'Gene', (66, 69))	('attenuated', 'NegReg', (223, 233))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('TTK', 'Gene', '7272', (198, 201))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('RNAi', 'biological_process', 'GO:0016246', ('151', '155'))	('solid cancers', 'Disease', 'MESH:D009369', (132, 145))	('inhibition of TTK', 'biological_process', 'GO:1902948', ('184', '201'))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Disease', (108, 121))	('solid cancers', 'Disease', (132, 145))	('cancer', 'Disease', (115, 121))	('TTK', 'Gene', '7272', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('TTK', 'molecular_function', 'GO:0050321', ('198', '201'))	('TTK', 'molecular_function', 'GO:0050321', ('66', '69'))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('TTK', 'Gene', (198, 201))	('cancer', 'Disease', (257, 263))
58220	25137017	RNAi-mediated silencing of TTK gene expression significantly inhibited proliferation and viability of three different pancreatic cancer cell lines as measured by BrdU and MTT assays, strongly induced cell death by both, apoptotic as well as necrotic pathways, and significantly attenuated anchorage-independent growth, a hallmark feature of malignantly transformed epithelial cells.	('viability', 'CPA', (89, 98))	('inhibited', 'NegReg', (61, 70))	('apoptotic', 'CPA', (220, 229))	('induced', 'Reg', (192, 199))	('BrdU', 'Chemical', 'MESH:D001973', (162, 166))	('proliferation', 'CPA', (71, 84))	('cell death', 'CPA', (200, 210))	('pancreatic cancer', 'Disease', 'MESH:D010190', (118, 135))	('TTK', 'Gene', (27, 30))	('silencing', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('necrotic', 'Disease', (241, 249))	('attenuated', 'NegReg', (278, 288))	('pancreatic cancer', 'Disease', (118, 135))	('necrotic', 'Disease', 'MESH:D009336', (241, 249))	('anchorage-independent growth', 'CPA', (289, 317))	('gene expression', 'biological_process', 'GO:0010467', ('31', '46'))	('TTK', 'molecular_function', 'GO:0050321', ('27', '30'))	('TTK', 'Gene', '7272', (27, 30))	('MTT', 'Chemical', 'MESH:C070243', (171, 174))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (118, 135))	('cell death', 'biological_process', 'GO:0008219', ('200', '210'))	('RNAi', 'biological_process', 'GO:0016246', ('0', '4'))
58222	25137017	In a report by, transient silencing of TTK decreased viability of the breast cancer cells, but did not inhibit growth of the non-malignant MCF10A cell line.	('TTK', 'molecular_function', 'GO:0050321', ('39', '42'))	('MCF10A', 'CellLine', 'CVCL:0598', (139, 145))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('silencing', 'Var', (26, 35))	('TTK', 'Gene', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('TTK', 'Gene', '7272', (39, 42))	('decreased', 'NegReg', (43, 52))	('inhibit', 'NegReg', (103, 110))	('viability', 'CPA', (53, 62))
58228	25137017	However, the p53 tumour suppressor is mutationally inactivated or deleted in many human cancers, including 50-75% of pancreatic tumours.	('tumour', 'Disease', (128, 134))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('deleted', 'Var', (66, 73))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('pancreatic tumours', 'Disease', (117, 135))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('pancreatic tumours', 'Disease', 'MESH:D010190', (117, 135))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Disease', (17, 23))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('p53', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('p53', 'Gene', '7157', (13, 16))	('human', 'Species', '9606', (82, 87))
58233	25137017	This is in agreement with observations in A2780 ovarian cancer and HCT colon cancer cells, where TTK inhibition caused an overall increase in cellular gammaH2AX levels, but did not result in DNA damage and formation of gammaH2AX foci.	('inhibition', 'Var', (101, 111))	('TTK', 'Gene', '7272', (97, 100))	('A2780 ovarian cancer', 'Disease', 'MESH:D010051', (42, 62))	('colon cancer', 'Disease', (71, 83))	('DNA', 'cellular_component', 'GO:0005574', ('191', '194'))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('men', 'Species', '9606', (16, 19))	('gammaH2AX', 'Chemical', '-', (151, 160))	('TTK', 'molecular_function', 'GO:0050321', ('97', '100'))	('TTK', 'Gene', (97, 100))	('colon cancer', 'Phenotype', 'HP:0003003', (71, 83))	('gammaH2AX levels', 'MPA', (151, 167))	('increase', 'PosReg', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('gammaH2AX', 'Chemical', '-', (219, 228))	('A2780 ovarian cancer', 'Disease', (42, 62))	('formation', 'biological_process', 'GO:0009058', ('206', '215'))	('colon cancer', 'Disease', 'MESH:D015179', (71, 83))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))
58234	25137017	As a final consequence, chromosomal segregation errors ultimately lead to massive aneuploidy, which is incompatible with cellular survival, inducing cell death by either apoptotic mechanisms or mitotic catastrophe.	('mitotic catastrophe', 'CPA', (194, 213))	('inducing', 'Reg', (140, 148))	('aneuploidy', 'Disease', 'MESH:D000782', (82, 92))	('chromosomal segregation errors', 'Var', (24, 54))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('194', '213'))	('cell death', 'biological_process', 'GO:0008219', ('149', '159'))	('cell death', 'CPA', (149, 159))	('lead to', 'Reg', (66, 73))	('aneuploidy', 'Disease', (82, 92))
58281	33680945	In that way, NK cells are well known key regulators of carcinogenesis and the inhibition of their function is detrimental for tumor suppression.	('inhibition', 'Var', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('carcinogenesis', 'Disease', (55, 69))	('tumor', 'Disease', (126, 131))
58300	33680945	The CD56dimCD16bright NK cells subset is highly cytotoxic and expresses high levels of perforin and granzyme B.	('CD56dimCD16bright', 'Var', (4, 21))	('granzyme B', 'Gene', '3002', (100, 110))	('granzyme B', 'Gene', (100, 110))
58304	33680945	Furthermore, previous exposure to haptens, viral infection (HCMV) or cytokines (IL12, IL15, and IL18) generates adaptive NK cells with immunological memory.Nevertheless, the potent immunosuppressive TME in PDAC impairs NK function and cytotoxicity by different ways such as downregulation of effector molecules and activation receptor.	('IL15', 'Gene', '3600', (86, 90))	('IL18', 'molecular_function', 'GO:0045515', ('96', '100'))	('impairs', 'NegReg', (211, 218))	('TME', 'Var', (199, 202))	('effector molecules', 'CPA', (292, 310))	('IL12', 'molecular_function', 'GO:0005143', ('80', '84'))	('memory', 'biological_process', 'GO:0007613', ('149', '155'))	('downregulation', 'NegReg', (274, 288))	('NK function', 'CPA', (219, 230))	('PDAC', 'Gene', (206, 210))	('IL15', 'Gene', (86, 90))	('viral infection', 'biological_process', 'GO:0016032', ('43', '58'))	('IL15', 'molecular_function', 'GO:0016170', ('86', '90'))	('IL18', 'Gene', (96, 100))	('IL18', 'Gene', '3606', (96, 100))	('cytotoxicity', 'Disease', (235, 247))	('PDAC', 'Chemical', '-', (206, 210))	('viral infection', 'Disease', (43, 58))	('cytotoxicity', 'Disease', 'MESH:D064420', (235, 247))	('activation', 'CPA', (315, 325))	('PDAC', 'Phenotype', 'HP:0006725', (206, 210))	('viral infection', 'Disease', 'MESH:D001102', (43, 58))
58313	33680945	In contrast, inhibition of IL-1 expression in tumor cells induces overexpression of p21 and p53, leading to tumor suppression.	('IL-1', 'Gene', '3552', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('IL-1', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('inhibition', 'Var', (13, 23))	('tumor', 'Disease', (46, 51))	('IL-1', 'molecular_function', 'GO:0005149', ('27', '31'))	('tumor', 'Disease', (108, 113))	('p53', 'Gene', (92, 95))	('p21', 'Gene', (84, 87))	('p53', 'Gene', '7157', (92, 95))	('p21', 'Gene', '644914', (84, 87))	('overexpression', 'MPA', (66, 80))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
58333	33680945	Similarly, inhibition of PIKfyve kinase, essential for endolysosomal vesicular trafficking, increases exosome release and reduces the degradative process via autophagy, probably due to reduced fusion of lysosomes with MVBs and autophagosomes.	('MVBs', 'Chemical', '-', (218, 222))	('reduces', 'NegReg', (122, 129))	('autophagy', 'biological_process', 'GO:0016236', ('158', '167'))	('fusion', 'Interaction', (193, 199))	('exosome release', 'MPA', (102, 117))	('degradative process via autophagy', 'CPA', (134, 167))	('PIKfyve', 'Gene', (25, 32))	('autophagy', 'biological_process', 'GO:0006914', ('158', '167'))	('exosome', 'cellular_component', 'GO:0070062', ('102', '109'))	('inhibition', 'Var', (11, 21))	('increases', 'PosReg', (92, 101))	('reduced', 'NegReg', (185, 192))
58337	33680945	Accordingly, depletion of ATG5 or ATG16L1 significantly reduces exosome release and attenuates exosomal enrichment in LC3B-II.	('exosome release', 'MPA', (64, 79))	('ATG16L1', 'Gene', (34, 41))	('LC3B', 'Gene', '81631', (118, 122))	('depletion', 'Var', (13, 22))	('reduces', 'NegReg', (56, 63))	('exosomal enrichment', 'MPA', (95, 114))	('attenuates', 'NegReg', (84, 94))	('exosome', 'cellular_component', 'GO:0070062', ('64', '71'))	('LC3B', 'Gene', (118, 122))	('ATG5', 'Gene', '9474', (26, 30))	('ATG16L1', 'Gene', '55054', (34, 41))	('ATG5', 'Gene', (26, 30))
58342	33680945	Hence, loss of ATG12-ATG3 alters the morphology of MVBs, impedes late endosome trafficking, and reduces exosome biogenesis.	('ATG12', 'Gene', (15, 20))	('exosome', 'cellular_component', 'GO:0070062', ('104', '111'))	('ATG3', 'Gene', (21, 25))	('alters', 'Reg', (26, 32))	('impedes', 'NegReg', (57, 64))	('reduces', 'NegReg', (96, 103))	('loss', 'Var', (7, 11))	('exosome biogenesis', 'MPA', (104, 122))	('morphology', 'MPA', (37, 47))	('late endosome trafficking', 'MPA', (65, 90))	('late endosome', 'cellular_component', 'GO:0005770', ('65', '78'))	('MVBs', 'Chemical', '-', (51, 55))	('ATG3', 'Gene', '64422', (21, 25))	('ATG12', 'Gene', '9140', (15, 20))	('exosome biogenesis', 'biological_process', 'GO:0097734', ('104', '122'))
58344	33680945	Interestingly, the lack of ALIX or the ATG12-ATG3 complex impairment do not affect starvation-induced autophagy, suggesting different regulatory machinery for basal and stress-induced autophagy, as well as the interaction of these pathways with endocytic compartments.	('lack', 'Var', (19, 23))	('ATG12', 'Gene', (39, 44))	('autophagy', 'biological_process', 'GO:0006914', ('184', '193'))	('ATG3', 'Gene', (45, 49))	('ALIX', 'Gene', '10015', (27, 31))	('interaction', 'Interaction', (210, 221))	('autophagy', 'biological_process', 'GO:0016236', ('102', '111'))	('ALIX', 'Gene', (27, 31))	('ATG3', 'Gene', '64422', (45, 49))	('ATG12', 'Gene', '9140', (39, 44))	('autophagy', 'biological_process', 'GO:0006914', ('102', '111'))	('autophagy', 'biological_process', 'GO:0016236', ('184', '193'))
58352	33680945	GIPC depletion in these cell lines generates metabolic stress with autophagy induction and increased exosome release.	('exosome release', 'MPA', (101, 116))	('depletion', 'Var', (5, 14))	('metabolic stress', 'CPA', (45, 61))	('exosome', 'cellular_component', 'GO:0070062', ('101', '108'))	('GIPC', 'Gene', (0, 4))	('autophagy', 'biological_process', 'GO:0006914', ('67', '76'))	('autophagy induction', 'CPA', (67, 86))	('GIPC', 'Gene', '10755', (0, 4))	('increased', 'PosReg', (91, 100))	('autophagy', 'biological_process', 'GO:0016236', ('67', '76'))
58353	33680945	Lack of GIPC increases LC3-II expression and biogenesis of autophagosomes and at the same time leads to increased secretion of exosomes by the PDAC cells.	('increases', 'PosReg', (13, 22))	('expression', 'MPA', (30, 40))	('GIPC', 'Gene', '10755', (8, 12))	('increased', 'PosReg', (104, 113))	('PDAC', 'Chemical', '-', (143, 147))	('Lack', 'Var', (0, 4))	('PDAC', 'Phenotype', 'HP:0006725', (143, 147))	('biogenesis of autophagosomes', 'CPA', (45, 73))	('LC3', 'Gene', '84557', (23, 26))	('GIPC', 'Gene', (8, 12))	('secretion of exosomes', 'MPA', (114, 135))	('secretion', 'biological_process', 'GO:0046903', ('114', '123'))	('LC3', 'Gene', (23, 26))
58354	33680945	Mechanistically, the absence of GIPC increases exosomes released by higher expression levels of ALIX, TSG101 and CHMP4B.	('TSG101', 'Gene', '7251', (102, 108))	('GIPC', 'Gene', '10755', (32, 36))	('higher', 'PosReg', (68, 74))	('ALIX', 'Gene', '10015', (96, 100))	('absence', 'Var', (21, 28))	('increases', 'PosReg', (37, 46))	('ALIX', 'Gene', (96, 100))	('CHMP4B', 'Gene', (113, 119))	('CHMP4B', 'Gene', '128866', (113, 119))	('GIPC', 'Gene', (32, 36))	('exosomes released', 'MPA', (47, 64))	('TSG101', 'Gene', (102, 108))	('expression levels', 'MPA', (75, 92))
58359	33680945	Moreover, exosomes derived from highly invasive cells are rich in miR-125b-5p which promotes migration and invasion and is associated with metastasis in PDAC through MEK2/ERK2 signaling.	('associated with', 'Reg', (123, 138))	('PDAC', 'Disease', (153, 157))	('PDAC', 'Phenotype', 'HP:0006725', (153, 157))	('miR-125b-5p', 'Var', (66, 77))	('MEK2', 'Gene', '5605', (166, 170))	('migration', 'CPA', (93, 102))	('ERK2', 'Gene', (171, 175))	('metastasis', 'CPA', (139, 149))	('ERK2', 'molecular_function', 'GO:0004707', ('171', '175'))	('MEK2', 'molecular_function', 'GO:0004708', ('166', '170'))	('signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('PDAC', 'Chemical', '-', (153, 157))	('ERK2', 'Gene', '5594', (171, 175))	('invasion', 'CPA', (107, 115))	('MEK2', 'Gene', (166, 170))	('promotes', 'PosReg', (84, 92))
58401	33680945	Recently, the presence of miR-3607-3p in EVs was associated with suppression of pancreatic cancer.	('suppression of pancreatic cancer', 'Disease', (65, 97))	('suppression of pancreatic cancer', 'Disease', 'MESH:D010190', (65, 97))	('miR-3607-3p', 'Chemical', '-', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('miR-3607-3p', 'Var', (26, 37))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))
58402	33680945	EVs derived from NK cells, enriched in miR-3607-3p, could suppress PDAC development and malignant transformation.	('PDAC', 'Phenotype', 'HP:0006725', (67, 71))	('miR-3607-3p', 'Chemical', '-', (39, 50))	('PDAC development', 'CPA', (67, 83))	('PDAC', 'Chemical', '-', (67, 71))	('malignant transformation', 'CPA', (88, 112))	('miR-3607-3p', 'Var', (39, 50))	('suppress', 'NegReg', (58, 66))
58405	33680945	Compared to healthy tissue IL-26 in highly expressed PDAC, miR-3607-3p directly suppresses its expression in these tumoral cells.	('miR-3607-3p', 'Var', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('PDAC', 'Phenotype', 'HP:0006725', (53, 57))	('IL-26', 'Gene', (27, 32))	('IL-26', 'Gene', '55801', (27, 32))	('miR-3607-3p', 'Chemical', '-', (59, 70))	('IL-26', 'molecular_function', 'GO:0045522', ('27', '32'))	('tumoral', 'Disease', (115, 122))	('suppresses', 'NegReg', (80, 90))	('PDAC', 'Chemical', '-', (53, 57))	('expression', 'MPA', (95, 105))	('tumoral', 'Disease', 'MESH:D009369', (115, 122))
58406	33680945	In sum, there is a significant negative correlation between the expression levels of miR-3607-3p and IL-26 in pancreatic cancer tissues.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (110, 127))	('IL-26', 'Gene', '55801', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('negative', 'NegReg', (31, 39))	('pancreatic cancer', 'Disease', (110, 127))	('miR-3607-3p', 'Chemical', '-', (85, 96))	('IL-26', 'Gene', (101, 106))	('pancreatic cancer', 'Disease', 'MESH:D010190', (110, 127))	('IL-26', 'molecular_function', 'GO:0045522', ('101', '106'))	('expression levels', 'MPA', (64, 81))	('miR-3607-3p', 'Var', (85, 96))
58509	33681467	We detected the main perfusion parameters BF and BV as the most reliable for adenocarcinoma, with cutoff values of <98.443 min-1 100 g-1 and 14.319 mL 100 g-1, respectively (using the deconvolution model).	('adenocarcinoma', 'Disease', 'MESH:D000230', (77, 91))	('adenocarcinoma', 'Disease', (77, 91))	('<98.443', 'Var', (115, 122))
58518	33404013	The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma Pancreatic adenosquamous carcinoma (PASC) is an aggressive cancer whose mutational origins are poorly understood.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('UPF1', 'Gene', '5976', (32, 36))	('pancreatic adenosquamous carcinoma', 'Disease', 'MESH:D010190', (49, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('UPF1', 'Gene', (32, 36))	('Pancreatic adenosquamous carcinoma', 'Disease', (84, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('carcinoma Pancreatic adenosquamous carcinoma', 'Phenotype', 'HP:0006725', (74, 118))	('variants', 'Var', (37, 45))	('Pancreatic adenosquamous carcinoma', 'Disease', 'MESH:D010190', (84, 118))	('pancreatic adenosquamous carcinoma', 'Disease', (49, 83))
58519	33404013	Here, we modeled two UPF1 mutations in human and mouse cells to find no significant effects on pancreatic cancer growth, acquisition of adenosquamous features, UPF1 splicing, UPF1 protein, or NMD efficiency.	('splicing', 'biological_process', 'GO:0045292', ('165', '173'))	('human', 'Species', '9606', (39, 44))	('UPF1', 'Gene', (21, 25))	('UPF1', 'PosReg', (175, 179))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (95, 112))	('mouse', 'Species', '10090', (49, 54))	('mutations', 'Var', (26, 35))	('protein', 'Protein', (180, 187))	('pancreatic cancer', 'Disease', (95, 112))	('UPF1', 'Gene', (160, 164))	('pancreatic cancer', 'Disease', 'MESH:D010190', (95, 112))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
58520	33404013	We subsequently discovered that 45% of UPF1 mutations reportedly present in PASCs are identical to standing genetic variants in the human population, suggesting that they may be non-pathogenic inherited variants rather than pathogenic mutations.	('UPF1', 'Gene', (39, 43))	('mutations', 'Var', (44, 53))	('human', 'Species', '9606', (132, 137))
58523	33404013	All types of cancers develop from changes - or mutations - in the genes that affect the pathways involved in controlling the growth of cells.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('develop from', 'Reg', (21, 33))	('mutations -', 'Var', (47, 58))	('cancers', 'Disease', (13, 20))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('genes', 'Gene', (66, 71))	('changes -', 'Var', (34, 43))
58524	33404013	Different cancers possess unique sets of mutations that affect specific genes, and often, it is difficult to determine which of them play the most important role in a particular type of cancer.	('affect', 'Reg', (56, 62))	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('cancers', 'Disease', (10, 17))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('cancer', 'Disease', (10, 16))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
58527	33404013	Using new technologies, some researchers have reported mutations in a 'quality control' gene called 'UPF1', which is responsible for destroying faulty forms of genetic material.	("UPF1'", 'Gene', (101, 106))	("UPF1'", 'Gene', '5976', (101, 106))	('mutations', 'Var', (55, 64))
58529	33404013	used mouse and human cancer cells with UPF1 mutations and monitored their effects on tumour growth and the development of features unique to this disease.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('UPF1', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('mouse', 'Species', '10090', (5, 10))	('tumour', 'Disease', (85, 91))	('mutations', 'Var', (44, 53))	('cancer', 'Disease', (21, 27))	('human', 'Species', '9606', (15, 20))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
58530	33404013	first injected mice with mouse pancreatic cancer cells containing mutations in UPF1 (mutated cells) and cancer cells without.	('mutations', 'Var', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('pancreatic cancer', 'Disease', (31, 48))	('mouse', 'Species', '10090', (25, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (31, 48))	('UPF1', 'Gene', (79, 83))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('mice', 'Species', '10090', (15, 19))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (31, 48))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
58533	33404013	Further analysis showed that the mutations did not stop UPF1 from working, in fact, over 40% of these mutations occurred naturally in humans without causing cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('humans', 'Species', '9606', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('mutations', 'Var', (102, 111))	('cancer', 'Disease', (157, 163))
58539	33404013	reported high-frequency mutations affecting UPF1, which encodes a core component of the nonsense-mediated mRNA decay (NMD) pathway, in 78% (18 of 23) of PASC patients.	('UPF1', 'Gene', (44, 48))	('PASC', 'Disease', (153, 157))	('patients', 'Species', '9606', (158, 166))	('mutations', 'Var', (24, 33))	('nonsense-mediated mRNA decay', 'biological_process', 'GO:0000184', ('88', '116'))	('core', 'cellular_component', 'GO:0019013', ('66', '70'))
58541	33404013	The authors used a combination of molecular and histological assays to find that the UPF1 mutations caused UPF1 mis-splicing, loss of UPF1 protein, and impaired NMD, resulting in stable expression of aberrant mRNAs containing premature termination codons that would normally be degraded by NMD.	('mis-splicing', 'MPA', (112, 124))	('mutations', 'Var', (90, 99))	('UPF1', 'Gene', (85, 89))	('caused', 'Reg', (100, 106))	('mRNAs', 'MPA', (209, 214))	('UPF1', 'Gene', (134, 138))	('impaired NMD', 'Disease', (152, 164))	('impaired NMD', 'Disease', 'MESH:D060825', (152, 164))	('protein', 'Protein', (139, 146))	('splicing', 'biological_process', 'GO:0045292', ('116', '124'))	('expression', 'MPA', (186, 196))	('UPF1', 'Gene', (107, 111))	('loss', 'NegReg', (126, 130))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))
58542	33404013	We first tested the role of the reported UPF1 mutations during tumorigenesis in vivo.	('tumor', 'Disease', (63, 68))	('mutations', 'Var', (46, 55))	('UPF1', 'Gene', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tested', 'Reg', (9, 15))
58543	33404013	reported that the majority of UPF1 mutations caused skipping of UPF1 exons 10 and 11, disrupting UPF1's RNA helicase domain that is essential for its NMD activity.	('UPF1', 'Gene', (64, 68))	('UPF1', 'Gene', (30, 34))	('skipping', 'MPA', (52, 60))	('RNA', 'cellular_component', 'GO:0005562', ('104', '107'))	('disrupting', 'NegReg', (86, 96))	("UPF1'", 'Gene', '5976', (97, 102))	('RNA helicase', 'Protein', (104, 116))	("UPF1'", 'Gene', (97, 102))	('mutations', 'Var', (35, 44))
58545	33404013	KPC cells are defined by mutations affecting KRAS and p53 (encoded by Kras and Trp53 in mouse) that also occur in the vast majority of PASC cases, making them a genetically appropriate system.	('mutations', 'Var', (25, 34))	('Kras', 'Gene', '16653', (70, 74))	('p53', 'Gene', (54, 57))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '22059', (81, 84))	('p53', 'Gene', '22059', (54, 57))	('mouse', 'Species', '10090', (88, 93))	('Kras', 'Gene', (70, 74))	('KRAS', 'Gene', (45, 49))
58555	33404013	measured the effects of each mutation on UPF1 splicing using a minigene assay, in which each mutation was introduced into a plasmid containing a small fragment of the UPF1 gene that was subsequently transfected into 293 T cells.	('UPF1', 'Gene', (167, 171))	('mutation', 'Var', (93, 101))	('introduced', 'Reg', (106, 116))	('293 T', 'CellLine', 'CVCL:0063', (216, 221))
58556	33404013	We modeled UPF1 mutations in 293 T cells in order to mimic Liu et al.	('UPF1', 'Gene', (11, 15))	('293 T', 'CellLine', 'CVCL:0063', (29, 34))	('mutations', 'Var', (16, 25))
58557	33404013	We selected IVS10+31G>A (patient 1; P1) because it was reportedly recurrent across three different patients (making it equally or more common than any other mutation) and induced strong mis-splicing on its own (36% mis-spliced mRNA, versus 0% for wild-type UPF1); we selected IVS10-17G>A (patient 9; P9) because it had one of the strongest effects on splicing (90% mis-spliced mRNA).	('patient', 'Species', '9606', (99, 106))	('splicing', 'biological_process', 'GO:0045292', ('190', '198'))	('IVS10-17G>A', 'Mutation', 'c.IVS10-17G>A', (276, 287))	('IVS10+31G>A', 'Mutation', 'c.IVS10+31G>A', (12, 23))	('mis-splicing', 'MPA', (186, 198))	('IVS10+31G>A', 'Var', (12, 23))	('patient', 'Species', '9606', (25, 32))	('patients', 'Species', '9606', (99, 107))	('splicing', 'biological_process', 'GO:0045292', ('351', '359'))	('patient', 'Species', '9606', (289, 296))	('IVS10-17G>A', 'Var', (276, 287))	('splicing', 'MPA', (351, 359))
58560	33404013	We performed high-coverage RNA-seq on each of the three 293 T cell lines that we engineered to lack or contain defined UPF1 mutations in biological triplicate, quantified transcript expression, and identified differentially expressed transcripts.	('293 T', 'CellLine', 'CVCL:0063', (56, 61))	('RNA', 'cellular_component', 'GO:0005562', ('27', '30'))	('mutations', 'Var', (124, 133))	('UPF1', 'Gene', (119, 123))
58561	33404013	Together, these data confirm that the tested mutations in UPF1 intron 10 do not affect NMD activity (Figure 2B-D and Supplementary file 1b and c).	('B', 'Chemical', 'MESH:D001895', (109, 110))	('NMD', 'CPA', (87, 90))	('mutations', 'Var', (45, 54))	('UPF1', 'Gene', (58, 62))
58563	33404013	We found genetic variants identical to 45% (18 of 40) of the reported UPF1 mutations, one of which is present in the reference human genome.	('human', 'Species', '9606', (127, 132))	('mutations', 'Var', (75, 84))	('UPF1', 'Gene', (70, 74))
58564	33404013	Eighty-nine percent (16 of 18) of UPF1-mutant patients had one or more reported mutations that corresponded to standing genetic variation (Figure 3A-F and Supplementary file 1d).	('patients', 'Species', '9606', (46, 54))	('UPF1-mutant', 'Gene', (34, 45))	('mutations', 'Var', (80, 89))
58565	33404013	First, when strongly cancer-linked mutations occur as germline variants, they frequently manifest as cancer predisposition syndromes.	('manifest', 'Reg', (89, 97))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (101, 107))	('germline variants', 'Var', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('mutations', 'Var', (35, 44))
58567	33404013	Given these discrepancies, we next sought to verify the somatic nature of the UPF1 mutations described in Liu et al., which was reportedly determined by sequencing both tumors and patient-matched controls.	('mutations', 'Var', (83, 92))	('UPF1', 'Gene', (78, 82))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))	('patient', 'Species', '9606', (180, 187))
58569	33404013	corresponded to short nucleotide sequences containing UPF1 mutations, without corresponding data for patient-matched controls.	('patient', 'Species', '9606', (101, 108))	('mutations', 'Var', (59, 68))	('UPF1', 'Gene', (54, 58))
58572	33404013	Using relaxed mutation-calling criteria to maximize sensitivity (details in Materials and methods), we identified somatic UPF1 mutations in samples from 6 of 17 PASC patients.	('PASC', 'Disease', (161, 165))	('mutations', 'Var', (127, 136))	('patients', 'Species', '9606', (166, 174))	('UPF1', 'Gene', (122, 126))
58573	33404013	None of those UPF1 mutations matched the UPF1 mutations reported by Liu et al., and only one was present at an allelic frequency equal to the allelic frequency of mutant KRAS, which is a known driver and which we detected in samples from all PASC patients (median allelic frequencies of 12% versus 34% for UPF1 versus KRAS mutations).	('mutations', 'Var', (46, 55))	('PASC', 'Disease', (242, 246))	('mutations', 'Var', (19, 28))	('UPF1', 'Gene', (14, 18))	('patients', 'Species', '9606', (247, 255))
58574	33404013	Furthermore, we also identified UPF1 mutations in samples from patients with non-adenosquamous tumors (3 of 34 pancreatic ductal adenocarcinomas), whereas Liu et al.	('non-adenosquamous tumors', 'Disease', 'MESH:D018196', (77, 101))	('non-adenosquamous tumors', 'Disease', (77, 101))	('pancreatic ductal adenocarcinomas', 'Disease', (111, 144))	('mutations', 'Var', (37, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('patients', 'Species', '9606', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (111, 144))	('UPF1', 'Gene', (32, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
58575	33404013	reported finding no UPF1 mutations in non-adenosquamous pancreatic cancers (0 of 29).	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('mutations', 'Var', (25, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (56, 73))	('UPF1', 'Gene', (20, 24))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (56, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('pancreatic cancers', 'Disease', 'MESH:D010190', (56, 74))	('pancreatic cancers', 'Disease', (56, 74))
58578	33404013	UPF1's status as an essential gene and our discovery that many reported UPF1 mutations occur as germline genetic variants of no known pathogenicity together suggest that other UPF1 mutations reported by Liu et al.	("UPF1'", 'Gene', (0, 5))	('mutations', 'Var', (77, 86))	('UPF1', 'Gene', (72, 76))	("UPF1'", 'Gene', '5976', (0, 5))
58584	33404013	Genomic DNA was extracted 48 hr post infection to confirm excision of Upf1 exons 10 and 11.	('Upf1', 'Gene', (70, 74))	('excision', 'Var', (58, 66))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('infection', 'Disease', (37, 46))	('infection', 'Disease', 'MESH:D007239', (37, 46))
58616	33404013	Cells were co-transfected 24 hr later with 1 microg of phCMV-MUP plasmid (transfection control) and 1 microg of either pmCMV-Gl-Norm (normal termination codon) or pmCMV-Gl-39Ter (premature termination codon) using Lipofectamine 3000 (Invitrogen) according to the manufacturer's protocol.	('MUP', 'Gene', '100129193', (61, 64))	('MUP', 'Gene', (61, 64))	('Ter', 'cellular_component', 'GO:0097047', ('174', '177'))	('Lipofectamine 3000', 'Chemical', '-', (214, 232))	('pmCMV-Gl-39Ter', 'Var', (163, 177))
58626	33404013	A positive control for the amplification of the truncated UPF1 variant missing exons 10 and 11 was synthesized as a double-stranded DNA gBlock (IDT).	('variant', 'Var', (63, 70))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('UPF1', 'Gene', (58, 62))	('B', 'Chemical', 'MESH:D001895', (137, 138))
58631	33404013	That criteria ensured that our thresholds were appropriate for discovering known cancer driver mutations in all samples.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('mutations', 'Var', (95, 104))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
58632	33404013	A genetic difference from the reference genome was defined as a somatic mutation if it was called in a tumor sample but not in the corresponding patient-matched normal control sample.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('genetic difference', 'Var', (2, 20))	('tumor', 'Disease', (103, 108))	('patient', 'Species', '9606', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
58640	33404013	Acceptance summary: The authors have sought to address what has become a considerably debated topic of whether mutations in Upf1 are tumorigenic in pancreatic adenosquamous carcinoma.	('mutations', 'Var', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('pancreatic adenosquamous carcinoma', 'Disease', 'MESH:D010190', (148, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('pancreatic adenosquamous carcinoma', 'Disease', (148, 182))	('Upf1', 'Gene', (124, 128))
58641	33404013	Specifically, the authors introduced Upf1 mutants found in pancreatic tumors into pancreatic adenosquamous carcinoma cells, and found they did not provide significant advantage for tumor progression.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('mutants', 'Var', (42, 49))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Upf1', 'Gene', (37, 41))	('tumor', 'Disease', (70, 75))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (59, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('pancreatic tumors into pancreatic adenosquamous carcinoma', 'Disease', 'MESH:D010190', (59, 116))
58642	33404013	Moreover, the authors described how a significant percentage of Upf1 mutants observed in pancreatic carcinoma are also present as germline variants in the human population, raising further doubts about their potential role as cancer drivers.	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (89, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('mutants', 'Var', (69, 76))	('human', 'Species', '9606', (155, 160))	('Upf1', 'Gene', (64, 68))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('pancreatic carcinoma', 'Disease', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
58644	33404013	Decision letter after peer review: Thank you for submitting your article "The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma" for consideration by eLife.	('UPF1', 'Gene', (106, 110))	('variants', 'Var', (111, 119))	('pancreatic adenosquamous carcinoma', 'Disease', (123, 157))	('pancreatic adenosquamous carcinoma', 'Disease', 'MESH:D010190', (123, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
58646	33404013	Summary: The authors have sought to address what has become a considerably debated topic of whether mutations in Upf1 are tumorigenic in pancreatic adenosquamous carcinoma.	('mutations', 'Var', (100, 109))	('pancreatic adenosquamous carcinoma', 'Disease', 'MESH:D010190', (137, 171))	('Upf1', 'Gene', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('pancreatic adenosquamous carcinoma', 'Disease', (137, 171))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
58647	33404013	Moreover, the authors described how a significant percentage of Upf1 mutants observed in pancreatic carcinoma are also present as variants in the human population, raising further doubts about their potential role as cancer drivers.	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (89, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('mutants', 'Var', (69, 76))	('Upf1', 'Gene', (64, 68))	('human', 'Species', '9606', (146, 151))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('pancreatic carcinoma', 'Disease', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
58650	33404013	Reviewer #1: This manuscript identifies that the UPF1 variants previously reported as frequent somatic mutations in pancreatic adenosquamous carcinoma are actually germline genetic variants with no clear effects on UPF1 splicing, protein splicing, or nonsense mediated decay.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('splicing', 'biological_process', 'GO:0045292', ('220', '228'))	('nonsense mediated decay', 'MPA', (251, 274))	('pancreatic adenosquamous carcinoma', 'Disease', (116, 150))	('protein splicing', 'biological_process', 'GO:0030908', ('230', '246'))	('UPF1', 'Gene', (49, 53))	('pancreatic adenosquamous carcinoma', 'Disease', 'MESH:D010190', (116, 150))	('variants', 'Var', (54, 62))	('protein splicing', 'MPA', (230, 246))	('protein', 'cellular_component', 'GO:0003675', ('230', '237'))
58651	33404013	At the same time, several points should be clarified to make sure the data are as comprehensive as possible: 1) In the experiments evaluating the effect of skipping exons 10-11 of UPF1, It is surprising that this genetic perturbation in UPF1 is actually tolerated in these cells as UPF1 is an essential gene in most cancer cell lines (this point also has likely motivated this current study).	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('UPF1', 'Gene', (237, 241))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('UPF1', 'Gene', (180, 184))	('cancer', 'Disease', (316, 322))	('skipping exons', 'Var', (156, 170))
58653	33404013	Reviewer #2: This paper aims to resolve the disparity between one report (Liu et al., 2014), which described somatic mutations in pancreatic adenosquamous carcinoma (PASC) that did not typify normal pancreatic tissue of the patients, and other reports (Witkiewicz et al., 2015; Fang et al., 2017; Hayashi et al., 2020), which did not find these mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('mutations', 'Var', (117, 126))	('pancreatic adenosquamous carcinoma', 'Disease', (130, 164))	('patients', 'Species', '9606', (224, 232))	('pancreatic adenosquamous carcinoma', 'Disease', 'MESH:D010190', (130, 164))
58655	33404013	The authors use CRISPR-Cas9 to generate in mouse pancreatic cancer (KPC) cells, which harbor Kras and Tp53 gene mutations (as do PASC patients), a Upf1 gene, and thus its product mRNA, lacking exons 10 and 11.	('pancreatic cancer', 'Disease', (49, 66))	('CRISPR', 'Gene', '70873', (16, 22))	('pancreatic cancer', 'Disease', 'MESH:D010190', (49, 66))	('Tp53', 'Gene', '22059', (102, 106))	('patients', 'Species', '9606', (134, 142))	('mutations', 'Var', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (49, 66))	('CRISPR', 'Gene', (16, 22))	('Cas', 'cellular_component', 'GO:0005650', ('23', '26'))	('Kras', 'Gene', '16653', (93, 97))	('Kras', 'Gene', (93, 97))	('Tp53', 'Gene', (102, 106))	('mouse', 'Species', '10090', (43, 48))
58656	33404013	previously reported this Upf1 variant not only inhibits NMD by disrupting UPF1 helicase activity, but also promotes tumorigenesis.	('NMD', 'CPA', (56, 59))	('helicase activity', 'molecular_function', 'GO:0004386', ('79', '96'))	('helicase', 'Protein', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('variant', 'Var', (30, 37))	('activity', 'MPA', (88, 96))	('UPF1 helicase', 'Protein', (74, 87))	('promotes', 'PosReg', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Upf1', 'Gene', (25, 29))	('disrupting', 'NegReg', (63, 73))	('tumor', 'Disease', (116, 121))	('inhibits', 'NegReg', (47, 55))
58659	33404013	mutations separately into the UPF1 gene of HEK293T cells.	('HEK293T', 'CellLine', 'CVCL:0063', (43, 50))	('mutations', 'Var', (0, 9))	('UPF1', 'Gene', (30, 34))
58661	33404013	This is a very well-written paper describing carefully executed experiments that lead the reader to discount three claims made about UPF1 gene mutations in PANC as described by Liu et al., namely, that these mutations: (i) have a somatic origin, (ii) lead to UPF1 pre-mRNA mis-splicing so as to inhibit NMD, and (iii) promote tumorigenesis.	('UPF1', 'Gene', (133, 137))	('UPF1', 'PosReg', (259, 263))	('NMD', 'MPA', (303, 306))	('promote', 'PosReg', (318, 325))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('pre', 'molecular_function', 'GO:0003904', ('264', '267'))	('mutations', 'Var', (208, 217))	('splicing', 'biological_process', 'GO:0045292', ('277', '285'))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('tumor', 'Disease', (326, 331))	('inhibit', 'NegReg', (295, 302))	('mutations', 'Var', (143, 152))
58664	33404013	[...] Together, these data confirm that the tested mutations in UPF1 intron 10 do not affect NMD activity (Figure 2B-D and Figure 2:source data 1-2)."	('UPF1', 'Gene', (64, 68))	('NMD activity', 'MPA', (93, 105))	('mutations', 'Var', (51, 60))	('B', 'Chemical', 'MESH:D001895', (115, 116))
58665	33404013	Figure 2B illustrates the abundance of NMD substrates arising from differential cassette exon inclusion ("poison exons," which we have previously shown to be sensitive biomarkers of NMD activity; see Feng et al., 2015 and Thomas et al., Nature Genetics, 2020) in wild-type (WT; x axis) and UPF1-mutant (P1; y axis) engineered 293T cells.	('B', 'Chemical', 'MESH:D001895', (8, 9))	('cassette exon', 'Var', (80, 93))	('293T', 'CellLine', 'CVCL:0063', (326, 330))	('UPF1-mutant', 'PosReg', (290, 301))
58666	33404013	Finally, please note that we addressed this reviewer request by studying our UPF1-mutant 293T cells, rather than the KPC system, because our 293T cells contain the exact mutations reported by Liu et al.	('293T', 'CellLine', 'CVCL:0063', (89, 93))	('UPF1-mutant', 'Var', (77, 88))	('mutations', 'Var', (170, 179))	('UPF1-mutant', 'PosReg', (77, 88))	('293T', 'CellLine', 'CVCL:0063', (141, 145))
58668	33404013	We feel that this was a reasonable approach to test the possible role of UPF1 mutations in PASC, but agree that our studies do not test how deletion of UPF1 exons 10 and 11 affects tumor cell growth in vitro.	('tumor', 'Disease', (181, 186))	('cell growth', 'biological_process', 'GO:0016049', ('187', '198'))	('mutations', 'Var', (78, 87))	('PASC', 'Disease', (91, 95))	('deletion', 'Var', (140, 148))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('UPF1', 'Gene', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('affects', 'Reg', (173, 180))
58671	33404013	We introduced the CRISPR/Cas9 construct that deleted exons 10 and 11 of Upf1 in KPC cells via an adenoviral vector, which induced gDNA deletion as desired; however, this deletion was incomplete (as is typical for adenoviral delivery of CRISPR/Cas9 constructs).	('Upf1', 'Gene', (72, 76))	('CRISPR', 'Gene', '70873', (236, 242))	('CRISPR', 'Gene', (18, 24))	('deleted', 'Var', (45, 52))	('Cas', 'cellular_component', 'GO:0005650', ('243', '246'))	('induced', 'Reg', (122, 129))	('Cas', 'cellular_component', 'GO:0005650', ('25', '28'))	('CRISPR', 'Gene', (236, 242))	('CRISPR', 'Gene', '70873', (18, 24))
58672	33404013	This is consistent with prior reports that although deletion of both Upf1 alleles is embryonic lethal in mice, mice that are heterozygous for Upf1 deletion are phenotypically normal (Medghalchi et al., 2001).	('mice', 'Species', '10090', (111, 115))	('deletion', 'Var', (147, 155))	('Upf1', 'Gene', (69, 73))	('Upf1', 'Gene', (142, 146))	('mice', 'Species', '10090', (105, 109))	('deletion', 'Var', (52, 60))
58677	33404013	Yes, we believe that a substantial fraction of the UPF1 variants that were initially reported as somatic mutations by Liu et al.	('variants', 'Var', (56, 64))	('UPF1', 'Gene', (51, 55))	('Y', 'Chemical', 'MESH:D015019', (0, 1))
58685	32865617	PDAC samples from the TCGA database with low and high TRGC2 expression were correlated with the expression of extracellular matrix genes.	('expression', 'MPA', (60, 70))	('PDAC', 'Chemical', '-', (0, 4))	('TRGC2', 'Gene', (54, 59))	('TRGC2', 'Gene', '6967', (54, 59))	('expression', 'MPA', (96, 106))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('high', 'Var', (49, 53))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('110', '130'))
58690	32865617	gammadelta T cells activated PSCs and modulation of this interaction may enhance the efficacy of combinational therapies in human PDAC.	('modulation', 'Var', (38, 48))	('PDAC', 'Phenotype', 'HP:0006725', (130, 134))	('efficacy', 'MPA', (85, 93))	('enhance', 'PosReg', (73, 80))	('human', 'Species', '9606', (124, 129))	('PDAC', 'Chemical', '-', (130, 134))	('PSCs', 'CPA', (29, 33))
58702	32865617	Blockade of PD-L1 in gammadelta T cells enhanced CD4+ and CD8+ T-cell infiltration and induced tumor protection in murine PDAC (Daley et al.).	('PDAC', 'Chemical', '-', (122, 126))	('PD-L1', 'Gene', (12, 17))	('CD8', 'Gene', (58, 61))	('Blockade', 'Var', (0, 8))	('PD-L1', 'Gene', '60533', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('CD8', 'Gene', '925', (58, 61))	('PDAC', 'Phenotype', 'HP:0006725', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('enhanced', 'PosReg', (40, 48))	('murine', 'Species', '10090', (115, 121))	('tumor', 'Disease', (95, 100))
58704	32865617	In contrast, several studies in other tumors, including melanoma, renal cell, and colon cancer, suggest that gammadelta T cells may have antitumoral effects (Gao et al.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('tumors', 'Disease', (38, 44))	('melanoma', 'Disease', (56, 64))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('colon cancer', 'Phenotype', 'HP:0003003', (82, 94))	('colon cancer', 'Disease', 'MESH:D015179', (82, 94))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', (141, 146))	('gammadelta T cells', 'Var', (109, 127))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('renal cell', 'Disease', (66, 76))	('colon cancer', 'Disease', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
58734	32865617	Consistent with this observation, PDAC samples from the TCGA database with high TRGC2 expression also had increased ACTA2 (alphaSMA) expression compared to samples with low TRGC2 expression (Fig.	('TRGC2', 'Gene', (173, 178))	('TRGC2', 'Gene', '6967', (80, 85))	('TRGC2', 'Gene', '6967', (173, 178))	('PDAC', 'Chemical', '-', (34, 38))	('high', 'Var', (75, 79))	('ACTA2', 'Gene', (116, 121))	('PDAC', 'Phenotype', 'HP:0006725', (34, 38))	('expression', 'Var', (86, 96))	('increased', 'PosReg', (106, 115))	('ACTA2', 'Gene', '59', (116, 121))	('TRGC2', 'Gene', (80, 85))
58739	32865617	Further analysis of the TCGA database revealed a significant correlation of IL6 with high TRGC2 expression compared to TRGC2 low PDAC samples (Fig.	('PDAC', 'Phenotype', 'HP:0006725', (129, 133))	('expression', 'MPA', (96, 106))	('high', 'Var', (85, 89))	('TRGC2', 'Gene', (119, 124))	('IL6', 'Gene', '3569', (76, 79))	('TRGC2', 'Gene', '6967', (119, 124))	('IL6', 'Gene', (76, 79))	('PDAC', 'Chemical', '-', (129, 133))	('IL6', 'molecular_function', 'GO:0005138', ('76', '79'))	('TRGC2', 'Gene', (90, 95))	('TRGC2', 'Gene', '6967', (90, 95))
58742	32865617	gammadelta T-cell depletion was protective against murine PDAC and resulted in increased infiltration, activation, and Th1 polarization of alphabeta T cells (Daley et al.).	('increased', 'PosReg', (79, 88))	('alphabeta T', 'Disease', 'MESH:D001260', (139, 150))	('Th1 polarization', 'CPA', (119, 135))	('PDAC', 'Chemical', '-', (58, 62))	('murine', 'Species', '10090', (51, 57))	('alphabeta T', 'Disease', (139, 150))	('infiltration', 'CPA', (89, 101))	('depletion', 'Var', (18, 27))	('PDAC', 'Disease', (58, 62))	('PDAC', 'Phenotype', 'HP:0006725', (58, 62))	('activation', 'CPA', (103, 113))
58752	32865617	While in transgenic Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice, deletion of alphaSMA+ myofibroblasts did not enhance gemcitabine efficacy, treatment with anti-CTLA-4 decreased disease acceleration and prolonged survival (Ozdemir et al.).	('CTLA-4', 'Gene', '12477', (169, 175))	('gemcitabine', 'Chemical', 'MESH:C056507', (127, 138))	('mice', 'Species', '10090', (68, 72))	('decreased disease', 'Disease', (176, 193))	('decreased disease', 'Disease', 'MESH:D002303', (176, 193))	('deletion', 'Var', (74, 82))	('Ptf1', 'Species', '32651', (20, 24))	('CTLA-4', 'Gene', (169, 175))	('survival', 'CPA', (221, 229))	('prolonged', 'PosReg', (211, 220))
58769	32865617	Modulation or inhibition of gammadelta T cells alone or in combination with IL-6-receptor blockade may enhance the efficacy of chemotherapy and immunotherapy in PDAC.	('Modulation', 'Var', (0, 10))	('IL-6', 'Gene', (76, 80))	('PDAC', 'Chemical', '-', (161, 165))	('IL-6', 'Gene', '3569', (76, 80))	('enhance', 'PosReg', (103, 110))	('PDAC', 'Disease', (161, 165))	('PDAC', 'Phenotype', 'HP:0006725', (161, 165))	('gammadelta T', 'Protein', (28, 40))	('IL-6', 'molecular_function', 'GO:0005138', ('76', '80'))	('inhibition', 'NegReg', (14, 24))
58783	32503262	Among all the reviewers, inter-reader agreement for the liver segments that were affected by malignancy was higher for MRI (kappa = 0.44, p < 0.001) than for CT (kappa = 0.43, p < 0.001).	('malignancy', 'Disease', (93, 103))	('higher', 'PosReg', (108, 114))	('MRI', 'Var', (119, 122))	('malignancy', 'Disease', 'MESH:D009369', (93, 103))
58851	32490337	Comparing the EOPC and LOPC groups using propensity score matching, the EOPC group had a significantly worse overall survival rate (OS) after 5 years (6.1% vs 8.6%, P = .003) as well as a significantly worse cancer-specific survival rate (CSS) (6.7% vs 9.7%, P < .001).	('cancer', 'Disease', (208, 214))	('worse', 'NegReg', (103, 108))	('worse', 'NegReg', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('overall', 'MPA', (109, 116))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('EOPC', 'Var', (72, 76))
58861	32490337	15  Takai et al 9  examined 21 genetic mutations involving hereditary pancreatic cancer syndromes among 54 cases of familial pancreatic cancer in which germ cell DNA could be collected.	('familial pancreatic cancer', 'Disease', (116, 142))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (116, 142))	('DNA', 'cellular_component', 'GO:0005574', ('162', '165'))	('mutations', 'Var', (39, 48))	('hereditary pancreatic cancer syndromes', 'Disease', (59, 97))	('hereditary pancreatic cancer syndromes', 'Disease', 'MESH:D010190', (59, 97))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))
58862	32490337	As a result, there were three cases of BRCA2 mutation (5.6%), two cases of PALB2 mutation (3.7%), two cases of ATM mutation (3.7%), and one case of MLH1 mutation (1.9%).	('ATM', 'Gene', (111, 114))	('BRCA2', 'Gene', (39, 44))	('PALB2', 'Gene', (75, 80))	('ATM', 'Gene', '472', (111, 114))	('PALB2', 'Gene', '79728', (75, 80))	('mutation', 'Var', (45, 53))	('BRCA2', 'Gene', '675', (39, 44))	('MLH1', 'Gene', '4292', (148, 152))	('MLH1', 'Gene', (148, 152))
58863	32490337	A US study reported on 17 cases of BRCA1/2 mutation (11.3%) detected from genetic testing among 151 pancreatic cancer cases.	('mutation', 'Var', (43, 51))	('pancreatic cancer', 'Disease', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('pancreatic cancer', 'Disease', 'MESH:D010190', (100, 117))	('BRCA', 'Gene', (35, 39))	('BRCA', 'Gene', '672', (35, 39))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (100, 117))
58864	32490337	16  According to a Canadian cohort study, 4.6% of pancreatic cancer patients had deleterious mutations in the BRCA genes and pancreatic cancer patients with deleterious mutations in BRCA genes exhibited no differences with patients without them in terms of age at diagnosis for pancreatic cancer, sex, or smoking history.	('BRCA', 'Gene', '672', (182, 186))	('pancreatic cancer', 'Disease', (278, 295))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 67))	('BRCA', 'Gene', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('pancreatic cancer', 'Disease', 'MESH:D010190', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('BRCA', 'Gene', (182, 186))	('pancreatic cancer', 'Disease', (125, 142))	('patients', 'Species', '9606', (68, 76))	('pancreatic cancer', 'Disease', 'MESH:D010190', (50, 67))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (278, 295))	('mutations', 'Var', (93, 102))	('pancreatic cancer', 'Disease', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))	('BRCA', 'Gene', '672', (110, 114))	('pancreatic cancer', 'Disease', 'MESH:D010190', (278, 295))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (223, 231))
58867	32490337	However, since it has been reported that platinum-based chemotherapy and poly ADP-ribose polymerase (PARP) inhibitors are effective for pancreatic cancer with BRCA2 genetic mutations and PALB2 genetic mutations (but not covered by insurance for pancreatic cancer), genetic testing may enable the selection of treatment based on precision medicine.	('PARP', 'Gene', '142', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('platinum', 'Chemical', 'MESH:D010984', (41, 49))	('PARP', 'Gene', (101, 105))	('pancreatic cancer', 'Disease', (245, 262))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('BRCA2', 'Gene', (159, 164))	('poly ADP-ribose polymerase', 'Gene', '142', (73, 99))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('poly ADP-ribose polymerase', 'Gene', (73, 99))	('PALB2', 'Gene', (187, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (245, 262))	('genetic mutations', 'Var', (193, 210))	('BRCA2', 'Gene', '675', (159, 164))	('PALB2', 'Gene', '79728', (187, 192))	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('genetic mutations', 'Var', (165, 182))	('pancreatic cancer', 'Disease', 'MESH:D010190', (245, 262))	('pancreatic cancer', 'Disease', (136, 153))
58878	32490337	8 ,  23  In relation to carcinogenesis, these gene mutations are thought to cause continuous chronic pancreatitis from childhood, leading to the formation of precancerous lesions.	('pancreatitis', 'Phenotype', 'HP:0001733', (101, 113))	('mutations', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('pancreatitis', 'Disease', 'MESH:D010195', (101, 113))	('precancerous lesions', 'Disease', 'MESH:D011230', (158, 178))	('precancerous lesions', 'Disease', (158, 178))	('cause', 'Reg', (76, 81))	('formation', 'biological_process', 'GO:0009058', ('145', '154'))	('pancreatitis', 'Disease', (101, 113))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (93, 113))
58879	32490337	24   Hereditary breast and ovarian cancer is an autosomal dominant genetic disease characterized by a mutation in the BRCA 1/2 genes.	('Hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (5, 41))	('mutation', 'Var', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('ovarian cancer', 'Phenotype', 'HP:0100615', (27, 41))	('BRCA', 'Gene', '672', (118, 122))	('BRCA', 'Gene', (118, 122))	('autosomal dominant genetic disease', 'Disease', (48, 82))	('autosomal dominant genetic disease', 'Disease', 'MESH:D030342', (48, 82))
58881	32490337	The onset risk of pancreatic cancer in patients with a BRCA gene mutation is 4.1 to 5.8-fold higher.	('higher', 'PosReg', (93, 99))	('BRCA', 'Gene', '672', (55, 59))	('patients', 'Species', '9606', (39, 47))	('pancreatic cancer', 'Disease', (18, 35))	('BRCA', 'Gene', (55, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('mutation', 'Var', (65, 73))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (18, 35))
58887	32490337	The CDKN2A gene mutation is one of the typical gene mutations triggering this disease.	('CDKN2A', 'Gene', '1029', (4, 10))	('CDKN2A', 'Gene', (4, 10))	('mutation', 'Var', (16, 24))
58893	32490337	Reduced repair function due to abnormalities in these MMR genes causes cancer.	('abnormalities', 'Var', (31, 44))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('Reduced', 'NegReg', (0, 7))	('MMR', 'biological_process', 'GO:0006298', ('54', '57'))	('repair function', 'MPA', (8, 23))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('MMR genes', 'Gene', (54, 63))
58916	31796877	For example, STAT3 activity inhibits the chemotaxis and activation of cytotoxic CD8 T cells in solid tumors, mediates the differentiation of suppressive T regulatory (Treg) cells and enhances the expression of immune checkpoints CTLA-4 and PD-L1.	('differentiation', 'CPA', (122, 137))	('chemotaxis', 'CPA', (41, 51))	('CD8', 'Gene', '925', (80, 83))	('inhibits', 'NegReg', (28, 36))	('CTLA-4', 'Gene', '1493', (229, 235))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('chemotaxis', 'biological_process', 'GO:0006935', ('41', '51'))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('expression', 'MPA', (196, 206))	('STAT3', 'Var', (13, 18))	('CTLA-4', 'Gene', (229, 235))	('mediates', 'Reg', (109, 117))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('PD-L1', 'Gene', (240, 245))	('CD8', 'Gene', (80, 83))	('enhances', 'PosReg', (183, 191))	('activation', 'CPA', (56, 66))	('tumors', 'Disease', (101, 107))
58919	31796877	Importantly, STAT3 is required for the evolution of pancreatic neoplasia into pancreatic cancer in the presence of KRAS mutations.	('neoplasia', 'Phenotype', 'HP:0002664', (63, 72))	('pancreatic neoplasia into pancreatic cancer', 'Disease', (52, 95))	('pancreatic neoplasia into pancreatic cancer', 'Disease', 'MESH:D010190', (52, 95))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('KRAS', 'Gene', (115, 119))	('pancreatic neoplasia', 'Phenotype', 'HP:0002894', (52, 72))	('KRAS', 'Gene', '3845', (115, 119))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
58972	31796877	By stratifying samples into STAT3 activity-high (STAT3 activity score > 0) and -low (STAT3 activity score < 0) groups, we indeed confirmed that high STAT3 activities conferred poor prognosis, irrespective of tumor compartment (Fig.	('poor', 'NegReg', (176, 180))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('high', 'Var', (144, 148))	('tumor', 'Disease', (208, 213))	('STAT3 activities', 'MPA', (149, 165))
58975	31796877	T-STAT3 was the most significant prognostic factor and conveyed a hazard ratio of 1.9 (p = 0.01, multivariate Cox regression).	('Cox', 'Gene', '1351', (110, 113))	('Cox', 'Gene', (110, 113))	('T-STAT3', 'Var', (0, 7))
58990	31796877	Next, tumor mutation burden did not differ between STAT3 groups (data not shown), an E-STAT3-dominant pattern was again observed for CNV burden and homologous recombination (HR) deficiency, which were significantly elevated in E-STAT3 high samples, irrespective of T-STAT3 activity (Fig.	('elevated', 'PosReg', (215, 223))	('E-STAT3 high', 'Var', (227, 239))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('recombination (HR) deficiency', 'Disease', 'MESH:C535296', (159, 188))	('CNV burden', 'MPA', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
58992	31796877	5C), implying that the coordination between T- and E-STAT3 provides some growth advantages to tumor cells compared to other STAT3 groups.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('coordination', 'Var', (23, 35))	('tumor', 'Disease', (94, 99))	('E-STAT3', 'Var', (51, 58))
58993	31796877	In conclusion, these results show that E-STAT3 is associated with intrinsic and extrinsic tumor characteristics in pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('E-STAT3', 'Var', (39, 46))	('pancreatic cancer', 'Disease', (115, 132))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('associated', 'Reg', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
59005	31796877	We found that STAT3 activities have prognostic features, high T- or E-STAT3 activity conferring poor prognosis, but STAT3 mRNA does not.	('E-STAT3 activity', 'MPA', (68, 84))	('N', 'Chemical', 'MESH:D009584', (124, 125))	('high', 'Var', (57, 61))
59008	31796877	We identified four STAT3 groups (T-STAT3-high/E-STAT3-high, T-STAT3-high/E-STAT3-low, T-STAT3-low/E-STAT3-high, and T-STAT3low/E-STAT3-low) with distinct tumor characteristics.	('T-STAT3-high/E-STAT3-low', 'Var', (60, 84))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('T-STAT3low/E-STAT3-low', 'Var', (116, 138))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('T-STAT3-low/E-STAT3-high', 'Var', (86, 110))	('tumor', 'Disease', (154, 159))
59011	31796877	The E-STAT3-depleted pattern was associated with elevated B, CD8 T, and NK cell infiltration.	('NK cell infiltration', 'CPA', (72, 92))	('CD8', 'Gene', (61, 64))	('CD8', 'Gene', '925', (61, 64))	('elevated', 'PosReg', (49, 57))	('N', 'Chemical', 'MESH:D009584', (72, 73))	('E-STAT3-depleted', 'Var', (4, 20))
59023	31796877	Myeloid cells are immunosuppressive and secrete cytokines that prevent the activation of tumor-eliminating immune cells, which is consistent with our observations of low CD8 T and NK cell infiltration in E-STAT3 high samples, but not in E-STAT3 low samples.	('NK cell infiltration', 'CPA', (180, 200))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('high', 'Var', (212, 216))	('E-STAT3 high', 'Var', (204, 216))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('prevent', 'NegReg', (63, 70))	('N', 'Chemical', 'MESH:D009584', (180, 181))	('low', 'NegReg', (166, 169))	('CD8', 'Gene', (170, 173))	('tumor', 'Disease', (89, 94))	('CD8', 'Gene', '925', (170, 173))
59026	31796877	Co-targeting IL-6, which is major factor in activating STAT3, and PD-L1 was shown to inhibit growth in a murine model of pancreatic cancer.	('growth', 'MPA', (93, 99))	('IL-6', 'molecular_function', 'GO:0005138', ('13', '17'))	('pancreatic cancer', 'Disease', (121, 138))	('pancreatic cancer', 'Disease', 'MESH:D010190', (121, 138))	('murine', 'Species', '10090', (105, 111))	('inhibit', 'NegReg', (85, 92))	('Co-targeting', 'Var', (0, 12))	('IL-6', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('PD-L1', 'Gene', (66, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (121, 138))
59028	31796877	Although no preliminary results are available yet, inhibitors of IL-6 and the IL-6 receptor have been proven to be effective in preclinical models of KRAS-driven pancreatic cancer.	('IL-6', 'molecular_function', 'GO:0005138', ('78', '82'))	('IL-6', 'molecular_function', 'GO:0005138', ('65', '69'))	('pancreatic cancer', 'Disease', (162, 179))	('IL-6', 'Gene', (78, 82))	('pancreatic cancer', 'Disease', 'MESH:D010190', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (162, 179))	('KRAS', 'Gene', (150, 154))	('IL-6', 'Gene', (65, 69))	('inhibitors', 'Var', (51, 61))	('KRAS', 'Gene', '3845', (150, 154))
59038	31796877	Four pancreatic cancer microarray datasets were obtained from Gene Expression Omnibus (GEO) under accession numbers GSE15471, GSE57495, GSE71729, GSE28735.	('GSE71729', 'Var', (136, 144))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (5, 22))	('GSE15471', 'Var', (116, 124))	('pancreatic cancer', 'Disease', (5, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Gene Expression', 'biological_process', 'GO:0010467', ('62', '77'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (5, 22))
59069	30154150	Inverse Correlation of STAT3 and MEK Signaling Mediates Resistance to RAS Pathway Inhibition in Pancreatic Cancer Major contributors to therapeutic resistance in pancreatic cancer (PDAC) include Kras mutations, a dense desmoplastic stroma that prevents drug delivery to the tumor, and activation of redundant signaling pathways.	('Signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('mutations', 'Var', (200, 209))	('STAT3', 'Gene', (23, 28))	('Kras', 'Gene', '16653', (195, 199))	('PDAC', 'Phenotype', 'HP:0006725', (181, 185))	('tumor', 'Disease', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('pancreatic cancer', 'Disease', 'MESH:D010190', (162, 179))	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (96, 113))	('pancreatic cancer', 'Disease', (162, 179))	('MEK', 'Gene', '17242', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('signaling', 'biological_process', 'GO:0023052', ('309', '318'))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (162, 179))	('STAT3', 'Gene', '20848', (23, 28))	('Kras', 'Gene', (195, 199))	('Pancreatic Cancer', 'Disease', (96, 113))	('drug delivery', 'MPA', (253, 266))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('MEK', 'Gene', (33, 36))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (96, 113))
59071	30154150	Amphiregulin (AREG) levels were determined in serum from human PDAC patients, LSL-KrasG12D/+;Trp53R172H/+;Pdx1Cre/+ (KPC), and PKT mice.	('Trp53R172H/+;Pdx1Cre/+', 'Var', (93, 115))	('Kras', 'Gene', (82, 86))	('Kras', 'Gene', '16653', (82, 86))	('Pdx1Cre/+', 'Var', (106, 115))	('patients', 'Species', '9606', (68, 76))	('Amphiregulin', 'Gene', (0, 12))	('PDAC', 'Disease', (63, 67))	('PDAC', 'Phenotype', 'HP:0006725', (63, 67))	('mice', 'Species', '10090', (131, 135))	('Amphiregulin', 'Gene', '374', (0, 12))	('Trp', 'Chemical', 'MESH:C509690', (93, 96))	('human', 'Species', '9606', (57, 62))
59074	30154150	Furthermore, MEKi/STAT3i altered the PDAC tumor microenvironment by depleting tumor fibrosis, maintaining pancreatic integrity, and downregulating CD44+ and CD133+ CSC.	('altered', 'Reg', (25, 32))	('tumor', 'Disease', (42, 47))	('tumor fibrosis', 'Disease', (78, 92))	('PDAC', 'Phenotype', 'HP:0006725', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor fibrosis', 'Disease', 'MESH:D005355', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('downregulating', 'NegReg', (132, 146))	('MEKi/STAT3i', 'Var', (13, 24))	('CD44', 'Gene', '12505', (147, 151))	('CD44', 'Gene', (147, 151))	('depleting', 'NegReg', (68, 77))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('pancreatic integrity', 'MPA', (106, 126))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('maintaining', 'PosReg', (94, 105))
59076	30154150	Activating Kras mutations, present in over 90% of PDAC tumors, are difficult to target due to the inter-dependence of redundant signaling pathways and feedback loops.	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('Activating', 'PosReg', (0, 10))	('PDAC', 'Disease', (50, 54))	('PDAC', 'Phenotype', 'HP:0006725', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Kras', 'Gene', '16653', (11, 15))	('mutations', 'Var', (16, 25))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('Kras', 'Gene', (11, 15))
59079	30154150	In PDAC, Kras activating mutations promote proliferation and inhibit apoptosis through the RAF/MEK/ERK and PIK3/AKT pathways.	('Kras', 'Gene', (9, 13))	('Kras', 'Gene', '16653', (9, 13))	('mutations', 'Var', (25, 34))	('RAF', 'Gene', '387609', (91, 94))	('ERK', 'molecular_function', 'GO:0004707', ('99', '102'))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('inhibit', 'NegReg', (61, 68))	('AKT', 'Gene', '11651', (112, 115))	('PDAC', 'Phenotype', 'HP:0006725', (3, 7))	('apoptosis', 'CPA', (69, 78))	('proliferation', 'CPA', (43, 56))	('promote', 'PosReg', (35, 42))	('RAF', 'Gene', (91, 94))	('AKT', 'Gene', (112, 115))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))
59086	30154150	In addition, we show MEKi/STAT3i inhibits tumor fibrosis and downregulates CSCs to enhance therapeutic response in PDAC.	('PDAC', 'Disease', (115, 119))	('PDAC', 'Phenotype', 'HP:0006725', (115, 119))	('downregulates', 'NegReg', (61, 74))	('tumor fibrosis', 'Disease', (42, 56))	('enhance', 'PosReg', (83, 90))	('tumor fibrosis', 'Disease', 'MESH:D005355', (42, 56))	('inhibits', 'NegReg', (33, 41))	('CSCs', 'MPA', (75, 79))	('MEKi/STAT3i', 'Var', (21, 32))	('therapeutic response', 'CPA', (91, 111))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
59087	30154150	Furthermore, elevated serum AREG levels are decreased with MEKi/STAT3i in PKT mice, suggesting a role for serum AREG as a prognostic biomarker of therapeutic response as well as a biomarker of therapeutic resistance to EGFR, MEK and STAT3 inhibition.	('elevated', 'PosReg', (13, 21))	('EGFR', 'molecular_function', 'GO:0005006', ('219', '223'))	('MEKi/STAT3i', 'Var', (59, 70))	('mice', 'Species', '10090', (78, 82))	('decreased', 'NegReg', (44, 53))	('serum AREG levels', 'MPA', (22, 39))
59094	30154150	LSL-KrasG12D/+, Pdx1Cre/+and p53R273H/+mice were intercrossed to generate indicated LSL-KrasG12D/+; Trp53R172H/+; Pdx1Cre/+ (KPC) animals.	('Kras', 'Gene', (88, 92))	('Kras', 'Gene', '16653', (88, 92))	('p53R273H/+mice', 'Var', (29, 43))	('Trp', 'Chemical', 'MESH:C509690', (100, 103))	('Kras', 'Gene', (4, 8))	('Kras', 'Gene', '16653', (4, 8))	('Trp53R172H/+; Pdx1Cre/+', 'Var', (100, 123))	('mice', 'Species', '10090', (39, 43))	('Pdx1Cre/+', 'Var', (114, 123))
59097	30154150	AZD1480 (30 mg/kg/day), AZD6244 (25 mg/kg/day), both drugs together or vehicle (Hydroxypropyl methyl cellulose/Tween 80) was administered by oral gavage for 41(MiaPaCa2), 49 (PANC1) and 27 (BxPC3) days.	('PANC1', 'Gene', (175, 180))	('AZD6244', 'Chemical', 'MESH:C517975', (24, 31))	('Tween 80', 'Chemical', 'MESH:D011136', (111, 119))	('MiaPaCa2', 'CellLine', 'CVCL:0428', (160, 168))	('BxPC3', 'CellLine', 'CVCL:0186', (190, 195))	('AZD1480', 'Chemical', 'MESH:C545606', (0, 7))	('AZD6244', 'Var', (24, 31))	('Hydroxypropyl methyl', 'Chemical', 'MESH:D065347', (80, 100))	('PANC1', 'Gene', '104066', (175, 180))
59098	30154150	PKT mice were treated with vehicle, AZD1480 (JAK/STAT3 inhibitor), AZD6244 (MEK inhibitor) or a combination of AZD6244 and AZD1480.	('AZD1480', 'Var', (36, 43))	('AZD1480', 'Chemical', 'MESH:C545606', (36, 43))	('mice', 'Species', '10090', (4, 8))	('AZD6244', 'Var', (67, 74))	('AZD6244', 'Chemical', 'MESH:C517975', (111, 118))	('AZD6244', 'Chemical', 'MESH:C517975', (67, 74))	('AZD1480', 'Chemical', 'MESH:C545606', (123, 130))	('JAK', 'molecular_function', 'GO:0004713', ('45', '48'))
59106	30154150	In addition, pancreatic tumors from Ptf1acre/+;LSL-KrasG12D/+; Tgfbr2flox/flox (PKT) mice (Fig.	('pancreatic tumors', 'Disease', (13, 30))	('Tgfbr2flox/flox', 'Var', (63, 78))	('mice', 'Species', '10090', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (13, 29))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (13, 30))	('Kras', 'Gene', (51, 55))	('Kras', 'Gene', '16653', (51, 55))	('Ptf1', 'Species', '32651', (36, 40))	('Ptf1acre/+', 'Var', (36, 46))	('pancreatic tumors', 'Disease', 'MESH:D010190', (13, 30))
59107	30154150	S1B) treated with the JAK/STAT3 inhibitor (STAT3i) AZD1480 showed increased pERK levels while mice treated with the MEK inhibitor (MEKi) AZD6244 showed increased pSTAT3 expression.	('JAK', 'molecular_function', 'GO:0004713', ('22', '25'))	('increased', 'PosReg', (66, 75))	('AZD1480', 'Chemical', 'MESH:C545606', (51, 58))	('increased', 'PosReg', (152, 161))	('pERK levels', 'MPA', (76, 87))	('AZD1480', 'Var', (51, 58))	('mice', 'Species', '10090', (94, 98))	('AZD6244', 'Chemical', 'MESH:C517975', (137, 144))	('pSTAT3 expression', 'MPA', (162, 179))
59108	30154150	Treatment with the MEK inhibitors AZD6244 or MEK162 effectively suppressed pERK while inducing pSTAT3 activation in PDAC cells in a time-dependent manner (Fig.	('MEK1', 'Gene', '26395', (45, 49))	('AZD6244', 'Chemical', 'MESH:C517975', (34, 41))	('suppressed', 'NegReg', (64, 74))	('PDAC', 'Phenotype', 'HP:0006725', (116, 120))	('inducing', 'Reg', (86, 94))	('pSTAT3 activation', 'MPA', (95, 112))	('AZD6244', 'Var', (34, 41))	('MEK1', 'Gene', (45, 49))	('pERK', 'MPA', (75, 79))
59109	30154150	Conversely, STAT3 inhibitors Stattic and AZD1480 resulted in pERK activation in a time- (Fig.	('AZD1480', 'Chemical', 'MESH:C545606', (41, 48))	('pERK', 'MPA', (61, 65))	('AZD1480', 'Var', (41, 48))	('activation', 'PosReg', (66, 76))
59115	30154150	Cells treated with both gemcitabine and AZD1480 exhibited similar effects on STAT3 and ERK signaling compared to AZD1480 (STAT3i) alone, demonstrating that gemcitabine did not alter the reciprocal activation of STAT3 or ERK signaling.	('STAT3', 'MPA', (77, 82))	('AZD1480', 'Chemical', 'MESH:C545606', (40, 47))	('AZD1480', 'Chemical', 'MESH:C545606', (113, 120))	('ERK signaling', 'MPA', (87, 100))	('gemcitabine', 'Chemical', 'MESH:C056507', (24, 35))	('ERK', 'molecular_function', 'GO:0004707', ('220', '223'))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('ERK', 'molecular_function', 'GO:0004707', ('87', '90'))	('gemcitabine', 'Chemical', 'MESH:C056507', (156, 167))	('signaling', 'biological_process', 'GO:0023052', ('224', '233'))	('AZD1480', 'Var', (40, 47))	('effects', 'Reg', (66, 73))
59119	30154150	2B) with combined AZD6244/AZD1480 showed sustained inhibition of both ERK and STAT3 activation.	('inhibition', 'NegReg', (51, 61))	('AZD6244', 'Chemical', 'MESH:C517975', (18, 25))	('AZD1480', 'Chemical', 'MESH:C545606', (26, 33))	('AZD6244/AZD1480', 'Var', (18, 33))	('STAT3 activation', 'MPA', (78, 94))	('ERK', 'molecular_function', 'GO:0004707', ('70', '73'))	('ERK', 'Pathway', (70, 73))
59122	30154150	These results show that combined MEKi/STAT3i suppresses pancreatic tumorigenicity.	('MEKi/STAT3i', 'Var', (33, 44))	('pancreatic tumorigenicity', 'Disease', (56, 81))	('pancreatic tumorigenicity', 'Disease', 'MESH:D002471', (56, 81))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('suppresses', 'NegReg', (45, 55))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (56, 72))
59124	30154150	3A, STAT3i with AZD1480 resulted in pSTAT3 inhibition, with subsequent activation of pERK and pEGFR in both time- and dose-dependent manner (Fig.	('AZD1480', 'Chemical', 'MESH:C545606', (16, 23))	('pEGFR', 'Gene', (94, 99))	('inhibition', 'NegReg', (43, 53))	('activation', 'PosReg', (71, 81))	('pSTAT3', 'MPA', (36, 42))	('pERK', 'MPA', (85, 89))	('AZD1480', 'Var', (16, 23))
59126	30154150	To further explore the mechanism by which STAT3i promotes EGFR tyrosine phosphorylation, we examined the upstream activators of EGFR signaling.	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('EGFR', 'molecular_function', 'GO:0005006', ('128', '132'))	('signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('promotes', 'PosReg', (49, 57))	('EGFR tyrosine phosphorylation', 'MPA', (58, 87))	('tyrosine', 'Chemical', 'None', (63, 71))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('STAT3i', 'Var', (42, 48))
59129	30154150	First, we confirmed EGFR inhibition with erlotinib activates STAT3 phosphorylation (Supplementary Fig.	('activates', 'PosReg', (51, 60))	('erlotinib', 'Chemical', 'MESH:C400278', (41, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('20', '24'))	('erlotinib', 'Gene', (41, 50))	('phosphorylation', 'biological_process', 'GO:0016310', ('67', '82'))	('inhibition', 'Var', (25, 35))	('STAT3 phosphorylation', 'MPA', (61, 82))
59131	30154150	STAT3i with AZD1480 and MEKi with AZD6244 resulted in significantly increased AREG levels in the CM from all three cell lines.	('AZD6244', 'Chemical', 'MESH:C517975', (34, 41))	('AREG levels', 'MPA', (78, 89))	('AZD1480', 'Chemical', 'MESH:C545606', (12, 19))	('AZD6244', 'Var', (34, 41))	('increased', 'PosReg', (68, 77))	('AZD1480', 'Var', (12, 19))
59134	30154150	Combined treatment with AZD1480 and C225 or erlotinib completely inhibited ERK and STAT3 activation along with EGFR signaling.	('erlotinib', 'Gene', (44, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('ERK', 'molecular_function', 'GO:0004707', ('75', '78'))	('AZD1480', 'Var', (24, 31))	('inhibited', 'NegReg', (65, 74))	('AZD1480', 'Chemical', 'MESH:C545606', (24, 31))	('C225', 'Var', (36, 40))	('erlotinib', 'Chemical', 'MESH:C400278', (44, 53))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))
59139	30154150	Serum AREG levels were significantly higher in KPC mice compared to WT mice, further corroborating the roles of AREG and activated TACE in PDAC progression.	('mice', 'Species', '10090', (71, 75))	('PDAC', 'Disease', (139, 143))	('mice', 'Species', '10090', (51, 55))	('higher', 'PosReg', (37, 43))	('PDAC', 'Phenotype', 'HP:0006725', (139, 143))	('KPC', 'Var', (47, 50))	('Serum AREG levels', 'MPA', (0, 17))
59142	30154150	4B) xenografts were subjected to vehicle, AZD1480, AZD6244 or combined treatment by daily oral gavage.	('AZD1480', 'Chemical', 'MESH:C545606', (42, 49))	('AZD6244', 'Chemical', 'MESH:C517975', (51, 58))	('AZD6244 or', 'Var', (51, 61))	('AZD1480', 'Var', (42, 49))
59149	30154150	There was a significant reduction in pancreatic tumor weight with combined AZD1480/AZD6244 treatment compared to vehicle or treatment with either agent alone (Fig.	('AZD1480/AZD6244', 'Var', (75, 90))	('AZD1480', 'Chemical', 'MESH:C545606', (75, 82))	('AZD6244', 'Chemical', 'MESH:C517975', (83, 90))	('pancreatic tumor', 'Disease', (37, 53))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (37, 53))	('reduction', 'NegReg', (24, 33))	('pancreatic tumor', 'Disease', 'MESH:D010190', (37, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
59150	30154150	Furthermore, while pancreata of vehicle or monotherapy treated mice were completely replaced with tumor burden, mice treated with combined MEKi/STAT3i had little or no tumor burden and maintained their pancreatic integrity (Fig.	('tumor', 'Disease', (168, 173))	('MEKi/STAT3i', 'Var', (139, 150))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mice', 'Species', '10090', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('maintained', 'Reg', (185, 195))	('tumor', 'Disease', (98, 103))	('pancreatic integrity', 'MPA', (202, 222))	('mice', 'Species', '10090', (112, 116))
59154	30154150	Pancreata of PKT mice treated with AZD1480 or AZD6244 alone had a slight reduction in staining of these markers compared to vehicle-treated mice.	('mice', 'Species', '10090', (17, 21))	('AZD6244', 'Var', (46, 53))	('mice', 'Species', '10090', (140, 144))	('AZD6244', 'Chemical', 'MESH:C517975', (46, 53))	('AZD1480', 'Var', (35, 42))	('AZD1480', 'Chemical', 'MESH:C545606', (35, 42))	('staining', 'MPA', (86, 94))	('reduction', 'NegReg', (73, 82))
59155	30154150	However, PKT mice treated with combined AZD1480/AZD6244 had significantly more normal pancreatic architecture and histology, demonstrating a staining profile similar to their wild type littermates (Fig.	('mice', 'Species', '10090', (13, 17))	('more', 'PosReg', (74, 78))	('AZD1480/AZD6244', 'Var', (40, 55))	('AZD6244', 'Chemical', 'MESH:C517975', (48, 55))	('AZD1480', 'Chemical', 'MESH:C545606', (40, 47))	('histology', 'CPA', (114, 123))	('pancreatic architecture', 'CPA', (86, 109))
59159	30154150	Furthermore, survival of PKT mice treated with MEKi/STAT3i was significantly improved when compared to vehicle-treated and STAT3i treated mice (53 vs 85 or 63 vs 85 days respectively; p=0.0002, log-rank test).	('survival', 'CPA', (13, 21))	('mice', 'Species', '10090', (138, 142))	('MEKi/STAT3i', 'Var', (47, 58))	('mice', 'Species', '10090', (29, 33))	('improved', 'PosReg', (77, 85))
59160	30154150	While there was an improvement in survival of mice treated with combined MEKi/STAT3i compared to MEKi treated mice (85 vs 76 days, Fig.	('mice', 'Species', '10090', (110, 114))	('improvement', 'PosReg', (19, 30))	('mice', 'Species', '10090', (46, 50))	('survival', 'MPA', (34, 42))	('MEKi/STAT3i', 'Var', (73, 84))
59179	30154150	Preclinical studies have identified distinct mechanisms by which cells acquire resistance to MEKi, including amplification of mutant BRAF, PI3K upregulation or EGFR activation.	('activation', 'PosReg', (165, 175))	('PI3K', 'Gene', (139, 143))	('BRAF', 'Gene', '109880', (133, 137))	('EGFR', 'molecular_function', 'GO:0005006', ('160', '164'))	('BRAF', 'Gene', (133, 137))	('EGFR', 'Gene', (160, 164))	('PI3K', 'molecular_function', 'GO:0016303', ('139', '143'))	('resistance', 'MPA', (79, 89))	('upregulation', 'PosReg', (144, 156))	('mutant', 'Var', (126, 132))
59182	30154150	We have previously shown that STAT3i with gemcitabine remodels the tumor stroma and enhances in vivo drug delivery to the tumor thereby improving survival in PKT mice.	('tumor stroma', 'Disease', 'MESH:D009369', (67, 79))	('enhances', 'PosReg', (84, 92))	('tumor stroma', 'Disease', (67, 79))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('STAT3i', 'Var', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('gemcitabine', 'Chemical', 'MESH:C056507', (42, 53))	('improving', 'PosReg', (136, 145))	('mice', 'Species', '10090', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('in vivo drug delivery to the', 'MPA', (93, 121))	('tumor', 'Disease', (67, 72))	('survival', 'CPA', (146, 154))	('tumor', 'Disease', (122, 127))
59184	30154150	We have previously shown knock down of AREG prevents STAT3 and ERK activation in response to deoxycholic acid in PDAC cells.	('knock down', 'Var', (25, 35))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (93, 109))	('prevents', 'NegReg', (44, 52))	('activation', 'PosReg', (67, 77))	('ERK', 'molecular_function', 'GO:0004707', ('63', '66'))	('PDAC', 'Phenotype', 'HP:0006725', (113, 117))	('ERK', 'Pathway', (63, 66))	('AREG', 'Gene', (39, 43))	('response to deoxycholic acid', 'MPA', (81, 109))	('STAT3', 'MPA', (53, 58))
59185	30154150	Previous studies have also suggested inhibiting AREG activity may be necessary to overcome resistance to EGFR-targeted therapies in NSCLC and hepatocellular carcinoma, which is consistent with recent reports showing that inhibition of AREG is associated with a better response to cetuximab therapy in colorectal cancer.	('inhibition', 'Var', (221, 231))	('colorectal cancer', 'Disease', (301, 318))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (142, 166))	('AREG', 'Gene', (235, 239))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('colorectal cancer', 'Disease', 'MESH:D015179', (301, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('NSCLC and hepatocellular carcinoma', 'Disease', 'MESH:D006528', (132, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (301, 318))	('EGFR-targeted', 'Gene', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))
59188	30154150	Combined MEKi/STAT3i results in enhanced therapeutic efficacy not only through sustained inhibition of the RAS pathway-associated redundant feedback loop reactivation, but also by suppressing the TME through reducing CD44+ and CD133+ CSCs.	('suppressing', 'NegReg', (180, 191))	('CD133+ CSCs', 'MPA', (227, 238))	('MEKi/STAT3i', 'Var', (9, 20))	('inhibition', 'NegReg', (89, 99))	('CD44', 'Gene', '12505', (217, 221))	('therapeutic efficacy', 'CPA', (41, 61))	('enhanced', 'PosReg', (32, 40))	('TME', 'MPA', (196, 199))	('reducing', 'NegReg', (208, 216))	('RAS pathway-associated', 'Pathway', (107, 129))	('CD44', 'Gene', (217, 221))
59197	31719634	Inhibition of Haspin leads to a decrease in Histone H3 phosphorylation and prevents Histone H3 binding to survivin, thus providing mechanistic insight of how Sangivamycin targets cell proliferation, mitosis and induces apoptotic cell death.	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('mitosis', 'biological_process', 'GO:0000278', ('199', '206'))	('prevents', 'NegReg', (75, 83))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('219', '239'))	('Haspin', 'Gene', (14, 20))	('Sangivamycin', 'Chemical', 'MESH:C005699', (158, 170))	('Histone H3 phosphorylation', 'MPA', (44, 70))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('Haspin', 'Gene', '83903', (14, 20))	('cell proliferation', 'biological_process', 'GO:0008283', ('179', '197'))	('apoptotic cell death', 'CPA', (219, 239))	('Inhibition', 'Var', (0, 10))	('mitosis', 'CPA', (199, 206))	('survivin', 'Protein', (106, 114))	('binding', 'Interaction', (95, 102))	('decrease', 'NegReg', (32, 40))	('induces', 'Reg', (211, 218))	('Histone H3', 'Protein', (84, 94))
59216	31719634	Inhibition of Haspin prevented Histone H3 binding to survivin, and targets cell proliferation, mitosis and induces apoptotic cell death.	('apoptotic cell death', 'CPA', (115, 135))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('115', '135'))	('mitosis', 'CPA', (95, 102))	('prevented', 'NegReg', (21, 30))	('mitosis', 'biological_process', 'GO:0000278', ('95', '102'))	('binding', 'Interaction', (42, 49))	('Haspin', 'Gene', (14, 20))	('survivin', 'Protein', (53, 61))	('induces', 'Reg', (107, 114))	('Inhibition', 'Var', (0, 10))	('Haspin', 'Gene', '83903', (14, 20))	('Histone H3', 'Protein', (31, 41))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('binding', 'molecular_function', 'GO:0005488', ('42', '49'))	('cell proliferation', 'CPA', (75, 93))
59239	31719634	Analyses of the overall survival probability of patients indicated that patients with tumors with high Haspin expression levels showed a decrease in survival as compared to patients with tumors that express low levels of this kinase (Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('decrease', 'NegReg', (137, 145))	('patients', 'Species', '9606', (173, 181))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('survival', 'MPA', (149, 157))	('high', 'Var', (98, 102))	('Haspin', 'Gene', '83903', (103, 109))	('tumors', 'Disease', (86, 92))	('Haspin', 'Gene', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('patients', 'Species', '9606', (48, 56))	('patients', 'Species', '9606', (72, 80))
59245	31719634	Histone phosphorylation by Haspin was decreased when cells were treated with Sangivamycin or Toyocamycin (Fig.	('Sangivamycin', 'Chemical', 'MESH:C005699', (77, 89))	('decreased', 'NegReg', (38, 47))	('Sangivamycin', 'Var', (77, 89))	('Haspin', 'Gene', '83903', (27, 33))	('Haspin', 'Gene', (27, 33))	('Toyocamycin', 'Chemical', 'MESH:D014127', (93, 104))	('Histone phosphorylation', 'biological_process', 'GO:0016572', ('0', '23'))	('Histone phosphorylation', 'MPA', (0, 23))
59250	31719634	Taken together, this mechanistic data indicates that Haspin overexpression in PDA cells drives mitosis and tumor cell proliferation and that the inhibition of Haspin signaling leads to a disassembly of the H3-survivin protein complex, resulting in growth arrest and eventually apoptosis (Fig.	('growth arrest', 'Phenotype', 'HP:0001510', (248, 261))	('tumor', 'Disease', (107, 112))	('apoptosis', 'CPA', (277, 286))	('apoptosis', 'biological_process', 'GO:0006915', ('277', '286'))	('disassembly', 'MPA', (187, 198))	('signaling', 'biological_process', 'GO:0023052', ('166', '175'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('growth arrest', 'Disease', 'MESH:D006323', (248, 261))	('Haspin', 'Gene', '83903', (53, 59))	('inhibition', 'Var', (145, 155))	('cell proliferation', 'biological_process', 'GO:0008283', ('113', '131'))	('PDA', 'Phenotype', 'HP:0006725', (78, 81))	('mitosis', 'CPA', (95, 102))	('overexpression', 'PosReg', (60, 74))	('Haspin', 'Gene', (159, 165))	('growth arrest', 'Disease', (248, 261))	('protein complex', 'cellular_component', 'GO:0032991', ('218', '233'))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('H3-survivin protein complex', 'Protein', (206, 233))	('Haspin', 'Gene', (53, 59))	('mitosis', 'biological_process', 'GO:0000278', ('95', '102'))	('Haspin', 'Gene', '83903', (159, 165))	('drives', 'PosReg', (88, 94))	('apoptosis', 'biological_process', 'GO:0097194', ('277', '286'))
59255	31719634	At the end point (day 44) tumors of mice treated with Sangivamycin showed a statistically-significant (approximately 50%) decrease in tumor weight and decrease (approximately 70%) in tumor volume (Fig.	('Sangivamycin', 'Chemical', 'MESH:C005699', (54, 66))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('decrease', 'NegReg', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (134, 139))	('decrease', 'NegReg', (151, 159))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (183, 188))	('mice', 'Species', '10090', (36, 40))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (26, 31))	('tumors', 'Disease', (26, 32))	('Sangivamycin', 'Var', (54, 66))
59263	31719634	In vivo, when administered to mice with established orthotopic pancreatic tumors, sangivamycin led to a significant decrease in tumor burden, correlating with a collapse of tumor vasculature, decrease in Ki67 positive cells and an increase in cleaved-caspase 3 expression (Fig.	('tumor vasculature', 'Disease', (173, 190))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('sangivamycin', 'Chemical', 'MESH:C005699', (82, 94))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (63, 80))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (74, 79))	('sangivamycin', 'Var', (82, 94))	('collapse', 'NegReg', (161, 169))	('mice', 'Species', '10090', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('decrease', 'NegReg', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor vasculature', 'Disease', 'MESH:C565633', (173, 190))	('pancreatic tumors', 'Disease', 'MESH:D010190', (63, 80))	('decrease', 'NegReg', (192, 200))	('Ki67', 'Gene', (204, 208))	('pancreatic tumors', 'Disease', (63, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('expression', 'MPA', (261, 271))	('tumor', 'Disease', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('increase', 'PosReg', (231, 239))	('tumor', 'Disease', (173, 178))	('Ki67', 'Gene', '17345', (204, 208))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (63, 79))	('cleaved-caspase', 'MPA', (243, 258))
59278	31719634	So far, a role for Haspin in cancer formation has not been formally established, although Haspin inhibitors such as CHR-6494 have been demonstrated to have antitumor activity in cervical cancer, breast cancer and colon cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('Haspin', 'Gene', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Haspin', 'Gene', (19, 25))	('colon cancer', 'Disease', (213, 225))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (29, 35))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('formation', 'biological_process', 'GO:0009058', ('36', '45'))	('breast cancer', 'Disease', (195, 208))	('Haspin', 'Gene', '83903', (90, 96))	('colon cancer', 'Phenotype', 'HP:0003003', (213, 225))	('CHR-6494', 'Var', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', (219, 225))	('inhibitors', 'NegReg', (97, 107))	('tumor', 'Disease', (160, 165))	('Haspin', 'Gene', '83903', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('cancer', 'Disease', (187, 193))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('colon cancer', 'Disease', 'MESH:D015179', (213, 225))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
59282	31719634	This may be explained by previously published data showing that inhibition of Haspin by the small molecule inhibitor CHR-6494 causes mitotic catastrophe.	('Haspin', 'Gene', (78, 84))	('causes', 'Reg', (126, 132))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('133', '152'))	('inhibition', 'Var', (64, 74))	('mitotic', 'CPA', (133, 140))	('Haspin', 'Gene', '83903', (78, 84))
59285	31719634	Such dysregulation of signaling in cells can cause a delay in progression through early mitosis, and it was shown for the sangivamycin derivative 5-iodotubericidin that it displaces the CPC from centromeres.	('dysregulation', 'Var', (5, 18))	('mitosis', 'biological_process', 'GO:0000278', ('88', '95'))	('progression through early mitosis', 'CPA', (62, 95))	('CPC', 'MPA', (186, 189))	('displaces', 'NegReg', (172, 181))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('sangivamycin', 'Chemical', 'MESH:C005699', (122, 134))	('CPC', 'cellular_component', 'GO:0032133', ('186', '189'))	('delay', 'NegReg', (53, 58))
59287	31719634	KMT2D in PDA cells mediates H3K4me3 methylation, and H3K4me3 strongly decreases Histone H3 substrate recognition by Haspin.	('H3K4me3', 'Var', (53, 60))	('H3K4me3', 'Chemical', 'MESH:C024755', (28, 35))	('H3K4me3', 'Protein', (28, 35))	('Histone', 'MPA', (80, 87))	('decreases', 'NegReg', (70, 79))	('H3K4me3', 'Chemical', 'MESH:C024755', (53, 60))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('KMT2D', 'Gene', (0, 5))	('KMT2D', 'Gene', '8085', (0, 5))	('PDA', 'Phenotype', 'HP:0006725', (9, 12))	('Haspin', 'Gene', (116, 122))	('Haspin', 'Gene', '83903', (116, 122))
59380	30006989	20% (236 out of 1,174 patients) of the cohort could be considered as "trial-ineligible" patients, defined by the presence of at least one of the common exclusion criteria in clinical trials at start of first-line therapy: ECOG >=2, renal insufficiency, moderate or severe liver disease, chronic heart failure, or brain metastases.	('heart failure', 'Disease', (295, 308))	('liver disease', 'Phenotype', 'HP:0001392', (272, 285))	('chronic heart failure', 'Phenotype', 'HP:0001635', (287, 308))	('brain metastases', 'Disease', 'MESH:D009362', (313, 329))	('renal insufficiency', 'Phenotype', 'HP:0000083', (232, 251))	('brain metastases', 'Disease', (313, 329))	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (22, 30))	('liver disease', 'Disease', 'MESH:D008107', (272, 285))	('ECOG >=2', 'Var', (222, 230))	('heart failure', 'Disease', 'MESH:D006333', (295, 308))	('renal insufficiency', 'Disease', (232, 251))	('liver disease', 'Disease', (272, 285))	('renal insufficiency', 'Disease', 'MESH:D051437', (232, 251))
59455	30868318	Secondly, recent literature suggests that specific genetic mutations affect tumor metabolism.	('genetic mutations', 'Var', (51, 68))	('affect', 'Reg', (69, 75))	('metabolism', 'biological_process', 'GO:0008152', ('82', '92'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
59460	30868318	In this study, we analyzed a large cohort of patients with proven PDAC scanned with [18F]FDG PET/CT during diagnostic work-up.	('PDAC', 'Chemical', '-', (66, 70))	('patients', 'Species', '9606', (45, 53))	('PDAC', 'Phenotype', 'HP:0006725', (66, 70))	('FDG', 'Chemical', 'MESH:D019788', (89, 92))	('PDAC', 'Disease', (66, 70))	('[18F]FDG', 'Var', (84, 92))
59475	30868318	Pancreatic lesions can present in a wide range of variations on [18F]FDG PET/CT, but commonly, ductal adenocarcinomas are FDG avid beyond the level of liver uptake, with corresponding hypodense lesions on ceCT.	('FDG', 'Chemical', 'MESH:D019788', (122, 125))	('adenocarcinomas', 'Disease', 'MESH:D000230', (102, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('Pancreatic lesions', 'Disease', (0, 18))	('FDG', 'Chemical', 'MESH:D019788', (69, 72))	('Pancreatic lesions', 'Disease', 'MESH:D010182', (0, 18))	('adenocarcinomas', 'Disease', (102, 117))	('uptake', 'biological_process', 'GO:0098739', ('157', '163'))	('[18F]FDG', 'Var', (64, 72))	('uptake', 'biological_process', 'GO:0098657', ('157', '163'))	('ceCT', 'Chemical', '-', (205, 209))
59517	30353690	Downregulation of ACTN4 by small interfering RNA also inhibited the motility and invasiveness of the cells through a decrease in cell protrusions.	('inhibited', 'NegReg', (54, 63))	('RNA', 'cellular_component', 'GO:0005562', ('45', '48'))	('Downregulation', 'NegReg', (0, 14))	('ACTN4', 'Gene', (18, 23))	('small interfering RNA', 'Var', (27, 48))	('cell protrusions', 'CPA', (129, 145))	('ACTN4', 'Gene', '81', (18, 23))	('decrease', 'NegReg', (117, 125))
59553	30353690	The overall survival time for postoperative PDAC patients with WAVE2 overexpression was significantly shorter than that of PDAC patients with low WAVE2 expression (Figure 2A,B, Kaplan-Meier curves, P < 0.001).	('shorter', 'NegReg', (102, 109))	('WAVE2', 'Gene', '10163', (146, 151))	('overexpression', 'Var', (69, 83))	('WAVE2', 'Gene', (63, 68))	('WAVE2', 'Gene', (146, 151))	('patients', 'Species', '9606', (49, 57))	('WAVE2', 'Gene', '10163', (63, 68))	('patients', 'Species', '9606', (128, 136))	('PDAC', 'Chemical', '-', (44, 48))	('survival time', 'CPA', (12, 25))	('PDAC', 'Chemical', '-', (123, 127))
59558	30353690	Fibronectin induces the formation of cell protrusions at the leading edge of PDAC cells.25 S2-013 and PANC-1 cells formed fewer cell protrusions when cultured without fibronectin than when cultured on fibronectin.25 In S2-013 and PANC-1 cells grown on fibronectin, WAVE2 was present in the cytoplasm of the cell bodies as well as in the cell protrusions, each of which contained many peripheral actin structures (Figure 3).	('fibronectin', 'Gene', '2335', (201, 212))	('PANC-1', 'CellLine', 'CVCL:0480', (230, 236))	('fibronectin', 'Gene', '2335', (252, 263))	('cytoplasm', 'cellular_component', 'GO:0005737', ('290', '299'))	('S2-013', 'Var', (219, 225))	('WAVE2', 'Gene', '10163', (265, 270))	('fibronectin', 'Gene', '2335', (167, 178))	('fibronectin', 'Gene', (201, 212))	('Fibronectin', 'Gene', '2335', (0, 11))	('Fibronectin', 'Gene', (0, 11))	('PANC-1', 'CellLine', 'CVCL:0480', (102, 108))	('fibronectin', 'Gene', (252, 263))	('fibronectin', 'Gene', (167, 178))	('PDAC', 'Chemical', '-', (77, 81))	('WAVE2', 'Gene', (265, 270))	('formation', 'biological_process', 'GO:0009058', ('24', '33'))
59559	30353690	WAVE2 was transiently suppressed by transfection with WAVE2 siRNA in S2-013 and PANC-1 cells (Figure 4A).	('suppressed', 'NegReg', (22, 32))	('PANC-1', 'CellLine', 'CVCL:0480', (80, 86))	('WAVE2', 'Gene', (54, 59))	('WAVE2', 'Gene', (0, 5))	('WAVE2', 'Gene', '10163', (54, 59))	('WAVE2', 'Gene', '10163', (0, 5))	('transfection', 'Var', (36, 48))
59575	30353690	ACTN4 was transiently suppressed by transfection with ACTN4 siRNA in S2-013 cells (Figure 6D).	('ACTN4', 'Gene', (54, 59))	('suppressed', 'NegReg', (22, 32))	('ACTN4', 'Gene', (0, 5))	('ACTN4', 'Gene', '81', (54, 59))	('ACTN4', 'Gene', '81', (0, 5))	('transfection', 'Var', (36, 48))
59579	30353690	Suppression of ACTN4 also decreased the level of actin polymerization in the cell protrusions in comparison with the scrambled control (Figure 7C,D).	('ACTN4', 'Gene', '81', (15, 20))	('actin polymerization in', 'MPA', (49, 72))	('Suppression', 'Var', (0, 11))	('actin polymerization', 'biological_process', 'GO:0030041', ('49', '69'))	('ACTN4', 'Gene', (15, 20))	('decreased', 'NegReg', (26, 35))
59580	30353690	The rescue WAVE protein restored the cell protrusions with peripheral actin assembly that was inhibited after WAVE2 silencing in S2-013 and PANC-1 cells (Figure 7E).	('protein', 'cellular_component', 'GO:0003675', ('16', '23'))	('peripheral actin assembly', 'MPA', (59, 84))	('WAVE2', 'Gene', '10163', (110, 115))	('PANC-1', 'CellLine', 'CVCL:0480', (140, 146))	('silencing', 'Var', (116, 125))	('cell protrusions', 'CPA', (37, 53))	('WAVE2', 'Gene', (110, 115))
59583	30353690	Silencing of ACTN4 significantly reduced cell motility (Figure 8A) and invasion (Figure 8B) of S2-013 and PANC-1 cells.	('ACTN4', 'Gene', (13, 18))	('cell motility', 'biological_process', 'GO:0048870', ('41', '54'))	('cell motility', 'CPA', (41, 54))	('invasion', 'CPA', (71, 79))	('ACTN4', 'Gene', '81', (13, 18))	('reduced', 'NegReg', (33, 40))	('PANC-1', 'CellLine', 'CVCL:0480', (106, 112))	('Silencing', 'Var', (0, 9))
59584	30353690	Transfection of a WAVE2 rescue construct into ACTN4 siRNA-transfected S2-013 and PANC-1 cells in which WAVE2 had been suppressed did not rescue cell motility and invasion after silencing of WAVE2 and ACTN4 (Figure 8C,D).	('WAVE2', 'Gene', '10163', (103, 108))	('WAVE2', 'Gene', (190, 195))	('ACTN4', 'Gene', '81', (46, 51))	('WAVE2', 'Gene', '10163', (18, 23))	('ACTN4', 'Gene', '81', (200, 205))	('cell motility', 'CPA', (144, 157))	('cell motility', 'biological_process', 'GO:0048870', ('144', '157'))	('ACTN4', 'Gene', (46, 51))	('WAVE2', 'Gene', (18, 23))	('ACTN4', 'Gene', (200, 205))	('silencing', 'Var', (177, 186))	('WAVE2', 'Gene', (103, 108))	('PANC-1', 'CellLine', 'CVCL:0480', (81, 87))	('WAVE2', 'Gene', '10163', (190, 195))
59588	30353690	Immunocytochemistry showed that phosphorylated p27 was mainly present in the cytoplasm, and it was also localized in the nucleus of S2-013 and PANC-1 cells (Figure 10A).	('p27', 'Gene', (47, 50))	('cytoplasm', 'cellular_component', 'GO:0005737', ('77', '86'))	('PANC-1', 'CellLine', 'CVCL:0480', (143, 149))	('p27', 'Gene', '10534', (47, 50))	('nucleus', 'cellular_component', 'GO:0005634', ('121', '128'))	('phosphorylated', 'Var', (32, 46))
59599	30353690	Suppression of p27 decreased the level of actin polymerization and the formation of cell protrusions compared to control siRNA-transfected S2-013 cells (Figure 11C,D).	('formation of cell protrusions', 'CPA', (71, 100))	('Suppression', 'Var', (0, 11))	('actin polymerization', 'MPA', (42, 62))	('p27', 'Gene', '10534', (15, 18))	('formation', 'biological_process', 'GO:0009058', ('71', '80'))	('decreased', 'NegReg', (19, 28))	('actin polymerization', 'biological_process', 'GO:0030041', ('42', '62'))	('p27', 'Gene', (15, 18))
59602	30353690	Transfection of a WAVE2 rescue construct into p27 siRNA-transfected S2-013 and PANC-1 cells in which WAVE2 had been suppressed did not restore cell motility and invasion after silencing of WAVE2 and p27 (Figure 12C,D).	('WAVE2', 'Gene', '10163', (189, 194))	('silencing', 'Var', (176, 185))	('p27', 'Gene', '10534', (199, 202))	('cell motility', 'biological_process', 'GO:0048870', ('143', '156'))	('WAVE2', 'Gene', '10163', (18, 23))	('cell motility', 'CPA', (143, 156))	('WAVE2', 'Gene', '10163', (101, 106))	('p27', 'Gene', (199, 202))	('p27', 'Gene', '10534', (46, 49))	('invasion', 'CPA', (161, 169))	('not', 'NegReg', (131, 134))	('WAVE2', 'Gene', (18, 23))	('WAVE2', 'Gene', (189, 194))	('p27', 'Gene', (46, 49))	('WAVE2', 'Gene', (101, 106))	('PANC-1', 'CellLine', 'CVCL:0480', (79, 85))
59609	30353690	Univariate and multivariate Cox regression analyses revealed that high WAVE2 expression was an independent predictor of a worse survival outcome.	('expression', 'MPA', (77, 87))	('WAVE2', 'Gene', (71, 76))	('Cox', 'Gene', '9377', (28, 31))	('Cox', 'Gene', (28, 31))	('WAVE2', 'Gene', '10163', (71, 76))	('high', 'Var', (66, 70))
59615	30353690	ACTN4 is an actin-binding protein that is abundantly localized in membrane protrusions, such as lamellipodia and filopodia,39 but not in cell-cell junctions.13 The expression of ACTN4 in the cytoplasm is associated with worse survival after resection of PDAC and increased lymph node metastases in PDAC.18 Knockdown of ACTN4 by siRNAs in PDAC cells reduces motility and invasiveness17 and inhibits the formation of microvilli,13 indicating that ACTN4 may play integral roles in protrusion formation, motility, and invasion of PDAC cells.	('PDAC', 'Chemical', '-', (338, 342))	('microvilli', 'cellular_component', 'GO:0005902', ('415', '425'))	('motility', 'CPA', (357, 365))	('PDAC', 'Chemical', '-', (298, 302))	('cytoplasm', 'cellular_component', 'GO:0005737', ('191', '200'))	('ACTN4', 'Gene', (178, 183))	('ACTN4', 'Gene', '81', (178, 183))	('Knockdown', 'Var', (306, 315))	('actin-binding', 'molecular_function', 'GO:0003779', ('12', '25'))	('reduces', 'NegReg', (349, 356))	('ACTN4', 'Gene', (319, 324))	('ACTN4', 'Gene', (0, 5))	('formation', 'biological_process', 'GO:0009058', ('489', '498'))	('formation', 'biological_process', 'GO:0009058', ('402', '411'))	('PDAC', 'Chemical', '-', (526, 530))	('ACTN4', 'Gene', '81', (319, 324))	('ACTN4', 'Gene', '81', (0, 5))	('metastases', 'Disease', 'MESH:D009362', (284, 294))	('ACTN4', 'Gene', (445, 450))	('membrane', 'cellular_component', 'GO:0016020', ('66', '74'))	('PDAC', 'Chemical', '-', (254, 258))	('inhibits', 'NegReg', (389, 397))	('ACTN4', 'Gene', '81', (445, 450))	('metastases', 'Disease', (284, 294))	('invasiveness17', 'CPA', (370, 384))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))
59617	30353690	Similar to WAVE2, knockdown of ACTN4 consistently suppressed the formation of cell protrusions driven by actin polymerization and inhibited the motility and invasion of PDAC cells.	('WAVE2', 'Gene', '10163', (11, 16))	('knockdown', 'Var', (18, 27))	('suppressed', 'NegReg', (50, 60))	('inhibited', 'NegReg', (130, 139))	('ACTN4', 'Gene', (31, 36))	('WAVE2', 'Gene', (11, 16))	('formation of cell protrusions', 'CPA', (65, 94))	('PDAC', 'Chemical', '-', (169, 173))	('actin polymerization', 'biological_process', 'GO:0030041', ('105', '125'))	('actin polymerization', 'MPA', (105, 125))	('ACTN4', 'Gene', '81', (31, 36))	('formation', 'biological_process', 'GO:0009058', ('65', '74'))
59625	30353690	In addition, this study indicated that inhibition of (a) WAVE2, (b) the binding of WAVE2 and ACTN4, (c) the binding of ACTN4 and actin filaments, or (d) some combination thereof may be effective for development of new therapeutic strategies, because any such therapy would inhibit WAVE2-mediated cell motility and invasion of PDAC cells.	('binding', 'Interaction', (108, 115))	('WAVE2', 'Gene', (83, 88))	('invasion of PDAC cells', 'CPA', (314, 336))	('WAVE2', 'Gene', (281, 286))	('WAVE2', 'Gene', '10163', (83, 88))	('inhibition', 'Var', (39, 49))	('WAVE2', 'Gene', (57, 62))	('binding', 'Interaction', (72, 79))	('WAVE2', 'Gene', '10163', (281, 286))	('binding', 'molecular_function', 'GO:0005488', ('108', '115'))	('PDAC', 'Chemical', '-', (326, 330))	('cell motility', 'biological_process', 'GO:0048870', ('296', '309'))	('ACTN4', 'Gene', (119, 124))	('ACTN4', 'Gene', (93, 98))	('ACTN4', 'Gene', '81', (119, 124))	('inhibit', 'NegReg', (273, 280))	('binding', 'molecular_function', 'GO:0005488', ('72', '79'))	('WAVE2', 'Gene', '10163', (57, 62))	('ACTN4', 'Gene', '81', (93, 98))
59633	30041660	Our data show that forced expression of miR-141 or miR-200c suppressed invasion and metastasis of PDAC cells both in vitro and in xenograft and identified WIPF1 as a direct target of miR-141 and miR-200c.	('miR-141', 'Var', (40, 47))	('suppressed', 'NegReg', (60, 70))	('WIPF1', 'Gene', (155, 160))	('PDAC', 'Phenotype', 'HP:0006725', (98, 102))	('miR-141', 'Var', (183, 190))	('WIPF1', 'Gene', '7456', (155, 160))	('miR-200c', 'Var', (195, 203))	('miR-200c', 'Gene', (51, 59))	('PDAC', 'Chemical', '-', (98, 102))
59634	30041660	Both miR-141 and miR-200c inhibit WIPF1 by directly interacting with its 3'-untranslated region.	('interacting', 'Interaction', (52, 63))	('miR-141', 'Var', (5, 12))	('inhibit', 'NegReg', (26, 33))	('WIPF1', 'Gene', '7456', (34, 39))	('miR-200c', 'Var', (17, 25))	('WIPF1', 'Gene', (34, 39))
59635	30041660	Remarkably, silencing of WIPF1 blocked PDAC growth and metastasis both in vitro and in vivo, whereas forced WIPF1 overexpression antagonized the tumor suppressive effect of miR-141/200c.	('overexpression', 'PosReg', (114, 128))	('WIPF1', 'Gene', (25, 30))	('metastasis', 'CPA', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('WIPF1', 'Gene', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('PDAC', 'Phenotype', 'HP:0006725', (39, 43))	('silencing', 'Var', (12, 21))	('tumor', 'Disease', (145, 150))	('WIPF1', 'Gene', '7456', (25, 30))	('WIPF1', 'Gene', '7456', (108, 113))	('blocked', 'NegReg', (31, 38))	('PDAC growth', 'CPA', (39, 50))	('PDAC', 'Chemical', '-', (39, 43))	('antagonized', 'NegReg', (129, 140))
59636	30041660	Additionally, by using TCGA database we showed that high expression of WIPF1 correlated with poor survival in patients with PDAC.	('WIPF1', 'Gene', '7456', (71, 76))	('PDAC', 'Chemical', '-', (124, 128))	('WIPF1', 'Gene', (71, 76))	('high', 'Var', (52, 56))	('PDAC', 'Phenotype', 'HP:0006725', (124, 128))	('PDAC', 'Disease', (124, 128))	('poor', 'NegReg', (93, 97))	('patients', 'Species', '9606', (110, 118))
59637	30041660	Moreover, we show that miR-141 and miR-200c blocked YAP/TAZ expression by suppressing WIPF1.	('suppressing', 'NegReg', (74, 85))	('WIPF1', 'Gene', (86, 91))	('blocked', 'NegReg', (44, 51))	('YAP', 'Gene', (52, 55))	('YAP', 'Gene', '10413', (52, 55))	('TAZ', 'Gene', '6901', (56, 59))	('WIPF1', 'Gene', '7456', (86, 91))	('miR-200c', 'Var', (35, 43))	('TAZ', 'Gene', (56, 59))	('miR-141', 'Var', (23, 30))
59638	30041660	We have identified WIPF1 as an oncoprotein in PDAC and a direct target of miR-141/miR-200c.	('PDAC', 'Disease', (46, 50))	('PDAC', 'Phenotype', 'HP:0006725', (46, 50))	('miR-141/miR-200c', 'Var', (74, 90))	('WIPF1', 'Gene', (19, 24))	('PDAC', 'Chemical', '-', (46, 50))	('WIPF1', 'Gene', '7456', (19, 24))
59646	30041660	Downregulation of miR-141, miR-200a, miR-200b and miR-200c have been shown to promote cancer cell proliferation and metastasis in prostate cancer, gastric cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma.	('prostate cancer', 'Phenotype', 'HP:0012125', (130, 145))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (163, 187))	('Downregulation', 'NegReg', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('metastasis in prostate cancer', 'Disease', 'MESH:D009362', (116, 145))	('miR-200a', 'Gene', (27, 35))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (163, 187))	('cell proliferation', 'biological_process', 'GO:0008283', ('93', '111'))	('neck squamous cell carcinoma', 'Disease', (198, 226))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (203, 226))	('cancer', 'Disease', (86, 92))	('miR-141', 'Gene', (18, 25))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (198, 226))	('promote', 'PosReg', (78, 85))	('miR-200b', 'Gene', (37, 45))	('miR-200c', 'Var', (50, 58))	('hepatocellular carcinoma', 'Disease', (163, 187))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('neck', 'cellular_component', 'GO:0044326', ('198', '202'))	('gastric cancer', 'Disease', (147, 161))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', (139, 145))	('miR-200a', 'Gene', '406983', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('metastasis in prostate cancer', 'Disease', (116, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (189, 226))	('miR-200b', 'Gene', '406984', (37, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
59647	30041660	In addition, miR-200c/429 was shown to suppress tumorignecity and invasion of breast cancer stem cells.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('tumor', 'Disease', (48, 53))	('miR-200c/429', 'Var', (13, 25))	('invasion of', 'CPA', (66, 77))	('suppress', 'NegReg', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('breast cancer', 'Disease', (78, 91))
59648	30041660	A study showed that miR-200a and miR-200b were hypomethylated in pancreatic cancer, distinct from the other findings in other malignancies suggesting that miR-200a/b may promote cell proliferation in pancreatic cancer.	('miR-200b', 'Gene', (33, 41))	('cell proliferation', 'CPA', (178, 196))	('hypomethylated', 'Var', (47, 61))	('miR-200a', 'Gene', (155, 163))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (200, 217))	('miR-200a', 'Gene', (20, 28))	('miR-200b', 'Gene', '406984', (33, 41))	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('malignancies', 'Disease', (126, 138))	('miR-200a', 'Gene', '406983', (155, 163))	('pancreatic cancer', 'Disease', 'MESH:D010190', (200, 217))	('pancreatic cancer', 'Disease', (65, 82))	('miR-200a', 'Gene', '406983', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('pancreatic cancer', 'Disease', (200, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cell proliferation', 'biological_process', 'GO:0008283', ('178', '196'))	('promote', 'PosReg', (170, 177))
59652	30041660	WIPF1 binds to a region of Wiskott-Aldrich syndrome protein (WASP) that is frequently mutated in Wiskott-Aldrich syndrome (WAS).	('Wiskott-Aldrich syndrome protein', 'Gene', '7454', (27, 59))	('WAS', 'Disease', 'None', (61, 64))	('mutated', 'Var', (86, 93))	('Wiskott-Aldrich syndrome', 'Disease', (97, 121))	('WAS', 'Disease', (61, 64))	('WAS', 'Disease', 'None', (123, 126))	('WAS', 'Disease', (123, 126))	('WIPF1', 'Gene', '7456', (0, 5))	('Wiskott-Aldrich syndrome', 'Disease', 'MESH:D014923', (97, 121))	('Wiskott-Aldrich syndrome protein', 'Gene', (27, 59))	('WASP', 'Gene', (61, 65))	('WASP', 'Gene', '7454', (61, 65))	('Wiskott-Aldrich syndrome', 'Disease', 'MESH:D014923', (27, 51))	('WIPF1', 'Gene', (0, 5))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
59660	30041660	We show that miR-141/200c is epigenetically silenced in PDAC both in vitro and in vivo.	('PDAC', 'Phenotype', 'HP:0006725', (56, 60))	('PDAC', 'Chemical', '-', (56, 60))	('miR-141/200c', 'Var', (13, 25))	('PDAC', 'Gene', (56, 60))
59661	30041660	Furthermore, we identified WIPF1 as a direct target of miR-141/200c and demonstrated that miR-141/200c interacts with the 3'-untranslated region of WIPF1 to inhibit WIPF1-YAP/TAZ pathway in PDAC, finally suppressing PDAC growth and metastasis.	('PDAC', 'Phenotype', 'HP:0006725', (190, 194))	('WIPF1', 'Gene', (27, 32))	('PDAC growth', 'CPA', (216, 227))	('WIPF1', 'Gene', '7456', (165, 170))	('inhibit', 'NegReg', (157, 164))	('interacts', 'Interaction', (103, 112))	('WIPF1', 'Gene', '7456', (148, 153))	('WIPF1', 'Gene', (165, 170))	('PDAC', 'Chemical', '-', (216, 220))	('YAP', 'Gene', (171, 174))	('WIPF1', 'Gene', (148, 153))	('PDAC', 'Phenotype', 'HP:0006725', (216, 220))	('TAZ', 'Gene', '6901', (175, 178))	('TAZ', 'Gene', (175, 178))	('WIPF1', 'Gene', '7456', (27, 32))	('PDAC', 'Chemical', '-', (190, 194))	('YAP', 'Gene', '10413', (171, 174))	('suppressing', 'NegReg', (204, 215))	('miR-141/200c', 'Var', (90, 102))
59682	30041660	The region of the 3'-untranslated region (UTR) of human WIPF1 containing three putative miR-200c binding sites and one putative miR-141 binding site were selected to generate four mutant variants (TargetScan, Additional file 1: Figure S1A and B).	('binding', 'molecular_function', 'GO:0005488', ('97', '104'))	('WIPF1', 'Gene', (56, 61))	('mutant', 'Gene', '4594', (180, 186))	('binding', 'molecular_function', 'GO:0005488', ('136', '143'))	('variants', 'Var', (187, 195))	('binding', 'Interaction', (97, 104))	('mutant', 'Gene', (180, 186))	('WIPF1', 'Gene', '7456', (56, 61))	('human', 'Species', '9606', (50, 55))
59683	30041660	Mutant 3'-UTR of human WIPF1 mRNA was generated by site-specific mutagenesis of the wild-type 3'-UTR segment of human WIPF1 mRNA using altered sequence in the complementary site (Additional file 1: Table S1B).	('WIPF1', 'Gene', '7456', (23, 28))	('WIPF1', 'Gene', '7456', (118, 123))	('Mutant', 'Gene', (0, 6))	('Mutant', 'Gene', '4594', (0, 6))	('mutagenesis', 'biological_process', 'GO:0006280', ('65', '76'))	('human', 'Species', '9606', (17, 22))	('mutagenesis', 'Var', (65, 76))	('WIPF1', 'Gene', (23, 28))	('WIPF1', 'Gene', (118, 123))	('human', 'Species', '9606', (112, 117))
59705	30041660	In contrast, the levels of the CpG methylation of miR-141 and miR-200c were significantly higher in human PDAC.	('PDAC', 'Phenotype', 'HP:0006725', (106, 110))	('human', 'Species', '9606', (100, 105))	('miR-200c', 'Var', (62, 70))	('PDAC', 'Chemical', '-', (106, 110))	('higher', 'PosReg', (90, 96))	('CpG methylation', 'MPA', (31, 46))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('miR-141', 'Var', (50, 57))
59706	30041660	To confirm this result, we derived the mean values from all the CpG sites and found that the levels of CpG methylation of miR-141/200c were significantly higher in the PDAC tissues compared to the surrounding non-cancerous tissues (Fig.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('miR-141/200c', 'Var', (122, 134))	('PDAC', 'Chemical', '-', (168, 172))	('higher', 'PosReg', (154, 160))	('methylation', 'biological_process', 'GO:0032259', ('107', '118'))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('methylation', 'MPA', (107, 118))	('PDAC', 'Phenotype', 'HP:0006725', (168, 172))	('cancer', 'Disease', (213, 219))	('PDAC', 'Disease', (168, 172))
59710	30041660	As expected, the relative expression levels of miR-141 and miR-200c in PDAC were significantly lower than that of the non-cancerous tissues (Fig.	('miR-141', 'Var', (47, 54))	('lower', 'NegReg', (95, 100))	('PDAC', 'Disease', (71, 75))	('PDAC', 'Phenotype', 'HP:0006725', (71, 75))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('PDAC', 'Chemical', '-', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('expression levels', 'MPA', (26, 43))	('miR-200c', 'Var', (59, 67))
59713	30041660	We treated the pancreatic cell lines with the DNA-demethylating agent 5-Aza-dC and found that 5-Aza-dC decreased the level of promoter methylation of miR-141 and miR-200c (Fig.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('miR-141', 'Var', (150, 157))	('miR-200c', 'Var', (162, 170))	('pancreatic', 'Disease', (15, 25))	('5-Aza-dC', 'Chemical', '-', (70, 78))	('5-Aza-dC', 'Chemical', '-', (94, 102))	('decreased', 'NegReg', (103, 112))	('pancreatic', 'Disease', 'MESH:D010195', (15, 25))	('methylation', 'biological_process', 'GO:0032259', ('135', '146'))	('promoter methylation', 'MPA', (126, 146))
59714	30041660	These results indicated that CpG hypermethylation silenced the expression of miR-141 and miR-200c in PDAC.	('PDAC', 'Phenotype', 'HP:0006725', (101, 105))	('miR-141', 'Gene', (77, 84))	('silenced', 'NegReg', (50, 58))	('expression', 'MPA', (63, 73))	('PDAC', 'Chemical', '-', (101, 105))	('hypermethylation', 'Var', (33, 49))	('miR-200c', 'Var', (89, 97))
59715	30041660	To determine whether epigenetically regulated miR-141/200c confers tumor-suppressive function in PDAC cells, we stably infected BxPC-3 and PANC-1 cells with a retroviral construct carrying miR-141, miR-200c or with an empty vector as control.	('PANC-1', 'CellLine', 'CVCL:0480', (139, 145))	('miR-200c', 'Var', (198, 206))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('BxPC-3', 'CellLine', 'CVCL:0186', (128, 134))	('PDAC', 'Chemical', '-', (97, 101))	('miR-141', 'Var', (189, 196))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('PDAC', 'Phenotype', 'HP:0006725', (97, 101))
59716	30041660	We verified the overexpression of these constructs (Additional file 1: Figure S3A and B) and showed that forced expression of anti-miR-141 and anti-miR-200c suppressed the expression of miR-141 and miR-200c (Additional file 1: Figure S3C and D).	('S3A and B', 'Gene', '6189', (78, 87))	('miR-200c', 'Gene', (198, 206))	('suppressed', 'NegReg', (157, 167))	('expression', 'MPA', (172, 182))	('miR-141', 'MPA', (186, 193))	('anti-miR-141', 'Var', (126, 138))	('anti-miR-200c', 'Var', (143, 156))
59717	30041660	Using xenograft by injecting the PDAC cells subcutaneously into the athymic nude mice, we found that overexpression of miR-141 but not miR-200c significantly suppressed the tumor growth (Fig.	('miR-141', 'Var', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('PDAC', 'Phenotype', 'HP:0006725', (33, 37))	('suppressed', 'NegReg', (158, 168))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('PDAC', 'Chemical', '-', (33, 37))	('nude mice', 'Species', '10090', (76, 85))
59718	30041660	We next investigated the role of miR-141 and miR-200c on the cell migration and invasion of PDAC using transwell chambers with or without Matrigel-coated membranes.	('miR-141', 'Var', (33, 40))	('PDAC', 'Phenotype', 'HP:0006725', (92, 96))	('investigated', 'Reg', (8, 20))	('cell migration', 'biological_process', 'GO:0016477', ('61', '75'))	('PDAC', 'Chemical', '-', (92, 96))	('miR-200c', 'Var', (45, 53))
59719	30041660	Both miR-141 and miR-200c suppressed the migration and invasion of PANC-1 and BxPC-3 cells (Fig.	('miR-141', 'Var', (5, 12))	('migration', 'CPA', (41, 50))	('suppressed', 'NegReg', (26, 36))	('PANC-1', 'CellLine', 'CVCL:0480', (67, 73))	('invasion', 'CPA', (55, 63))	('miR-200c', 'Var', (17, 25))	('BxPC-3', 'CellLine', 'CVCL:0186', (78, 84))
59720	30041660	We also determined that miR-141 and miR-200c suppressed the expression of epithelial-to-mesenchymal transition (EMT) markers ZEB1 and Vimentin while stimulated the expression of E-cadherin, a suppressor of EMT (Fig.	('expression', 'MPA', (60, 70))	('Vimentin', 'cellular_component', 'GO:0045098', ('134', '142'))	('ZEB1', 'Gene', (125, 129))	('Vimentin', 'Gene', '7431', (134, 142))	('miR-200c', 'Var', (36, 44))	('EMT', 'biological_process', 'GO:0001837', ('206', '209'))	('epithelial-to-mesenchymal transition', 'CPA', (74, 110))	('E-cadherin', 'Gene', (178, 188))	('E-cadherin', 'Gene', '999', (178, 188))	('Vimentin', 'Gene', (134, 142))	('cadherin', 'molecular_function', 'GO:0008014', ('180', '188'))	('suppressed', 'NegReg', (45, 55))	('EMT', 'biological_process', 'GO:0001837', ('112', '115'))	('ZEB1', 'Gene', '6935', (125, 129))	('Vimentin', 'cellular_component', 'GO:0045099', ('134', '142'))	('expression', 'MPA', (164, 174))	('miR-141', 'Var', (24, 31))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('74', '110'))	('stimulated', 'PosReg', (149, 159))
59721	30041660	These results indicate that both miR-141 and miR-200c suppress the stemness of PDAC cells.	('stemness', 'Disease', 'MESH:D020295', (67, 75))	('stemness', 'Disease', (67, 75))	('miR-141', 'Var', (33, 40))	('PDAC', 'Chemical', '-', (79, 83))	('suppress', 'NegReg', (54, 62))	('PDAC', 'Phenotype', 'HP:0006725', (79, 83))	('miR-200c', 'Var', (45, 53))
59722	30041660	To investigate the role of miR-141 and miR-200c on PDAC metastasis, PDAC cells were infected with a lentiviral vector expressing miR-141 or miR-200c, or an empty vector as control and the resulting cells were then injected into the spleens of NOD/SCID mice.	('mice', 'Species', '10090', (252, 256))	('PDAC', 'Chemical', '-', (51, 55))	('PDAC', 'Phenotype', 'HP:0006725', (68, 72))	('SCID', 'Disease', (247, 251))	('SCID', 'Disease', 'MESH:D053632', (247, 251))	('NOD', 'Gene', '1822', (243, 246))	('PDAC', 'Phenotype', 'HP:0006725', (51, 55))	('miR-200c', 'Var', (140, 148))	('PDAC', 'Chemical', '-', (68, 72))	('NOD', 'Gene', (243, 246))	('miR-141', 'Var', (129, 136))
59724	30041660	However the mice injected with the cells overexpressing miR-141 or miR-200c had significantly lower number of metastatic nodules in the liver and lungs compared with the mice injected with the cells infected with an empty vector (Fig.	('mice', 'Species', '10090', (12, 16))	('metastatic nodules in the liver', 'CPA', (110, 141))	('miR-200c', 'Var', (67, 75))	('lower', 'NegReg', (94, 99))	('mice', 'Species', '10090', (170, 174))	('miR-141', 'Var', (56, 63))
59725	30041660	These findings demonstrate that miR-141 but not miR-200c retained the ability to inhibit the cell proliferation in vitro and the growth of primary tumor in xenograft, while both were capable of suppressing the migration, invasion and metastasis of PDAC cells.	('suppressing', 'NegReg', (194, 205))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('migration', 'CPA', (210, 219))	('PDAC', 'Chemical', '-', (248, 252))	('inhibit', 'NegReg', (81, 88))	('cell proliferation', 'biological_process', 'GO:0008283', ('93', '111'))	('cell proliferation in vitro', 'CPA', (93, 120))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('PDAC', 'Phenotype', 'HP:0006725', (248, 252))	('miR-141', 'Var', (32, 39))
59726	30041660	To investigate the mechanism underlying the tumor suppressive function of miR-141 and miR-200c, we set out to identify the putative binding sites of their potential target genes.	('miR-141', 'Var', (74, 81))	('miR-200c', 'Var', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('binding', 'molecular_function', 'GO:0005488', ('132', '139'))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
59729	30041660	5a, the relative luciferase activity with WT but not the mutant 3'-UTR of WIPF1 was significantly suppressed by the miR-141 or miR-200c mimic.	('miR-200c mimic', 'Var', (127, 141))	('luciferase activity', 'molecular_function', 'GO:0045289', ('17', '36'))	('suppressed', 'NegReg', (98, 108))	('luciferase activity', 'molecular_function', 'GO:0050397', ('17', '36'))	('activity', 'MPA', (28, 36))	('luciferase activity', 'molecular_function', 'GO:0050248', ('17', '36'))	('miR-141', 'Var', (116, 123))	('WIPF1', 'Gene', (74, 79))	('luciferase', 'Enzyme', (17, 27))	('luciferase activity', 'molecular_function', 'GO:0047077', ('17', '36'))	('mutant', 'Gene', '4594', (57, 63))	('WIPF1', 'Gene', '7456', (74, 79))	('luciferase activity', 'molecular_function', 'GO:0047712', ('17', '36'))	('mutant', 'Gene', (57, 63))
59730	30041660	These results indicate that both miR-141 and miR-200c suppress WIPF1 expression through binding to their binding sites on the 3'-UTR of WIPF1.	('binding', 'molecular_function', 'GO:0005488', ('105', '112'))	('WIPF1', 'Gene', (63, 68))	('miR-141', 'Var', (33, 40))	('binding', 'molecular_function', 'GO:0005488', ('88', '95'))	('WIPF1', 'Gene', '7456', (136, 141))	('suppress', 'NegReg', (54, 62))	('expression', 'MPA', (69, 79))	('binding', 'Interaction', (88, 95))	('WIPF1', 'Gene', '7456', (63, 68))	('WIPF1', 'Gene', (136, 141))	('miR-200c', 'Var', (45, 53))	('binding', 'Interaction', (105, 112))
59731	30041660	Consistent with these results, using HPDE as positive control we found that both the mRNA and protein levels of WIPF1 in both PANC-1 and BxPC-3 cells were downregulated by the miR-141 and miR-200c mimics, while upregulated by anti-miR-141 and anti-miR-200c (Fig.	('WIPF1', 'Gene', '7456', (112, 117))	('upregulated', 'PosReg', (211, 222))	('protein levels', 'MPA', (94, 108))	('HPDE', 'Chemical', '-', (37, 41))	('WIPF1', 'Gene', (112, 117))	('PANC-1', 'CellLine', 'CVCL:0480', (126, 132))	('anti-miR-141', 'Var', (226, 238))	('BxPC-3', 'CellLine', 'CVCL:0186', (137, 143))	('downregulated', 'NegReg', (155, 168))	('anti-miR-200c', 'Var', (243, 256))	('miR-141', 'Var', (176, 183))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
59732	30041660	To further confirm that WIPF1 is the target of miR-141/200c, we investigated if there is a correlation between their expression.	('WIPF1', 'Gene', '7456', (24, 29))	('WIPF1', 'Gene', (24, 29))	('miR-141/200c', 'Var', (47, 59))
59737	30041660	To investigate the functional roles of WIPF1 in PDAC, we constructed a cell line with stable knockdown of WIPF1 using a lentivirus vector expressing a short hairpin WIPF1 (shWIPF1) and a control cell line with vector only (shCtrl).	('WIPF1', 'Gene', (174, 179))	('knockdown', 'Var', (93, 102))	('WIPF1', 'Gene', '7456', (39, 44))	('WIPF1', 'Gene', '7456', (106, 111))	('PDAC', 'Chemical', '-', (48, 52))	('WIPF1', 'Gene', '7456', (165, 170))	('WIPF1', 'Gene', '7456', (174, 179))	('WIPF1', 'Gene', (39, 44))	('WIPF1', 'Gene', (106, 111))	('PDAC', 'Phenotype', 'HP:0006725', (48, 52))	('WIPF1', 'Gene', (165, 170))
59740	30041660	Knockdown of WIPF1 also inhibited migration and invasion of both PANC-1 and BxPC-3 cells (Fig.	('Knockdown', 'Var', (0, 9))	('BxPC-3', 'CellLine', 'CVCL:0186', (76, 82))	('WIPF1', 'Gene', '7456', (13, 18))	('inhibited', 'NegReg', (24, 33))	('WIPF1', 'Gene', (13, 18))	('invasion', 'CPA', (48, 56))	('migration', 'CPA', (34, 43))	('PANC-1', 'CellLine', 'CVCL:0480', (65, 71))
59741	30041660	Moreover, knockdown of WIPF1 decreased the number of metastatic nodules in the liver and lungs (Fig.	('WIPF1', 'Gene', '7456', (23, 28))	('WIPF1', 'Gene', (23, 28))	('knockdown', 'Var', (10, 19))	('decreased', 'NegReg', (29, 38))
59743	30041660	To determine whether miR-141/200c targets WIPF1 to suppress the invasion and metastasis of PDAC cells, PANC-1 and BxPC-3 cells were transfected with a plasmid carrying the cDNA that encodes the entire coding sequence of WIPF1 but with the deletion of the 3'-UTR (WIPF1/- 3'-UTR).	('PDAC', 'Chemical', '-', (91, 95))	('suppress', 'NegReg', (51, 59))	('WIPF1', 'Gene', (220, 225))	('WIPF1', 'Gene', (42, 47))	('WIPF1', 'Gene', '7456', (263, 268))	('miR-141/200c', 'Var', (21, 33))	('BxPC-3', 'CellLine', 'CVCL:0186', (114, 120))	('deletion', 'Var', (239, 247))	('WIPF1', 'Gene', '7456', (42, 47))	('PDAC', 'Phenotype', 'HP:0006725', (91, 95))	('WIPF1', 'Gene', '7456', (220, 225))	('WIPF1', 'Gene', (263, 268))	('PANC-1', 'CellLine', 'CVCL:0480', (103, 109))
59744	30041660	We found that WIPF1/- 3'-UTR was resistant to the suppressive effect of miR-141 and miR-200c on its expression (Additional file 1: Figure S7A).	('miR-141', 'Var', (72, 79))	('miR-200c', 'Var', (84, 92))	('WIPF1', 'Gene', '7456', (14, 19))	('WIPF1', 'Gene', (14, 19))
59745	30041660	Moreover, WIPF1/- 3'-UTR overcame the suppressive effect of miR-141/200c on the migration, invasion and metastasis of PDAC cells (Fig.	('WIPF1', 'Gene', (10, 15))	('PDAC', 'Phenotype', 'HP:0006725', (118, 122))	('PDAC', 'Disease', (118, 122))	('metastasis', 'CPA', (104, 114))	('invasion', 'CPA', (91, 99))	('migration', 'CPA', (80, 89))	('WIPF1', 'Gene', '7456', (10, 15))	('PDAC', 'Chemical', '-', (118, 122))	('miR-141/200c', 'Var', (60, 72))
59746	30041660	These results demonstrate that WIPF1 is indeed a functional target of miR-141/200c.	('WIPF1', 'Gene', '7456', (31, 36))	('miR-141/200c', 'Var', (70, 82))	('WIPF1', 'Gene', (31, 36))
59750	30041660	Using Kaplan-Meier estimate, we found that the patients with low WIPF1 expression was associated with significantly longer OS compared to the patients with high WIPF1 expression (P = 0.03).	('longer', 'PosReg', (116, 122))	('WIPF1', 'Gene', '7456', (161, 166))	('low', 'NegReg', (61, 64))	('expression', 'Var', (71, 81))	('patients', 'Species', '9606', (47, 55))	('WIPF1', 'Gene', '7456', (65, 70))	('patients', 'Species', '9606', (142, 150))	('WIPF1', 'Gene', (161, 166))	('OS', 'Chemical', '-', (123, 125))	('WIPF1', 'Gene', (65, 70))
59751	30041660	The median OS was 38 months in the low WIPF1 expression group versus 19 months in the high WIPF1 expression group (Fig.	('WIPF1', 'Gene', '7456', (91, 96))	('OS', 'Chemical', '-', (11, 13))	('WIPF1', 'Gene', (39, 44))	('WIPF1', 'Gene', (91, 96))	('low', 'Var', (35, 38))	('WIPF1', 'Gene', '7456', (39, 44))
59752	30041660	This result indicates that WIPF1 expression is associated with a more aggressive disease course and possibly resistance to treatment in human PDAC.	('human', 'Species', '9606', (136, 141))	('aggressive disease', 'Disease', (70, 88))	('WIPF1', 'Gene', (27, 32))	('expression', 'Var', (33, 43))	('associated with', 'Reg', (47, 62))	('PDAC', 'Chemical', '-', (142, 146))	('PDAC', 'Phenotype', 'HP:0006725', (142, 146))	('WIPF1', 'Gene', '7456', (27, 32))	('aggressive disease', 'Disease', 'MESH:D001523', (70, 88))
59754	30041660	Previously it was also shown that miR-141 inhibited the expression of YAP1 in pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('YAP1', 'Gene', (70, 74))	('YAP1', 'Gene', '10413', (70, 74))	('expression', 'MPA', (56, 66))	('inhibited', 'NegReg', (42, 51))	('miR-141', 'Var', (34, 41))	('pancreatic cancer', 'Disease', (78, 95))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
59755	30041660	We investigated if miR-141/200c suppress YAP/TAZ expression by inhibiting WIPF1.	('YAP', 'Gene', (41, 44))	('suppress', 'NegReg', (32, 40))	('WIPF1', 'Gene', (74, 79))	('TAZ', 'Gene', '6901', (45, 48))	('inhibiting', 'NegReg', (63, 73))	('TAZ', 'Gene', (45, 48))	('YAP', 'Gene', '10413', (41, 44))	('WIPF1', 'Gene', '7456', (74, 79))	('miR-141/200c', 'Var', (19, 31))
59756	30041660	We found that expression of both YAP and TAZ was indeed suppressed by the overexpression of miR-141 or miR-200c in both PANC-1 and BxPC3 cells (Fig.	('miR-200c', 'Var', (103, 111))	('miR-141', 'Var', (92, 99))	('BxPC3', 'CellLine', 'CVCL:0186', (131, 136))	('overexpression', 'PosReg', (74, 88))	('TAZ', 'Gene', (41, 44))	('TAZ', 'Gene', '6901', (41, 44))	('YAP', 'Gene', '10413', (33, 36))	('suppressed', 'NegReg', (56, 66))	('expression', 'MPA', (14, 24))	('PANC-1', 'CellLine', 'CVCL:0480', (120, 126))	('YAP', 'Gene', (33, 36))
59757	30041660	While miR-141 or miR-200c inhibitor (anti-miR-141 or anti-miR-200c) increased the expression of YAP and TAZ (Fig.	('YAP', 'Gene', '10413', (96, 99))	('YAP', 'Gene', (96, 99))	('anti-miR-141', 'Var', (37, 49))	('expression', 'MPA', (82, 92))	('TAZ', 'Gene', '6901', (104, 107))	('anti-miR-200c', 'Var', (53, 66))	('TAZ', 'Gene', (104, 107))	('increased', 'PosReg', (68, 77))
59759	30041660	In addition, forced expression of the mutant WIPF1 with the deletion of its 3'-UTR (WIPF1/- 3'-UTR) stimulated the expression of YAP/TAZ and blocked the suppressive effect of miR141/200c on YAP/TAZ expression (Fig.	('TAZ', 'Gene', '6901', (133, 136))	('TAZ', 'Gene', (133, 136))	('mutant', 'Gene', '4594', (38, 44))	('YAP', 'Gene', '10413', (129, 132))	('YAP', 'Gene', (190, 193))	('stimulated', 'PosReg', (100, 110))	('mutant', 'Gene', (38, 44))	('miR141', 'Gene', '406933', (175, 181))	('TAZ', 'Gene', (194, 197))	('TAZ', 'Gene', '6901', (194, 197))	('WIPF1', 'Gene', '7456', (84, 89))	('deletion', 'Var', (60, 68))	('YAP', 'Gene', '10413', (190, 193))	('WIPF1', 'Gene', (84, 89))	('WIPF1', 'Gene', '7456', (45, 50))	('YAP', 'Gene', (129, 132))	('miR141', 'Gene', (175, 181))	('WIPF1', 'Gene', (45, 50))	('expression', 'MPA', (115, 125))	('blocked', 'NegReg', (141, 148))
59760	30041660	Hence, WIPF1 mediates the suppressive effect of miR-141/200c on YAP/TAZ.	('WIPF1', 'Gene', (7, 12))	('TAZ', 'Gene', '6901', (68, 71))	('TAZ', 'Gene', (68, 71))	('suppressive', 'NegReg', (26, 37))	('YAP', 'Gene', '10413', (64, 67))	('WIPF1', 'Gene', '7456', (7, 12))	('miR-141/200c', 'Var', (48, 60))	('YAP', 'Gene', (64, 67))
59761	30041660	These results demonstrate that silencing of miR-141/200c stimulates PDAC growth and metastasis by activating the WIPF1-YAP/TAZ pathway, leading to poor patient survival (Fig.	('silencing', 'Var', (31, 40))	('TAZ', 'Gene', '6901', (123, 126))	('stimulates', 'PosReg', (57, 67))	('PDAC', 'Phenotype', 'HP:0006725', (68, 72))	('TAZ', 'Gene', (123, 126))	('WIPF1', 'Gene', '7456', (113, 118))	('YAP', 'Gene', '10413', (119, 122))	('metastasis', 'CPA', (84, 94))	('patient', 'Species', '9606', (152, 159))	('poor', 'NegReg', (147, 151))	('patient survival', 'CPA', (152, 168))	('PDAC', 'Chemical', '-', (68, 72))	('WIPF1', 'Gene', (113, 118))	('YAP', 'Gene', (119, 122))	('PDAC growth', 'CPA', (68, 79))	('miR-141/200c', 'Var', (44, 56))	('activating', 'PosReg', (98, 108))
59762	30041660	MicroRNA miR-141 and miR-200c are upregulated in several malignancies while downregulated in several others, playing dual regulatory roles on cell growth and differentiation, tumor invasion and metastasis, depending on the cellular context.	('cell growth', 'CPA', (142, 153))	('tumor', 'Disease', (175, 180))	('malignancies', 'Disease', (57, 69))	('upregulated', 'PosReg', (34, 45))	('metastasis', 'CPA', (194, 204))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('miR-200c', 'Var', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('cell growth', 'biological_process', 'GO:0016049', ('142', '153'))	('malignancies', 'Disease', 'MESH:D009369', (57, 69))
59763	30041660	For example, miR-141/200c is downregulated in triple negative breast cancer and its overexpression stimulates its invasive and migratory property.	('miR-141/200c', 'Var', (13, 25))	('overexpression stimulates', 'PosReg', (84, 109))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('downregulated', 'NegReg', (29, 42))
59764	30041660	In non-small cell lung cancer, high expression of miR-141/200c was associated with worse survival.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('non-small cell lung cancer', 'Disease', (3, 29))	('miR-141/200c', 'Var', (50, 62))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))
59765	30041660	While in renal cell carcinoma, miR-141/200c suppresses cell proliferation and metastasis by targeting EphA2.	('targeting', 'Reg', (92, 101))	('renal cell carcinoma', 'Disease', (9, 29))	('suppresses', 'NegReg', (44, 54))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (9, 29))	('miR-141/200c', 'Var', (31, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('55', '73'))	('cell proliferation', 'CPA', (55, 73))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (9, 29))	('EphA2', 'Gene', (102, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('EphA2', 'Gene', '1969', (102, 107))
59766	30041660	In PDAC, miR141 and miR-200c are downregulated and target several genes including YAP1, as well as MAP4K4, MUC1, and TM4SF1.	('MUC1', 'Gene', (107, 111))	('TM4SF1', 'Gene', '4071', (117, 123))	('TM4SF1', 'Gene', (117, 123))	('MUC1', 'Gene', '4582', (107, 111))	('MAP4K4', 'Gene', '9448', (99, 105))	('PDAC', 'Chemical', '-', (3, 7))	('YAP1', 'Gene', '10413', (82, 86))	('MAP', 'molecular_function', 'GO:0004239', ('99', '102'))	('miR141', 'Gene', '406933', (9, 15))	('MAP4K4', 'Gene', (99, 105))	('miR141', 'Gene', (9, 15))	('PDAC', 'Phenotype', 'HP:0006725', (3, 7))	('miR-200c', 'Var', (20, 28))	('YAP1', 'Gene', (82, 86))	('downregulated', 'NegReg', (33, 46))	('target', 'Reg', (51, 57))
59768	30041660	This was further confirmed by the restoration of miR-141/200c expression by the demethylating agent 5-azacitidine-dC in PDAC cell lines.	('PDAC', 'Phenotype', 'HP:0006725', (120, 124))	('5-azacitidine', 'Chemical', 'MESH:D001374', (100, 113))	('expression', 'MPA', (62, 72))	('miR-141/200c', 'Var', (49, 61))	('PDAC', 'Chemical', '-', (120, 124))
59769	30041660	In contrast, the other cluster of miR-200 family members including miR-200a, miR-200b and miR-429 were hypomethylated in PDAC, suggesting that the different cluster of the same microRNA family may play opposing roles.	('miR-200a', 'Gene', (67, 75))	('miR', 'Gene', (77, 80))	('miR-200b', 'Gene', '406984', (77, 85))	('miR-200b', 'Gene', (77, 85))	('PDAC', 'Chemical', '-', (121, 125))	('miR', 'Gene', '220972', (34, 37))	('miR-429', 'Gene', '554210', (90, 97))	('miR', 'Gene', (34, 37))	('PDAC', 'Phenotype', 'HP:0006725', (121, 125))	('miR-429', 'Gene', (90, 97))	('miR', 'Gene', '220972', (90, 93))	('miR', 'Gene', (90, 93))	('hypomethylated', 'Var', (103, 117))	('miR', 'Gene', '220972', (67, 70))	('miR', 'Gene', (67, 70))	('miR-200a', 'Gene', '406983', (67, 75))	('miR', 'Gene', '220972', (77, 80))
59771	30041660	Interestingly, our data showed the lack of inhibition on cell proliferation by miR-200c, despite both microRNAs displayed the inhibitory effect on tumor cell invasion, migration, metastasis as well as expression of WIPF1.	('WIPF1', 'Gene', '7456', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('migration', 'CPA', (168, 177))	('inhibitory', 'NegReg', (126, 136))	('metastasis', 'CPA', (179, 189))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cell proliferation', 'biological_process', 'GO:0008283', ('57', '75'))	('WIPF1', 'Gene', (215, 220))	('miR-200c', 'Var', (79, 87))
59772	30041660	This suggests that the inhibitory effect on the cell proliferation and the metastasis of PDAC by miR-200c may be two separate and decoupled mechanisms independent of each other and miR-200c is a key regulator for the metastasis but not for primary tumor growth, similar to a previous study.	('miR-200c', 'Gene', (97, 105))	('PDAC', 'Chemical', '-', (89, 93))	('tumor', 'Disease', (248, 253))	('cell proliferation', 'CPA', (48, 66))	('PDAC', 'Disease', (89, 93))	('metastasis', 'CPA', (75, 85))	('PDAC', 'Phenotype', 'HP:0006725', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('miR-200c', 'Var', (181, 189))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))
59773	30041660	This is consistent with that two transmembrane mucins involved in invasion and metastasis, MUC4 and MUC16, are targeted by miR-200c.	('MUC16', 'Gene', (100, 105))	('transmembrane', 'cellular_component', 'GO:0044214', ('33', '46'))	('transmembrane', 'cellular_component', 'GO:0016021', ('33', '46'))	('miR-200c', 'Var', (123, 131))	('MUC16', 'Gene', '94025', (100, 105))	('MUC4', 'Gene', '4585', (91, 95))	('MUC4', 'Gene', (91, 95))
59775	30041660	There are likely other unidentified factors that are involved in the miR-200c dependent regulation of primary tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('regulation', 'biological_process', 'GO:0065007', ('88', '98'))	('miR-200c', 'Var', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
59776	30041660	Importantly, we showed that both miR-141 and miR-200c suppressed the expression of EMT markers while stimulating the expression of tumor suppressor E-cadherin.	('E-cadherin', 'Gene', (148, 158))	('miR-141', 'Var', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('suppressed', 'NegReg', (54, 64))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('131', '147'))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('expression', 'MPA', (117, 127))	('EMT markers', 'Gene', (83, 94))	('E-cadherin', 'Gene', '999', (148, 158))	('expression', 'MPA', (69, 79))	('tumor', 'Disease', (131, 136))	('cadherin', 'molecular_function', 'GO:0008014', ('150', '158'))	('EMT', 'biological_process', 'GO:0001837', ('83', '86'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('131', '147'))	('stimulating', 'PosReg', (101, 112))	('miR-200c', 'Var', (45, 53))
59777	30041660	Using TargetScan program, we identified WIPF1 as a direct target of miR-141/miR-200c.	('WIPF1', 'Gene', '7456', (40, 45))	('WIPF1', 'Gene', (40, 45))	('miR-141/miR-200c', 'Var', (68, 84))
59778	30041660	The 3'-UTR of WIPF1 contains the miR-141 and miR-200c binding sites and the deletion of this 3'-UTR from WIPF1 rendered its expression no longer responsive to the suppression by miR-141/miR-200c.	('deletion', 'Var', (76, 84))	('responsive', 'MPA', (145, 155))	('WIPF1', 'Gene', '7456', (105, 110))	('WIPF1', 'Gene', (14, 19))	('binding', 'molecular_function', 'GO:0005488', ('54', '61'))	('WIPF1', 'Gene', '7456', (14, 19))	('expression', 'MPA', (124, 134))	('WIPF1', 'Gene', (105, 110))
59779	30041660	Consistent with this, our data with 37 PDAC cases showed that the expression of miR-141/200c and WIPF1 in human PDAC inversely correlated.	('human', 'Species', '9606', (106, 111))	('WIPF1', 'Gene', (97, 102))	('PDAC', 'Phenotype', 'HP:0006725', (39, 43))	('PDAC', 'Phenotype', 'HP:0006725', (112, 116))	('expression', 'MPA', (66, 76))	('miR-141/200c', 'Var', (80, 92))	('WIPF1', 'Gene', '7456', (97, 102))	('PDAC', 'Chemical', '-', (39, 43))	('PDAC', 'Chemical', '-', (112, 116))
59781	30041660	The mutations on the WIPF1 binding site of WASP cause Wiskott-Aldrich syndrome (WAS) with increased susceptibility to leukemia and lymphoma.	('WIPF1', 'Gene', (21, 26))	('WAS', 'Disease', (43, 46))	('leukemia and lymphoma', 'Disease', 'MESH:D007938', (118, 139))	('binding', 'molecular_function', 'GO:0005488', ('27', '34'))	('Wiskott-Aldrich syndrome', 'Disease', (54, 78))	('WASP', 'Gene', (43, 47))	('cause', 'Reg', (48, 53))	('WIPF1', 'Gene', '7456', (21, 26))	('WASP', 'Gene', '7454', (43, 47))	('Wiskott-Aldrich syndrome', 'Disease', 'MESH:D014923', (54, 78))	('leukemia', 'Phenotype', 'HP:0001909', (118, 126))	('lymphoma', 'Phenotype', 'HP:0002665', (131, 139))	('mutations', 'Var', (4, 13))	('WAS', 'Disease', 'None', (80, 83))	('WAS', 'Disease', (80, 83))	('WAS', 'Disease', 'None', (43, 46))
59783	30041660	Our data show that silencing of WIPF1 blocks tumor growth and metastasis while high expression of WIPF1 in human PDAC was associated with inferior patient survival, consistent with the previous study that high expression of WIPF1 was associated with poor survival in other types of malignancy.	('WIPF1', 'Gene', '7456', (98, 103))	('WIPF1', 'Gene', '7456', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('WIPF1', 'Gene', (224, 229))	('patient survival', 'CPA', (147, 163))	('blocks tumor', 'Disease', 'MESH:D006327', (38, 50))	('patient', 'Species', '9606', (147, 154))	('human', 'Species', '9606', (107, 112))	('malignancy', 'Disease', (282, 292))	('silencing', 'Var', (19, 28))	('malignancy', 'Disease', 'MESH:D009369', (282, 292))	('PDAC', 'Phenotype', 'HP:0006725', (113, 117))	('WIPF1', 'Gene', (32, 37))	('WIPF1', 'Gene', '7456', (224, 229))	('inferior', 'NegReg', (138, 146))	('WIPF1', 'Gene', (98, 103))	('PDAC', 'Chemical', '-', (113, 117))	('blocks tumor', 'Disease', (38, 50))
59785	30041660	Importantly, our study shows that miR-141 and miR200c suppress YAP/TAZ expression by repressing the expression of WIPF1.	('miR200c', 'Gene', (46, 53))	('YAP', 'Gene', (63, 66))	('WIPF1', 'Gene', (114, 119))	('suppress', 'NegReg', (54, 62))	('expression', 'MPA', (100, 110))	('miR200c', 'Gene', '406985', (46, 53))	('miR-141', 'Var', (34, 41))	('YAP', 'Gene', '10413', (63, 66))	('TAZ', 'Gene', '6901', (67, 70))	('WIPF1', 'Gene', '7456', (114, 119))	('TAZ', 'Gene', (67, 70))
59789	30041660	In conclusion, we have characterized a new oncoprotein expression profile of WIPF1 in PDAC and demonstrated that miR-141/200c regulates the invasion and metastasis of PDAC cells via miR-141/200c-WIPF1-YAP/TAZ pathway.	('miR-141/200c', 'Var', (113, 125))	('YAP', 'Gene', '10413', (201, 204))	('WIPF1', 'Gene', '7456', (77, 82))	('PDAC', 'Phenotype', 'HP:0006725', (167, 171))	('metastasis', 'CPA', (153, 163))	('WIPF1', 'Gene', '7456', (195, 200))	('PDAC', 'Chemical', '-', (86, 90))	('regulates', 'Reg', (126, 135))	('YAP', 'Gene', (201, 204))	('invasion', 'CPA', (140, 148))	('WIPF1', 'Gene', (77, 82))	('WIPF1', 'Gene', (195, 200))	('TAZ', 'Gene', '6901', (205, 208))	('PDAC', 'Chemical', '-', (167, 171))	('PDAC', 'Disease', (86, 90))	('PDAC', 'Phenotype', 'HP:0006725', (86, 90))	('TAZ', 'Gene', (205, 208))
59791	30041660	5-Aza-dC 5-aza-2'-deoxycitidine Ctrl Control EMT Epithelial-to-mesenchymal transition HPDE Human pancreatic duct epithelial cells miR-200 microRNA-200 MUT Mutant NC Negative control OS Overall survival PDAC Pancreatic ductal adenocarcinoma shRNA Short hairpin RNA TAZ Transcriptional coactivator with PDZ-binding motif TCGA The cancer genome atlas UTR Untranslated region WAS Wiskott-Aldrich syndrome WASP Wiskott-Aldrich syndrome protein WIPF1 Wiskott-Aldrich syndrome protein interacting protein family member 1 WIPF1/- 3'-UTR Entire coding sequence of WIPF1 but with the deletion of the 3'-UTR WT Wild-type YAP Yes-associated protein YP, FL, and HH conceived the research.	('Wiskott-Aldrich syndrome protein', 'Gene', (445, 477))	('Wiskott-Aldrich syndrome protein', 'Gene', (406, 438))	('Epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('49', '85'))	('Wiskott-Aldrich syndrome', 'Disease', 'MESH:D014923', (376, 400))	('Pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (207, 239))	('YAP', 'Gene', (610, 613))	('cancer', 'Disease', (328, 334))	('protein', 'cellular_component', 'GO:0003675', ('629', '636'))	('EMT', 'biological_process', 'GO:0001837', ('45', '48'))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('5-Aza-dC', 'Chemical', '-', (0, 8))	('protein', 'cellular_component', 'GO:0003675', ('431', '438'))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('PDAC', 'Chemical', '-', (202, 206))	('WIPF1', 'Gene', '7456', (555, 560))	('Mutant', 'Gene', '4594', (155, 161))	('miR', 'Gene', '220972', (130, 133))	('Wiskott-Aldrich syndrome', 'Disease', 'MESH:D014923', (406, 430))	('PDAC', 'Phenotype', 'HP:0006725', (202, 206))	('WAS', 'Disease', 'None', (372, 375))	('Wiskott-Aldrich syndrome', 'Disease', 'MESH:D014923', (445, 469))	('WAS', 'Disease', (372, 375))	('RNA', 'cellular_component', 'GO:0005562', ('260', '263'))	('WIPF1', 'Gene', (555, 560))	('HPDE', 'Chemical', '-', (86, 90))	('OS', 'Chemical', '-', (182, 184))	('YAP', 'Gene', '10413', (610, 613))	('WIPF1', 'Gene', '7456', (514, 519))	('Pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (207, 239))	('pancreatic', 'Disease', 'MESH:D010195', (97, 107))	('miR', 'Gene', (130, 133))	("5-aza-2'-deoxycitidine", 'Chemical', '-', (9, 31))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('TAZ', 'Gene', (264, 267))	('TAZ', 'Gene', '6901', (264, 267))	('WASP', 'Gene', '7454', (401, 405))	('deletion', 'Var', (574, 582))	('WIPF1', 'Gene', (514, 519))	('Wiskott-Aldrich syndrome', 'Disease', (376, 400))	('Human', 'Species', '9606', (91, 96))	('Pancreatic ductal adenocarcinoma', 'Disease', (207, 239))	('Wiskott-Aldrich syndrome protein interacting protein family member 1', 'Gene', '7456', (445, 513))	('WAS', 'Disease', (401, 404))	('Mutant', 'Gene', (155, 161))	('WIPF1', 'Gene', '7456', (439, 444))	('WAS', 'Disease', 'None', (401, 404))	('pancreatic', 'Disease', (97, 107))	('WASP', 'Gene', (401, 405))	('protein', 'cellular_component', 'GO:0003675', ('490', '497'))	('binding', 'molecular_function', 'GO:0005488', ('305', '312'))	('Wiskott-Aldrich syndrome protein', 'Gene', '7454', (406, 438))	('Wiskott-Aldrich syndrome protein', 'Gene', '7454', (445, 477))	('WIPF1', 'Gene', (439, 444))	('protein', 'cellular_component', 'GO:0003675', ('470', '477'))
59806	29340019	In support of this hypothesis, our recent data demonstrate that long-term oncologic outcomes of minimally invasive radical pancreatectomy for left-sided pancreatic cancer that meets the YC were more favorable compared to those obtained with an open approach.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (153, 170))	('pancreatic cancer', 'Disease', (153, 170))	('pancreatic cancer', 'Disease', 'MESH:D010190', (153, 170))	('minimally', 'Var', (96, 105))
59847	29340019	Modifications to the YC might improve their ability to preoperatively define tumor characteristics more objectively, and thus more accurately represent tumor biology, in left-sided pancreatic cancer.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('improve', 'PosReg', (30, 37))	('pancreatic cancer', 'Disease', 'MESH:D010190', (181, 198))	('pancreatic cancer', 'Disease', (181, 198))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', (152, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (181, 198))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Modifications', 'Var', (0, 13))	('tumor', 'Disease', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
59866	29056856	The results of multivariate analysis showed that surgical resection of the primary tumor was associated with CSS (hazard ratio [HR]=0.58, 95% CI=0.52-0.64, p<0.001) and OS (HR=0.59, 95% CI=0.53-0.65, p<0.001) benefits.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('CSS', 'Disease', (109, 112))	('tumor', 'Disease', (83, 88))	('OS', 'Chemical', '-', (169, 171))	('CSS', 'Chemical', '-', (109, 112))	('surgical resection', 'Var', (49, 67))	('benefits', 'PosReg', (209, 217))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
59884	29056856	We identified patients diagnosed between January 1, 2004, and December 31, 2013, with a primary site of "pancreas", with American Joint Committee on Cancer (AJCC) stage (sixth edition) IV and with International Classification of Diseases for Oncology, Third Edition (ICD-O-3) codes 8010, 8020, 8140, 8141, and 8144 from the SEER database (variants of adenocarcinoma).	('8010', 'Var', (282, 286))	('8140', 'Var', (294, 298))	('ICD', 'Disease', 'OMIM:252500', (267, 270))	('Cancer', 'Phenotype', 'HP:0002664', (149, 155))	('adenocarcinoma', 'Disease', (351, 365))	('ICD', 'Disease', (267, 270))	('adenocarcinoma', 'Disease', 'MESH:D000230', (351, 365))	('Cancer', 'Disease', 'MESH:D009369', (149, 155))	('Cancer', 'Disease', (149, 155))	('Oncology', 'Phenotype', 'HP:0002664', (242, 250))	('patients', 'Species', '9606', (14, 22))
59902	29056856	As shown in Table 2, the univariate analysis demonstrated that age <80 years, diagnosed at 2004-2008, married, T3 stage, N1 stage, other histological types other than adenocarcinoma, and receipt of chemotherapy, and tumor of the pancreatic head were associated with an increased possibility of receiving surgery, compared to each referent group.	('N1 stage', 'Var', (121, 129))	('tumor of the pancreatic head', 'Phenotype', 'HP:0002894', (216, 244))	('T3 stage', 'Var', (111, 119))	('tumor of the pancreatic', 'Disease', (216, 239))	('adenocarcinoma', 'Disease', 'MESH:D000230', (167, 181))	('adenocarcinoma', 'Disease', (167, 181))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor of the pancreatic', 'Disease', 'MESH:D010190', (216, 239))
59914	29056856	The results showed that surgical resection of the primary tumor was associated with a survival benefit (p<0.001).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('survival', 'MPA', (86, 94))	('surgical resection', 'Var', (24, 42))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('benefit', 'PosReg', (95, 102))
59927	29056856	Culp et al used the SEER database to show that the 5-year OS and predicted disease-free survival are each significantly higher in patients undergoing radical prostatectomy (67.4% and 75.8%, respectively) or brachytherapy (52.6% and 61.3%, respectively) compared with patients who have no local treatment (22.5% and 48.7%, respectively; p<0.001).	('OS', 'Chemical', '-', (58, 60))	('disease-free survival', 'CPA', (75, 96))	('patients', 'Species', '9606', (267, 275))	('radical prostatectomy', 'Disease', (150, 171))	('brachytherapy', 'Var', (207, 220))	('higher', 'PosReg', (120, 126))	('patients', 'Species', '9606', (130, 138))
59935	29056856	We noted that, for CSS analysis, patients with T1, T3, and T4 stages had a better survival than patients with T0 stage.	('T4 stages', 'Var', (59, 68))	('better', 'PosReg', (75, 81))	('patients', 'Species', '9606', (33, 41))	('survival', 'CPA', (82, 90))	('CSS', 'Chemical', '-', (19, 22))	('patients', 'Species', '9606', (96, 104))
59952	28392481	To this date, a wide variety of biomarkers in the forms of proteins (e.g., antigens or antibodies), nucleic acids (e.g., mutations in genomic DNA, microRNAs, or other non-coding RNAs), or protein PTMs, have been identified and routinely used for clinical diagnoses of different diseases including cancers.	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('cancers', 'Phenotype', 'HP:0002664', (297, 304))	('cancers', 'Disease', 'MESH:D009369', (297, 304))	('mutations', 'Var', (121, 130))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('cancers', 'Disease', (297, 304))	('clinical', 'Species', '191496', (246, 254))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))
59961	28392481	Although the exact molecular mechanisms underlying this phenomenon still remain unclear, it is generally speculated that a patient's own aberrantly-expressed proteins in cancerous tissues could trigger an immune response.	('immune response', 'CPA', (205, 220))	('cancerous', 'Disease', (170, 179))	('proteins', 'Protein', (158, 166))	('patient', 'Species', '9606', (123, 130))	('trigger', 'Reg', (194, 201))	('cancerous', 'Disease', 'MESH:D009369', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('aberrantly-expressed', 'Var', (137, 157))	('immune response', 'biological_process', 'GO:0006955', ('205', '220'))
60004	28392481	Next, captured human immunoglobulin on the human protein arrays is detected using fluorescently-labeled anti-human secondary antibodies (e.g., anti-IgG, anti-IgM, or anti-IgA) for detection.	('human', 'Species', '9606', (109, 114))	('IgA', 'Gene', (171, 174))	('anti-IgG', 'Var', (143, 151))	('IgA', 'Gene', '973', (171, 174))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('21', '35'))	('human', 'Species', '9606', (15, 20))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('human', 'Species', '9606', (43, 48))
60010	28392481	Moreover, since cancer-associated autoantibodies often target proteins that are mutated, modified, or aberrantly expressed in tumor cells, they could also be considered immunologic reporters that could uncover the etiology underlying tumorigenesis.	('tumor', 'Disease', (234, 239))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('proteins', 'Protein', (62, 70))	('cancer', 'Disease', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutated', 'Var', (80, 87))	('modified', 'Var', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', (126, 131))
60031	28392481	Furthermore, they found that linkage between syndecan-1, pY576/577-focal adhesion kinase (FAK), pY317-SH2 domain containing transforming protein (SHC) and EGFR, pY1135/1136-insulin-like growth factor (IGF), PI3K/AKT was a prominent feature of STS bone metastasis, while elevated linkage between receptor activator of nuclear factor kappa-B ligand (RANKL) and pT37/46-eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), EGFR, pY1135/1136- IGF-1 receptor (IGF1R), pY41-Src, pY317-SHC, PI3K p110 gamma (PI3Kp110gamma) was associated with short survival.	('ligand', 'molecular_function', 'GO:0005488', ('340', '346'))	('SHC', 'Gene', '6464', (497, 500))	('protein', 'cellular_component', 'GO:0003675', ('419', '426'))	('IGF1R', 'Gene', (473, 478))	('EGFR', 'Gene', (155, 159))	('syndecan-1', 'Gene', (45, 55))	('syndecan', 'molecular_function', 'GO:0015023', ('45', '53'))	('pY1135/1136-', 'Var', (444, 456))	('4EBP1', 'Gene', '1978', (430, 435))	('FAK', 'Gene', (90, 93))	('IGF-1 receptor', 'Gene', '3480', (457, 471))	('SHC', 'Gene', '6464', (146, 149))	('AKT', 'Gene', (212, 215))	('RANKL', 'Gene', '8600', (348, 353))	('syndecan-1', 'Gene', '6382', (45, 55))	('linkage', 'Interaction', (279, 286))	('binding', 'molecular_function', 'GO:0005488', ('411', '418'))	('IGF-1 receptor', 'Gene', (457, 471))	('STS', 'Phenotype', 'HP:0030448', (243, 246))	('EGFR', 'molecular_function', 'GO:0005006', ('438', '442'))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('EGFR', 'Gene', (438, 442))	('FAK', 'Gene', '5747', (90, 93))	('focal adhesion', 'cellular_component', 'GO:0005925', ('67', '81'))	('eukaryotic translation initiation factor 4E-binding protein 1', 'Gene', '1978', (367, 428))	('EGFR', 'molecular_function', 'GO:0005006', ('155', '159'))	('EGFR', 'Gene', '1956', (155, 159))	('elevated', 'PosReg', (270, 278))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('173', '199'))	('PI3K p110 gamma', 'Var', (502, 517))	('AKT', 'Gene', '207', (212, 215))	('SHC', 'Gene', (497, 500))	('FAK', 'molecular_function', 'GO:0004717', ('90', '93'))	('pY576/577-focal adhesion kinase', 'Gene', '5747', (57, 88))	('translation initiation', 'biological_process', 'GO:0006413', ('378', '400'))	('Src', 'Gene', (486, 489))	('RANKL', 'Gene', (348, 353))	('short survival', 'CPA', (554, 568))	('4EBP1', 'Gene', (430, 435))	('receptor activator of nuclear factor kappa-B ligand', 'Gene', '8600', (295, 346))	('EGFR', 'Gene', '1956', (438, 442))	('PI3K', 'molecular_function', 'GO:0016303', ('502', '506'))	('SHC', 'Gene', (146, 149))	('PI3K', 'molecular_function', 'GO:0016303', ('207', '211'))	('STS bone metastasis', 'CPA', (243, 262))	('IGF1R', 'Gene', '3480', (473, 478))	('Src', 'Gene', '6714', (486, 489))	('pY576/577-focal adhesion kinase', 'Gene', (57, 88))
60032	28392481	used RPPAs to quantitatively detect EGFR phosphorylations in samples from patients of non-small-cell lung cancer (NSCLC) carrying mutant EGFR compared with those carrying wild type EGFR, and revealed simultaneously-elevated phosphorylation at Tyr-1148 and Tyr-1068 and reduced phosphorylation at Tyr-1045 of EGFR.	('phosphorylation', 'MPA', (224, 239))	('EGFR', 'Gene', '1956', (308, 312))	('Tyr', 'Chemical', 'MESH:D014443', (243, 246))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))	('EGFR', 'Gene', '1956', (181, 185))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('EGFR', 'Gene', (137, 141))	('Tyr', 'Chemical', 'MESH:D014443', (296, 299))	('phosphorylation', 'biological_process', 'GO:0016310', ('277', '292'))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('EGFR', 'Gene', '1956', (36, 40))	('Tyr', 'Chemical', 'MESH:D014443', (256, 259))	('reduced', 'NegReg', (269, 276))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (86, 112))	('patients', 'Species', '9606', (74, 82))	('EGFR', 'Gene', (36, 40))	('non-small-cell lung cancer', 'Disease', (86, 112))	('phosphorylation', 'biological_process', 'GO:0016310', ('224', '239'))	('Tyr-1068', 'Var', (256, 264))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('EGFR', 'Gene', '1956', (137, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('308', '312'))	('EGFR', 'Gene', (308, 312))	('EGFR', 'molecular_function', 'GO:0005006', ('181', '185'))	('EGFR', 'Gene', (181, 185))	('NSCLC', 'Disease', (114, 119))	('simultaneously-elevated', 'PosReg', (200, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('phosphorylation at Tyr-1045', 'MPA', (277, 304))	('mutant', 'Var', (130, 136))
60033	28392481	In addition, they also detected reduced phosphorylation in signaling proteins related to EGFR including the human epidermal growth factor receptor 2 (HER2) at Tyr-1248, insulin receptor substrate 1 (IRS-1) at Ser-612, and SMAD at Ser-465/467.	('insulin receptor substrate 1', 'Gene', (169, 197))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('Tyr-1248', 'Var', (159, 167))	('IRS-1', 'Gene', '3667', (199, 204))	('epidermal growth factor receptor 2', 'Gene', '2064', (114, 148))	('Ser', 'cellular_component', 'GO:0005790', ('230', '233'))	('Ser', 'Chemical', 'MESH:D012694', (209, 212))	('insulin receptor substrate 1', 'Gene', '3667', (169, 197))	('phosphorylation', 'MPA', (40, 55))	('signaling proteins', 'MPA', (59, 77))	('reduced', 'NegReg', (32, 39))	('epidermal growth factor receptor 2', 'Gene', (114, 148))	('HER2', 'Gene', '2064', (150, 154))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('114', '137'))	('EGFR', 'Gene', (89, 93))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('Tyr', 'Chemical', 'MESH:D014443', (159, 162))	('insulin', 'molecular_function', 'GO:0016088', ('169', '176'))	('IRS-1', 'Gene', (199, 204))	('Ser', 'Chemical', 'MESH:D012694', (230, 233))	('HER2', 'Gene', (150, 154))	('human', 'Species', '9606', (108, 113))	('Ser', 'cellular_component', 'GO:0005790', ('209', '212'))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('EGFR', 'Gene', '1956', (89, 93))
60034	28392481	To assess which subset of phosphorylations was associated with ligand induction, they also evaluated the phosphorylation time course of 115 signaling proteins in NSCLC cell lines with mutant and wild-type EGFR after EGF ligand stimulation.	('EGF', 'molecular_function', 'GO:0005154', ('216', '219'))	('ligand', 'molecular_function', 'GO:0005488', ('63', '69'))	('mutant', 'Var', (184, 190))	('NSCLC', 'Disease', (162, 167))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'molecular_function', 'GO:0005006', ('205', '209'))	('EGFR', 'Gene', (205, 209))	('NSCLC', 'Disease', 'MESH:D002289', (162, 167))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))	('signaling', 'biological_process', 'GO:0023052', ('140', '149'))	('ligand', 'molecular_function', 'GO:0005488', ('220', '226'))
60035	28392481	Interestingly, following EGF ligand stimulation, EGFR mutant cell line H1975 with L858R showed phosphorylation at Tyr-1045 of EGFR and at Tyr-1248 of HER2 with a similar pattern to that found in tumor tissue.	('tumor', 'Disease', (195, 200))	('ligand', 'molecular_function', 'GO:0005488', ('29', '35'))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('phosphorylation', 'MPA', (95, 110))	('EGFR', 'Gene', '1956', (126, 130))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('Tyr', 'Chemical', 'MESH:D014443', (138, 141))	('L858R', 'Mutation', 'rs121434568', (82, 87))	('Tyr', 'Chemical', 'MESH:D014443', (114, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('EGFR', 'Gene', (49, 53))	('phosphorylation', 'biological_process', 'GO:0016310', ('95', '110'))	('HER2', 'Gene', '2064', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('EGF', 'molecular_function', 'GO:0005154', ('25', '28'))	('L858R', 'Var', (82, 87))	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (126, 130))	('H1975', 'CellLine', 'CVCL:1511', (71, 76))	('HER2', 'Gene', (150, 154))
60036	28392481	Additionally, persistence of phosphorylation for AKT at Ser-473 was found in EGFR mutant cell line H1975.	('Ser', 'cellular_component', 'GO:0005790', ('56', '59'))	('H1975', 'CellLine', 'CVCL:1511', (99, 104))	('AKT', 'Gene', (49, 52))	('Ser', 'Chemical', 'MESH:D012694', (56, 59))	('phosphorylation', 'biological_process', 'GO:0016310', ('29', '44'))	('EGFR', 'Gene', '1956', (77, 81))	('AKT', 'Gene', '207', (49, 52))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('EGFR', 'Gene', (77, 81))	('phosphorylation', 'MPA', (29, 44))	('mutant', 'Var', (82, 88))
60037	28392481	Their studies explored multiple site-specific phosphoproteins in vivo in cell lines containing the EGFR tyrosine kinase domain mutations and provided the key insights into the potential drug targets for NSCLC.	('EGFR', 'Gene', '1956', (99, 103))	('EGFR', 'Gene', (99, 103))	('NSCLC', 'Disease', (203, 208))	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('EGFR', 'molecular_function', 'GO:0005006', ('99', '103'))	('mutations', 'Var', (127, 136))
60039	28392481	This is because many cancer-relevant mutations, as well as aberrant expression, are protein-based and happen somatically.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('expression', 'MPA', (68, 78))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
60062	28024083	Pharmacological and genetic inhibition of macropinocytosis can inhibit cell line proliferation and xenograft tumor growth, presenting a potential therapeutic target for a subset of tumors.	('inhibition of macropinocytosis', 'biological_process', 'GO:1905302', ('28', '58'))	('tumor', 'Disease', (181, 186))	('tumors', 'Disease', (181, 187))	('genetic inhibition', 'Var', (20, 38))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cell line proliferation', 'CPA', (71, 94))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('inhibit', 'NegReg', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', (109, 114))
60066	28024083	Intratumoral inhibition of macropinocytosis results in a decrease in amino acid levels.	('decrease', 'NegReg', (57, 65))	('amino acid levels', 'MPA', (69, 86))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('inhibition', 'Var', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('inhibition of macropinocytosis', 'biological_process', 'GO:1905302', ('13', '43'))	('tumor', 'Disease', (5, 10))
60072	28024083	PDAC was initiated by pancreas restricted Cre-recombinase (Pdx1-Cre) expression in KrasLSL-G12D/+; p53loxP/loxP (KP) mice to induce mutant KrasG12D expression and loss of p53.	('PDAC', 'Chemical', '-', (0, 4))	('G12D', 'Mutation', 'p.G12D', (143, 147))	('p53', 'Gene', '22060', (99, 102))	('G12D', 'Mutation', 'p.G12D', (91, 95))	('loss', 'NegReg', (163, 167))	('p53', 'Gene', '22060', (171, 174))	('induce', 'Reg', (125, 131))	('mice', 'Species', '10090', (117, 121))	('mutant KrasG12D expression', 'Var', (132, 158))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('p53', 'Gene', (99, 102))	('Pdx1', 'Gene', (59, 63))	('p53', 'Gene', (171, 174))	('Pdx1', 'Gene', '18609', (59, 63))
60112	28024083	24h after device delivery, tissue adjacent to device reservoirs containing DQ-BSA exhibits fluorescence only when reservoirs were adjacent to tumor tissue (Fig.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('DQ-BSA', 'Var', (75, 81))	('fluorescence', 'MPA', (91, 103))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
60120	28024083	To determine whether tumor cells can internalize ECM-derived proteins, we utilized the microdevice to deliver TRITC-labeled fibronectin (440kDa), one of the largest protein components of the extracellular matrix.	('extracellular matrix', 'cellular_component', 'GO:0031012', ('191', '211'))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('TRITC', 'Chemical', 'MESH:C009434', (110, 115))	('tumor', 'Disease', (21, 26))	('fibronectin', 'Gene', (124, 135))	('440kDa', 'Var', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('fibronectin', 'Gene', '14268', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
60125	28024083	We observed decreased DQ-BSA signal around reservoirs with hydroxychloroquine as compared to vehicle reservoirs (Fig.	('DQ-BSA signal', 'MPA', (22, 35))	('hydroxychloroquine', 'Chemical', 'MESH:D006886', (59, 77))	('decreased', 'NegReg', (12, 21))	('hydroxychloroquine', 'Var', (59, 77))
60132	28024083	The relative concentrations of all four amino acids were decreased in tissue exposed to EIPA as compared to the adjacent tissue that was not exposed to EIPA, and amino acid levels were not changed in tumor tissue exposed to vehicle alone (Fig.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('decreased', 'NegReg', (57, 66))	('EIPA', 'Chemical', 'MESH:C039614', (152, 156))	('EIPA', 'Var', (88, 92))	('EIPA', 'Chemical', 'MESH:C039614', (88, 92))
60137	28024083	EIPA inhibits macropinocytosis at the concentrations used for these studies; however, EIPA is also an inhibitor of Na+/H+ exchange and may affect amino acid levels by other mechanisms.	('affect', 'Reg', (139, 145))	('inhibitor', 'MPA', (102, 111))	('macropinocytosis', 'biological_process', 'GO:0044351', ('14', '30'))	('amino acid levels', 'MPA', (146, 163))	('macropinocytosis', 'MPA', (14, 30))	('EIPA', 'Chemical', 'MESH:C039614', (0, 4))	('EIPA', 'Var', (86, 90))	('EIPA', 'Chemical', 'MESH:C039614', (86, 90))	('inhibits', 'NegReg', (5, 13))	('Na+/H+ exchange', 'MPA', (115, 130))
60142	28024083	4d, e), including glutamine, glutamate and aspartate, three of the amino acids found to be depleted by EIPA in tumors.	('aspartate', 'Chemical', 'MESH:D001224', (43, 52))	('glutamate', 'MPA', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('EIPA', 'Var', (103, 107))	('glutamine', 'MPA', (18, 27))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('glutamate', 'Chemical', 'MESH:D018698', (29, 38))	('EIPA', 'Chemical', 'MESH:C039614', (103, 107))	('aspartate', 'MPA', (43, 52))	('glutamine', 'Chemical', 'MESH:D005973', (18, 27))
60166	28024083	For the autochthonous genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC), tumors were initiated using a pancreas-restricted Pdx1 promoter to express Cre-recombinase (Pdx1-Cre) in KrasLSL-G12D/+; p53loxP/loxP animals from a mixed 129/Sv and C57Bl6/J background.	('Pdx1', 'Gene', (193, 197))	('pancreatic ductal adenocarcinoma', 'Disease', (60, 92))	('KrasLSL-G12D/+', 'Var', (206, 220))	('PDAC', 'Chemical', '-', (94, 98))	('PDAC', 'Phenotype', 'HP:0006725', (94, 98))	('Pdx1', 'Gene', '18609', (151, 155))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (60, 92))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('G12D', 'Mutation', 'p.G12D', (214, 218))	('Pdx1', 'Gene', (151, 155))	('mouse', 'Species', '10090', (45, 50))	('129/Sv', 'Species', '10090', (256, 262))	('p53', 'Gene', (222, 225))	('tumors', 'Disease', (101, 107))	('p53', 'Gene', '22060', (222, 225))	('Pdx1', 'Gene', '18609', (193, 197))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (60, 92))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
60202	27486767	Identification of genetic variants predictive of early onset pancreatic cancer through a population science analysis of functional genomic datasets Biomarkers are critically needed for the early detection of pancreatic cancer (PC) are urgently needed.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (208, 225))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('pancreatic cancer', 'Disease', (208, 225))	('pancreatic cancer', 'Disease', 'MESH:D010190', (208, 225))	('PC', 'Phenotype', 'HP:0002894', (227, 229))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('pancreatic cancer', 'Disease', (61, 78))	('variants', 'Var', (26, 34))
60203	27486767	Previously, we identified genes using a functional genomic approach that were aberrantly expressed in early pathways to PC tumorigenesis.	('tumor', 'Disease', (123, 128))	('aberrantly expressed', 'Var', (78, 98))	('PC', 'Phenotype', 'HP:0002894', (120, 122))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
60210	27486767	We have focused on intervals of recurrent cytogenetic loss and gain associated with deletion/loss of function of tumor suppressor loci and overexpression/gain of function of oncogenes.	('tumor', 'Disease', (113, 118))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('113', '129'))	('deletion/loss of function', 'NegReg', (84, 109))	('overexpression/gain of function', 'PosReg', (139, 170))	('gain', 'PosReg', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('deletion/loss', 'Var', (84, 97))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor suppressor', 'biological_process', 'GO:0051726', ('113', '129'))
60212	27486767	Published studies suggest that multiple tumor types share a common 3p12 pathway to tumorigenesis and that regions of loss and amplification of chromosome 20q occur early in tumorigenic transformation and may initiate cancer.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('loss', 'NegReg', (117, 121))	('tumor', 'Disease', (83, 88))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('chromosome 20q', 'Gene', (143, 157))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('p12', 'Gene', '56655', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (40, 45))	('p12', 'Gene', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('initiate', 'Reg', (208, 216))	('tumor', 'Disease', (173, 178))	('cancer', 'Disease', (217, 223))	('amplification', 'Var', (126, 139))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
60213	27486767	Significantly, early losses of chromosome 3p or 1p and amplification of chromosome 20q have been reported in smoking-related cancers.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('amplification', 'Var', (55, 68))	('chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('cancers', 'Disease', (125, 132))	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('losses', 'NegReg', (21, 27))	('chromosome 3p', 'Protein', (31, 44))
60215	27486767	It is therefore reasonable to hypothesize that combinations of genetic variants in these genes may help in driving the process of tumorigenesis.	('combinations', 'Var', (47, 59))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('help', 'Reg', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
60216	27486767	Our previous studies indicate that single nucleotide polymorphisms (SNPs) in several different genes, including SEL1L, Aurora-A, p16, p21, and p27, can modify the age at diagnosis of PC.	('Aurora-A', 'Gene', '6790', (119, 127))	('p27', 'Gene', '3429', (143, 146))	('SEL1L', 'Gene', '6400', (112, 117))	('Aurora-A', 'Gene', (119, 127))	('p16', 'Gene', (129, 132))	('modify', 'Reg', (152, 158))	('single nucleotide polymorphisms', 'Var', (35, 66))	('p27', 'Gene', (143, 146))	('p21', 'Gene', '644914', (134, 137))	('p16', 'Gene', '1029', (129, 132))	('PC', 'Phenotype', 'HP:0002894', (183, 185))	('SEL1L', 'Gene', (112, 117))	('p21', 'Gene', (134, 137))
60217	27486767	We hypothesized that variants of genes involved in the 3p12 and 20q pathways may work together to modify age at diagnosis of PC.	('variants', 'Var', (21, 29))	('work', 'Reg', (81, 85))	('p12', 'Gene', (56, 59))	('modify', 'Reg', (98, 104))	('PC', 'Phenotype', 'HP:0002894', (125, 127))	('p12', 'Gene', '56655', (56, 59))
60219	27486767	Secondly, we used a two-phase study design to identify SNPs in these genes associated with early age at diagnosis of PC in total 1729 PC patients.	('PC', 'Phenotype', 'HP:0002894', (134, 136))	('patients', 'Species', '9606', (137, 145))	('PC', 'Phenotype', 'HP:0002894', (117, 119))	('SNPs', 'Var', (55, 59))	('associated', 'Reg', (75, 85))
60220	27486767	Our study integrated data from a systems biology approach and population science methods to discover genetic variants as susceptibility markers for earlier pancreatic cancer diagnosis.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (156, 173))	('pancreatic cancer', 'Disease', (156, 173))	('pancreatic cancer', 'Disease', 'MESH:D010190', (156, 173))	('variants', 'Var', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
60227	27486767	After the Benjamini-Hochberg false discovery rate correction, SNP rs61992671 in miR-412 remained strongly associated with age at diagnosis of PC, with a P-value of 7.19 x 10-5, hazard ratio (HR) = 1.28 (95% confidence interval [CI] = 1.14-1.45), corrected P = 0.011 (Supplementary Table 2).	('associated', 'Reg', (106, 116))	('miR-412', 'Gene', '574433', (80, 87))	('false', 'biological_process', 'GO:0071878', ('29', '34'))	('rs61992671', 'Mutation', 'rs61992671', (66, 76))	('SNP rs61992671', 'Var', (62, 76))	('miR-412', 'Gene', (80, 87))	('false', 'biological_process', 'GO:0071877', ('29', '34'))	('PC', 'Phenotype', 'HP:0002894', (142, 144))
60228	27486767	The association remained significant for 8 SNPs (rs61992671 in miR-412, rs2766669 in ZNF217, rs6128327 in RAB22A, rs2282544 in SMAD4, rs1076064 in PPARGC1B, rs7799635 in KDELR2, rs4940086 in SMAD2, and rs3217992 in CDKN2B) after multiple testing correction (threshold with false discovery rate of 10%), with P-values of 2.09 x 10-6, 8.11 x 10-4, 1.07 x 10-3, 2.66 x 10-3, 2.80 x 10-3, 3.30 x 10-3, 3.45 x 10-3, and 4.93 x 10-3, respectively (Supplementary Table 3).	('CDKN2B', 'Gene', (215, 221))	('RAB22A', 'Gene', (106, 112))	('SMAD4', 'Gene', (127, 132))	('rs2766669', 'Mutation', 'rs2766669', (72, 81))	('rs7799635', 'Var', (157, 166))	('false', 'biological_process', 'GO:0071877', ('273', '278'))	('rs7799635', 'Mutation', 'rs7799635', (157, 166))	('rs1076064', 'Mutation', 'rs1076064', (134, 143))	('RAB22A', 'Gene', '57403', (106, 112))	('rs4940086', 'Mutation', 'rs4940086', (178, 187))	('miR-412', 'Gene', (63, 70))	('CDKN2B', 'Gene', '1030', (215, 221))	('rs2766669', 'Var', (72, 81))	('SMAD2', 'Gene', '4087', (191, 196))	('rs61992671', 'Mutation', 'rs61992671', (49, 59))	('rs2282544', 'Var', (114, 123))	('PPARGC1B', 'Gene', (147, 155))	('KDELR2', 'Gene', '11014', (170, 176))	('rs4940086', 'Var', (178, 187))	('rs2282544', 'Mutation', 'rs2282544', (114, 123))	('SMAD4', 'Gene', '4089', (127, 132))	('rs6128327', 'Mutation', 'rs6128327', (93, 102))	('rs1076064', 'Var', (134, 143))	('SMAD2', 'Gene', (191, 196))	('false', 'biological_process', 'GO:0071878', ('273', '278'))	('rs6128327', 'Var', (93, 102))	('rs3217992', 'Mutation', 'rs3217992', (202, 211))	('KDELR2', 'Gene', (170, 176))	('miR-412', 'Gene', '574433', (63, 70))	('rs3217992', 'Var', (202, 211))	('rs61992671', 'Var', (49, 59))	('PPARGC1B', 'Gene', '133522', (147, 155))
60229	27486767	Altogether, we found 8 SNPs (rs61992671 in miR-412, rs2766669 in ZNF217, rs6128327 in RAB22A, rs7799635 in KDELR2, rs4940086 in SMAD2, rs3217992 in CDKN2B, rs12803915 in miR-612, and rs1559849 in SERAC1) that were consistently associated with age at diagnosis in the discovery phase, validation phase, and pooled analysis, with P-values < 0.05 (Table 2).	('miR-412', 'Gene', (43, 50))	('rs6128327', 'Mutation', 'rs6128327', (73, 82))	('rs12803915', 'Mutation', 'rs12803915', (156, 166))	('KDELR2', 'Gene', '11014', (107, 113))	('rs3217992', 'Mutation', 'rs3217992', (135, 144))	('rs4940086', 'Mutation', 'rs4940086', (115, 124))	('rs6128327', 'Var', (73, 82))	('rs3217992', 'Var', (135, 144))	('rs61992671', 'Var', (29, 39))	('rs1559849', 'Var', (183, 192))	('rs7799635', 'Var', (94, 103))	('SMAD2', 'Gene', '4087', (128, 133))	('rs4940086', 'Var', (115, 124))	('rs1559849', 'Mutation', 'rs1559849', (183, 192))	('RAB22A', 'Gene', (86, 92))	('CDKN2B', 'Gene', (148, 154))	('rs7799635', 'Mutation', 'rs7799635', (94, 103))	('miR-612', 'Gene', '693197', (170, 177))	('SERAC1', 'Gene', (196, 202))	('KDELR2', 'Gene', (107, 113))	('SERAC1', 'Gene', '84947', (196, 202))	('associated', 'Reg', (227, 237))	('miR-412', 'Gene', '574433', (43, 50))	('RAB22A', 'Gene', '57403', (86, 92))	('SMAD2', 'Gene', (128, 133))	('rs61992671', 'Mutation', 'rs61992671', (29, 39))	('rs2766669', 'Mutation', 'rs2766669', (52, 61))	('miR-612', 'Gene', (170, 177))	('CDKN2B', 'Gene', '1030', (148, 154))	('rs2766669', 'Var', (52, 61))	('rs12803915', 'Var', (156, 166))
60233	27486767	ENCODE data and the F-SNP, HaploReg, and RegulomeDB tools indicate that all of the 8 identified SNPs (rs61992671, rs2766669, rs6128327, rs7799635, rs4940086, rs3217992, rs12803915, and rs1559849) have potential for disruption of transcription factor and/or enhancer binding sites.	('rs7799635', 'Var', (136, 145))	('rs2766669', 'Mutation', 'rs2766669', (114, 123))	('transcription', 'Protein', (229, 242))	('rs7799635', 'Mutation', 'rs7799635', (136, 145))	('rs12803915', 'Var', (169, 179))	('rs3217992', 'Mutation', 'rs3217992', (158, 167))	('rs2766669', 'Var', (114, 123))	('rs12803915', 'Mutation', 'rs12803915', (169, 179))	('rs3217992', 'Var', (158, 167))	('rs61992671', 'Var', (102, 112))	('rs4940086', 'Mutation', 'rs4940086', (147, 156))	('enhancer', 'PosReg', (257, 265))	('rs4940086', 'Var', (147, 156))	('rs6128327', 'Mutation', 'rs6128327', (125, 134))	('disruption', 'NegReg', (215, 225))	('rs6128327', 'Var', (125, 134))	('rs61992671', 'Mutation', 'rs61992671', (102, 112))	('rs1559849', 'Var', (185, 194))	('rs1559849', 'Mutation', 'rs1559849', (185, 194))
60234	27486767	rs4940086 (SMAD2) and rs12803915 (miR-612) are located in potential enhancer regions, based on histone marks, in normal breast, lymphocyte, or leukemia cells.	('leukemia', 'Phenotype', 'HP:0001909', (143, 151))	('leukemia', 'Disease', 'MESH:D007938', (143, 151))	('rs4940086', 'Var', (0, 9))	('SMAD2', 'Gene', '4087', (11, 16))	('leukemia', 'Disease', (143, 151))	('rs4940086', 'Mutation', 'rs4940086', (0, 9))	('SMAD2', 'Gene', (11, 16))	('rs12803915', 'Mutation', 'rs12803915', (22, 32))	('miR-612', 'Gene', (34, 41))	('enhancer', 'PosReg', (68, 76))	('miR-612', 'Gene', '693197', (34, 41))	('rs12803915', 'Var', (22, 32))
60235	27486767	In addition, rs12803915 (miR-612) is located in a "hot spot" of DNase I hypersensitivity sites in 9 cell types and is predicted to affect binding of proteins, including POLR2A, REST, TFAP2C, and ZBTB7A.	('rs12803915', 'Mutation', 'rs12803915', (13, 23))	('TFAP2C', 'Gene', '7022', (183, 189))	('ZBTB7A', 'Gene', (195, 201))	('affect', 'Reg', (131, 137))	('POLR2A', 'Gene', '5430', (169, 175))	('hypersensitivity', 'Disease', (72, 88))	('ZBTB7A', 'Gene', '51341', (195, 201))	('hypersensitivity', 'Disease', 'MESH:D004342', (72, 88))	('POLR2A', 'Gene', (169, 175))	('proteins', 'Protein', (149, 157))	('binding', 'Interaction', (138, 145))	('miR-612', 'Gene', (25, 32))	('TFAP2C', 'Gene', (183, 189))	('miR-612', 'Gene', '693197', (25, 32))	('rs12803915', 'Var', (13, 23))
60236	27486767	rs3217992 (CDKN2B) and rs7799635 (KDELR2) are also located in DNase I hypersensitivity sites.	('KDELR2', 'Gene', (34, 40))	('rs3217992', 'Mutation', 'rs3217992', (0, 9))	('hypersensitivity', 'biological_process', 'GO:0002524', ('70', '86'))	('hypersensitivity', 'Disease', (70, 86))	('hypersensitivity', 'Disease', 'MESH:D004342', (70, 86))	('rs7799635', 'Mutation', 'rs7799635', (23, 32))	('KDELR2', 'Gene', '11014', (34, 40))	('rs3217992', 'Var', (0, 9))	('CDKN2B', 'Gene', '1030', (11, 17))	('rs7799635', 'Var', (23, 32))	('DNase I', 'molecular_function', 'GO:0004530', ('62', '69'))	('CDKN2B', 'Gene', (11, 17))
60237	27486767	Furthermore, rs7799635 (KDELR2) is predicted to affect binding and was linked to expression of the CTCF gene target as well as the cis-eQTL of KDELR2.	('affect', 'Reg', (48, 54))	('CTCF', 'Gene', (99, 103))	('KDELR2', 'Gene', (24, 30))	('KDELR2', 'Gene', (143, 149))	('rs7799635', 'Var', (13, 22))	('KDELR2', 'Gene', '11014', (24, 30))	('CTCF', 'Gene', '10664', (99, 103))	('KDELR2', 'Gene', '11014', (143, 149))	('binding', 'Interaction', (55, 62))	('rs7799635', 'Mutation', 'rs7799635', (13, 22))	('linked', 'Reg', (71, 77))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('expression', 'MPA', (81, 91))
60238	27486767	rs61992671 (miR-412) is predicted to be located in a conserved transcription factor binding site and to be an exonic splicing enhancer.	('miR-412', 'Gene', '574433', (12, 19))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('63', '91'))	('rs61992671', 'Mutation', 'rs61992671', (0, 10))	('splicing', 'biological_process', 'GO:0045292', ('117', '125'))	('transcription', 'biological_process', 'GO:0006351', ('63', '76'))	('rs61992671', 'Var', (0, 10))	('miR-412', 'Gene', (12, 19))
60239	27486767	In cis-eQTL analysis based on the public dataset Genevar, we found that rs4940086 AA genotype was associated with significantly higher expression level of SMAD2 in 3 cell types (fibroblasts [P = 1.2 x 10-5], a lymphoblastoid cell line [P = 2.0 x 10-4], and T cells [P = 0.0058]) derived from umbilical cords of 75 Geneva GenCord individuals than the AG or GG genotypes.	('rs4940086 AA', 'Var', (72, 84))	('expression level', 'MPA', (135, 151))	('SMAD2', 'Gene', (155, 160))	('SMAD2', 'Gene', '4087', (155, 160))	('rs4940086', 'Mutation', 'rs4940086', (72, 81))	('higher', 'PosReg', (128, 134))
60240	27486767	rs7799635 was also significantly associated with the expression level of KDELR2 in 3 tissue types (adipose, lymphoblastoid cell line, and skin) derived from a subset of ~160 MuTHER healthy female twins (Figure 3).	('rs7799635', 'Var', (0, 9))	('rs7799635', 'Mutation', 'rs7799635', (0, 9))	('expression level', 'MPA', (53, 69))	('associated', 'Reg', (33, 43))	('KDELR2', 'Gene', (73, 79))	('KDELR2', 'Gene', '11014', (73, 79))
60241	27486767	In addition, rs1559849, rs6128327, and rs3217992 were significantly associated with the expression levels of SERAC1, RAB22A, and IFNA1 in lymphoblastoid cell lines from 726 HapMap3 (Supplementary Figure 1).	('SERAC1', 'Gene', (109, 115))	('rs1559849', 'Var', (13, 22))	('SERAC1', 'Gene', '84947', (109, 115))	('rs6128327', 'Mutation', 'rs6128327', (24, 33))	('associated', 'Reg', (68, 78))	('rs1559849', 'Mutation', 'rs1559849', (13, 22))	('rs3217992', 'Mutation', 'rs3217992', (39, 48))	('IFNA1', 'Gene', (129, 134))	('rs3217992', 'Var', (39, 48))	('RAB22A', 'Gene', '57403', (117, 123))	('expression levels', 'MPA', (88, 105))	('IFNA1', 'Gene', '3439', (129, 134))	('RAB22A', 'Gene', (117, 123))	('rs6128327', 'Var', (24, 33))
60242	27486767	We hypothesized that focusing on aberrantly expressed genes related to early cytogenetic pathways to PC tumorigenesis might be a feasible approach to discover early detection biomarkers.	('PC', 'Phenotype', 'HP:0002894', (101, 103))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('aberrantly expressed', 'Var', (33, 53))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
60245	27486767	Of the 8 SNPs consistently associated with age at diagnosis, the most significant one is rs61992671, which is found in precursor miR-412.	('miR-412', 'Gene', (129, 136))	('miR-412', 'Gene', '574433', (129, 136))	('associated', 'Reg', (27, 37))	('rs61992671', 'Mutation', 'rs61992671', (89, 99))	('rs61992671', 'Var', (89, 99))
60248	27486767	Our previous studies showed that SEL1L was downregulated by aberrantly upregulated hsa-mir-155 in human PDAC, and a SNP in SEL1L gene plays a role in modifying age at diagnosis of PDAC in white nonsmokers and may serve as a prognostic marker in PDAC patients.	('downregulated', 'NegReg', (43, 56))	('PDAC', 'Disease', (180, 184))	('mir-155', 'Gene', '406947', (87, 94))	('SEL1L', 'Gene', '6400', (33, 38))	('SEL1L', 'Gene', (123, 128))	('patients', 'Species', '9606', (250, 258))	('SEL1L', 'Gene', '6400', (123, 128))	('modifying', 'Reg', (150, 159))	('mir-155', 'Gene', (87, 94))	('SEL1L', 'Gene', (33, 38))	('human', 'Species', '9606', (98, 103))	('SNP', 'Var', (116, 119))	('upregulated', 'PosReg', (71, 82))
60251	27486767	SNPs in precursor miRNA genes may potentially affect the processing of miRNAs and may thus significantly affect risk of cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('affect', 'Reg', (46, 52))	('affect', 'Reg', (105, 111))	('processing of miRNAs', 'MPA', (57, 77))	('SNPs', 'Var', (0, 4))	('miRNA genes', 'Gene', (18, 29))
60253	27486767	rs61992671 (miR-412) was predicted to be located in a conserved transcription factor binding site that may be an exonic splicing enhancer.	('splicing', 'biological_process', 'GO:0045292', ('120', '128'))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('64', '92'))	('miR-412', 'Gene', '574433', (12, 19))	('transcription', 'biological_process', 'GO:0006351', ('64', '77'))	('rs61992671', 'Mutation', 'rs61992671', (0, 10))	('rs61992671', 'Var', (0, 10))	('miR-412', 'Gene', (12, 19))
60254	27486767	The other significant miRNA SNP identified by our study is rs12803915, which is located in precursor miR-612.	('miR-612', 'Gene', '693197', (101, 108))	('rs12803915', 'Var', (59, 69))	('rs12803915', 'Mutation', 'rs12803915', (59, 69))	('miR-612', 'Gene', (101, 108))
60259	27486767	observed that, in several cell lines, the minor allele of rs12803915 significantly alters the cellular processing of pre-miR-612 and, consequently, the expression levels of mature miR-612.	('rs12803915', 'Mutation', 'rs12803915', (58, 68))	('miR-612', 'Gene', '693197', (121, 128))	('miR-612', 'Gene', '693197', (180, 187))	('miR-612', 'Gene', (180, 187))	('rs12803915', 'Var', (58, 68))	('cellular processing', 'MPA', (94, 113))	('expression levels', 'MPA', (152, 169))	('alters', 'Reg', (83, 89))	('pre', 'molecular_function', 'GO:0003904', ('117', '120'))	('miR-612', 'Gene', (121, 128))
60266	27486767	The SNP rs3217992 is located in the 3'-UTR region of CDKN2B and also in DNase I hypersensitivity site.	('rs3217992', 'Var', (8, 17))	('CDKN2B', 'Gene', (53, 59))	('DNase I', 'molecular_function', 'GO:0004530', ('72', '79'))	('CDKN2B', 'Gene', '1030', (53, 59))	('hypersensitivity', 'biological_process', 'GO:0002524', ('80', '96'))	('hypersensitivity', 'Disease', (80, 96))	('hypersensitivity', 'Disease', 'MESH:D004342', (80, 96))	('rs3217992', 'Mutation', 'rs3217992', (8, 17))
60270	27486767	We also did cis-eQTL analysis based on public data sets and found that rs4940086, rs7799635, rs1559849, rs6128327, and rs3217992 were significantly associated with gene expression.	('rs3217992', 'Mutation', 'rs3217992', (119, 128))	('rs1559849', 'Var', (93, 102))	('rs4940086', 'Mutation', 'rs4940086', (71, 80))	('gene expression', 'MPA', (164, 179))	('rs6128327', 'Var', (104, 113))	('rs1559849', 'Mutation', 'rs1559849', (93, 102))	('rs7799635', 'Mutation', 'rs7799635', (82, 91))	('rs6128327', 'Mutation', 'rs6128327', (104, 113))	('rs3217992', 'Var', (119, 128))	('associated', 'Reg', (148, 158))	('gene expression', 'biological_process', 'GO:0010467', ('164', '179'))	('rs4940086', 'Var', (71, 80))	('rs7799635', 'Var', (82, 91))
60273	27486767	Since the SNPs identified herein increase risk for early onset disease, it would be interesting for future studies to examine hereditary cancers that predispose to PC to determine whether these SNPs are associated with earlier ages of PC development or disease development itself since previous studies provided strong evidence of an increased risk of PC in BRCA2 mutation carriers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('early onset disease', 'Disease', (51, 70))	('PC', 'Phenotype', 'HP:0002894', (352, 354))	('BRCA2', 'Gene', (358, 363))	('PC', 'Phenotype', 'HP:0002894', (235, 237))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('mutation', 'Var', (364, 372))	('hereditary cancers', 'Disease', (126, 144))	('BRCA2', 'Gene', '675', (358, 363))	('PC', 'Phenotype', 'HP:0002894', (164, 166))	('hereditary cancers', 'Disease', 'MESH:D009369', (126, 144))
60274	27486767	In conclusion, we analyzed functional genomic data sets to identify SNPs in the 3p12 pathway genes and genes related to the chromosome 20q interval and systematically assessed the associations of a large panel of tagging SNPs in the genes with age at diagnosis of PC.	('chromosome', 'cellular_component', 'GO:0005694', ('124', '134'))	('SNPs', 'Var', (68, 72))	('p12', 'Gene', '56655', (81, 84))	('associations', 'Interaction', (180, 192))	('p12', 'Gene', (81, 84))	('PC', 'Phenotype', 'HP:0002894', (264, 266))
60282	27486767	We finally selected 135 genes that interact in the 3p12 pathway and pathways affected by altered gene expression in the 20q interval.	('gene expression', 'biological_process', 'GO:0010467', ('97', '112'))	('p12', 'Gene', '56655', (52, 55))	('pathways', 'Pathway', (68, 76))	('p12', 'Gene', (52, 55))	('altered', 'Var', (89, 96))
60348	27916293	For statistical reasons, tumors were classified into two groups: (-),negative; (+), (++) and (+++), positive.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('+++', 'Var', (94, 97))
60349	27916293	In survival analysis, tumors were classified into two groups according to the Glut-1 expression: (-), (+) and (++), low reactivity group, (+++)high reactivity group.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('Glut-1', 'Gene', '6513', (78, 84))	('Glut-1', 'Gene', (78, 84))	('++', 'Var', (111, 113))	('low', 'NegReg', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (22, 28))
60431	27916293	In addition, the Glut-3 expression had been demonstrated to have considerable impact on 18F-FDG uptake in head and neck cancer, lymphoma,thyroid cancer and malignant melanoma.	('lymphoma,thyroid cancer', 'Disease', 'MESH:D013964', (128, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('uptake', 'biological_process', 'GO:0098657', ('96', '102'))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('FDG', 'Gene', '23583', (92, 95))	('uptake', 'biological_process', 'GO:0098739', ('96', '102'))	('malignant melanoma', 'Disease', (156, 174))	('head and neck cancer', 'Phenotype', 'HP:0012288', (106, 126))	('neck cancer', 'Disease', 'MESH:D006258', (115, 126))	('neck cancer', 'Disease', (115, 126))	('Glut-3', 'Gene', '6515', (17, 23))	('FDG', 'Gene', (92, 95))	('expression', 'Var', (24, 34))	('Glut-3', 'Gene', (17, 23))	('impact', 'Reg', (78, 84))	('malignant melanoma', 'Phenotype', 'HP:0002861', (156, 174))	('thyroid cancer', 'Phenotype', 'HP:0002890', (137, 151))	('neck', 'cellular_component', 'GO:0044326', ('115', '119'))	('malignant melanoma', 'Disease', 'MESH:D008545', (156, 174))
60531	26677336	Deregulation of FGF/FGFR signaling through genetic modification or over-expression of its ligands/receptors has been observed to promote cell proliferation, survival, and tumor angiogenesis in numerous tumor settings including pancreatic cancer, prostate cancer, and some squamous cell carcinomas.	('over-expression', 'Var', (67, 82))	('promote', 'PosReg', (129, 136))	('squamous cell carcinomas', 'Disease', (272, 296))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('numerous tumor', 'Disease', (193, 207))	('cell proliferation', 'biological_process', 'GO:0008283', ('137', '155'))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))	('genetic modification', 'Var', (43, 63))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('carcinomas', 'Phenotype', 'HP:0030731', (286, 296))	('survival', 'CPA', (157, 165))	('numerous tumor', 'Disease', 'MESH:D009369', (193, 207))	('tumor', 'Disease', (202, 207))	('cell proliferation', 'CPA', (137, 155))	('pancreatic cancer', 'Disease', 'MESH:D010190', (227, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('prostate cancer', 'Disease', 'MESH:D011471', (246, 261))	('prostate cancer', 'Phenotype', 'HP:0012125', (246, 261))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('pancreatic cancer', 'Disease', (227, 244))	('prostate cancer', 'Disease', (246, 261))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (272, 296))	('FGFR', 'molecular_function', 'GO:0005007', ('20', '24'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('Deregulation', 'Var', (0, 12))	('angiogenesis', 'biological_process', 'GO:0001525', ('177', '189'))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (272, 296))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (227, 244))	('tumor', 'Disease', (171, 176))	('FGF/FGFR', 'Gene', (16, 24))
60584	26677336	A Phase III, double-blind, randomized trial of nintedanib (200 mg, bid, n=565) or placebo (n=569) on days 2-21, in combination with docetaxel (75 mg/m2 on day 1) in patients with previously treated NSCLC (LUME-Lung 1 trial), reported that median PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (3.4 months vs 2.7 months, hazard ratio (HR) 0.79, P=0.0019).	('NSCLC', 'Phenotype', 'HP:0030358', (198, 203))	('improved', 'PosReg', (268, 276))	('docetaxel', 'Chemical', 'MESH:D000077143', (334, 343))	('docetaxel', 'Var', (284, 293))	('nintedanib', 'Chemical', 'MESH:C530716', (299, 309))	('bid', 'Gene', (67, 70))	('docetaxel', 'Chemical', 'MESH:D000077143', (284, 293))	('nintedanib', 'Chemical', 'MESH:C530716', (47, 57))	('docetaxel', 'Chemical', 'MESH:D000077143', (132, 141))	('bid', 'Gene', '637', (67, 70))	('patients', 'Species', '9606', (165, 173))	('NSCLC', 'Disease', (198, 203))	('PFS', 'MPA', (246, 249))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))
60608	26677336	However, grade 3 or more AEs occurred in 47% of patients after nintedanib compared with 56% after sunitinib.	('nintedanib', 'Chemical', 'MESH:C530716', (63, 73))	('nintedanib', 'Var', (63, 73))	('AEs', 'Chemical', '-', (25, 28))	('sunitinib', 'Chemical', 'MESH:D000077210', (98, 107))	('AEs', 'Disease', (25, 28))	('patients', 'Species', '9606', (48, 56))
60611	26677336	Two Phase II studies evaluated the efficacy and safety of nintedanib (200 mg, bid) in comparison with sorafenib (400 mg, bid) continuously in 28-day cycle, in patients with unresectable, advanced HCC in Europe (NCT0100434003) and Asia (NCT00987935).	('bid', 'Gene', '637', (78, 81))	('nintedanib', 'Chemical', 'MESH:C530716', (58, 68))	('bid', 'Gene', (121, 124))	('NCT0100434003', 'Var', (211, 224))	('HCC', 'Disease', (196, 199))	('bid', 'Gene', '637', (121, 124))	('sorafenib', 'Chemical', 'MESH:D000077157', (102, 111))	('patients', 'Species', '9606', (159, 167))	('HCC', 'Phenotype', 'HP:0001402', (196, 199))	('bid', 'Gene', (78, 81))
60614	26677336	However, the rates of grade >=3 AEs (62% vs 87%) and AEs leading to dose reduction (19% vs 51%) were lower in the nintedanib group compared to sorafenib (Table 2).	('AEs', 'Chemical', '-', (32, 35))	('sorafenib', 'Chemical', 'MESH:D000077157', (143, 152))	('nintedanib', 'Var', (114, 124))	('nintedanib', 'Chemical', 'MESH:C530716', (114, 124))	('AEs', 'Chemical', '-', (53, 56))	('lower', 'NegReg', (101, 106))
60625	26677336	Rash was more frequent with afatinib and elevation in transaminase was more frequent with nintedanib monotherapy.	('afatinib', 'Var', (28, 36))	('nintedanib', 'Chemical', 'MESH:C530716', (90, 100))	('afatinib', 'Chemical', 'MESH:D000077716', (28, 36))	('Rash', 'Disease', (0, 4))	('elevation in transaminase', 'Phenotype', 'HP:0002910', (41, 66))	('transaminase', 'MPA', (54, 66))	('Rash', 'Phenotype', 'HP:0000988', (0, 4))
60634	26677336	SD frequency was lower in the nintedanib than in the bevacizumab group (27.1% vs 36.6%).	('bevacizumab', 'Chemical', 'MESH:D000068258', (53, 64))	('lower', 'NegReg', (17, 22))	('nintedanib', 'Var', (30, 40))	('nintedanib', 'Chemical', 'MESH:C530716', (30, 40))	('SD', 'Disease', 'MESH:D029461', (0, 2))
60637	26677336	Incidences of AEs leading to discontinuation of nintedanib or bevacizumab, with or without discontinuation of mFOLFOX, were 27.1% for nintedanib and 31.7% in the bevacizumab group.	('AEs', 'Disease', (14, 17))	('bevacizumab', 'Chemical', 'MESH:D000068258', (162, 173))	('nintedanib', 'Var', (134, 144))	('mFOLFOX', 'Chemical', '-', (110, 117))	('AEs', 'Chemical', '-', (14, 17))	('nintedanib', 'Chemical', 'MESH:C530716', (134, 144))	('bevacizumab', 'Chemical', 'MESH:D000068258', (62, 73))	('nintedanib', 'Chemical', 'MESH:C530716', (48, 58))
60648	26677336	Based on promising efficacy and safety results of nintedanib in the above-mentioned solid tumors, nintedanib is currently under investigation in several other solid tumors including thyroid cancer (NCT01788982), neuroendocrine tumors (NCT02399215), cervix cancer (NCT02009579), endometrial cancer (NCT01225887), esophagogastric cancer (NCT02234596), urothelial carcinoma (NCT02278978), and glioblastoma (NCT01666600).	('gastric cancer', 'Disease', 'MESH:D013274', (320, 334))	('thyroid cancer', 'Disease', 'MESH:D013964', (182, 196))	('NCT01225887', 'Var', (298, 309))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (212, 233))	('NCT02399215', 'Var', (235, 246))	('endometrial cancer', 'Disease', 'MESH:D016889', (278, 296))	('urothelial carcinoma', 'Disease', (350, 370))	('cervix cancer', 'Disease', (249, 262))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('solid tumors', 'Disease', (84, 96))	('NCT01666600', 'Var', (404, 415))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('thyroid cancer', 'Phenotype', 'HP:0002890', (182, 196))	('gastric cancer', 'Phenotype', 'HP:0012126', (320, 334))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('NCT02009579', 'Var', (264, 275))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('neuroendocrine tumors', 'Disease', (212, 233))	('nintedanib', 'Chemical', 'MESH:C530716', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('NCT01788982', 'Var', (198, 209))	('glioblastoma', 'Disease', 'MESH:D005909', (390, 402))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('cervix cancer', 'Phenotype', 'HP:0030079', (249, 262))	('cervix cancer', 'Disease', 'MESH:D002583', (249, 262))	('NCT02234596', 'Var', (336, 347))	('solid tumors', 'Disease', 'MESH:D009369', (84, 96))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (350, 370))	('solid tumors', 'Disease', (159, 171))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('nintedanib', 'Chemical', 'MESH:C530716', (50, 60))	('thyroid cancer', 'Disease', (182, 196))	('gastric cancer', 'Disease', (320, 334))	('glioblastoma', 'Disease', (390, 402))	('carcinoma', 'Phenotype', 'HP:0030731', (361, 370))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (212, 233))	('glioblastoma', 'Phenotype', 'HP:0012174', (390, 402))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('endometrial cancer', 'Phenotype', 'HP:0012114', (278, 296))	('NCT02278978', 'Var', (372, 383))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('solid tumors', 'Disease', 'MESH:D009369', (159, 171))	('endometrial cancer', 'Disease', (278, 296))
60662	25679067	The G + nP + T triplet exhibited enhanced efficacy compared with T-alone or the G + nP doublet.	('G + nP + T', 'Chemical', '-', (4, 14))	('G + nP', 'Chemical', '-', (4, 10))	('G + nP', 'Chemical', '-', (80, 86))	('G + nP + T', 'Var', (4, 14))	('efficacy', 'MPA', (42, 50))	('enhanced', 'PosReg', (33, 41))
60663	25679067	Compared with vehicle (V), G + nP induced body weight loss, reduced neutrophil and lymphocyte counts, increased the levels of liver function parameters, and induced neurotoxicity.	('neutrophil', 'CPA', (68, 78))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('weight loss', 'Disease', (47, 58))	('G + nP', 'Var', (27, 33))	('G + nP', 'Chemical', '-', (27, 33))	('weight loss', 'Disease', 'MESH:D015431', (47, 58))	('weight loss', 'Phenotype', 'HP:0001824', (47, 58))	('induced', 'Reg', (157, 164))	('neurotoxicity', 'Disease', 'MESH:D020258', (165, 178))	('increased the levels of liver function parameters', 'Phenotype', 'HP:0002910', (102, 151))	('reduced', 'NegReg', (60, 67))	('increased', 'PosReg', (102, 111))	('levels of liver function parameters', 'MPA', (116, 151))	('neurotoxicity', 'Disease', (165, 178))
60666	25679067	Furthermore, the triplet further inhibited cell proliferation and reduced stroma density and intratumoral hypoxia.	('reduced', 'NegReg', (66, 73))	('inhibited', 'NegReg', (33, 42))	('cell proliferation', 'biological_process', 'GO:0008283', ('43', '61'))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('hypoxia', 'Disease', (106, 113))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('stroma density', 'CPA', (74, 88))	('tumor', 'Disease', (98, 103))	('cell proliferation', 'CPA', (43, 61))	('triplet', 'Var', (17, 24))
60667	25679067	The triplet combination of G + nP + T exhibited superior efficacy but additive toxicity was not evident compared to the G + nP doublet in this study.	('G + nP + T', 'Chemical', '-', (27, 37))	('G + nP + T', 'Var', (27, 37))	('G + nP', 'Chemical', '-', (27, 33))	('toxicity', 'Disease', 'MESH:D064420', (79, 87))	('toxicity', 'Disease', (79, 87))	('G + nP', 'Chemical', '-', (120, 126))
60687	25679067	Nab-paclitaxel has been shown to affect the tumor stoma.	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('Nab-paclitaxel', 'Var', (0, 14))	('affect', 'Reg', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor stoma', 'Disease', (44, 55))	('tumor stoma', 'Disease', 'MESH:D009369', (44, 55))
60691	25679067	This preclinical dosing sequence is consistent with Phase 2 and Phase 3 clinical trial design of G and T combination (NCT01144455 and NCT01746979, respectively) as well as the administration of G and nP in PDAC patients approved by the FDA and EMA.	('PDAC', 'Chemical', '-', (206, 210))	('patients', 'Species', '9606', (211, 219))	('C', 'Chemical', 'MESH:D002244', (135, 136))	('NCT01746979', 'Var', (134, 145))	('NCT01144455', 'Var', (118, 129))	('C', 'Chemical', 'MESH:D002244', (119, 120))	('C', 'Chemical', 'MESH:D002244', (209, 210))
60697	25679067	The doublet of G + nP significantly inhibited tumor growth in all 4 models, exhibiting TGIs from 85% to 107%.	('inhibited', 'NegReg', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('G + nP', 'Var', (15, 21))	('G + nP', 'Chemical', '-', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
60702	25679067	Similar results were also observed in the MIA PaCa-2, PANC-1, and BxPC-3 models: the G + nP doublet combination therapy demonstrated antitumor activity, and when T was added, the efficacy was enhanced.	('BxPC-3', 'CellLine', 'CVCL:0186', (66, 72))	('tumor', 'Disease', (137, 142))	('enhanced', 'PosReg', (192, 200))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('PANC-1', 'Gene', '104066', (54, 60))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (42, 52))	('PANC-1', 'Gene', (54, 60))	('efficacy', 'MPA', (179, 187))	('G + nP', 'Var', (85, 91))	('G + nP', 'Chemical', '-', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
60706	25679067	Of note, the CR rate of the G + nP + T combination therapy in the PANC-1 model reached 100%, compared to 10% and 60% in the T monotherapy and G + nP combination therapy groups, respectively.	('G + nP + T', 'Chemical', '-', (28, 38))	('G + nP', 'Chemical', '-', (28, 34))	('PANC-1', 'Gene', (66, 72))	('G + nP + T', 'Var', (28, 38))	('G + nP', 'Chemical', '-', (142, 148))	('PANC-1', 'Gene', '104066', (66, 72))	('CR', 'Chemical', '-', (13, 15))
60708	25679067	In the Hs766t and MIA PaCa-2 models, approximately 10 days after the last treatment, a further tumor growth regression in the treatment groups, particularly in G+ nP + T group, was observed.	('Hs766t', 'Var', (7, 13))	('G+ nP + T', 'Var', (160, 169))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
60709	25679067	We performed an experiment to compare morphology of vehicle and G + nP + T treated tumors at a similar size in Hs766t xenograft tumors.	('G + nP + T', 'Var', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('xenograft tumors', 'Disease', 'MESH:D009369', (118, 134))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('xenograft tumors', 'Disease', (118, 134))	('G + nP + T', 'Chemical', '-', (64, 74))
60710	25679067	Hs766t xenograft exhibited morphology of a cystic tumor.	('cystic tumor', 'Disease', 'MESH:D009369', (43, 55))	('cystic tumor', 'Disease', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('Hs766t', 'Var', (0, 6))
60711	25679067	After G + nP + T treatment, the majority of the tumor exhibited a necrotic phenotype, manifested as a viable rim with a large necrotic core.	('G + nP + T', 'Chemical', '-', (6, 16))	('G +', 'Var', (6, 9))	('tumor', 'Disease', (48, 53))	('core', 'cellular_component', 'GO:0019013', ('135', '139'))	('necrotic', 'Disease', (66, 74))	('exhibited', 'Reg', (54, 63))	('necrotic', 'Disease', 'MESH:D009336', (126, 134))	('necrotic', 'Disease', 'MESH:D009336', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('necrotic', 'Disease', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
60714	25679067	As shown in Figure 2 and Table 2, maximum BW loss (percentage of mean maximum BW loss compared with pretreatment) in the T monotherapy group was 0, G + nP induced maximum BW loss from 4 to 16%, and the G + nP + T triplet did not induce more body weight loss compared to the G + nP doublet.	('G + nP + T', 'Chemical', '-', (202, 212))	('G + nP', 'Var', (148, 154))	('weight loss', 'Disease', 'MESH:D015431', (246, 257))	('G + nP', 'Chemical', '-', (148, 154))	('weight loss', 'Phenotype', 'HP:0001824', (246, 257))	('G + nP', 'Chemical', '-', (274, 280))	('loss', 'NegReg', (45, 49))	('weight loss', 'Disease', (246, 257))	('loss', 'NegReg', (174, 178))	('G + nP', 'Chemical', '-', (202, 208))
60718	25679067	As shown in Figure 3A and B, G + nP combination therapy or T monotherapy reduced neutrophils, lymphocytes, and monocytes, compared with V, but there was no additional decrease in neutrophil, lymphocyte, or monocyte counts when T was added to G + nP (compared to G + nP).	('G + nP', 'Chemical', '-', (262, 268))	('G + nP', 'Chemical', '-', (29, 35))	('reduced', 'NegReg', (73, 80))	('G +', 'Var', (242, 245))	('G + nP', 'Chemical', '-', (242, 248))	('G +', 'Var', (29, 32))	('neutrophils', 'CPA', (81, 92))
60723	25679067	Plasma AST levels were elevated after G + nP combination therapy, and G + nP + T combination therapy did not further increase these liver function parameter levels.	('AST', 'Gene', '235504', (7, 10))	('G + nP combination', 'Var', (38, 56))	('G + nP + T', 'Chemical', '-', (70, 80))	('elevated', 'PosReg', (23, 31))	('G + nP', 'Chemical', '-', (70, 76))	('AST', 'Gene', (7, 10))	('G + nP', 'Chemical', '-', (38, 44))
60728	25679067	However, 9 days after the initiation of the treatment, G + nP doublet combination treated mice exhibited a significant hind paw mechanical hyperalgesia compared to V controls (P < 0.05).	('mechanical hyperalgesia', 'Disease', (128, 151))	('G + nP', 'Chemical', '-', (55, 61))	('hyperalgesia', 'Phenotype', 'HP:0031005', (139, 151))	('G +', 'Var', (55, 58))	('mechanical hyperalgesia', 'Disease', 'MESH:D006930', (128, 151))	('mice', 'Species', '10090', (90, 94))
60730	25679067	A similar change in mechanical hypersensitivity was observed in mice treated with the G + nP + T triplet combination compared to V over time.	('hypersensitivity', 'biological_process', 'GO:0002524', ('31', '47'))	('G + nP + T', 'Chemical', '-', (86, 96))	('hypersensitivity', 'Disease', (31, 47))	('G + nP + T triplet', 'Var', (86, 104))	('mice', 'Species', '10090', (64, 68))	('hypersensitivity', 'Disease', 'MESH:D004342', (31, 47))
60733	25679067	The results suggest that the triplet of G + nP + T did not add neuropathy compared with the G + nP doublet combination.	('neuropathy', 'Disease', 'MESH:D009422', (63, 73))	('neuropathy', 'Phenotype', 'HP:0009830', (63, 73))	('G + nP + T', 'Chemical', '-', (40, 50))	('G + nP', 'Chemical', '-', (92, 98))	('G + nP', 'Chemical', '-', (40, 46))	('G + nP + T', 'Var', (40, 50))	('neuropathy', 'Disease', (63, 73))
60734	25679067	We used a panel of histological and immunohistological markers to characterize Hs766t, MIA PaCa-2, PANC-1 and BxPC3 xenograft tumors.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('Hs766t', 'Var', (79, 85))	('xenograft tumors', 'Disease', (116, 132))	('PANC-1', 'Gene', '104066', (99, 105))	('BxPC3', 'CellLine', 'CVCL:0186', (110, 115))	('xenograft tumors', 'Disease', 'MESH:D009369', (116, 132))	('PANC-1', 'Gene', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (87, 97))
60737	25679067	PANC-1 tumor-bearing animals were treated with V, T at 50 mg/kg alone, G + nP (60 mg/kg, ip and 30 mg/kg iv, respectively), and G + nP + T when tumor size was approximately 500 mm3 with a Q3Dx5 dosing regimen.	('tumor', 'Disease', (144, 149))	('PANC-1', 'Gene', (0, 6))	('tumor', 'Disease', (7, 12))	('G + nP + T', 'Chemical', '-', (128, 138))	('G + nP + T', 'Var', (128, 138))	('G + nP', 'Chemical', '-', (128, 134))	('G + nP', 'Chemical', '-', (71, 77))	('PANC-1', 'Gene', '104066', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
60739	25679067	Representative assessments of necrosis, apoptosis, DNA damage, and proliferation of the tumor cells with or without treatment are shown in Figure 5A, and morphometric analysis results are shown in Figure 5B-F. Tumor necrotic fraction was significantly increased to 64% after the G + nP + T triplet combination, compared with 9% in V, 35% in T alone, and 33% in the G + nP doublet group (P < 0.01).	('G + nP', 'Chemical', '-', (365, 371))	('G + nP', 'Chemical', '-', (279, 285))	('increased', 'PosReg', (252, 261))	('necrosis', 'biological_process', 'GO:0008219', ('30', '38'))	('Tumor necrotic', 'Disease', 'MESH:D009369', (210, 224))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('necrosis', 'Disease', 'MESH:D009336', (30, 38))	('necrosis', 'biological_process', 'GO:0008220', ('30', '38'))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('G + nP + T', 'Var', (279, 289))	('Tumor necrotic', 'Disease', (210, 224))	('necrosis', 'biological_process', 'GO:0070265', ('30', '38'))	('necrosis', 'biological_process', 'GO:0019835', ('30', '38'))	('necrosis', 'Disease', (30, 38))	('necrosis', 'biological_process', 'GO:0001906', ('30', '38'))	('G + nP + T', 'Chemical', '-', (279, 289))	('Tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
60745	25679067	Cells with DNA damage were evenly distributed in both the hypoxic and oxic compartments in non-necrotic regions after the G + nP + T triplet treatment.	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('non-necrotic', 'Disease', (91, 103))	('non-necrotic', 'Disease', 'MESH:D009336', (91, 103))	('G + nP + T', 'Chemical', '-', (122, 132))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('G + nP + T', 'Var', (122, 132))
60747	25679067	Immunostaining demonstrated that Ki67-positive cells were significantly reduced after drug treatment but reduced by a greater magnitude in the G + nP + T triplet combination group.	('reduced', 'NegReg', (72, 79))	('G + nP', 'Var', (143, 149))	('Ki67', 'Gene', (33, 37))	('reduced', 'NegReg', (105, 112))	('Ki67', 'Gene', '17345', (33, 37))	('G + nP + T', 'Chemical', '-', (143, 153))
60752	25679067	T-alone had no effect on alpha-SMA or collagen expression compared to V. Of note, after treatment of G + nP or G + nP + T, the thinner, disrupted, and disorganized collagen appeared by Picrosirius red staining, relative to V. Hypoxic regions in the tumors were detected by pimonidazole immunostaining.	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('disorganized collagen', 'CPA', (151, 172))	('collagen', 'molecular_function', 'GO:0005202', ('164', '172'))	('collagen', 'molecular_function', 'GO:0005202', ('38', '46'))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('G + nP + T', 'Chemical', '-', (111, 121))	('G + nP', 'Chemical', '-', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('G + nP + T', 'Var', (111, 121))	('Picrosirius red', 'Chemical', 'MESH:C009798', (185, 200))	('G + nP', 'Var', (101, 107))	('G + nP', 'Chemical', '-', (101, 107))	('disrupted', 'CPA', (136, 145))	('pimonidazole', 'Chemical', 'MESH:C033815', (273, 285))	('tumors', 'Disease', (249, 255))
60758	25679067	TH-302 induced- Caspase-3 positivity was significantly increased and mainly located in the hypoxia zone, while further increased apoptotic cells by G + nP treatment were mainly in the normoxic (oxic) compartment.	('TH-302', 'Chemical', 'MESH:C552526', (0, 6))	('Caspase-3', 'Gene', '12367', (16, 25))	('hypoxia', 'Disease', (91, 98))	('hypoxia', 'Disease', 'MESH:D000860', (91, 98))	('increased', 'PosReg', (55, 64))	('G + nP', 'Var', (148, 154))	('G + nP', 'Chemical', '-', (148, 154))	('TH-302', 'Gene', (0, 6))	('positivity', 'MPA', (26, 36))	('Caspase-3', 'Gene', (16, 25))	('increased', 'PosReg', (119, 128))	('apoptotic cells', 'CPA', (129, 144))
60759	25679067	The triplet of G + nP + T resulted in apoptotic cells throughout the tumor (Fig.	('apoptotic cells', 'CPA', (38, 53))	('resulted in', 'Reg', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('G + nP + T', 'Chemical', '-', (15, 25))	('tumor', 'Disease', (69, 74))	('G + nP + T', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
60764	25679067	The G + nP doublet showed good antitumor activity in all 4 models, with TGIs ranging from 85% to 107%.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('G + nP', 'Var', (4, 10))	('G + nP', 'Chemical', '-', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))
60772	25679067	Treatment with nab-paclitaxel alone or nab-paclitaxel in combination with gemcitabine has been shown to decrease cancer-associated fibroblast (CAF) content, inducing a marked alteration in cancer stroma that result in tumor softening both preclinically and clinically.	('nab', 'Chemical', '-', (15, 18))	('nab-paclitaxel', 'Var', (39, 53))	('nab-paclitaxel', 'Var', (15, 29))	('nab', 'Chemical', '-', (39, 42))	('paclitaxel', 'Chemical', 'MESH:D017239', (43, 53))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('tumor', 'Disease', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('gemcitabine', 'Chemical', 'MESH:C056507', (74, 85))	('cancer stroma', 'Disease', (189, 202))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('paclitaxel', 'Chemical', 'MESH:D017239', (19, 29))	('cancer stroma', 'Disease', 'MESH:D009369', (189, 202))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('decrease', 'NegReg', (104, 112))	('alteration', 'Reg', (175, 185))	('cancer', 'Disease', (189, 195))	('C', 'Chemical', 'MESH:D002244', (143, 144))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))
60773	25679067	In our studies, we also found that the G + nP doublet significantly reduced the number of alpha-SMA positive fibroblasts as well as reduced extracellular collagen.	('G + nP doublet', 'Var', (39, 53))	('collagen', 'molecular_function', 'GO:0005202', ('154', '162'))	('extracellular', 'cellular_component', 'GO:0005576', ('140', '153'))	('reduced', 'NegReg', (132, 139))	('G + nP', 'Chemical', '-', (39, 45))	('extracellular collagen', 'MPA', (140, 162))	('reduced', 'NegReg', (68, 75))	('alpha-SMA', 'Protein', (90, 99))
60779	25679067	Interestingly, we did see that adding TH-302 reduced the hypoxic fraction relative to that of G + nP doublet.	('reduced', 'NegReg', (45, 52))	('hypoxic fraction', 'MPA', (57, 73))	('G + nP', 'Chemical', '-', (94, 100))	('TH-302', 'Chemical', 'MESH:C552526', (38, 44))	('TH-302', 'Var', (38, 44))
60780	25679067	In published preclinical studies, exposure to nab-paclitaxel collapsed the PDAC stroma and as a result, intratumoral concentration of gemcitabine was increased.	('collapsed', 'NegReg', (61, 70))	('nab', 'Chemical', '-', (46, 49))	('nab-paclitaxel', 'Var', (46, 60))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('paclitaxel', 'Chemical', 'MESH:D017239', (50, 60))	('increased', 'PosReg', (150, 159))	('PDAC', 'Chemical', '-', (75, 79))	('gemcitabine', 'Chemical', 'MESH:C056507', (134, 145))	('tumor', 'Disease', (109, 114))
60788	25679067	The results showed that adding TH-302 to the G + nP doublet did not induce further body weight loss or further reductions in neutrophil, lymphocyte, or platelet counts compared with those observed with the G + nP doublet.	('platelet', 'MPA', (152, 160))	('weight loss', 'Disease', (88, 99))	('TH-302', 'Var', (31, 37))	('G + nP', 'Chemical', '-', (206, 212))	('G + nP', 'Chemical', '-', (45, 51))	('weight loss', 'Phenotype', 'HP:0001824', (88, 99))	('lymphocyte', 'MPA', (137, 147))	('weight loss', 'Disease', 'MESH:D015431', (88, 99))	('neutrophil', 'MPA', (125, 135))	('reductions', 'NegReg', (111, 121))	('TH-302', 'Chemical', 'MESH:C552526', (31, 37))
60790	25679067	Given the fact that the cytotoxic effector of TH-302 is structurally very similar to that of ifosfamide, we tested whether TH-302 might cause neuropathy as a monotherapy or add more neurotoxicity when combined with gemcitabine and nab-paclitaxel.	('tested', 'Reg', (108, 114))	('neurotoxicity', 'Disease', (182, 195))	('cause', 'Reg', (136, 141))	('nab', 'Chemical', '-', (231, 234))	('TH-302', 'Chemical', 'MESH:C552526', (46, 52))	('ifosfamide', 'Chemical', 'MESH:D007069', (93, 103))	('paclitaxel', 'Chemical', 'MESH:D017239', (235, 245))	('neurotoxicity', 'Disease', 'MESH:D020258', (182, 195))	('neuropathy', 'Disease', 'MESH:D009422', (142, 152))	('neuropathy', 'Phenotype', 'HP:0009830', (142, 152))	('gemcitabine', 'Chemical', 'MESH:C056507', (215, 226))	('TH-302', 'Chemical', 'MESH:C552526', (123, 129))	('TH-302', 'Var', (123, 129))	('neuropathy', 'Disease', (142, 152))
60792	25679067	To our knowledge, this is the first report of nab-paclitaxel and gemcitabine combination-induced neuropathy in mice.	('neuropathy', 'Disease', (97, 107))	('nab', 'Chemical', '-', (46, 49))	('nab-paclitaxel', 'Var', (46, 60))	('gemcitabine', 'Chemical', 'MESH:C056507', (65, 76))	('mice', 'Species', '10090', (111, 115))	('paclitaxel', 'Chemical', 'MESH:D017239', (50, 60))	('neuropathy', 'Disease', 'MESH:D009422', (97, 107))	('neuropathy', 'Phenotype', 'HP:0009830', (97, 107))
60793	25679067	Consistent with the other safety profiling observations described, the addition of TH-302 did not add to the neuropathy observed in the G + nP doublet.	('neuropathy', 'Disease', 'MESH:D009422', (109, 119))	('TH-302', 'Chemical', 'MESH:C552526', (83, 89))	('neuropathy', 'Phenotype', 'HP:0009830', (109, 119))	('TH-302', 'Var', (83, 89))	('neuropathy', 'Disease', (109, 119))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('G + nP', 'Chemical', '-', (136, 142))
60795	25679067	In summary, 4 PDAC models, Hs766t, PANC-1, MIA PaCa-2 and BxPC-3, were used to study the triplet of G + nP + T in comparison to G + nP doublet or TH-302 monotherapy.	('PDAC', 'Chemical', '-', (14, 18))	('G + nP + T', 'Chemical', '-', (100, 110))	('G + nP', 'Chemical', '-', (100, 106))	('PANC-1', 'Gene', (35, 41))	('G + nP + T', 'Var', (100, 110))	('TH-302', 'Chemical', 'MESH:C552526', (146, 152))	('G + nP', 'Chemical', '-', (128, 134))	('PANC-1', 'Gene', '104066', (35, 41))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (43, 53))	('BxPC-3', 'CellLine', 'CVCL:0186', (58, 64))
60796	25679067	A statistically significant difference in antitumor activity was observed between the triplet of G + nP + T and the G + nP doublet in the Hs766t, MIA PaCa-2, and PANC-1 models based on TGI and Kaplan-Meier survival time.	('PANC-1', 'Gene', '104066', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PANC-1', 'Gene', (162, 168))	('tumor', 'Disease', (46, 51))	('G + nP', 'Chemical', '-', (97, 103))	('G + nP + T', 'Chemical', '-', (97, 107))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (146, 156))	('G + nP', 'Chemical', '-', (116, 122))	('G + nP + T', 'Var', (97, 107))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
60797	25679067	The triplet of G + nP + T did not increase the safety markers of body weight loss, hematologic toxicity, hepatotoxicity, or neuropathy compared with the G + nP doublet.	('weight loss', 'Disease', 'MESH:D015431', (70, 81))	('hematologic toxicity', 'Disease', 'MESH:D006402', (83, 103))	('hepatotoxicity', 'Disease', 'MESH:D056486', (105, 119))	('G + nP + T', 'Chemical', '-', (15, 25))	('weight loss', 'Phenotype', 'HP:0001824', (70, 81))	('weight loss', 'Disease', (70, 81))	('G + nP', 'Chemical', '-', (153, 159))	('G + nP + T', 'Var', (15, 25))	('neuropathy', 'Disease', 'MESH:D009422', (124, 134))	('neuropathy', 'Phenotype', 'HP:0009830', (124, 134))	('hepatotoxicity', 'Disease', (105, 119))	('G + nP', 'Chemical', '-', (15, 21))	('hematologic toxicity', 'Disease', (83, 103))	('neuropathy', 'Disease', (124, 134))
60798	25679067	This favorable preclinical antitumor activity and safety profile of the triplet G + nP + T against PDAC supports exploration of this regimen in human clinical trials.	('PDAC', 'Chemical', '-', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('human', 'Species', '9606', (144, 149))	('tumor', 'Disease', (31, 36))	('G + nP + T', 'Chemical', '-', (80, 90))	('PDAC', 'Disease', (99, 103))	('G + nP + T', 'Var', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
60804	25679067	Hs766t, MIA PaCa-2, PANC-1, and BxPC-3 were obtained from the American Type Culture Collection (ATCC).	('C', 'Chemical', 'MESH:D002244', (14, 15))	('C', 'Chemical', 'MESH:D002244', (76, 77))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('BxPC-3', 'CellLine', 'CVCL:0186', (32, 38))	('PANC-1', 'Gene', '104066', (20, 26))	('C', 'Chemical', 'MESH:D002244', (84, 85))	('C', 'Chemical', 'MESH:D002244', (23, 24))	('C', 'Chemical', 'MESH:D002244', (98, 99))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (8, 18))	('PANC-1', 'Gene', (20, 26))	('C', 'Chemical', 'MESH:D002244', (99, 100))	('Hs766t', 'Var', (0, 6))
60811	25679067	nP prior to G is employed in both clinica and preclinical settings, and it has been shown that nP is able to increase intratumoral concentration of G. In this study, the animals were first dosed with TH-302 ip, followed by nP iv 2 hrs later, and then after 1 more hr, G was given ip.	('TH-302', 'Chemical', 'MESH:C552526', (200, 206))	('TH-302', 'Var', (200, 206))	('tumor', 'Disease', (123, 128))	('increase', 'PosReg', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
60955	26177391	For instance, our group has previously shown that Survivin, a protein highly expressed in cancers and essential for carcinogenesis, is localized in intra-cellular an extracellular pools, and that extracellular Survivin enters cancer cells, increasing proliferation, resistance, and invasive potential.	('resistance', 'CPA', (266, 276))	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('carcinogenesis', 'Disease', (116, 130))	('invasive potential', 'CPA', (282, 300))	('extracellular', 'cellular_component', 'GO:0005576', ('196', '209'))	('Survivin', 'Protein', (210, 218))	('extracellular', 'Var', (196, 209))	('extracellular', 'cellular_component', 'GO:0005576', ('166', '179'))	('carcinogenesis', 'Disease', 'MESH:D063646', (116, 130))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('proliferation', 'CPA', (251, 264))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('Survivin', 'Gene', (50, 58))	('cancer', 'Disease', (226, 232))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('increasing', 'PosReg', (240, 250))	('cancer', 'Disease', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
60957	26177391	Exosomes have also been shown to transport mutant KRAS proteins to colon cancer cells, increasing tumor growth.	('proteins', 'Protein', (55, 63))	('colon cancer', 'Phenotype', 'HP:0003003', (67, 79))	('colon cancer', 'Disease', 'MESH:D015179', (67, 79))	('transport', 'biological_process', 'GO:0006810', ('33', '42'))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('KRAS', 'Gene', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('colon cancer', 'Disease', (67, 79))	('mutant', 'Var', (43, 49))	('KRAS', 'Gene', '3845', (50, 54))	('tumor', 'Disease', (98, 103))	('increasing', 'PosReg', (87, 97))
60972	26177391	Remarkably, our results indicate that curcumin is able to be packaged into exosomes derived from pancreatic cancer cells treated with curcumin.	('curcumin', 'Var', (134, 142))	('pancreatic cancer', 'Disease', 'MESH:D010190', (97, 114))	('curcumin', 'Chemical', 'MESH:D003474', (134, 142))	('pancreatic cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('curcumin', 'Chemical', 'MESH:D003474', (38, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (97, 114))
60973	26177391	Furthermore, our work shows that exosomal curcumin enters recipient pancreatic cancer cells, reducing cell viability.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('exosomal', 'Var', (33, 41))	('reducing', 'NegReg', (93, 101))	('curcumin', 'Chemical', 'MESH:D003474', (42, 50))	('pancreatic cancer', 'Disease', (68, 85))	('cell viability', 'CPA', (102, 116))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))
60974	26177391	Using Hoffman modulation microscopy, we were able to demonstrate that exosomal curcumin induces cell death with morphological features suggestive of apoptosis.	('apoptosis', 'CPA', (149, 158))	('exosomal', 'Var', (70, 78))	('cell death', 'biological_process', 'GO:0008219', ('96', '106'))	('apoptosis', 'biological_process', 'GO:0097194', ('149', '158'))	('apoptosis', 'biological_process', 'GO:0006915', ('149', '158'))	('cell death', 'CPA', (96, 106))	('curcumin', 'Chemical', 'MESH:D003474', (79, 87))
60978	26177391	Taken together, these findings suggest that exosomal curcumin induces apoptosis in recipient pancreatic adenocarcinoma cells; however, further work must be performed to elucidate the key mediators of exosomal curcumin-induced cell death.	('curcumin', 'Chemical', 'MESH:D003474', (53, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (93, 118))	('exosomal', 'Var', (44, 52))	('pancreatic adenocarcinoma', 'Disease', (93, 118))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('curcumin', 'Chemical', 'MESH:D003474', (209, 217))	('cell death', 'biological_process', 'GO:0008219', ('226', '236'))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (93, 118))
60995	26161297	Indeed, mutant DNA derived from dying or lysed cancer cells can be isolated from patient serum samples, subjected to DNA sequencing and to analysis of abundance as a measure of tumor burden.	('patient', 'Species', '9606', (81, 88))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('cancer', 'Disease', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('mutant', 'Var', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (177, 182))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))
60996	26161297	Thus, the combined serial analysis of mutant DNA and miR in the circulation has the potential to provide a molecular footprint of pancreatic cancer and can be used to monitor treatment responses or resistance to treatment in real time with a minimally invasive procedure.	('mutant', 'Var', (38, 44))	('miR', 'Gene', (53, 56))	('DNA', 'Gene', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (130, 147))	('pancreatic cancer', 'Disease', (130, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (130, 147))
61003	26161297	Identification of specific pancreatic cancer markers is crucial for the improvement of controlling this disease and recent studies have shown that circulating mutant DNA can be found in the majority of cancer patients and can provide a measurement of tumor burden.	('DNA', 'cellular_component', 'GO:0005574', ('166', '169'))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Disease', (251, 256))	('pancreatic cancer', 'Disease', (27, 44))	('mutant', 'Var', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('pancreatic cancer', 'Disease', 'MESH:D010190', (27, 44))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('DNA', 'Gene', (166, 169))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('patients', 'Species', '9606', (209, 217))	('cancer', 'Disease', (202, 208))	('cancer', 'Disease', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (27, 44))
61013	26161297	It is widely accepted that circulating mutant DNA originates from cancer cells.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutant', 'Var', (39, 45))	('DNA', 'Gene', (46, 49))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
61015	26161297	Intra-tumor heterogeneity and the amount of wild type tumor stroma DNA will have a great impact on the relative amount of mutant cfDNA.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('impact', 'Reg', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('type tumor stroma', 'Disease', (49, 66))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('type tumor stroma', 'Disease', 'MESH:D009369', (49, 66))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('tumor', 'Disease', (54, 59))	('mutant', 'Var', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
61019	26161297	As a consequence, cfDNA from cancer patients should harbor these mutations and will be indicative of tumor-derived DNA.	('cancer', 'Disease', (29, 35))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('mutations', 'Var', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('harbor', 'Reg', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
61020	26161297	Data from numerous studies show the presence of mutant KRAS DNA in the circulation of patients with pancreatic cancer and are summarized in (Table 1).	('mutant', 'Var', (48, 54))	('patients', 'Species', '9606', (86, 94))	('pancreatic cancer', 'Disease', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('pancreatic cancer', 'Disease', 'MESH:D010190', (100, 117))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (100, 117))	('presence', 'Reg', (36, 44))	('KRAS DNA', 'Gene', (55, 63))
61021	26161297	These results from a number of research groups show that the detection of circulating mutant KRAS DNA can be used to monitor pancreatic cancer progression.	('KRAS DNA', 'Gene', (93, 101))	('mutant', 'Var', (86, 92))	('pancreatic cancer', 'Disease', 'MESH:D010190', (125, 142))	('pancreatic cancer', 'Disease', (125, 142))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))
61022	26161297	With respect to the specificity of mutant KRAS cfDNA for the detection of pancreatic cancer, the findings are mixed.	('KRAS', 'Gene', (42, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('mutant', 'Var', (35, 41))	('pancreatic cancer', 'Disease', (74, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
61024	26161297	However, two studies described mutant KRAS in the circulation of 13% and 5% of patients (4 of 31; 2 of 37) with chronic pancreatitis.	('mutant', 'Var', (31, 37))	('pancreatitis', 'Disease', (120, 132))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (112, 132))	('pancreatitis', 'Disease', 'MESH:D010195', (120, 132))	('patients', 'Species', '9606', (79, 87))	('pancreatitis', 'Phenotype', 'HP:0001733', (120, 132))	('KRAS', 'Gene', (38, 42))
61026	26161297	However, surgical pathology analysis of the tissues did not detect pancreatic cancer and after a follow-up of 6 to 36 months, none of the chronic pancreatitis patients with cfDNA KRAS mutations had developed pancreatic cancer.	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (138, 158))	('pancreatitis', 'Disease', 'MESH:D010195', (146, 158))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('pancreatitis', 'Phenotype', 'HP:0001733', (146, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (208, 225))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (67, 84))	('mutations', 'Var', (184, 193))	('pancreatic cancer', 'Disease', (208, 225))	('pancreatitis', 'Disease', (146, 158))	('pancreatic cancer', 'Disease', 'MESH:D010190', (208, 225))	('pancreatic cancer', 'Disease', 'MESH:D010190', (67, 84))	('pancreatic cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('patients', 'Species', '9606', (159, 167))
61027	26161297	The transiently detected mutant KRAS DNA in the circulation likely originated from hyperplastic, mucous cells of chronically inflamed pancreas that had been removed and it thus appears that mutant KRAS cfDNA is not a reliable indicator of the presence of pancreatic cancer.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('mutant', 'Var', (25, 31))	('pancreatic cancer', 'Disease', (255, 272))	('KRAS DNA', 'Gene', (32, 40))	('pancreatic cancer', 'Disease', 'MESH:D010190', (255, 272))	('mucous', 'cellular_component', 'GO:0070701', ('97', '103'))	('mutant', 'Var', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('KRAS cfDNA', 'Gene', (197, 207))	('originated', 'Reg', (67, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (255, 272))
61028	26161297	The majority of published studies on pancreatic cancer utilize mutant KRAS cfDNA as a diagnostic marker to confirm the presence of malignancy.	('mutant', 'Var', (63, 69))	('KRAS cfDNA', 'Gene', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (37, 54))	('malignancy', 'Disease', 'MESH:D009369', (131, 141))	('malignancy', 'Disease', (131, 141))	('pancreatic cancer', 'Disease', (37, 54))	('pancreatic cancer', 'Disease', 'MESH:D010190', (37, 54))
61030	26161297	Overall, the ratio of cancer cell to desmoplastic wildtype stroma will likely impact the abundance of circulating mutant KRAS and variability in the assessment of tumor/stroma ratio could explain the inconsistent findings across studies.	('KRAS', 'Gene', (121, 125))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cancer', 'Disease', (22, 28))	('impact', 'Reg', (78, 84))	('desmoplastic wildtype stroma', 'Disease', (37, 65))	('mutant', 'Var', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('abundance', 'MPA', (89, 98))	('desmoplastic wildtype stroma', 'Disease', 'MESH:D018220', (37, 65))
61031	26161297	found circulating mutant KRAS DNA in 5 out of 25 patients with stage III pancreatic cancer, in contrast to 25 out of 37 patients with stage IV disease.	('pancreatic cancer', 'Disease', (73, 90))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('mutant', 'Var', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (120, 128))	('patients', 'Species', '9606', (49, 57))	('KRAS DNA', 'Gene', (25, 33))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))
61034	26161297	found that surgery and/or chemoradiation treatment resulted in the disappearance of mutant KRAS from plasma DNA in 12 out of 15 patients.	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('disappearance', 'NegReg', (67, 80))	('mutant', 'Var', (84, 90))	('KRAS', 'Gene', (91, 95))	('patients', 'Species', '9606', (128, 136))
61035	26161297	in lung cancer patients they used a more sensitive DNA detection method for mutant cfDNA levels and found a correlation with tumor volumes during chemotherapy and surgery and with CT and PET scan data.	('cfDNA levels', 'MPA', (83, 95))	('patients', 'Species', '9606', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('lung cancer', 'Disease', (3, 14))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('mutant', 'Var', (76, 82))	('tumor', 'Disease', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('DNA detection', 'MPA', (51, 64))
61041	26161297	on mutant KRAS cfDNA in colon cancer patients could serve as a paradigm: They found that 9 of 24 patients whose colorectal tumors were initially KRAS wildtype, developed detectable mutations in KRAS in their cfDNA after treatment with an EGFR antibody.	('antibody', 'molecular_function', 'GO:0003823', ('243', '251'))	('colorectal tumors', 'Disease', 'MESH:D015179', (112, 129))	('EGFR', 'Gene', '1956', (238, 242))	('antibody', 'cellular_component', 'GO:0042571', ('243', '251'))	('patients', 'Species', '9606', (37, 45))	('KRAS', 'Gene', (194, 198))	('colon cancer', 'Phenotype', 'HP:0003003', (24, 36))	('mutations', 'Var', (181, 190))	('antibody', 'cellular_component', 'GO:0019815', ('243', '251'))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('EGFR', 'Gene', (238, 242))	('colorectal tumors', 'Disease', (112, 129))	('colon cancer', 'Disease', 'MESH:D015179', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('patients', 'Species', '9606', (97, 105))	('antibody', 'cellular_component', 'GO:0019814', ('243', '251'))	('cfDNA', 'Gene', (208, 213))	('colon cancer', 'Disease', (24, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('238', '242'))
61042	26161297	This suggests that the emergence of KRAS mutant clones was due to the selection for resistance to EGFR blockade.	('EGFR', 'Gene', (98, 102))	('mutant', 'Var', (41, 47))	('KRAS', 'Gene', (36, 40))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))
61057	26161297	After validation studies, 3 miR, miR -22, miR -642b and miR-885-5p were confirmed to show consistent expression between microarray and qPCR.	('miR -642b', 'Var', (42, 51))	('miR-885', 'Gene', '100126334', (56, 63))	('miR -22', 'Gene', '407004', (33, 40))	('miR-885', 'Gene', (56, 63))	('miR -22', 'Gene', (33, 40))
61060	26161297	They found that a combination of 8 miRs (miR-125a-3p, miR-4294, miR-4476, miR-4530, miR-6075, miR-6799-5p, miR-6836-3p and miR-6880-5p) achieved the best discriminant performance.	('miR-6075', 'Gene', '102466103', (84, 92))	('miR-6836', 'Gene', (107, 115))	('miR-4530', 'Gene', (74, 82))	('miR-6799-5p', 'Var', (94, 105))	('miR-4476', 'Gene', (64, 72))	('miR-6880', 'Gene', (123, 131))	('miR-6075', 'Gene', (84, 92))	('miR-6880', 'Gene', '102466204', (123, 131))	('miR-4476', 'Gene', '100616456', (64, 72))	('miR-6836', 'Gene', '102465503', (107, 115))	('miR-4294', 'Gene', '100422895', (54, 62))	('miR-4294', 'Gene', (54, 62))	('miR-4530', 'Gene', '100616163', (74, 82))	('miR-125a-3p', 'Var', (41, 52))
61082	26161297	The loss of miR-296 may be one of the mechanisms for primary resistance of colorectal cancer to chemotherapy and this could be translated to studies in pancreatic cancer patients using similar drug regimen.	('patients', 'Species', '9606', (170, 178))	('colorectal cancer', 'Disease', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('miR-296', 'Gene', '407022', (12, 19))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('pancreatic cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('miR-296', 'Gene', (12, 19))	('pancreatic cancer', 'Disease', 'MESH:D010190', (152, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (152, 169))	('loss', 'Var', (4, 8))
61084	26161297	Both circulating microRNA and cancer cell derived mutant DNA have been tested as potential surrogates or complements for direct tissue biopsies.	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('mutant', 'Var', (50, 56))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
61087	26161297	Thus, we propose to use a combination analysis of circulating mutant DNA and microRNAs to monitor treatment responses in patients with pancreatic cancer (Figure 1).	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (135, 152))	('mutant', 'Var', (62, 68))	('pancreatic cancer', 'Disease', (135, 152))	('pancreatic cancer', 'Disease', 'MESH:D010190', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('patients', 'Species', '9606', (121, 129))
61099	25245095	Binding of miRNAs to mRNAs occurs via partial complementarity through the seed region, nucleotides (nts) 2-7 or 2-8 at the 5'end of the miRNA.	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (136, 139))	('miR', 'Gene', (11, 14))	('partial complementarity', 'Var', (38, 61))	('Binding', 'Interaction', (0, 7))
61115	25245095	Activating mutations in KRAS including G12D and G13D lock KRAS in the GTP-bound, constitutively active state to deregulate multiple downstream pathways resulting in deregulated cell growth, evasion from apoptosis and angiogenesis.	('KRAS', 'Gene', (58, 62))	('deregulate', 'Reg', (112, 122))	('KRAS', 'Gene', '3845', (24, 28))	('KRAS', 'Gene', '3845', (58, 62))	('G13D', 'Mutation', 'rs112445441', (48, 52))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))	('cell growth', 'CPA', (177, 188))	('G12D', 'Var', (39, 43))	('GTP', 'Chemical', 'MESH:D006160', (70, 73))	('deregulated', 'MPA', (165, 176))	('G12D', 'Mutation', 'rs121913529', (39, 43))	('angiogenesis', 'biological_process', 'GO:0001525', ('217', '229'))	('cell growth', 'biological_process', 'GO:0016049', ('177', '188'))	('evasion', 'CPA', (190, 197))	('angiogenesis', 'CPA', (217, 229))	('G13D', 'Var', (48, 52))	('KRAS', 'Gene', (24, 28))
61122	25245095	We identified the genes miR-126 regulates in KRAS-WT and KRAS-Mutant cells and found that miR-126 suppresses the expression of multiple genes that are synthetic lethal interactors of mutant KRAS.	('KRAS', 'Gene', '3845', (45, 49))	('expression', 'MPA', (113, 123))	('suppresses', 'NegReg', (98, 108))	('KRAS', 'Gene', (190, 194))	('KRAS', 'Gene', '3845', (190, 194))	('KRAS', 'Gene', (57, 61))	('miR-126', 'Gene', (24, 31))	('KRAS', 'Gene', '3845', (57, 61))	('miR-126', 'Var', (90, 97))	('KRAS', 'Gene', (45, 49))
61124	25245095	To identify miRNAs that selectively alter the viability of CRC cells harboring mutant KRAS, we decided to perform replica parallel screens (Figure 1A) of synthetic miRNA mimics corresponding to 879 human miRNAs in isogenic HCT116 KRAS-wild-type (KRAS-WT) and KRAS-Mutant (G13D/-) cells.	('G13D', 'Mutation', 'rs112445441', (272, 276))	('KRAS', 'Gene', (86, 90))	('alter', 'Reg', (36, 41))	('miR', 'Gene', (164, 167))	('KRAS', 'Gene', (259, 263))	('miR', 'Gene', (204, 207))	('miR', 'Gene', (12, 15))	('CRC', 'Phenotype', 'HP:0003003', (59, 62))	('HCT116', 'CellLine', 'CVCL:0291', (223, 229))	('human', 'Species', '9606', (198, 203))	('KRAS', 'Gene', '3845', (230, 234))	('mutant', 'Var', (79, 85))	('KRAS', 'Gene', (230, 234))	('KRAS', 'Gene', '3845', (246, 250))	('miR', 'Gene', '220972', (164, 167))	('KRAS', 'Gene', '3845', (86, 90))	('KRAS', 'Gene', (246, 250))	('KRAS', 'Gene', '3845', (259, 263))	('miR', 'Gene', '220972', (204, 207))	('miR', 'Gene', '220972', (12, 15))
61138	25245095	Next, we transfected 6 additional CRC lines that included 2 that were KRAS-WT (RKO and CaCo2) and 4 that harbor mutations in KRAS (LoVo, SW403, SW1116 and SW620) to determine whether the KRAS mutant-specific effects of these 15 miRNAs extended to other CRC lines.	('miR', 'Gene', (228, 231))	('CRC', 'Phenotype', 'HP:0003003', (34, 37))	('KRAS', 'Gene', (125, 129))	('LoVo', 'CellLine', 'CVCL:0399', (131, 135))	('KRAS', 'Gene', (187, 191))	('KRAS', 'Gene', (70, 74))	('KRAS', 'Gene', '3845', (125, 129))	('SW403', 'CellLine', 'CVCL:0545', (137, 142))	('KRAS', 'Gene', '3845', (187, 191))	('SW1116', 'Var', (144, 150))	('SW403', 'Var', (137, 142))	('mutations', 'Var', (112, 121))	('KRAS', 'Gene', '3845', (70, 74))	('SW1116', 'CellLine', 'CVCL:0544', (144, 150))	('CRC', 'Phenotype', 'HP:0003003', (253, 256))	('SW620', 'CellLine', 'CVCL:0547', (155, 160))	('miR', 'Gene', '220972', (228, 231))	('SW620', 'Var', (155, 160))
61147	25245095	As expected, siCelldeath transfections resulted in dramatic reduction in viability irrespective of KRAS mutation status.	('transfections', 'Var', (25, 38))	('reduction', 'NegReg', (60, 69))	('KRAS', 'Gene', (99, 103))	('KRAS', 'Gene', '3845', (99, 103))	('viability', 'MPA', (73, 82))
61158	25245095	The HCT116 KRAS-WT and KRAS-Mutant cells proliferated at similar rates (Figure 2C).	('KRAS', 'Gene', (11, 15))	('HCT116', 'Var', (4, 10))	('KRAS', 'Gene', '3845', (11, 15))	('KRAS', 'Gene', (23, 27))	('HCT116', 'CellLine', 'CVCL:0291', (4, 10))	('KRAS', 'Gene', '3845', (23, 27))	('proliferated', 'CPA', (41, 53))
61159	25245095	However, introduction of miR-126 was more effective in inhibiting the viability of KRAS-Mutant as compared to KRAS-WT cells (Figure 2D and 2E).	('KRAS', 'Gene', (83, 87))	('KRAS', 'Gene', '3845', (83, 87))	('KRAS', 'Gene', '3845', (110, 114))	('miR-126', 'Var', (25, 32))	('viability', 'CPA', (70, 79))	('inhibiting', 'NegReg', (55, 65))	('KRAS', 'Gene', (110, 114))
61160	25245095	To determine whether the selective effect of miR-126 was due to increased apoptosis or cell cycle arrest, we performed flow cytometry analysis after propidium iodide staining of the isogenic lines transfected with siCTL or miR-126 mimics for 48 h. MiR-126 mimics specifically increased the G1 compartment in the HCT116 KRAS-Mutant cells (Figure 2F).	('arrest', 'Disease', (98, 104))	('mimics', 'Var', (256, 262))	('KRAS', 'Gene', '3845', (319, 323))	('HCT116', 'CellLine', 'CVCL:0291', (312, 318))	('G1 compartment', 'MPA', (290, 304))	('propidium iodide', 'Chemical', 'MESH:D011419', (149, 165))	('increased', 'PosReg', (276, 285))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('MiR-126', 'Gene', (248, 255))	('MiR-126', 'Gene', '406913', (248, 255))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('87', '104'))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('arrest', 'Disease', 'MESH:D006323', (98, 104))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (87, 104))	('KRAS', 'Gene', (319, 323))
61170	25245095	Decreased tumor growth (>40%) was observed in xenografts formed from miR-126 transfected cells (p<0.03; Figure 3E).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('Decreased tumor', 'Disease', (0, 15))	('Decreased tumor', 'Disease', 'MESH:D009369', (0, 15))	('miR-126', 'Gene', (69, 76))	('transfected', 'Var', (77, 88))
61174	25245095	However, miR-126 did not repress the 3'UTR of HRAS, KRAS, or NRAS mRNAs (Figure 4B).	('KRAS', 'Gene', (52, 56))	('KRAS', 'Gene', '3845', (52, 56))	('HRAS', 'Gene', '3265', (46, 50))	('HRAS', 'Gene', (46, 50))	('NRAS', 'Gene', (61, 65))	("3'UTR", 'MPA', (37, 42))	('NRAS', 'Gene', '4893', (61, 65))	('miR-126', 'Var', (9, 16))
61183	25245095	Therefore, we performed microarray analysis from HCT116 KRAS-WT and KRAS-Mutant cells transfected with siCTL or miR-126 mimics (20 nM) for 48 h. Using arbitrary cut-offs of 2.0- or 1.5-fold, respectively (p<0.05), 69 and 321 genes were down-regulated by miR-126 in HCT116 KRAS-Mutant cells, respectively (Table S3).	('down-regulated', 'NegReg', (236, 250))	('KRAS', 'Gene', (56, 60))	('KRAS', 'Gene', '3845', (272, 276))	('KRAS', 'Gene', '3845', (56, 60))	('miR-126', 'Var', (254, 261))	('KRAS', 'Gene', (68, 72))	('HCT116', 'CellLine', 'CVCL:0291', (49, 55))	('KRAS', 'Gene', '3845', (68, 72))	('HCT116', 'CellLine', 'CVCL:0291', (265, 271))	('genes', 'Gene', (225, 230))	('KRAS', 'Gene', (272, 276))
61199	25245095	Although DCBLD2 mRNA does not contain sites complementary to the miR-126 seed sequence and is not predicted by TargetScan, its 3'UTR was repressed by miR-126, indicating that it may be regulated by non-canonical miR-126 binding sites that can be identified by RNA22 or RNAHybrid.	('DCBLD2', 'Gene', '131566', (9, 15))	('miR-126', 'Var', (150, 157))	('binding', 'molecular_function', 'GO:0005488', ('220', '227'))	('DCBLD2', 'Gene', (9, 15))	('RNA', 'cellular_component', 'GO:0005562', ('260', '263'))
61203	25245095	Although CPA4 3'UTR was not repressed by miR-126, we included CPA4 in this analysis as this was the most strongly down-regulated gene in the microarrays following over-expression of miR-126.	('CPA4', 'Gene', (62, 66))	('CPA4', 'Gene', '51200', (9, 13))	('CPA4', 'Gene', (9, 13))	('miR-126', 'Var', (182, 189))	('over-expression', 'PosReg', (163, 178))	('down-regulated', 'NegReg', (114, 128))	('CPA4', 'Gene', '51200', (62, 66))
61205	25245095	We next examined the effect of silencing each of these genes in HCT116 KRAS-WT and KRAS-Mutant cells on cell viability and soft agar colony formation.	('KRAS', 'Gene', (83, 87))	('silencing', 'Var', (31, 40))	('HCT116', 'CellLine', 'CVCL:0291', (64, 70))	('KRAS', 'Gene', '3845', (83, 87))	('KRAS', 'Gene', (71, 75))	('agar', 'Chemical', 'MESH:D000362', (128, 132))	('KRAS', 'Gene', '3845', (71, 75))	('formation', 'biological_process', 'GO:0009058', ('140', '149'))
61206	25245095	Only the silencing of ILK, PIK3R2, and UBQLN2 resulted in a greater reduction (<40%) in the viability of HCT116 KRAS-Mutant cells as compared to KRAS-WT cells 72 h after transfection, though the silencing of ILK also substantially reduced the viability of KRAS-WT cells (Figure 5C).	('PIK3R2', 'Gene', '5296', (27, 33))	('UBQLN2', 'Gene', (39, 45))	('HCT116', 'Gene', (105, 111))	('HCT116', 'CellLine', 'CVCL:0291', (105, 111))	('UBQLN2', 'Gene', '29978', (39, 45))	('KRAS', 'Gene', '3845', (145, 149))	('reduced', 'NegReg', (231, 238))	('reduction', 'NegReg', (68, 77))	('KRAS', 'Gene', '3845', (256, 260))	('KRAS', 'Gene', '3845', (112, 116))	('ILK', 'Gene', (208, 211))	('ILK', 'Gene', '3611', (208, 211))	('KRAS', 'Gene', (145, 149))	('KRAS', 'Gene', (256, 260))	('KRAS', 'Gene', (112, 116))	('PIK3R2', 'Gene', (27, 33))	('ILK', 'Gene', (22, 25))	('silencing', 'Var', (9, 18))	('ILK', 'Gene', '3611', (22, 25))
61207	25245095	In contrast, silencing of all but one of the selected genes reduced clonogenicity of the KRAS-Mutant cells, in some cases to nearly the same level as observed with KRAS siRNA.	('KRAS', 'Gene', '3845', (164, 168))	('clonogenicity', 'CPA', (68, 81))	('reduced', 'NegReg', (60, 67))	('KRAS', 'Gene', (164, 168))	('KRAS', 'Gene', (89, 93))	('silencing', 'Var', (13, 22))	('KRAS', 'Gene', '3845', (89, 93))
61209	25245095	UBQLN2 was one of the genes whose knockdown selectively reduced the viability of HCT116 KRAS-Mutant cells and also resulted in a highly significant decrease in the colony forming ability of HCT116 KRAS-Mutant cells.	('HCT116', 'CellLine', 'CVCL:0291', (81, 87))	('viability', 'CPA', (68, 77))	('reduced', 'NegReg', (56, 63))	('UBQLN2', 'Gene', (0, 6))	('HCT116', 'CellLine', 'CVCL:0291', (190, 196))	('KRAS', 'Gene', (88, 92))	('KRAS', 'Gene', (197, 201))	('KRAS', 'Gene', '3845', (88, 92))	('KRAS', 'Gene', '3845', (197, 201))	('knockdown', 'Var', (34, 43))	('colony forming ability', 'CPA', (164, 186))	('decrease', 'NegReg', (148, 156))	('UBQLN2', 'Gene', '29978', (0, 6))
61212	25245095	Silencing UBQLN2 or over-expressing miR-126 significantly inhibited clonogenicity of the KRAS-Mutant LoVo and SW620 cells (Figure 5E and 5F).	('miR-126', 'Gene', (36, 43))	('LoVo', 'CellLine', 'CVCL:0399', (101, 105))	('UBQLN2', 'Gene', '29978', (10, 16))	('clonogenicity', 'CPA', (68, 81))	('UBQLN2', 'Gene', (10, 16))	('over-expressing', 'PosReg', (20, 35))	('Silencing', 'Var', (0, 9))	('KRAS', 'Gene', (89, 93))	('SW620', 'CellLine', 'CVCL:0547', (110, 115))	('inhibited', 'NegReg', (58, 67))	('KRAS', 'Gene', '3845', (89, 93))
61213	25245095	Moreover, when we silenced UBQLN2 in a panel of CRC lines that expressed KRAS-WT or KRAS-Mutant, we observed reduction in the viability of the KRAS-Mutant lines but not KRAS-WT lines (Figure S7A).	('KRAS', 'Gene', (73, 77))	('viability', 'CPA', (126, 135))	('KRAS', 'Gene', '3845', (73, 77))	('UBQLN2', 'Gene', (27, 33))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('KRAS', 'Gene', (169, 173))	('reduction', 'NegReg', (109, 118))	('KRAS', 'Gene', (84, 88))	('silenced', 'Var', (18, 26))	('KRAS', 'Gene', '3845', (169, 173))	('KRAS', 'Gene', '3845', (84, 88))	('KRAS', 'Gene', (143, 147))	('KRAS', 'Gene', '3845', (143, 147))	('UBQLN2', 'Gene', '29978', (27, 33))
61223	25245095	Importantly, the context-dependent effect of miR-126 was not restricted to HCT116 cells and was also observed in a panel of CRC lines expressing mutant KRAS.	('HCT116', 'CellLine', 'CVCL:0291', (75, 81))	('mutant', 'Var', (145, 151))	('KRAS', 'Gene', (152, 156))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('miR-126', 'Gene', (45, 52))	('KRAS', 'Gene', '3845', (152, 156))
61226	25245095	The expression of miR-126 and its host gene is reduced in most cancers including those with a high frequency of KRAS mutations such as colorectal cancer, lung cancer and pancreatic ductal carcinoma.	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('expression', 'MPA', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('pancreatic ductal carcinoma', 'Disease', (170, 197))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (181, 197))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('miR-126', 'Gene', (18, 25))	('KRAS', 'Gene', '3845', (112, 116))	('colorectal cancer', 'Disease', (135, 152))	('cancers', 'Disease', (63, 70))	('mutations', 'Var', (117, 126))	('lung cancer', 'Disease', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('KRAS', 'Gene', (112, 116))	('pancreatic ductal carcinoma', 'Disease', 'MESH:D021441', (170, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('reduced', 'NegReg', (47, 54))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
61231	25245095	Interestingly, in a recent study miR-126 was found to inhibit KRAS expression via a seedless binding site in the KRAS 3'UTR in pancreatic cancer cell lines.	('pancreatic cancer', 'Disease', (127, 144))	('miR-126', 'Var', (33, 40))	('KRAS', 'Gene', (62, 66))	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('inhibit', 'NegReg', (54, 61))	('KRAS', 'Gene', '3845', (62, 66))	('binding', 'molecular_function', 'GO:0005488', ('93', '100'))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('KRAS', 'Gene', (113, 117))	('KRAS', 'Gene', '3845', (113, 117))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))
61233	25245095	Moreover, KRAS was not identified as a miR-126 target gene in another recent report where microarrays were used to identify mRNAs down-regulated by miR-126 in HT-29 cells (CRC).	('down-regulated', 'NegReg', (130, 144))	('CRC', 'Phenotype', 'HP:0003003', (172, 175))	('KRAS', 'Gene', '3845', (10, 14))	('HT-29 cells', 'CellLine', 'CVCL:0320', (159, 170))	('mRNAs', 'MPA', (124, 129))	('miR-126', 'Var', (148, 155))	('KRAS', 'Gene', (10, 14))
61244	25245095	Multiple recent reports demonstrate that alterations in the length of the 3'UTR due to APA plays a role in the context-dependent effect of some miRNAs such as miR-34a, miR-124 and miR-155.	('miR', 'Gene', '220972', (168, 171))	('miR', 'Gene', (168, 171))	('APA', 'Gene', (87, 90))	('miR', 'Gene', '220972', (144, 147))	('miR', 'Gene', (144, 147))	('miR', 'Gene', '220972', (159, 162))	('miR', 'Gene', (159, 162))	('miR', 'Gene', '220972', (180, 183))	('miR', 'Gene', (180, 183))	('alterations', 'Var', (41, 52))
61250	25245095	We have utilized a novel strategy for identifying key downstream effectors of miR-126 in KRAS-Mutant cells by comparing the genes down-regulated by miR-126 with the genes identified in a synthetic lethal RNAi screen for KRAS.	('down-regulated', 'NegReg', (130, 144))	('RNAi', 'biological_process', 'GO:0016246', ('204', '208'))	('KRAS', 'Gene', '3845', (220, 224))	('KRAS', 'Gene', (220, 224))	('KRAS', 'Gene', (89, 93))	('miR-126', 'Var', (148, 155))	('KRAS', 'Gene', '3845', (89, 93))
61259	25245095	A recent study identified mutations in ubiquilin-2 as causative of a familial form of ALS (Amyotrophic lateral sclerosis).	('Amyotrophic lateral sclerosis', 'Disease', (91, 120))	('Amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (91, 120))	('ubiquilin-2', 'Gene', (39, 50))	('ALS', 'Disease', 'MESH:C565957', (86, 89))	('Amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (91, 120))	('ALS', 'Disease', (86, 89))	('mutations', 'Var', (26, 35))	('causative', 'Reg', (54, 63))	('ubiquilin-2', 'Gene', '29978', (39, 50))
61260	25245095	Although the proteins UBQLN2 targets have not been identified yet, reporter assays have shown that mutations in UBQLN2 lead to impaired protein degradation.	('protein degradation', 'biological_process', 'GO:0030163', ('136', '155'))	('UBQLN2', 'Gene', '29978', (112, 118))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('mutations', 'Var', (99, 108))	('UBQLN2', 'Gene', '29978', (22, 28))	('impaired', 'NegReg', (127, 135))	('UBQLN2', 'Gene', (112, 118))	('protein degradation', 'MPA', (136, 155))	('UBQLN2', 'Gene', (22, 28))
61262	25245095	Knockdown of UBQLN2 significantly reduced clonogenicity in three KRAS-Mutant CRC lines, validating our recent study where we found a synthetic lethal interaction between UBQLN2 and mutant KRAS in DLD1 cells.	('UBQLN2', 'Gene', (13, 19))	('mutant', 'Var', (181, 187))	('reduced', 'NegReg', (34, 41))	('KRAS', 'Gene', '3845', (65, 69))	('UBQLN2', 'Gene', '29978', (170, 176))	('clonogenicity', 'CPA', (42, 55))	('KRAS', 'Gene', (188, 192))	('UBQLN2', 'Gene', '29978', (13, 19))	('UBQLN2', 'Gene', (170, 176))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))	('KRAS', 'Gene', '3845', (188, 192))	('KRAS', 'Gene', (65, 69))
61264	25245095	Given the importance of UBQLN2 mutations in ALS and our results on the selective targeting of KRAS-Mutant cells by miR-126 and upon UBQLN2 knockdown, it will be important to identify the proteins whose stability is regulated by UBQLN2.	('UBQLN2', 'Gene', (24, 30))	('ALS', 'Disease', (44, 47))	('mutations', 'Var', (31, 40))	('KRAS', 'Gene', (94, 98))	('UBQLN2', 'Gene', '29978', (132, 138))	('UBQLN2', 'Gene', '29978', (228, 234))	('KRAS', 'Gene', '3845', (94, 98))	('UBQLN2', 'Gene', (132, 138))	('ALS', 'Disease', 'MESH:C565957', (44, 47))	('UBQLN2', 'Gene', (228, 234))	('UBQLN2', 'Gene', '29978', (24, 30))	('miR-126', 'Gene', (115, 122))
61266	25245095	The miR-126 gene targets CPA4, DCBLD2, PIK3R2, SLC39A6 and UBQLN2 are interesting candidates for future work and it will be important to understand the molecular mechanism by which these genes regulate viability and clonogenicity in the context of mutant KRAS.	('UBQLN2', 'Gene', '29978', (59, 65))	('clonogenicity', 'CPA', (216, 229))	('KRAS', 'Gene', '3845', (255, 259))	('DCBLD2', 'Gene', (31, 37))	('mutant', 'Var', (248, 254))	('UBQLN2', 'Gene', (59, 65))	('viability', 'CPA', (202, 211))	('CPA4', 'Gene', '51200', (25, 29))	('miR-126', 'Gene', (4, 11))	('PIK3R2', 'Gene', (39, 45))	('PIK3R2', 'Gene', '5296', (39, 45))	('SLC39A6', 'Gene', '25800', (47, 54))	('KRAS', 'Gene', (255, 259))	('DCBLD2', 'Gene', '131566', (31, 37))	('CPA4', 'Gene', (25, 29))	('SLC39A6', 'Gene', (47, 54))	('regulate', 'Reg', (193, 201))
61272	25245095	SW403, SW1116 and SW620 were maintained in Leibovitz's L-15 Medium containing 10% fetal bovine serum (FBS) at 37 C. The siRNAs corresponding to cyclophilin B, KRAS, the negative control siRNA (siCTL), control miRNA mimics (cel-miR-67), and all miRNA mimics were purchased from Dharmacon/Thermo scientific (Pittsburg, USA).	('FBS', 'Disease', 'MESH:D005198', (102, 105))	('KRAS', 'Gene', (159, 163))	('SW403', 'CellLine', 'CVCL:0545', (0, 5))	('miR', 'Gene', (209, 212))	('miR', 'Gene', '220972', (209, 212))	('bovine', 'Species', '9913', (88, 94))	('cyclophilin', 'molecular_function', 'GO:0004600', ('144', '155'))	('SW620', 'CellLine', 'CVCL:0547', (18, 23))	('miR', 'Gene', '220972', (244, 247))	('KRAS', 'Gene', '3845', (159, 163))	('miR', 'Gene', (244, 247))	('SW620', 'Var', (18, 23))	('SW1116', 'CellLine', 'CVCL:0544', (7, 13))	('miR', 'Gene', '220972', (227, 230))	('miR', 'Gene', (227, 230))	('FBS', 'Disease', (102, 105))	('cyclophilin', 'molecular_function', 'GO:0016018', ('144', '155'))	('L-15 Medium', 'Chemical', '-', (55, 66))
61298	24837184	Mesenchymal-like pancreatic cancer cells harbor specific genomic alterations more frequently than their epithelial-like counterparts The aggressiveness of pancreatic cancer is associated with the acquisition of mesenchymal characteristics by a subset of pancreatic cancer cells.	('alterations', 'Var', (65, 76))	('pancreatic cancer', 'Disease', (17, 34))	('pancreatic cancer', 'Disease', (254, 271))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mesenchymal characteristics', 'CPA', (211, 238))	('aggressiveness of pancreatic cancer', 'Disease', 'MESH:D010190', (137, 172))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('pancreatic cancer', 'Disease', 'MESH:D010190', (254, 271))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('pancreatic cancer', 'Disease', 'MESH:D010190', (155, 172))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (254, 271))	('aggressiveness', 'Phenotype', 'HP:0000718', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('aggressiveness of pancreatic cancer', 'Disease', (137, 172))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (155, 172))
61301	24837184	CDKN2A was altered in more than 50% of both groups, but co-deletions in neighboring genes, and concomitant loss of gene expression, were more prevalent in the mesenchymal group, suggesting that the size of the loss around CDKN2A affects cell phenotype.	('affects', 'Reg', (229, 236))	('loss', 'NegReg', (107, 111))	('CDKN2A', 'Gene', (222, 228))	('gene expression', 'biological_process', 'GO:0010467', ('115', '130'))	('loss', 'Var', (210, 214))	('CDKN2A', 'Gene', '1029', (222, 228))	('CDKN2A', 'Gene', (0, 6))	('mesenchymal group', 'CPA', (159, 176))	('CDKN2A', 'Gene', '1029', (0, 6))	('gene expression', 'MPA', (115, 130))
61317	24837184	The most common mutations in pancreatic cancers are in KRAS, TP53, SMAD4, and CDKN2A, and other regions of genetic amplification and deletion frequently appear at multiple loci.	('KRAS', 'Gene', (55, 59))	('pancreatic cancers', 'Disease', 'MESH:D010190', (29, 47))	('pancreatic cancers', 'Disease', (29, 47))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (29, 46))	('SMAD4', 'Gene', (67, 72))	('CDKN2A', 'Gene', (78, 84))	('KRAS', 'Gene', '3845', (55, 59))	('mutations', 'Var', (16, 25))	('CDKN2A', 'Gene', '1029', (78, 84))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (29, 47))	('SMAD4', 'Gene', '4089', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
61318	24837184	Such mutations likely contribute to the initiation of cancer and may not necessarily be involved in the progression of a subset of cells to an invasive and resistant phenotype.	('initiation of cancer', 'Disease', (40, 60))	('contribute', 'Reg', (22, 32))	('initiation of cancer', 'Disease', 'MESH:D009369', (40, 60))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
61319	24837184	A study finding specific amplifications and deletions enriched in patients with venous invasion and shortened survival points to genetic hits that affect cancer cell progression, similar to findings that amplifications at the 7q21-q22 locus involving the SMURF1 and ARPCIA genes promote cellular invasiveness.	('SMURF1', 'Gene', '57154', (255, 261))	('deletions', 'Var', (44, 53))	('ARPCIA', 'Gene', (266, 272))	('cancer', 'Disease', (154, 160))	('cellular invasiveness', 'CPA', (287, 308))	('amplifications', 'Var', (25, 39))	('affect', 'Reg', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('promote', 'PosReg', (279, 286))	('patients', 'Species', '9606', (66, 74))	('amplifications', 'Var', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('SMURF1', 'Gene', (255, 261))
61332	24837184	For each hybridization, 1 g of genomic DNA from each sample and 1 mug of pooled commercial 46XX reference DNA (Promega Corp., Madison, WI) were digested with DNaseI and labeled with Cy-5 dUTP and Cy-3 dUTP, respectively, using a BioPrime labeling kit (Invitrogen).	('Cy-5 dUTP', 'Var', (182, 191))	('dUTP', 'Chemical', 'MESH:C027078', (201, 205))	('dUTP', 'Chemical', 'MESH:C027078', (187, 191))	('mug', 'molecular_function', 'GO:0043739', ('66', '69'))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('Cy-5', 'Chemical', 'MESH:C085321', (182, 186))	('Cy-3 dUTP', 'Var', (196, 205))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('Cy-3 dUTP', 'Chemical', 'MESH:C088941', (196, 205))	('N', 'Chemical', 'MESH:D009584', (159, 160))
61351	24837184	We initially used the student's t-test to identify regions with significantly different levels between the groups but found the method insufficient to distinguish meaningful from irrelevant information, mainly because the test does not include a threshold for minimum level of amplification or deletion.	('deletion', 'Var', (294, 302))	('insufficient', 'Disease', (135, 147))	('insufficient', 'Disease', 'MESH:D000309', (135, 147))
61352	24837184	For example, the TTN gene on chromosome 2 was significantly different between the groups (p < 0.0001), but none of the individual cell lines showed major amplification or deletion for that probe (defined as a two-fold change relative to the reference DNA) (Fig.	('N', 'Chemical', 'MESH:D009584', (252, 253))	('TTN', 'Gene', (17, 20))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('deletion', 'Var', (171, 179))	('TTN', 'Gene', '7273', (17, 20))	('DNA', 'cellular_component', 'GO:0005574', ('251', '254'))
61358	24837184	This relationship suggests that the size of the deletion of the CDKN2A locus may affect cell phenotype; loss of CDKN2A promotes tumor formation, but the co-deletion of certain neighboring genes may promote cancer plasticity and invasiveness.	('promotes', 'PosReg', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('loss', 'Var', (104, 108))	('promote', 'PosReg', (198, 205))	('CDKN2A', 'Gene', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('CDKN2A', 'Gene', (64, 70))	('formation', 'biological_process', 'GO:0009058', ('134', '143'))	('CDKN2A', 'Gene', '1029', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CDKN2A', 'Gene', '1029', (64, 70))	('affect', 'Reg', (81, 87))	('invasiveness', 'CPA', (228, 240))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('tumor', 'Disease', (128, 133))	('cancer', 'Disease', (206, 212))	('deletion', 'Var', (48, 56))
61364	24837184	Other well-known pancreatic cancer associated genes such as KRAS and TP53 did not show up in the final lists because they typically are affected by point mutations and low copy number aberrations.	('pancreatic cancer', 'Disease', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('TP53', 'Gene', '7157', (69, 73))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('TP53', 'Gene', (69, 73))	('KRAS', 'Gene', (60, 64))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('affected by', 'Reg', (136, 147))	('KRAS', 'Gene', '3845', (60, 64))	('low copy number aberrations', 'Var', (168, 195))	('point mutations', 'Var', (148, 163))
61366	24837184	The qPCR data correlated well with the CGH data for the genes KIAA1797, TUSC3, AF103097, M34428 and SMAD4 (Fig.	('AF103097', 'Var', (79, 87))	('TUSC3', 'Gene', (72, 77))	('SMAD4', 'Gene', '4089', (100, 105))	('M34428', 'Var', (89, 95))	('KIAA1797', 'Gene', '54914', (62, 70))	('TUSC3', 'Gene', '7991', (72, 77))	('KIAA1797', 'Gene', (62, 70))	('SMAD4', 'Gene', (100, 105))
61369	24837184	Genomic amplifications and deletions could contribute to cancer progression by affecting the expression levels of certain genes.	('contribute', 'Reg', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('expression levels', 'MPA', (93, 110))	('affecting', 'Reg', (79, 88))	('Genomic amplifications', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('deletions', 'Var', (27, 36))
61373	24837184	3A), supporting the potential cancer-promoting functions of losses near CDKN2A.	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('losses', 'Var', (60, 66))	('CDKN2A', 'Gene', (72, 78))	('CDKN2A', 'Gene', '1029', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
61374	24837184	The amplification of M34428 DNA copy number levels correlated with higher gene expression (Fig.	('higher', 'PosReg', (67, 73))	('gene expression', 'MPA', (74, 89))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('M34428 DNA copy number', 'Var', (21, 43))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('gene expression', 'biological_process', 'GO:0010467', ('74', '89'))
61376	24837184	On the other hand, M34428 and DQ515897 are located on either side of the MYC gene, an oncogene that also is amplified in 6 of the cell lines, so they could be co-altered as passengers with MYC.	('M34428', 'Var', (19, 25))	('DQ515897', 'Var', (30, 38))	('MYC', 'Gene', (189, 192))	('MYC', 'Gene', (73, 76))	('MYC', 'Gene', '4609', (189, 192))	('MYC', 'Gene', '4609', (73, 76))
61377	24837184	Although we were not able to detect expression of the AF103097 putative gene:interesting due to its gain in epithelial cells and loss in mesenchymal cells:genetic alterations to this locus nevertheless could contribute to cancer progression, perhaps through affecting the expression of other genes.	('genetic alterations', 'Var', (155, 174))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('expression', 'MPA', (272, 282))	('cancer', 'Disease', (222, 228))	('affecting', 'Reg', (258, 267))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('contribute', 'Reg', (208, 218))
61383	24837184	SGCZ, AF103097, KLHL9 and TUSC3 also were aberrant in a high proportion of the samples.	('AF103097', 'Var', (6, 14))	('TUSC3', 'Gene', '7991', (26, 31))	('SGCZ', 'Gene', '137868', (0, 4))	('KLHL9', 'Gene', '55958', (16, 21))	('TUSC3', 'Gene', (26, 31))	('SGCZ', 'Gene', (0, 4))	('KLHL9', 'Gene', (16, 21))
61388	24837184	We found that specific deletions and amplifications are more prevalent in cancer cells with a mesenchymal phenotype relative to those with an epithelial phenotype.	('deletions', 'Var', (23, 32))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('prevalent', 'Reg', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('amplifications', 'Var', (37, 51))
61392	24837184	Our study is the first to find that some previously identified alterations, including the losses at 8p22, 9p21-p22, and 18q21 and the amplification at 8q24, may be associated with the development of a mesenchymal phenotype affecting aggressiveness.	('aggressiveness', 'Disease', 'MESH:D001523', (233, 247))	('p22', 'Gene', '11261', (111, 114))	('associated', 'Reg', (164, 174))	('losses', 'Var', (90, 96))	('18q21', 'Gene', (120, 125))	('aggressiveness', 'Disease', (233, 247))	('p22', 'Gene', (111, 114))	('p22', 'Gene', '11261', (101, 104))	('p22', 'Gene', (101, 104))	('amplification', 'Var', (134, 147))	('aggressiveness', 'Phenotype', 'HP:0000718', (233, 247))
61393	24837184	The deletion of SMAD4 at 18q21 is one of the most frequent events in pancreatic cancer.	('pancreatic cancer', 'Disease', (69, 86))	('SMAD4', 'Gene', (16, 21))	('pancreatic cancer', 'Disease', 'MESH:D010190', (69, 86))	('frequent', 'Reg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('SMAD4', 'Gene', '4089', (16, 21))	('deletion', 'Var', (4, 12))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (69, 86))
61406	24837184	The loss of KLHL9 potentially could disrupt regulation of mitosis.	('KLHL9', 'Gene', (12, 17))	('regulation of mitosis', 'biological_process', 'GO:0007088', ('44', '65'))	('mitosis', 'Disease', (58, 65))	('regulation', 'MPA', (44, 54))	('disrupt', 'NegReg', (36, 43))	('KLHL9', 'Gene', '55958', (12, 17))	('mitosis', 'Disease', 'None', (58, 65))	('loss', 'Var', (4, 8))
61407	24837184	Losses to the p arm of chromosome 8, affecting SGCZ and TUSC3, also were highly prevalent in the mesenchymal cells.	('prevalent', 'Reg', (80, 89))	('TUSC3', 'Gene', (56, 61))	('SGCZ', 'Gene', (47, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('SGCZ', 'Gene', '137868', (47, 51))	('Losses', 'Var', (0, 6))	('TUSC3', 'Gene', '7991', (56, 61))
61409	24837184	The downregulation of TUSC3, either through epigenetic silencing or DNA deletion, is prevalent in prostate cancer.	('TUSC3', 'Gene', '7991', (22, 27))	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('prostate cancer', 'Disease', (98, 113))	('prostate cancer', 'Disease', 'MESH:D011471', (98, 113))	('downregulation', 'NegReg', (4, 18))	('TUSC3', 'Gene', (22, 27))	('N', 'Chemical', 'MESH:D009584', (69, 70))	('epigenetic silencing', 'Var', (44, 64))	('DNA deletion', 'Var', (68, 80))
61413	24837184	In summary, this study supports the hypothesis that specific genetic alterations enable phenotypic switches or cell plasticity that contributes to cancer progression.	('phenotypic switches', 'CPA', (88, 107))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('genetic alterations', 'Var', (61, 80))	('cell plasticity', 'CPA', (111, 126))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
61415	24837184	The mesenchymal cells also show losses in the p arm of chromosome 8 involving SGCZ and TUSC3, and highly focal amplifications and deletions to the AF103097 putative gene on chromosome 14.	('deletions', 'Var', (130, 139))	('chromosome', 'cellular_component', 'GO:0005694', ('173', '183'))	('amplifications', 'MPA', (111, 125))	('SGCZ', 'Gene', '137868', (78, 82))	('TUSC3', 'Gene', (87, 92))	('losses', 'NegReg', (32, 38))	('AF103097', 'Gene', (147, 155))	('SGCZ', 'Gene', (78, 82))	('TUSC3', 'Gene', '7991', (87, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))
61416	24837184	Future studies of human tissue should further explore the relationship of the alterations identified here with the phenotype of the cancer cell.	('cancer', 'Disease', (132, 138))	('human', 'Species', '9606', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('alterations', 'Var', (78, 89))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
61421	24837184	Alterations near the tumor suppressor p16 might be more than passenger mutations.	('tumor', 'Disease', (21, 26))	('tumor suppressor', 'biological_process', 'GO:0051726', ('21', '37'))	('Alterations', 'Var', (0, 11))	('p16', 'Gene', (38, 41))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('21', '37'))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('p16', 'Gene', '1029', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
61422	24837184	'Mesenchymal-like pancreatic cancer cells harbor specific genomic alterations more frequently than their epithelial-like counterparts'	('genomic alterations', 'Var', (58, 77))	('pancreatic cancer', 'Disease', (18, 35))	('pancreatic cancer', 'Disease', 'MESH:D010190', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (18, 35))
61427	23801748	Mechanistic analyses demonstrated that over-expression of FOXL1 induces apoptosis and inhibits proliferation and invasion in pancreatic cancer cells, whereas silencing of FOXL1 by siRNA inhibits apoptosis and enhances tumor cell growth and invasion.	('induces', 'Reg', (64, 71))	('apoptosis', 'biological_process', 'GO:0006915', ('195', '204'))	('FOXL1', 'Gene', (171, 176))	('pancreatic cancer', 'Disease', 'MESH:D010190', (125, 142))	('enhances', 'PosReg', (209, 217))	('silencing', 'Var', (158, 167))	('tumor', 'Disease', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('apoptosis', 'CPA', (195, 204))	('inhibits', 'NegReg', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('pancreatic cancer', 'Disease', (125, 142))	('invasion', 'CPA', (240, 248))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('FOXL1', 'Gene', (58, 63))	('expression', 'Species', '29278', (44, 54))	('cell growth', 'biological_process', 'GO:0016049', ('224', '235'))	('inhibits', 'NegReg', (186, 194))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))	('apoptosis', 'CPA', (72, 81))	('over-expression', 'PosReg', (39, 54))	('apoptosis', 'biological_process', 'GO:0097194', ('195', '204'))
61442	23801748	Loss of Foxl1 led to a marked increase in cellular proliferation of intestinal epithelia in mice, leading to the distortion in the tissue architecture of the stomach and small intestine.	('intestinal epithelia', 'Disease', (68, 88))	('tissue architecture of the stomach', 'CPA', (131, 165))	('cellular proliferation', 'CPA', (42, 64))	('increase', 'PosReg', (30, 38))	('Foxl1', 'Gene', (8, 13))	('intestinal epithelia', 'Disease', 'MESH:D007410', (68, 88))	('Foxl1', 'Gene', '14241', (8, 13))	('Loss', 'Var', (0, 4))	('mice', 'Species', '10090', (92, 96))
61443	23801748	The altered proliferation rate in Foxl1-null mutant mice is correlated with an activated Wnt/ beta-catenin pathway as demonstrated by increased nuclear translocation of beta-catenin.	('mutant', 'Var', (45, 51))	('Foxl1', 'Gene', (34, 39))	('Foxl1', 'Gene', '14241', (34, 39))	('beta-catenin', 'Gene', (169, 181))	('beta-catenin', 'Gene', (94, 106))	('proliferation rate', 'CPA', (12, 30))	('mice', 'Species', '10090', (52, 56))	('activated', 'PosReg', (79, 88))	('increased', 'PosReg', (134, 143))	('beta-catenin', 'Gene', '12387', (169, 181))	('beta-catenin', 'Gene', '12387', (94, 106))
61509	23801748	An elevated expression of FOXL1 was demonstrated using qRT-PCR and western blot in cells transfected with pCMV-FOXL1, as compared with control cells (Figure 2A).	('FOXL1', 'Gene', (26, 31))	('pCMV-FOXL1', 'Var', (106, 116))	('expression', 'Species', '29278', (12, 22))	('elevated', 'PosReg', (3, 11))	('expression', 'MPA', (12, 22))
61510	23801748	Overexpression of FOXL1 significantly inhibited cell proliferation in both Panc1 and MIApaca2 cells (P<0.05, Figure 2B).	('expression', 'Species', '29278', (4, 14))	('cell proliferation', 'CPA', (48, 66))	('inhibited', 'NegReg', (38, 47))	('Panc1', 'CellLine', 'CVCL:0480', (75, 80))	('MIApaca2', 'CellLine', 'CVCL:0428', (85, 93))	('Overexpression', 'Var', (0, 14))	('FOXL1', 'Gene', (18, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))
61511	23801748	In contrast, knock-down of FOXL1 in pancreatic cancer cells using siRNA significantly increased cell growth (P<0.05, supplementary Figure S3C).	('pancreatic cancer', 'Disease', 'MESH:D010190', (36, 53))	('knock-down', 'Var', (13, 23))	('increased', 'PosReg', (86, 95))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (36, 53))	('cell growth', 'biological_process', 'GO:0016049', ('96', '107'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('pancreatic cancer', 'Disease', (36, 53))	('FOXL1', 'Gene', (27, 32))	('cell growth', 'CPA', (96, 107))
61513	23801748	Overexpression of FOXL1 led to a significant reduction in tumor volume (p<0.05) and tumor weight (p<0.01) (Figure 2D).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('expression', 'Species', '29278', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Overexpression', 'Var', (0, 14))	('FOXL1', 'Gene', (18, 23))	('reduction', 'NegReg', (45, 54))
61516	23801748	Over-expression of FOXL1 led to a significant increase in caspase-3/7 activity in Panc1 and MIApaca2 cells (P<0.01, Figure 3A), whereas silencing of FOXL1 by siRNA reduced apoptosis as determined by caspase-3/7 activity (P<0.01, supplementary Figure S3D).	('caspase-3', 'Gene', (58, 67))	('Over-expression', 'PosReg', (0, 15))	('caspase-3', 'Gene', '836', (199, 208))	('activity', 'MPA', (70, 78))	('increase', 'PosReg', (46, 54))	('FOXL1', 'Gene', (19, 24))	('caspase-3', 'Gene', '836', (58, 67))	('MIApaca2', 'CellLine', 'CVCL:0428', (92, 100))	('Panc1', 'CellLine', 'CVCL:0480', (82, 87))	('apoptosis', 'biological_process', 'GO:0097194', ('172', '181'))	('apoptosis', 'CPA', (172, 181))	('silencing', 'Var', (136, 145))	('caspase-3', 'Gene', (199, 208))	('reduced', 'NegReg', (164, 171))	('expression', 'Species', '29278', (5, 15))	('apoptosis', 'biological_process', 'GO:0006915', ('172', '181'))	('FOXL1', 'Gene', (149, 154))
61518	23801748	Consistent with the gene expression, the protein level of TRAIL was also increased about 2 fold in FOXL1 overexpressing cells.	('increased', 'PosReg', (73, 82))	('gene expression', 'biological_process', 'GO:0010467', ('20', '35'))	('TRAIL', 'Gene', '8743', (58, 63))	('expression', 'Species', '29278', (25, 35))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('FOXL1', 'Gene', (99, 104))	('overexpressing', 'Var', (105, 119))	('TRAIL', 'Gene', (58, 63))	('protein level', 'MPA', (41, 54))
61519	23801748	Next, we investigated the mechanism of TRAIL induction following FOXL1 expression.	('expression', 'Species', '29278', (71, 81))	('expression', 'Var', (71, 81))	('FOXL1', 'Gene', (65, 70))	('TRAIL', 'Gene', '8743', (39, 44))	('TRAIL', 'Gene', (39, 44))
61522	23801748	The luciferase activities of pGL4-TRAIL were significantly upregulated by 4.4-fold (P<0.01) when it was co-transfected with pCMV-FOXL1 compared with pCMV-CTRL in Panc1 cells, and 5.7-fold in Miapaca2 cells (P<0.01, Figure 3D).	('pGL4', 'Gene', '6390', (29, 33))	('Panc1', 'CellLine', 'CVCL:0480', (162, 167))	('CTRL', 'Gene', '1506', (154, 158))	('Miapaca2', 'CellLine', 'CVCL:0428', (191, 199))	('TRAIL', 'Gene', (34, 39))	('CTRL', 'Gene', (154, 158))	('upregulated', 'PosReg', (59, 70))	('activities', 'MPA', (15, 25))	('pGL4', 'Gene', (29, 33))	('pGL', 'molecular_function', 'GO:0004598', ('29', '32'))	('pCMV-FOXL1', 'Var', (124, 134))	('luciferase', 'Enzyme', (4, 14))	('TRAIL', 'Gene', '8743', (34, 39))
61529	23801748	In addition, high level of FOXL1 expression also significantly impaired the invasiveness of both Panc1 and MIApaca2 in Matrigel invasion assays using 10% FBS as a chemoattractant (P<0.01, Figure 4B).	('Panc1', 'CellLine', 'CVCL:0480', (97, 102))	('FBS', 'Disease', 'MESH:D005198', (154, 157))	('MIApaca2', 'CellLine', 'CVCL:0428', (107, 115))	('expression', 'Var', (33, 43))	('invasiveness', 'CPA', (76, 88))	('expression', 'Species', '29278', (33, 43))	('FBS', 'Disease', (154, 157))	('FOXL1', 'Gene', (27, 32))	('impaired', 'NegReg', (63, 71))	('Panc1', 'Gene', (97, 102))
61530	23801748	In contrast, knock-down of FOXL1 promoted pancreatic cancer cell invasion (P<0.05, supplementary Figure S3B).	('promoted', 'PosReg', (33, 41))	('pancreatic cancer', 'Disease', (42, 59))	('knock-down', 'Var', (13, 23))	('pancreatic cancer', 'Disease', 'MESH:D010190', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (42, 59))	('FOXL1', 'Gene', (27, 32))
61537	23801748	In contrast, knock-down of FOXL1 increases the expression of ZEB1 (P<0.05, supplementary Figure S1).	('knock-down', 'Var', (13, 23))	('increases', 'PosReg', (33, 42))	('ZEB1', 'Gene', '6935', (61, 65))	('ZEB1', 'Gene', (61, 65))	('expression', 'Species', '29278', (47, 57))	('FOXL1', 'Gene', (27, 32))	('expression', 'MPA', (47, 57))
61538	23801748	To determine whether ZEB1 is involved in inhibitory effect of FOXL1 on cell invasion in pancreatic cancer, pancreatic cancer cell lines were transfected with si-FOXL1 alone or together with si-ZEB1.	('ZEB1', 'Gene', (193, 197))	('pancreatic cancer', 'Disease', (107, 124))	('ZEB1', 'Gene', '6935', (193, 197))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))	('pancreatic cancer', 'Disease', 'MESH:D010190', (107, 124))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('si-FOXL1', 'Var', (158, 166))	('pancreatic cancer', 'Disease', (88, 105))	('ZEB1', 'Gene', '6935', (21, 25))	('pancreatic cancer', 'Disease', 'MESH:D010190', (88, 105))	('ZEB1', 'Gene', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
61539	23801748	The stimulatory effect of FOXL1 knockdown on cell invasion was ablated by simultaneous siRNA mediated knockdown of ZEB1 (supplementary Figure S3B).	('ZEB1', 'Gene', (115, 119))	('ZEB1', 'Gene', '6935', (115, 119))	('FOXL1', 'Gene', (26, 31))	('cell invasion', 'CPA', (45, 58))	('knockdown', 'Var', (32, 41))	('ablated', 'NegReg', (63, 70))	('knockdown', 'Var', (102, 111))
61548	23801748	As shown in Figure 5D, the luciferase activities of pGL4-ZEB1 were significantly decreased when it was co-transfected with pCMV-FOXL1 compared to pCMV-CTRL (P<0.01, Figure 5D).	('decreased', 'NegReg', (81, 90))	('CTRL', 'Gene', '1506', (151, 155))	('pCMV-FOXL1', 'Var', (123, 133))	('CTRL', 'Gene', (151, 155))	('ZEB1', 'Gene', (57, 61))	('ZEB1', 'Gene', '6935', (57, 61))	('pGL4', 'Gene', (52, 56))	('luciferase', 'Enzyme', (27, 37))	('pGL4', 'Gene', '6390', (52, 56))	('pGL', 'molecular_function', 'GO:0004598', ('52', '55'))	('activities', 'MPA', (38, 48))
61560	23801748	Functional studies revealed that restoration of FOXL1 in Panc1 and MIApaca2 pancreatic cancer cells significantly promoted apoptosis, inhibited cell proliferation, and suppressed cell invasion.	('cell proliferation', 'CPA', (144, 162))	('cell invasion', 'CPA', (179, 192))	('MIApaca2', 'CellLine', 'CVCL:0428', (67, 75))	('suppressed', 'NegReg', (168, 178))	('pancreatic cancer', 'Disease', (76, 93))	('inhibited', 'NegReg', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('pancreatic cancer', 'Disease', 'MESH:D010190', (76, 93))	('apoptosis', 'CPA', (123, 132))	('promoted', 'PosReg', (114, 122))	('Panc1', 'CellLine', 'CVCL:0480', (57, 62))	('restoration', 'Var', (33, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('FOXL1', 'Gene', (48, 53))	('cell proliferation', 'biological_process', 'GO:0008283', ('144', '162'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))
61566	23801748	Vice versa, knockdown of ZEB factors in cancer cells inhibit cell invasion.	('inhibit', 'NegReg', (53, 60))	('ZEB', 'Protein', (25, 28))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('knockdown', 'Var', (12, 21))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cell invasion', 'CPA', (61, 74))
61574	23801748	The ligation of TRAIL with two receptors, called death receptor 4 (DR4, TRAIL-R1) and death receptor 5 (DR5, TRAIL-R2), triggers apoptosis by recruiting the initiator caspase-8, which can directly activate downstream effector caspases, including caspase-3, caspase-6, and caspase-7.	('TRAIL', 'Gene', (16, 21))	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('apoptosis', 'CPA', (129, 138))	('DR5', 'Var', (104, 107))	('TRAIL', 'Gene', (109, 114))	('caspase-6', 'Enzyme', (257, 266))	('TRAIL', 'Gene', '8743', (72, 77))	('caspase-3', 'Gene', (246, 255))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('triggers', 'Reg', (120, 128))	('TRAIL', 'Gene', (72, 77))	('activate', 'PosReg', (197, 205))	('TRAIL', 'Gene', '8743', (16, 21))	('TRAIL', 'Gene', '8743', (109, 114))	('ligation', 'Var', (4, 12))	('recruiting', 'PosReg', (142, 152))	('caspase-3', 'Gene', '836', (246, 255))
61578	23801748	There was no difference in TRAIL-R1 or R2 expression in FOXL1 overexpressing cells as compared to control cells.	('TRAIL', 'Gene', '8743', (27, 32))	('expression', 'Species', '29278', (42, 52))	('TRAIL', 'Gene', (27, 32))	('FOXL1', 'Gene', (56, 61))	('overexpressing', 'Var', (62, 76))
61598	22896694	In PDAC, early data have suggested that the identification of CSCs in primary tumors is associated with shorter overall survival, and it is likely that additional functional properties including relative resistance to the standard cytotoxic agent gemcitabine and enhanced metastatic potential are in part responsible for these findings.	('gemcitabine', 'Chemical', 'MESH:C056507', (247, 258))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('shorter', 'NegReg', (104, 111))	('primary tumors', 'Disease', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('PDAC', 'Phenotype', 'HP:0006725', (3, 7))	('primary tumors', 'Disease', 'MESH:D009369', (70, 84))	('CSCs', 'Gene', (62, 66))	('identification', 'Var', (44, 58))	('enhanced', 'PosReg', (263, 271))	('overall', 'MPA', (112, 119))	('metastatic potential', 'CPA', (272, 292))
61647	22896694	Recurrent genetic alterations are a hallmark of cancer, and mutations in KRas are present in the vast majority of PDAC.	('genetic alterations', 'Var', (10, 29))	('PDAC', 'Disease', (114, 118))	('PDAC', 'Phenotype', 'HP:0006725', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('KRas', 'Gene', (73, 77))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('mutations', 'Var', (60, 69))	('KRas', 'Gene', '3845', (73, 77))	('present', 'Reg', (82, 89))
61648	22896694	On the other hand, mutations in other genes, such as p53 and Smad4/DPC4, can be identified in some, but not all tumors.	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('identified', 'Reg', (80, 90))	('mutations', 'Var', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Smad4', 'Gene', (61, 66))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('DPC4', 'Gene', '4089', (67, 71))	('Smad4', 'Gene', '4089', (61, 66))	('DPC4', 'Gene', (67, 71))	('tumors', 'Disease', (112, 118))
61650	22896694	If alterations in specific genes are prognostic and CSCs truly dictate the natural history of PDAC given their potential roles in tumor formation, drug resistance, and metastatic progression, it is likely that specific mutations influence both the phenotype and function of CSCs.	('dictate', 'Reg', (63, 70))	('drug resistance', 'Phenotype', 'HP:0020174', (147, 162))	('CSCs', 'Disease', (274, 278))	('drug resistance', 'biological_process', 'GO:0042493', ('147', '162'))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('drug resistance', 'biological_process', 'GO:0009315', ('147', '162'))	('formation', 'biological_process', 'GO:0009058', ('136', '145'))	('mutations', 'Var', (219, 228))	('alterations', 'Var', (3, 14))	('tumor', 'Disease', (130, 135))	('PDAC', 'Disease', (94, 98))	('PDAC', 'Phenotype', 'HP:0006725', (94, 98))	('influence', 'Reg', (229, 238))
61672	22896694	The pharmacological inhibition or knockdown of ALK4 abrogated self-renewal and tumorigenicity as well as sensitized CSCs to gemcitabine.	('abrogated', 'NegReg', (52, 61))	('tumor', 'Disease', (79, 84))	('ALK4', 'Gene', '91', (47, 51))	('ALK4', 'Gene', (47, 51))	('CSCs', 'Disease', (116, 120))	('gemcitabine', 'Chemical', 'MESH:C056507', (124, 135))	('self-renewal', 'CPA', (62, 74))	('knockdown', 'Var', (34, 43))	('sensitized', 'Reg', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
61673	22896694	Another series of studies has examined the Hh signaling pathway in pancreatic CSCs and found that pharmacological pathway inhibition reduced the frequency of CSCs and decreased tumor formation and metastasis.	('CSCs', 'Disease', (158, 162))	('inhibition', 'Var', (122, 132))	('pharmacological', 'Gene', (98, 113))	('Hh signaling pathway', 'biological_process', 'GO:0007224', ('43', '63'))	('decreased tumor', 'Disease', 'MESH:D009369', (167, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('pancreatic CSCs', 'Disease', 'MESH:D010195', (67, 82))	('decreased tumor', 'Disease', (167, 182))	('reduced', 'NegReg', (133, 140))	('pancreatic CSCs', 'Disease', (67, 82))	('formation', 'biological_process', 'GO:0009058', ('183', '192'))
61676	22896694	Finally, the inhibition of Notch signaling has been found to inhibit EMT and cellular invasion as well as decrease the frequency of ALDH+ CSCs.	('Notch signaling', 'Gene', (27, 42))	('EMT', 'biological_process', 'GO:0001837', ('69', '72'))	('ALDH', 'molecular_function', 'GO:0004030', ('132', '136'))	('inhibition', 'Var', (13, 23))	('decrease', 'NegReg', (106, 114))	('signaling', 'biological_process', 'GO:0023052', ('33', '42'))	('inhibit', 'NegReg', (61, 68))	('ALDH', 'Gene', '11670', (132, 136))	('ALDH', 'Gene', (132, 136))
61723	33832071	KRAS and TP53 mutations were more frequently found in subgroup 1 and subgroup 2 than those in subgroup 3.	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('found', 'Reg', (45, 50))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('KRAS', 'Gene', '3845', (0, 4))
61726	33832071	Subgroup 2 showed amplification for DNM1P47, GTF2IRD2P1, TCF20, and RRN3P2 with deletion of BAGE2 and LINC00969.	('BAGE2', 'Gene', '85319', (92, 97))	('deletion', 'Var', (80, 88))	('LINC00969', 'Gene', '440993', (102, 111))	('LINC00969', 'Gene', (102, 111))	('DNM1P47', 'Gene', '100216544', (36, 43))	('BAGE2', 'Gene', (92, 97))	('RRN3P2', 'Gene', '653390', (68, 74))	('TCF20', 'Gene', '6942', (57, 62))	('GTF2IRD2P1', 'Gene', (45, 55))	('GTF2IRD2P1', 'Gene', '401375', (45, 55))	('RRN3P2', 'Gene', (68, 74))	('DNM1P47', 'Gene', (36, 43))	('TCF20', 'Gene', (57, 62))
61735	33832071	Sanjeev et al demonstrated that restoration of miR-200 resulted in the reversal of drug resistance and sensitizes pancreatic cancer cells to gemcitabine cytotoxicity.	('miR-200', 'Gene', (47, 54))	('drug resistance', 'Phenotype', 'HP:0020174', (83, 98))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cytotoxicity', 'Disease', 'MESH:D064420', (153, 165))	('gemcitabine', 'Chemical', 'MESH:C056507', (141, 152))	('drug resistance', 'biological_process', 'GO:0009315', ('83', '98'))	('drug resistance', 'MPA', (83, 98))	('pancreatic cancer', 'Disease', (114, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))	('restoration', 'Var', (32, 43))	('pancreatic cancer', 'Disease', 'MESH:D010190', (114, 131))	('drug resistance', 'biological_process', 'GO:0042493', ('83', '98'))	('sensitizes', 'Reg', (103, 113))	('reversal', 'Reg', (71, 79))	('cytotoxicity', 'Disease', (153, 165))
61739	33832071	When we used Kaplan-Meier survival analysis, the overall survival rate of patients in subtype 3 was significantly higher than that in subtype 1 or subtype 2.	('patients', 'Species', '9606', (74, 82))	('subtype 3', 'Var', (86, 95))	('higher', 'PosReg', (114, 120))
61742	33832071	Oncoprint analysis revealed different copy number alteration patterns among these three molecular subtypes of pancreatic cancer (Fig.	('copy number alteration', 'Var', (38, 60))	('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))
61743	33832071	Regarding somatic mutation, KRAS and TP53 mutations were more frequently found in subgroup 1 and subgroup 2 than those in subgroup 3.	('KRAS', 'Gene', (28, 32))	('found', 'Reg', (73, 78))	('KRAS', 'Gene', '3845', (28, 32))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
61745	33832071	All these findings indicate that chromosome instability might be the reason for the poor prognosis of pancreatic cancer patients, especially for those in subgroup 1 and subgroup 2.	('chromosome', 'cellular_component', 'GO:0005694', ('33', '43'))	('chromosome instability', 'Var', (33, 55))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('patients', 'Species', '9606', (120, 128))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('chromosome instability', 'Phenotype', 'HP:0040012', (33, 55))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
61772	32703318	Epigenetic mechanisms play critical roles in individual development and tissue-specific gene expression, while their dysregulation frequently occurs in human diseases, notably cancer.	('gene expression', 'biological_process', 'GO:0010467', ('88', '103'))	('human diseases', 'Disease', (152, 166))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Epigenetic', 'Var', (0, 10))	('human diseases', 'Disease', 'MESH:D015658', (152, 166))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
61780	32703318	In addition, we investigated the genomic distribution of 5mC and 5hmC as well as the modification level changes at H3K36me3, H3K27ac, H3K4me3, H3K4me1, and H3K27me3.	('H3K27me3', 'Var', (156, 164))	('H3K4me3', 'Var', (134, 141))	('H3K27ac', 'Var', (125, 132))	('5mC', 'Chemical', 'MESH:D044503', (57, 60))	('H3K36me3', 'Var', (115, 123))	('5hmC', 'Chemical', 'MESH:C011865', (65, 69))	('H3K4me1', 'Var', (143, 150))
61796	32703318	The PDAC samples showed a significantly higher odds ratio in 5'UTRs, 3'UTRs, and exons, while no significant difference was observed within promoters and CDS compared to the controls (Supplementary Figure 3C, D).	("5'UTRs", 'MPA', (61, 67))	('PDAC', 'Chemical', '-', (4, 8))	('higher', 'PosReg', (40, 46))	("3'UTRs", 'MPA', (69, 75))	('PDAC', 'Phenotype', 'HP:0006725', (4, 8))	('exons', 'Var', (81, 86))
61812	32703318	Given that histone modifications have a biological relationship with DNA methylation, we investigated the overlap of 5mC and 5hmC modification peaks in five types of histone modifications, including H3K36me3, H3K27ac, H3K4me1, H3K4me3, and H3K27me3.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('5mC', 'Chemical', 'MESH:D044503', (117, 120))	('H3K36me3', 'Var', (199, 207))	('H3K27me3', 'Var', (240, 248))	('H3K4me1', 'Var', (218, 225))	('DNA methylation', 'biological_process', 'GO:0006306', ('69', '84'))	('H3K4me3', 'Var', (227, 234))	('H3K27ac', 'Var', (209, 216))	('5hmC', 'Chemical', 'MESH:C011865', (125, 129))
61813	32703318	The intersection of 5hmC profiling data with the histone map of the PANC-1 cell line from the ENCODE Project exhibited increased fragments per kilobase of gene per million mapped reads (FPKM) in H3K36me3 (P value = 7.25E-12), H3K27ac (P value = 2.55E-06), and H3K4me1 (P value = 1.79E-09) in the PDAC cohorts relative to the healthy cohorts (Fig.	('H3K27ac', 'Var', (226, 233))	('PDAC', 'Chemical', '-', (296, 300))	('H3K36me3', 'Var', (195, 203))	('PANC-1', 'CellLine', 'CVCL:0480', (68, 74))	('5hmC', 'Chemical', 'MESH:C011865', (20, 24))	('H3K4me1', 'Var', (260, 267))	('PDAC', 'Disease', (296, 300))	('PDAC', 'Phenotype', 'HP:0006725', (296, 300))	('increased', 'PosReg', (119, 128))
61814	32703318	In contrast, 5mC modifications located in H3K4me1 (P value = 2.73E-05) and H3K27ac (P value = 1.59E-05) peaks decreased in the PDAC samples compared to those in the healthy control samples (Fig.	('modifications', 'Var', (17, 30))	('PDAC', 'Phenotype', 'HP:0006725', (127, 131))	('decreased', 'NegReg', (110, 119))	('PDAC', 'Disease', (127, 131))	('H3K27ac', 'Var', (75, 82))	('5mC', 'Chemical', 'MESH:D044503', (13, 16))	('H3K4me1', 'Protein', (42, 49))	('PDAC', 'Chemical', '-', (127, 131))
61815	32703318	Given that H3K36me3, H3K27ac, and H3K4me1 are marks of active regulatory elements, increased 5hmC levels and reduced 5mC levels in these regions suggested the active transcription of genes regulated by the elements.	('H3K4me1', 'Var', (34, 41))	('5mC levels', 'MPA', (117, 127))	('5hmC', 'Chemical', 'MESH:C011865', (93, 97))	('H3K27ac', 'Var', (21, 28))	('increased', 'PosReg', (83, 92))	('5mC', 'Chemical', 'MESH:D044503', (117, 120))	('H3K36me3', 'Var', (11, 19))	('5hmC levels', 'MPA', (93, 104))	('reduced', 'NegReg', (109, 116))	('transcription', 'biological_process', 'GO:0006351', ('166', '179'))
61816	32703318	For the repressive histone modification H3K27me3, 5hmC level significantly decreased in PDAC samples (P value = 5.80E-05), while 5mC level changes were not statistically significant (Fig.	('5hmC', 'Chemical', 'MESH:C011865', (50, 54))	('PDAC', 'Phenotype', 'HP:0006725', (88, 92))	('H3K27me3', 'Var', (40, 48))	('5hmC level', 'MPA', (50, 60))	('5mC', 'Chemical', 'MESH:D044503', (129, 132))	('histone modification', 'biological_process', 'GO:0016570', ('19', '39'))	('PDAC', 'Chemical', '-', (88, 92))	('decreased', 'NegReg', (75, 84))
61852	32703318	Global DNA hypomethylation and a reduction in 5hmC levels are frequently observed in cancer.	('5hmC', 'Chemical', 'MESH:C011865', (46, 50))	('reduction', 'NegReg', (33, 42))	('Global DNA hypomethylation', 'Var', (0, 26))	('hypomethylation', 'Var', (11, 26))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('5hmC levels', 'MPA', (46, 57))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('7', '26'))
61858	32703318	Likewise, in our study, the number of DMPs hypermethylated in PDAC was much larger than that in controls.	('hypermethylated', 'Var', (43, 58))	('PDAC', 'Chemical', '-', (62, 66))	('DMPs', 'Chemical', '-', (38, 42))	('PDAC', 'Disease', (62, 66))	('PDAC', 'Phenotype', 'HP:0006725', (62, 66))
61862	32703318	In addition, the prediction accuracy is much higher than that of the diagnostic method combining CA199 and Kras mutation (sensitivity 0.94 vs 0.78; specificity 0.95 vs 0.77).	('CA199', 'Chemical', '-', (97, 102))	('Kras', 'Gene', '3845', (107, 111))	('higher', 'PosReg', (45, 51))	('Kras', 'Gene', (107, 111))	('CA199', 'Var', (97, 102))
61863	32703318	In our study, the CA199 positive patients (> 37 U/L) were 80.3% (Supplementary Table 5), lower than the diagnostic sensitivity of the prediction models.	('lower', 'NegReg', (89, 94))	('CA199', 'Var', (18, 23))	('patients', 'Species', '9606', (33, 41))	('CA199', 'Chemical', '-', (18, 23))
61873	32703318	Interestingly, we found that patients with tumor size less than 3 cm had higher wd-scores, suggesting further exploration of the mechanism of early tumor progression through gene epigenetic modification.	('patients', 'Species', '9606', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('wd-scores', 'MPA', (80, 89))	('tumor', 'Disease', (43, 48))	('gene epigenetic modification', 'Var', (174, 202))	('higher', 'PosReg', (73, 79))
61912	32703318	ChIP-Seq files of H3K4me1, H3K4me3, H3K36me3, H3K27ac, and H3K27me3 of the pancreatic cancer cell line PANC-1 provided by ENCODE were downloaded with the following identifiers: ENCFF520QXI, ENCFF213GUQ, ENCFF922RLL, ENCFF629BRY, and ENCFF915XVA.	('ENCFF213GUQ', 'Var', (190, 201))	('pancreatic cancer', 'Disease', 'MESH:D010190', (75, 92))	('ENCFF915', 'CellLine', 'CVCL:1019', (233, 241))	('ENCFF520QXI', 'Var', (177, 188))	('ENCFF213', 'CellLine', 'CVCL:V755', (190, 198))	('PANC-1', 'CellLine', 'CVCL:0480', (103, 109))	('ENCFF922', 'CellLine', 'CVCL:1102', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (75, 92))	('ENCFF922RLL', 'Var', (203, 214))	('pancreatic cancer', 'Disease', (75, 92))	('ENCFF629BRY', 'CellLine', 'CVCL:W873', (216, 227))	('ENCFF915XVA', 'Var', (233, 244))	('ENCFF629BRY', 'Var', (216, 227))
61968	30595868	The typical appearance of pancreatic carcinoma on MRI is hypointense on T1-weighted images and hyperintense or isointense on T2-weighted images (fig 1 c,d).	('pancreatic carcinoma', 'Disease', (26, 46))	('hyperintense', 'Var', (95, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (26, 46))
62000	24786846	Several miRNAs have been found to regulate drug resistance genes such as ABCG2 and MDR1 and the modulation of miRNAs expression or function has been reported to alter the sensitivity of cancer cells to anticancer drugs.	('sensitivity', 'MPA', (171, 182))	('alter', 'Reg', (161, 166))	('MDR1', 'Gene', (83, 87))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('drug resistance', 'biological_process', 'GO:0009315', ('43', '58'))	('drug resistance', 'biological_process', 'GO:0042493', ('43', '58'))	('MDR', 'molecular_function', 'GO:0004745', ('83', '86'))	('drug resistance genes', 'Gene', (43, 64))	('cancer', 'Disease', (206, 212))	('miR', 'Gene', '220972', (8, 11))	('drug resistance', 'Phenotype', 'HP:0020174', (43, 58))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('modulation', 'Var', (96, 106))	('ABCG2', 'Gene', (73, 78))	('ABCG2', 'Gene', '9429', (73, 78))	('regulate', 'Reg', (34, 42))	('miR', 'Gene', '220972', (110, 113))	('miR', 'Gene', (8, 11))	('cancer', 'Disease', (186, 192))	('miR', 'Gene', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
62097	29556322	The Cox regression model revealed that age (P = 0.003), lymphatic invasion (P = 0.015), TNM stage (P = 0.003), histological grade (P < 0.001), preoperative CA19-9 (P = 0.049), and P38alpha expression (P = 0.008) were statistically significant independent risk factors affecting prognosis.	('P38alpha', 'Gene', '1432', (180, 188))	('CA19-9', 'Var', (156, 162))	('Cox', 'Gene', '1351', (4, 7))	('TNM', 'Gene', (88, 91))	('lymphatic invasion', 'CPA', (56, 74))	('Cox', 'Gene', (4, 7))	('TNM', 'Gene', '10178', (88, 91))	('P38alpha', 'Gene', (180, 188))
62098	29556322	Specifically, overall survival was 28.4 months in the P38alpha-low and CA19-9 < 43.63 groups, 16.3 months in the P38alpha-high or CA19-9 > 43.63 groups, and 9.7 months in the P38alpha-high and CA19-9 > 43.63 groups (P < 0.001).	('P38alpha', 'Gene', (54, 62))	('P38alpha', 'Gene', '1432', (54, 62))	('P38alpha', 'Gene', (113, 121))	('P38alpha', 'Gene', (175, 183))	('P38alpha', 'Gene', '1432', (113, 121))	('P38alpha', 'Gene', '1432', (175, 183))	('CA19-9 > 43.63', 'Var', (130, 144))	('CA19-9 < 43.63', 'Var', (71, 85))
62117	29556322	The combination of P38alpha and CA19-9 improves the prognostic prediction in patients with pancreatic ductal adenocarcinoma.	('P38alpha', 'Gene', (19, 27))	('CA19-9', 'Var', (32, 38))	('improves', 'PosReg', (39, 47))	('P38alpha', 'Gene', '1432', (19, 27))	('pancreatic ductal adenocarcinoma', 'Disease', (91, 123))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (91, 123))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (91, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('prognostic', 'MPA', (52, 62))	('patients', 'Species', '9606', (77, 85))
62146	29556322	The multivariate analysis showed that overall survival was significantly correlated to age (P = 0.003), N Category (P = 0.015), histologic grade (P < 0.001), TNM stage (P = 0.003), preoperative CA19-9 (P = 0.049), P38alpha (P = 0.008) and the combination of P38alpha and preoperative CA19-9 (P = 0.008).	('CA19-9', 'Var', (194, 200))	('correlated', 'Reg', (73, 83))	('P38alpha', 'Gene', (214, 222))	('P38alpha', 'Gene', '1432', (214, 222))	('TNM', 'Gene', (158, 161))	('overall', 'CPA', (38, 45))	('P38alpha', 'Gene', (258, 266))	('P38alpha', 'Gene', '1432', (258, 266))	('TNM', 'Gene', '10178', (158, 161))
62154	29556322	Kaplan-Meier survival analysis of patients with high CA19-9 value (> 43.63 U/mL) revealed a significantly poor overall survival compared to the patients with low CA19-9 value (< 43.63 U/mL) (P < 0.001, Fig 7).	('CA19-9', 'Gene', (53, 59))	('overall survival', 'MPA', (111, 127))	('poor', 'NegReg', (106, 110))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (34, 42))	('high', 'Var', (48, 52))
62163	29556322	For example, inhibiting P38 activity leads to excessive proliferation of lung epithelial cells and activation of K-RASG12V-mediated tumorigenesis, and the mechanism may be related to the ability of P38alpha to inhibit the proliferation and differentiation of lung stem cells.	('P38alpha', 'Gene', (198, 206))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('activity', 'MPA', (28, 36))	('P38', 'Gene', (198, 201))	('P38', 'Gene', '1432', (198, 201))	('excessive', 'PosReg', (46, 55))	('P38', 'Gene', (24, 27))	('P38alpha', 'Gene', '1432', (198, 206))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('P38', 'Gene', '1432', (24, 27))	('activation', 'PosReg', (99, 109))	('tumor', 'Disease', (132, 137))	('proliferation', 'CPA', (222, 235))	('inhibit', 'NegReg', (210, 217))	('inhibiting', 'Var', (13, 23))
62164	29556322	In liver cancer, P38alpha can maintain the homeostasis of hepatocytes, and knockout of P38 can promote N-nitrosodiethylamine-induced hepatocellular carcinoma through enhanced production of reactive oxygen species and activation of the JNK/c-Jun pathway.	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('production of reactive oxygen species', 'MPA', (175, 212))	('c-Jun', 'Gene', (239, 244))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (133, 157))	('promote', 'PosReg', (95, 102))	('liver cancer', 'Disease', 'MESH:D006528', (3, 15))	('P38', 'Gene', '1432', (17, 20))	('knockout', 'Var', (75, 83))	('enhanced production of reactive oxygen species', 'Phenotype', 'HP:0025464', (166, 212))	('JNK', 'molecular_function', 'GO:0004705', ('235', '238'))	('N-nitrosodiethylamine-induced', 'MPA', (103, 132))	('enhanced', 'PosReg', (166, 174))	('hepatocellular carcinoma', 'Disease', (133, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('N-nitrosodiethylamine', 'Chemical', 'MESH:D004052', (103, 124))	('P38', 'Gene', (17, 20))	('liver cancer', 'Phenotype', 'HP:0002896', (3, 15))	('liver cancer', 'Disease', (3, 15))	('JNK', 'Gene', (235, 238))	('P38', 'Gene', '1432', (87, 90))	('JNK', 'Gene', '5599', (235, 238))	('homeostasis of hepatocytes', 'MPA', (43, 69))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (189, 212))	('P38alpha', 'Gene', (17, 25))	('P38', 'Gene', (87, 90))	('P38alpha', 'Gene', '1432', (17, 25))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (133, 157))	('homeostasis', 'biological_process', 'GO:0042592', ('43', '54'))	('c-Jun', 'Gene', '3725', (239, 244))
62167	29556322	The P38 MAPK inhibitor LY2228820 suppresses the growth of transplanted breast cancer in mice.	('breast cancer', 'Disease', (71, 84))	('suppresses', 'NegReg', (33, 43))	('LY2228820', 'Var', (23, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('P38 MAPK', 'Gene', '26416', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('MAPK', 'molecular_function', 'GO:0004707', ('8', '12'))	('growth of transplanted', 'CPA', (48, 70))	('LY2228820', 'Chemical', 'MESH:C580958', (23, 32))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('mice', 'Species', '10090', (88, 92))	('P38 MAPK', 'Gene', (4, 12))
62170	29556322	For example, activation of P38 promotes the proliferation, invasion, and metastasis of pancreatic cancer cells.	('metastasis of pancreatic cancer', 'Disease', 'MESH:D009362', (73, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('P38', 'Gene', (27, 30))	('activation', 'Var', (13, 23))	('promotes', 'PosReg', (31, 39))	('metastasis of pancreatic cancer', 'Disease', (73, 104))	('P38', 'Gene', '1432', (27, 30))	('invasion', 'CPA', (59, 67))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('proliferation', 'CPA', (44, 57))
62178	29556322	Moreover, the overall survival of patients with CA19-9 < 43.63 U/ml was significantly better than that of patients with CA19-9 > 43.63 U/ml.	('CA19-9 < 43.63 U/ml', 'Var', (48, 67))	('patients', 'Species', '9606', (34, 42))	('patients', 'Species', '9606', (106, 114))	('better', 'PosReg', (86, 92))
62204	29371937	In this study, the median overall survival (OS) of the nab-paclitaxel plus gemcitabine group was significantly longer than that of the gemcitabine alone group (8.7 vs 6.6 months, hazard ratio [HR] = 0.72, p < 0.01).	('nab-paclitaxel', 'Var', (55, 69))	('paclitaxel', 'Chemical', 'MESH:D017239', (59, 69))	('overall survival', 'MPA', (26, 42))	('longer', 'PosReg', (111, 117))	('gemcitabine', 'Chemical', 'MESH:C056507', (135, 146))	('nab', 'Chemical', '-', (55, 58))	('gemcitabine', 'Chemical', 'MESH:C056507', (75, 86))
62213	29371937	Hence, we hypothesized that disrupting the interaction between C16orf74 and CN might be a good approach to developing an effective treatment for PDAC.	('disrupting', 'Var', (28, 38))	('C16orf74', 'Gene', (63, 71))	('PDAC', 'Disease', (145, 149))	('C16orf74', 'Gene', '404550', (63, 71))	('PDAC', 'Chemical', '-', (145, 149))	('interaction', 'Interaction', (43, 54))	('PDAC', 'Phenotype', 'HP:0006725', (145, 149))
62227	29371937	A previous report showed that knockdown of NFAT1 increased the phosphorylation levels of Akt and, conversely, overexpression of NFAT1 or NFAT4 decreased the phosphorylation levels of Akt in a colorectal cancer cell line.	('colorectal cancer', 'Disease', (192, 209))	('NFAT1', 'Gene', (43, 48))	('NFAT4', 'Gene', '4775', (137, 142))	('knockdown', 'Var', (30, 39))	('NFAT1', 'Gene', '4773', (43, 48))	('phosphorylation', 'biological_process', 'GO:0016310', ('157', '172'))	('NFAT4', 'Gene', (137, 142))	('colorectal cancer', 'Phenotype', 'HP:0003003', (192, 209))	('NFAT1', 'Gene', (128, 133))	('decreased', 'NegReg', (143, 152))	('NFAT1', 'Gene', '4773', (128, 133))	('Akt', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('phosphorylation', 'biological_process', 'GO:0016310', ('63', '78'))	('Akt', 'Gene', (183, 186))	('increased', 'PosReg', (49, 58))	('phosphorylation levels', 'MPA', (157, 179))	('Akt', 'Gene', '207', (89, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (192, 209))	('phosphorylation levels', 'MPA', (63, 85))	('Akt', 'Gene', '207', (183, 186))
62231	29371937	In Capan-1 with high C16orf74 expression, the expression levels of p-Akt and p-mTOR decreased in response to treatment with DN-C16orf74, while no change was observed in cells treated with the control peptide or PBS.	('mTOR', 'Gene', (79, 83))	('Akt', 'Gene', (69, 72))	('mTOR', 'Gene', '2475', (79, 83))	('C16orf74', 'Gene', (127, 135))	('high', 'Var', (16, 20))	('C16orf74', 'Gene', (21, 29))	('C16orf74', 'Gene', '404550', (21, 29))	('C16orf74', 'Gene', '404550', (127, 135))	('expression levels', 'MPA', (46, 63))	('PBS', 'Disease', 'MESH:D011535', (211, 214))	('PBS', 'Disease', (211, 214))	('Akt', 'Gene', '207', (69, 72))	('decreased', 'NegReg', (84, 93))	('Capan-1', 'CellLine', 'CVCL:0237', (3, 10))
62241	29371937	The median Ki67-index was w37.9% (range, 21.1-42.0%) in the PBS group and 32.5% (range, 23.1-44.5%) in the control peptide group, but that in the DN-C16orf74 group was significantly lower, 23.3% (range, 12.1-29.3%) (vs the PBS group; p < 0.001, and vs the control peptide group; p < 0.01, Figure 4B).	('PBS', 'Disease', 'MESH:D011535', (223, 226))	('PBS', 'Disease', (223, 226))	('lower', 'NegReg', (182, 187))	('PBS', 'Disease', 'MESH:D011535', (60, 63))	('Ki67', 'Gene', '17345', (11, 15))	('PBS', 'Disease', (60, 63))	('C16orf74', 'Gene', (149, 157))	('w37.9', 'Var', (26, 31))	('C16orf74', 'Gene', '404550', (149, 157))	('Ki67', 'Gene', (11, 15))
62252	29371937	The polyarginine sequence in DN-C16orf74 facilitates highly efficient nonspecific uptake of peptides into cells.	('facilitates', 'PosReg', (41, 52))	('polyarginine sequence', 'Var', (4, 25))	('uptake', 'biological_process', 'GO:0098739', ('82', '88'))	('nonspecific uptake of peptides into cells', 'MPA', (70, 111))	('polyarginine', 'Chemical', 'MESH:C015462', (4, 16))	('C16orf74', 'Gene', (32, 40))	('uptake', 'biological_process', 'GO:0098657', ('82', '88'))	('C16orf74', 'Gene', '404550', (32, 40))
62312	29245934	The results show that L-4F substantially reduced the tumorigenicity of H7 cells.	('L-4F', 'Chemical', '-', (22, 26))	('reduced', 'NegReg', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('L-4F', 'Var', (22, 26))	('tumor', 'Disease', (53, 58))	('H7', 'CellLine', 'CVCL:9772', (71, 73))
62313	29245934	L-4F inhibited inflammation by reducing the accumulation of inflammatory cells, such as IL-17A-, IL-4-, GM-CSF-, IL-1beta-, and IL-6-producing cells and Th1 and Th17.	('accumulation', 'MPA', (44, 56))	('IL-4', 'Gene', '16189', (97, 101))	('inhibited', 'NegReg', (5, 14))	('L-4F', 'Chemical', '-', (0, 4))	('reducing', 'NegReg', (31, 39))	('Th1', 'Gene', (153, 156))	('Th1', 'Gene', '57314', (153, 156))	('inflammation', 'Disease', 'MESH:D007249', (15, 27))	('IL-17', 'molecular_function', 'GO:0030367', ('88', '93'))	('IL-1', 'molecular_function', 'GO:0005149', ('113', '117'))	('inflammation', 'biological_process', 'GO:0006954', ('15', '27'))	('inflammation', 'Disease', (15, 27))	('IL-6', 'molecular_function', 'GO:0005138', ('128', '132'))	('Th1', 'Gene', '57314', (161, 164))	('IL-4', 'Gene', (97, 101))	('IL-4', 'molecular_function', 'GO:0005136', ('97', '101'))	('L-4F', 'Var', (0, 4))	('Th1', 'Gene', (161, 164))
62314	29245934	Notably, L-4F also decreased the percentage of macrophages in tumor tissues, especially M2 macrophages (CD11b+F4/80+CD206+), which was also confirmed in vitro.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('F4/80', 'Gene', (110, 115))	('tumor', 'Disease', (62, 67))	('F4/80', 'Gene', '13733', (110, 115))	('L-4F', 'Var', (9, 13))	('L-4F', 'Chemical', '-', (9, 13))	('CD206', 'Gene', (116, 121))	('decreased', 'NegReg', (19, 28))	('CD206', 'Gene', '17533', (116, 121))	('M2 macrophages', 'CPA', (88, 102))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
62315	29245934	Additionally, the expression of the M2 marker genes Arg1, MRC1, and CCL22 and the inflammatory genes IL-6, iNOS, and IL-12 was decreased by L-4F, indicating that L-4F prevents M2 type macrophage polarization.	('M2 type macrophage polarization', 'CPA', (176, 207))	('IL-12', 'molecular_function', 'GO:0005143', ('117', '122'))	('IL-6', 'Gene', (101, 105))	('L-4F', 'Chemical', '-', (140, 144))	('iNOS', 'Gene', '18126', (107, 111))	('L-4F', 'Chemical', '-', (162, 166))	('expression', 'MPA', (18, 28))	('IL-6', 'molecular_function', 'GO:0005138', ('101', '105'))	('CCL', 'molecular_function', 'GO:0044101', ('68', '71'))	('L-4F', 'Var', (140, 144))	('MRC1', 'Gene', '17533', (58, 62))	('decreased', 'NegReg', (127, 136))	('CCL22', 'Gene', '20299', (68, 73))	('Arg1', 'Gene', '11846', (52, 56))	('iNOS', 'Gene', (107, 111))	('MRC1', 'Gene', (58, 62))	('macrophage polarization', 'biological_process', 'GO:0042116', ('184', '207'))	('IL-12', 'Gene', (117, 122))	('prevents', 'NegReg', (167, 175))	('CCL22', 'Gene', (68, 73))	('Arg1', 'Gene', (52, 56))
62316	29245934	However, L-4F could not directly attenuate H7 cell invasion or proliferation and did not induce apoptosis.	('rat', 'Species', '10116', (70, 73))	('H7 cell invasion', 'CPA', (43, 59))	('L-4F', 'Var', (9, 13))	('attenuate', 'NegReg', (33, 42))	('L-4F', 'Chemical', '-', (9, 13))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('H7', 'CellLine', 'CVCL:9772', (43, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
62317	29245934	In addition, L-4F potently down-regulated STAT3, JNK and ERK signaling pathways but not affects the phosphorylation of p38 in RAW 264.7 cells.	('STAT3', 'Gene', (42, 47))	('p38', 'Gene', '26416', (119, 122))	('L-4F', 'Chemical', '-', (13, 17))	('phosphorylation', 'biological_process', 'GO:0016310', ('100', '115'))	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('ERK', 'molecular_function', 'GO:0004707', ('57', '60'))	('RAW 264.7', 'CellLine', 'CVCL:0493', (126, 135))	('down-regulated', 'NegReg', (27, 41))	('p38', 'Gene', (119, 122))	('JNK', 'Gene', '26419', (49, 52))	('JNK', 'molecular_function', 'GO:0004705', ('49', '52'))	('ERK', 'Gene', (57, 60))	('ERK', 'Gene', '26413', (57, 60))	('STAT3', 'Gene', '20848', (42, 47))	('L-4F', 'Var', (13, 17))	('JNK', 'Gene', (49, 52))
62318	29245934	These results suggest that L-4F exhibits an effective therapeutic effect on pancreatic cancer progression by inhibiting tumor-associated macrophages and inflammation.	('L-4F', 'Var', (27, 31))	('inhibiting', 'NegReg', (109, 119))	('inflammation', 'Disease', 'MESH:D007249', (153, 165))	('L-4F', 'Chemical', '-', (27, 31))	('inflammation', 'biological_process', 'GO:0006954', ('153', '165'))	('pancreatic cancer', 'Disease', (76, 93))	('inflammation', 'Disease', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('pancreatic cancer', 'Disease', 'MESH:D010190', (76, 93))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))	('tumor', 'Disease', (120, 125))
62326	29245934	It has been reported that L-4F suppresses tumor progression by inhibiting the expression and activity of hypoxia-inducible factor-1alpha and tumor angiogenesis in human ovarian cancer, reduces cell viability and proliferation in ovarian cancer cells, and decreases plasma levels of lysophosphatidic acid in colon cancer.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('ovarian cancer', 'Disease', (229, 243))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('ovarian cancer', 'Disease', 'MESH:D010051', (169, 183))	('ovarian cancer', 'Phenotype', 'HP:0100615', (229, 243))	('hypoxia-inducible factor-1alpha', 'Gene', (105, 136))	('cell viability', 'CPA', (193, 207))	('proliferation', 'CPA', (212, 225))	('tumor', 'Disease', (42, 47))	('reduces', 'NegReg', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('colon cancer', 'Disease', (307, 319))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('plasma levels of lysophosphatidic acid', 'MPA', (265, 303))	('ovarian cancer', 'Disease', (169, 183))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('activity', 'MPA', (93, 101))	('colon cancer', 'Phenotype', 'HP:0003003', (307, 319))	('hypoxia-inducible factor-1alpha', 'Gene', '3091', (105, 136))	('ovarian cancer', 'Phenotype', 'HP:0100615', (169, 183))	('suppresses', 'NegReg', (31, 41))	('angiogenesis', 'biological_process', 'GO:0001525', ('147', '159'))	('rat', 'Species', '10116', (219, 222))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('ovarian cancer', 'Disease', 'MESH:D010051', (229, 243))	('L-4F', 'Chemical', '-', (26, 30))	('expression', 'MPA', (78, 88))	('decreases', 'NegReg', (255, 264))	('lysophosphatidic acid', 'Chemical', 'MESH:C032881', (282, 303))	('tumor', 'Disease', (141, 146))	('human', 'Species', '9606', (163, 168))	('inhibiting', 'NegReg', (63, 73))	('L-4F', 'Var', (26, 30))	('colon cancer', 'Disease', 'MESH:D015179', (307, 319))
62327	29245934	It has also recently been found that L-4F inhibits LPS-mediated elevation of TNF-alpha and IL-6 in LPS-stimulated neutrophils.	('LPS-mediated', 'Disease', (51, 63))	('inhibits', 'NegReg', (42, 50))	('LPS', 'Chemical', 'MESH:D008070', (51, 54))	('TNF-alpha', 'Gene', '21926', (77, 86))	('L-4F', 'Var', (37, 41))	('TNF-alpha', 'Gene', (77, 86))	('L-4F', 'Chemical', '-', (37, 41))	('IL-6', 'molecular_function', 'GO:0005138', ('91', '95'))	('LPS', 'Chemical', 'MESH:D008070', (99, 102))
62329	29245934	In this study, we aimed to explore whether L-4F can inhibit pancreatic cancer progression and to determine its cellular and molecular mechanisms.	('inhibit', 'NegReg', (52, 59))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('L-4F', 'Var', (43, 47))	('pancreatic cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('L-4F', 'Chemical', '-', (43, 47))
62330	29245934	We first evaluated whether L-4F might exhibit suppressive effects on pancreatic cancer development in a mouse model.	('pancreatic cancer', 'Disease', (69, 86))	('L-4F', 'Var', (27, 31))	('L-4F', 'Chemical', '-', (27, 31))	('pancreatic cancer', 'Disease', 'MESH:D010190', (69, 86))	('suppressive', 'NegReg', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mouse', 'Species', '10090', (104, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (69, 86))
62333	29245934	As shown in Figure 1A-1C, compared with tumors in Sc-4F-treated mice, L-4F treatment significantly reduced both tumor size (Figure 1A, 1B) and tumor weight (0.77 g vs 0.52 g, P<0.01) (Figure 1C).	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('Sc-4F', 'Chemical', '-', (50, 55))	('tumor', 'Disease', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('L-4F', 'Var', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('L-4F', 'Chemical', '-', (70, 74))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (40, 45))	('reduced', 'NegReg', (99, 106))	('mice', 'Species', '10090', (64, 68))	('tumors', 'Disease', (40, 46))
62336	29245934	As shown in Figure 2B, the proliferative index (PI) of the L-4F-treated cells was not obviously reduced compared to the untreated or low dose-treated cells (PI = 62.74, 63.17, 62.28, and 60.22 for 0, 5, 10, and 20 mug/mL, respectively, NS).	('proliferative index', 'CPA', (27, 46))	('L-4F-treated', 'Var', (59, 71))	('L-4F', 'Chemical', '-', (59, 63))	('rat', 'Species', '10116', (34, 37))	('mug', 'molecular_function', 'GO:0043739', ('214', '217'))	('reduced', 'NegReg', (96, 103))
62337	29245934	In addition, compared with the untreated cells, the populations of early apoptotic, necrotic, and late apoptotic cells were not obviously changed in the L-4F-treated cells (4.43%, 4.68%, 5.44% and 5.88%, for 0, 5, 10, and 20 mug/mL, respectively, NS) (Figure 2C).	('mug', 'molecular_function', 'GO:0043739', ('225', '228'))	('L-4F-treated', 'Var', (153, 165))	('necrotic', 'Disease', (84, 92))	('L-4F', 'Chemical', '-', (153, 157))	('necrotic', 'Disease', 'MESH:D009336', (84, 92))
62338	29245934	As shown in Figure 3D, L-4F treatment obviously reduced inflammatory cell infiltration in tumor tissues collected from mice.	('mice', 'Species', '10090', (119, 123))	('rat', 'Species', '10116', (80, 83))	('reduced', 'NegReg', (48, 55))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('reduced inflammatory cell infiltration', 'Phenotype', 'HP:0012648', (48, 86))	('L-4F', 'Var', (23, 27))	('L-4F', 'Chemical', '-', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
62341	29245934	To further confirm the anti-inflammatory effects of L-4F, we analyzed mRNA levels of the inflammatory cytokines IL-17A, IFN-gamma, IL-6, and IL-1beta in tumor tissues from Sc-4F- or L-4F-treated tumor-bearing mice.	('mRNA levels', 'MPA', (70, 81))	('Sc-4F-', 'Var', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('mice', 'Species', '10090', (209, 213))	('tumor', 'Disease', (195, 200))	('IL-1', 'molecular_function', 'GO:0005149', ('141', '145'))	('IL-17', 'molecular_function', 'GO:0030367', ('112', '117'))	('L-4F', 'Chemical', '-', (182, 186))	('IL-6', 'molecular_function', 'GO:0005138', ('131', '135'))	('Sc-4F', 'Chemical', '-', (172, 177))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('L-4F', 'Chemical', '-', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('L-4F-treated', 'Var', (182, 194))
62342	29245934	As shown in Figure 3C, L-4F substantially decreased the mRNA levels of the inflammatory cytokines IL-17A, IFN-gamma, IL-6 and IL-1beta (average fold-change of 0.107 for IL-17A, 0.155 for IFN-gamma, 0.069 for IL-6, 0.340 for IL-1beta, P<0.001).	('decreased', 'NegReg', (42, 51))	('IL-1', 'molecular_function', 'GO:0005149', ('224', '228'))	('IL-6', 'molecular_function', 'GO:0005138', ('208', '212'))	('IL-17', 'molecular_function', 'GO:0030367', ('98', '103'))	('mRNA levels of the inflammatory cytokines IL-17A', 'MPA', (56, 104))	('IL-6', 'molecular_function', 'GO:0005138', ('117', '121'))	('IL-17', 'molecular_function', 'GO:0030367', ('169', '174'))	('L-4F', 'Var', (23, 27))	('L-4F', 'Chemical', '-', (23, 27))	('IL-1', 'molecular_function', 'GO:0005149', ('126', '130'))
62343	29245934	We further analyzed the percentages of IL-17A-, IL-6-, IFN-gamma-, IL-4- and GM-CSF-producing Th cells (T helper cells) in tumor-infiltrating lymphocytes (TILs) from H7 tumor-bearing mice treated with Sc-4F or L-4F.	('IL-4', 'Gene', (67, 71))	('L-4F', 'Var', (210, 214))	('Sc-4F', 'Var', (201, 206))	('tumor', 'Disease', (123, 128))	('rat', 'Species', '10116', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('IL-17', 'molecular_function', 'GO:0030367', ('39', '44'))	('L-4F', 'Chemical', '-', (210, 214))	('IL-4', 'Gene', '16189', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mice', 'Species', '10090', (183, 187))	('IL-4', 'molecular_function', 'GO:0005136', ('67', '71'))	('H7', 'CellLine', 'CVCL:9772', (166, 168))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('IL-6', 'molecular_function', 'GO:0005138', ('48', '52'))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('Sc-4F', 'Chemical', '-', (201, 206))
62347	29245934	Compared with the Sc-4F-treated group, the percentage of CD11b+F4/80+ macrophages (41.4% vs 21.6%, P < 0.05) significantly decreased (Figure 4C, 4D) in the L-4F treated group.	('F4/80', 'Gene', '13733', (63, 68))	('decreased', 'NegReg', (123, 132))	('Sc-4F', 'Chemical', '-', (18, 23))	('L-4F', 'Var', (156, 160))	('L-4F', 'Chemical', '-', (156, 160))	('F4/80', 'Gene', (63, 68))
62348	29245934	Similarly, L-4F effectively inhibited the augmentation of F4/80+CD206+ M2 macrophage populations (28.3% vs 20.3%, P<0.01) (Figure 4C, 4D).	('CD206', 'Gene', (64, 69))	('F4/80', 'Gene', '13733', (58, 63))	('augmentation', 'PosReg', (42, 54))	('L-4F', 'Var', (11, 15))	('L-4F', 'Chemical', '-', (11, 15))	('inhibited', 'NegReg', (28, 37))	('CD206', 'Gene', '17533', (64, 69))	('F4/80', 'Gene', (58, 63))
62349	29245934	To further examine the effect of L-4F in macrophages in vitro, we differentiated mouse bone marrow-derived macrophages to M1 or M2 macrophages using LPS (for M1) or IL-4 (for M2) in the presence of Sc-4F or L-4F.	('LPS', 'Chemical', 'MESH:D008070', (149, 152))	('L-4F', 'Var', (207, 211))	('IL-4', 'Gene', (165, 169))	('IL-4', 'molecular_function', 'GO:0005136', ('165', '169'))	('IL-4', 'Gene', '16189', (165, 169))	('L-4F', 'Chemical', '-', (207, 211))	('mouse', 'Species', '10090', (81, 86))	('L-4F', 'Chemical', '-', (33, 37))	('Sc-4F', 'Chemical', '-', (198, 203))
62351	29245934	As shown in Figure 5A-5C, the number of M2 macrophages significantly decreased in the group treated with L-4F compared to the Sc-4F-treated group (31.3% vs 20.1%, P<0.05).	('L-4F', 'Chemical', '-', (105, 109))	('decreased', 'NegReg', (69, 78))	('L-4F', 'Var', (105, 109))	('Sc-4F', 'Chemical', '-', (126, 131))
62352	29245934	These results indicate that L-4F treatment inhibits the augmentation of M2 macrophage populations in vitro.	('L-4F', 'Var', (28, 32))	('L-4F', 'Chemical', '-', (28, 32))	('augmentation', 'CPA', (56, 68))	('M2 macrophage populations', 'CPA', (72, 97))	('inhibits', 'NegReg', (43, 51))
62354	29245934	Compared to undifferentiated macrophages, M1- or M2-differentiated macrophages showed significant upregulation of M1- or M2-specific inflammatory genes, and expression of these genes was substantially decreased in the L-4F-treated group (average fold-change of 0.0042 for IL-6, 0.0014 for iNOS, 0.0842 for IL-12, 0.415 for ARG-1, 0.82 for MRC1, 0.317 for CCL22, , P < 0.001) (Figure 5D).	('M1-', 'Gene', (114, 117))	('M2-specific inflammatory genes', 'Gene', (121, 151))	('ARG-1', 'Gene', (323, 328))	('expression', 'MPA', (157, 167))	('iNOS', 'Gene', (289, 293))	('iNOS', 'Gene', '18126', (289, 293))	('decreased', 'NegReg', (201, 210))	('MRC1', 'Gene', (339, 343))	('upregulation', 'PosReg', (98, 110))	('ARG-1', 'Gene', '11846', (323, 328))	('CCL22', 'Gene', '20299', (355, 360))	('L-4F-treated', 'Var', (218, 230))	('MRC1', 'Gene', '17533', (339, 343))	('L-4F', 'Chemical', '-', (218, 222))	('CCL22', 'Gene', (355, 360))
62356	29245934	As shown in Figure 5, compared to the LPS control group, L-4F treatment significantly suppressed the phosphorylation of STAT3 (Figure 6A) and inhibited the phosphorylation of JNK and ERK1/2 (Figure 6C and 6D) in LPS-treated RAW 264.7 cells in a low dose-dependent manner.	('ERK1', 'molecular_function', 'GO:0004707', ('183', '187'))	('phosphorylation', 'biological_process', 'GO:0016310', ('156', '171'))	('JNK', 'Gene', (175, 178))	('LPS', 'Chemical', 'MESH:D008070', (212, 215))	('JNK', 'Gene', '26419', (175, 178))	('LPS', 'Chemical', 'MESH:D008070', (38, 41))	('JNK', 'molecular_function', 'GO:0004705', ('175', '178'))	('ERK1/2', 'Gene', (183, 189))	('suppressed', 'NegReg', (86, 96))	('ERK1/2', 'Gene', '26417;26413', (183, 189))	('STAT3', 'Gene', '20848', (120, 125))	('inhibited', 'NegReg', (142, 151))	('L-4F', 'Chemical', '-', (57, 61))	('phosphorylation', 'MPA', (156, 171))	('phosphorylation', 'MPA', (101, 116))	('RAW 264.7', 'CellLine', 'CVCL:0493', (224, 233))	('L-4F', 'Var', (57, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('101', '116'))	('STAT3', 'Gene', (120, 125))
62357	29245934	However, L-4F had no obvious effect on the p38MAPK (Figure 6B) signaling pathway.	('signaling pathway', 'biological_process', 'GO:0007165', ('63', '80'))	('p38MAPK', 'Gene', '26416', (43, 50))	('p38MAPK', 'Gene', (43, 50))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('L-4F', 'Var', (9, 13))	('L-4F', 'Chemical', '-', (9, 13))
62358	29245934	It has been reported that L-4F can suppress tumor progression in ovarian cancer and colon cancer by reducing cell viability and proliferation.	('colon cancer', 'Phenotype', 'HP:0003003', (84, 96))	('colon cancer', 'Disease', 'MESH:D015179', (84, 96))	('L-4F', 'Chemical', '-', (26, 30))	('suppress', 'NegReg', (35, 43))	('rat', 'Species', '10116', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('colon cancer', 'Disease', (84, 96))	('reducing', 'NegReg', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (65, 79))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (65, 79))	('L-4F', 'Var', (26, 30))	('tumor', 'Disease', (44, 49))	('ovarian cancer', 'Disease', (65, 79))	('cell viability', 'CPA', (109, 123))
62359	29245934	In addition, L-4F was shown to significantly reduce cell viability in the human ovarian cancer cell lines SKOV3, OV2008, and A2780 by binding and removing lysophosphatidic acid, which is a well-known activator of proliferation in cancer cells.	('cancer', 'Disease', (88, 94))	('L-4F', 'Chemical', '-', (13, 17))	('SKOV3', 'CellLine', 'CVCL:0532', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('L-4F', 'Var', (13, 17))	('lysophosphatidic acid', 'MPA', (155, 176))	('reduce', 'NegReg', (45, 51))	('cancer', 'Disease', (230, 236))	('rat', 'Species', '10116', (220, 223))	('ovarian cancer', 'Disease', 'MESH:D010051', (80, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('binding', 'molecular_function', 'GO:0005488', ('134', '141'))	('binding', 'Interaction', (134, 141))	('ovarian cancer', 'Disease', (80, 94))	('removing', 'NegReg', (146, 154))	('cell viability', 'CPA', (52, 66))	('lysophosphatidic acid', 'Chemical', 'MESH:C032881', (155, 176))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('human', 'Species', '9606', (74, 79))
62361	29245934	These reports indicate that L-4F can suppress cancer growth, but not all tumor cells are sensitive to L-4F.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('L-4F', 'Var', (28, 32))	('L-4F', 'Chemical', '-', (102, 106))	('cancer', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('suppress', 'NegReg', (37, 45))	('L-4F', 'Chemical', '-', (28, 32))	('tumor', 'Disease', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
62362	29245934	In our in vivo study, we found that L-4F substantially reduced the tumorigenicity of H7 pancreatic tumors in a mouse model.	('H7', 'CellLine', 'CVCL:9772', (85, 87))	('tumor', 'Disease', (99, 104))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (88, 105))	('reduced', 'NegReg', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('mouse', 'Species', '10090', (111, 116))	('pancreatic tumors', 'Disease', 'MESH:D010190', (88, 105))	('L-4F', 'Var', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('L-4F', 'Chemical', '-', (36, 40))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('pancreatic tumors', 'Disease', (88, 105))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
62363	29245934	However, our in vitro results demonstrated that L-4F could not suppress the invasion (Figure 2A) or proliferation (Figure 2B) capacity of H7 cells (or Panc1 cells, Supplementary Figure 1) and did not induce cell apoptosis in these cells (Figure 2C).	('apoptosis', 'biological_process', 'GO:0006915', ('212', '221'))	('L-4F', 'Var', (48, 52))	('induce', 'Reg', (200, 206))	('proliferation', 'CPA', (100, 113))	('rat', 'Species', '10116', (37, 40))	('L-4F', 'Chemical', '-', (48, 52))	('H7', 'CellLine', 'CVCL:9772', (138, 140))	('Panc1', 'CellLine', 'CVCL:0480', (151, 156))	('apoptosis', 'biological_process', 'GO:0097194', ('212', '221'))	('suppress', 'NegReg', (63, 71))	('invasion', 'CPA', (76, 84))	('rat', 'Species', '10116', (107, 110))
62371	29245934	Several studies have determined that L-4F possesses effective anti-inflammatory properties.	('L-4F', 'Var', (37, 41))	('L-4F', 'Chemical', '-', (37, 41))	('anti-inflammatory', 'MPA', (62, 79))
62372	29245934	For example, L-4F stimulates HDL anti-inflammatory activity and inhibits LDL pro-inflammatory activity in the plasma of patients with end-stage renal disease.	('end-stage renal disease', 'Disease', (134, 157))	('L-4F', 'Chemical', '-', (13, 17))	('end-stage renal disease', 'Disease', 'MESH:D007676', (134, 157))	('LDL pro-inflammatory activity', 'MPA', (73, 102))	('renal disease', 'Phenotype', 'HP:0000112', (144, 157))	('LDL', 'molecular_function', 'GO:0005322', ('73', '76'))	('HDL', 'molecular_function', 'GO:0005321', ('29', '32'))	('HDL anti-inflammatory activity', 'MPA', (29, 59))	('end-stage renal disease', 'Phenotype', 'HP:0003774', (134, 157))	('patients', 'Species', '9606', (120, 128))	('stimulates', 'PosReg', (18, 28))	('inhibits', 'NegReg', (64, 72))	('L-4F', 'Var', (13, 17))
62373	29245934	L-4F also significantly decreased serum interleukin (IL)-6, TNF-alpha and IL-1beta in obese mice.	('interleukin (IL)-6', 'Gene', (40, 58))	('decreased', 'NegReg', (24, 33))	('IL-1', 'molecular_function', 'GO:0005149', ('74', '78'))	('L-4F', 'Chemical', '-', (0, 4))	('mice', 'Species', '10090', (92, 96))	('IL-1beta', 'MPA', (74, 82))	('interleukin (IL)-6', 'Gene', '16193', (40, 58))	('TNF-alpha', 'Gene', '21926', (60, 69))	('IL)-6', 'molecular_function', 'GO:0005138', ('53', '58'))	('obese', 'Disease', 'MESH:D009765', (86, 91))	('obese', 'Disease', (86, 91))	('L-4F', 'Var', (0, 4))	('TNF-alpha', 'Gene', (60, 69))
62374	29245934	Moreover, L-4F was shown to inhibit LPS-induced inflammatory responses by reducing the synthesis of cytokines, chemokines, and adhesion molecules; reduce pro-inflammatory gene expression in activated human coronary artery endothelial cells and macrophage foam cells; and prevent reactive oxygen species formation in activated neutrophils.	('inflammatory responses', 'CPA', (48, 70))	('synthesis of cytokines', 'MPA', (87, 109))	('human', 'Species', '9606', (200, 205))	('macrophage foam', 'Phenotype', 'HP:0003651', (244, 259))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (279, 302))	('chemokines', 'MPA', (111, 121))	('LPS-induced', 'CPA', (36, 47))	('synthesis', 'biological_process', 'GO:0009058', ('87', '96'))	('LPS', 'Chemical', 'MESH:D008070', (36, 39))	('reactive oxygen species formation', 'biological_process', 'GO:1903409', ('279', '312'))	('gene expression', 'biological_process', 'GO:0010467', ('171', '186'))	('L-4F', 'Chemical', '-', (10, 14))	('reduce', 'NegReg', (147, 153))	('inhibit', 'NegReg', (28, 35))	('reactive oxygen species formation', 'MPA', (279, 312))	('L-4F', 'Var', (10, 14))	('prevent', 'NegReg', (271, 278))	('pro-inflammatory gene expression', 'MPA', (154, 186))	('reducing', 'NegReg', (74, 82))
62375	29245934	In this study, we investigated the anti-inflammatory effect of L-4F in a mouse pancreatic cancer model.	('L-4F', 'Var', (63, 67))	('pancreatic cancer', 'Disease', 'MESH:D010190', (79, 96))	('pancreatic cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('L-4F', 'Chemical', '-', (63, 67))	('mouse', 'Species', '10090', (73, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (79, 96))	('anti-inflammatory', 'MPA', (35, 52))
62376	29245934	Our results show that L-4F treatment significantly inhibited tumor progression (Figure 1A-1C), decreased inflammatory cell infiltration in tumor tissues (Figure 3D), and reduced percentages of IL-17A-, IL-6-, GM-CSF- and IL-1beta-producing cells to varying degrees in tumor tissues (Figure 3A, 3B).	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('reduced', 'NegReg', (170, 177))	('tumor', 'Disease', (139, 144))	('IL-6', 'molecular_function', 'GO:0005138', ('202', '206'))	('IL-17', 'molecular_function', 'GO:0030367', ('193', '198'))	('L-4F', 'Chemical', '-', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('L-4F', 'Var', (22, 26))	('inflammatory cell infiltration', 'CPA', (105, 135))	('inhibited', 'NegReg', (51, 60))	('decreased inflammatory cell', 'Phenotype', 'HP:0012648', (95, 122))	('decreased', 'NegReg', (95, 104))	('IL-1', 'molecular_function', 'GO:0005149', ('221', '225'))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('rat', 'Species', '10116', (129, 132))	('tumor', 'Disease', (268, 273))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
62377	29245934	Moreover, L-4F decreased mRNA levels of the inflammatory cytokines IL-17A, IFN-gamma, IL-6, and IL-1beta (Figure 3C).	('L-4F', 'Var', (10, 14))	('IL-1', 'molecular_function', 'GO:0005149', ('96', '100'))	('mRNA levels of the inflammatory cytokines IL-17A', 'MPA', (25, 73))	('L-4F', 'Chemical', '-', (10, 14))	('IL-17', 'molecular_function', 'GO:0030367', ('67', '72'))	('decreased', 'NegReg', (15, 24))	('IL-6', 'molecular_function', 'GO:0005138', ('86', '90'))
62378	29245934	These results indicate that L-4F suppresses pancreatic cancer progression through inhibition of inflammation by decreasing the infiltration of pro-inflammatory and inflammatory cytokine-producing cells in mice with pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (215, 232))	('suppresses', 'NegReg', (33, 43))	('L-4F', 'Var', (28, 32))	('decreasing', 'NegReg', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('L-4F', 'Chemical', '-', (28, 32))	('rat', 'Species', '10116', (133, 136))	('pancreatic cancer', 'Disease', (215, 232))	('mice', 'Species', '10090', (205, 209))	('inhibition', 'NegReg', (82, 92))	('inflammation', 'Disease', 'MESH:D007249', (96, 108))	('pancreatic cancer', 'Disease', 'MESH:D010190', (215, 232))	('inflammation', 'biological_process', 'GO:0006954', ('96', '108'))	('pancreatic cancer', 'Disease', (44, 61))	('inflammation', 'Disease', (96, 108))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
62383	29245934	Therefore, we conclude that L-4F inhibited pancreatic cancer progression by decreasing the infiltration of Th17 and Th1 inflammatory cells, but not other Th cell subpopulations, in a mouse model of pancreatic cancer.	('rat', 'Species', '10116', (97, 100))	('infiltration', 'MPA', (91, 103))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (43, 60))	('mouse', 'Species', '10090', (183, 188))	('decreasing', 'NegReg', (76, 86))	('pancreatic cancer', 'Disease', (198, 215))	('L-4F', 'Chemical', '-', (28, 32))	('Th1', 'Gene', '57314', (116, 119))	('inhibited', 'NegReg', (33, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (43, 60))	('Th1', 'Gene', '57314', (107, 110))	('L-4F', 'Var', (28, 32))	('Th1', 'Gene', (116, 119))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (198, 215))	('Th1', 'Gene', (107, 110))	('pancreatic cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('pancreatic cancer', 'Disease', 'MESH:D010190', (198, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
62397	29245934	Furthermore, higher numbers of M2-polarized TAMs are associated with an increased risk of lymph node metastasis, neural invasion, and chemoresistance in PDA and hence a worse prognosis and reduced survival.	('lymph node metastasis', 'CPA', (90, 111))	('neural invasion', 'CPA', (113, 128))	('reduced', 'NegReg', (189, 196))	('chemoresistance', 'CPA', (134, 149))	('M2-polarized', 'Var', (31, 43))	('increased risk of lymph node', 'Phenotype', 'HP:0032536', (72, 100))	('TAMs', 'Chemical', '-', (44, 48))
62399	29245934	In the present study, we elucidated the effect of L-4F on TAMs using a pancreatic mouse model.	('pancreatic', 'Disease', 'MESH:D010195', (71, 81))	('pancreatic', 'Disease', (71, 81))	('TAMs', 'Chemical', '-', (58, 62))	('L-4F', 'Var', (50, 54))	('L-4F', 'Chemical', '-', (50, 54))	('mouse', 'Species', '10090', (82, 87))
62400	29245934	Our results show (Figure 4C, 4D) that L-4F treatment augmented CD11b+F4/80+ macrophage populations and significantly decreased CD11b+F4/80+CD206+ M2-macrophage populations.	('L-4F', 'Var', (38, 42))	('F4/80', 'Gene', (69, 74))	('F4/80', 'Gene', '13733', (69, 74))	('L-4F', 'Chemical', '-', (38, 42))	('decreased', 'NegReg', (117, 126))	('CD206', 'Gene', (139, 144))	('CD206', 'Gene', '17533', (139, 144))	('F4/80', 'Gene', (133, 138))	('F4/80', 'Gene', '13733', (133, 138))	('augmented', 'PosReg', (53, 62))
62401	29245934	This finding was further demonstrated in the in vitro, where IL-4-induced M2 polarization was directly reversed by L-4F (Figure 5A).	('IL-4', 'Gene', (61, 65))	('rat', 'Species', '10116', (32, 35))	('L-4F', 'Var', (115, 119))	('IL-4', 'Gene', '16189', (61, 65))	('IL-4', 'molecular_function', 'GO:0005136', ('61', '65'))	('L-4F', 'Chemical', '-', (115, 119))	('M2 polarization', 'MPA', (74, 89))
62402	29245934	Furthermore, L-4F led to down-regulation of IL-17A and IL-4 (Figure 3), suggesting that, in addition to its direct anti-inflammatory effect, L-4F can change the phenotypes of TAMs in pancreatic tumors by altering the microenvironment.	('change', 'Reg', (150, 156))	('TAMs', 'Disease', (175, 179))	('TAMs', 'Chemical', '-', (175, 179))	('L-4F', 'Chemical', '-', (13, 17))	('regulation', 'biological_process', 'GO:0065007', ('30', '40'))	('L-4F', 'Var', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('pancreatic tumors', 'Disease', 'MESH:D010190', (183, 200))	('L-4F', 'Chemical', '-', (141, 145))	('IL-4', 'Gene', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('pancreatic tumors', 'Disease', (183, 200))	('IL-17', 'molecular_function', 'GO:0030367', ('44', '49'))	('IL-17A', 'Gene', (44, 50))	('down-regulation', 'NegReg', (25, 40))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (183, 200))	('IL-4', 'Gene', '16189', (55, 59))	('IL-4', 'molecular_function', 'GO:0005136', ('55', '59'))
62409	29245934	Here, our results demonstrated that L-4F could not inhibited the IFN-gamma producing cells in tumor tissues and L-4F inhibited phosphorylation of LPS-induced JNK in mouse RAW264.7 macrophages, but not inhibit p38MAPK.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('p38MAPK', 'Gene', (209, 216))	('RAW264.7', 'CellLine', 'CVCL:0493', (171, 179))	('JNK', 'Gene', (158, 161))	('L-4F', 'Chemical', '-', (36, 40))	('mouse', 'Species', '10090', (165, 170))	('JNK', 'Gene', '26419', (158, 161))	('phosphorylation', 'MPA', (127, 142))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('p38MAPK', 'Gene', '26416', (209, 216))	('MAPK', 'molecular_function', 'GO:0004707', ('212', '216'))	('phosphorylation', 'biological_process', 'GO:0016310', ('127', '142'))	('LPS', 'Chemical', 'MESH:D008070', (146, 149))	('L-4F', 'Chemical', '-', (112, 116))	('inhibited', 'NegReg', (117, 126))	('tumor', 'Disease', (94, 99))	('LPS-induced', 'Protein', (146, 157))	('rat', 'Species', '10116', (25, 28))	('L-4F', 'Var', (112, 116))	('JNK', 'molecular_function', 'GO:0004705', ('158', '161'))
62410	29245934	On the other hand, L-4F inhibited both the cytokines (IL-4 and IL-17A) producing cells in tumor tissues and the important signaling molecules (phosphorylation of ERK and STAT3).	('IL-4', 'Gene', (54, 58))	('IL-4', 'molecular_function', 'GO:0005136', ('54', '58'))	('ERK', 'Gene', (162, 165))	('STAT3', 'Gene', '20848', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('STAT3', 'Gene', (170, 175))	('ERK', 'Gene', '26413', (162, 165))	('inhibited', 'NegReg', (24, 33))	('L-4F', 'Var', (19, 23))	('IL-4', 'Gene', '16189', (54, 58))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('IL-17', 'molecular_function', 'GO:0030367', ('63', '68'))	('L-4F', 'Chemical', '-', (19, 23))	('phosphorylation', 'biological_process', 'GO:0016310', ('143', '158'))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('ERK', 'molecular_function', 'GO:0004707', ('162', '165'))
62411	29245934	These results indicated that L-4F could inhibit all of the key regulators of M2 macrophage, but not M1 macrophage.	('L-4F', 'Var', (29, 33))	('inhibit', 'NegReg', (40, 47))	('L-4F', 'Chemical', '-', (29, 33))
62413	29245934	In conclusion, we have demonstrated that L-4F substantially inhibits pancreatic cancer progression mostly by exerting anti-inflammatory activity.	('pancreatic cancer', 'Disease', (69, 86))	('L-4F', 'Var', (41, 45))	('L-4F', 'Chemical', '-', (41, 45))	('pancreatic cancer', 'Disease', 'MESH:D010190', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('anti-inflammatory activity', 'MPA', (118, 144))	('rat', 'Species', '10116', (30, 33))	('inhibits', 'NegReg', (60, 68))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (69, 86))
62415	29245934	Notably, L-4F prevents M2 macrophage differentiation through inhibition of the STAT3 and MAPK pathways in macrophages.	('M2 macrophage differentiation', 'CPA', (23, 52))	('MAPK pathways', 'Pathway', (89, 102))	('macrophage differentiation', 'biological_process', 'GO:0030225', ('26', '52'))	('inhibition', 'NegReg', (61, 71))	('L-4F', 'Var', (9, 13))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('STAT3', 'Gene', '20848', (79, 84))	('L-4F', 'Chemical', '-', (9, 13))	('prevents', 'NegReg', (14, 22))	('STAT3', 'Gene', (79, 84))
62433	29245934	The following monoclonal anti-mouse antibodies were used: anti-CD11b-FITC (or anti-CD11b-PE), anti-F4/80-APC, anti-MHC II-PE and anti-CD206-FITC (eBioscience).	('F4/80', 'Gene', '13733', (99, 104))	('anti-CD11b-FITC', 'Var', (58, 73))	('mouse', 'Species', '10090', (30, 35))	('MHC II', 'Gene', (115, 121))	('MHC II', 'Gene', '111364', (115, 121))	('APC', 'cellular_component', 'GO:0005680', ('105', '108'))	('CD206', 'Gene', (134, 139))	('CD206', 'Gene', '17533', (134, 139))	('F4/80', 'Gene', (99, 104))
62463	29156694	Exo expanded myeloid derived suppressor cells (gMDSC and mMDSC, flow cytometry) and altered intracellular calcium fluxes in an SMAD4 dependent manner.	('intracellular', 'cellular_component', 'GO:0005622', ('92', '105'))	('SMAD4', 'Gene', '4089', (127, 132))	('Exo', 'Var', (0, 3))	('calcium', 'Chemical', 'MESH:D002118', (106, 113))	('altered', 'Reg', (84, 91))	('intracellular calcium fluxes', 'MPA', (92, 120))	('SMAD4', 'Gene', (127, 132))
62467	29156694	A reverse Warburg effect was observed by treating PBMCs with PDAC-derived Exo: BxPC3 Exo induced a higher glucose consumption and lactate production than BxPC3-SMAD4+ Exo.	('glucose consumption', 'Disease', (106, 125))	('BxPC3 Exo', 'Var', (79, 88))	('higher', 'PosReg', (99, 105))	('lactate', 'Chemical', 'MESH:D019344', (130, 137))	('SMAD4', 'Gene', (160, 165))	('lactate production', 'MPA', (130, 148))	('BxPC3', 'CellLine', 'CVCL:0186', (154, 159))	('SMAD4', 'Gene', '4089', (160, 165))	('PDAC', 'Chemical', '-', (61, 65))	('glucose consumption', 'Disease', 'MESH:D014397', (106, 125))	('BxPC3', 'CellLine', 'CVCL:0186', (79, 84))
62470	29156694	Recent studies exploring the whole genome and exome sequences revealed that the genetic landscape of PDAC is much more complex than previously believed, but they also confirmed that activating mutations of KRAS and inactivating mutations in the tumor suppressor genes p53, CDKN2A and SMAD4 characterize this tumor type.	('CDKN2A', 'Gene', (273, 279))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('PDAC', 'Chemical', '-', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('activating', 'PosReg', (182, 192))	('CDKN2A', 'Gene', '1029', (273, 279))	('SMAD4', 'Gene', (284, 289))	('KRAS', 'Gene', '3845', (206, 210))	('p53', 'Gene', '7157', (268, 271))	('tumor', 'Disease', (245, 250))	('inactivating mutations', 'Var', (215, 237))	('tumor', 'Disease', (308, 313))	('KRAS', 'Gene', (206, 210))	('SMAD4', 'Gene', '4089', (284, 289))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('245', '261'))	('p53', 'Gene', (268, 271))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('tumor suppressor', 'biological_process', 'GO:0051726', ('245', '261'))
62471	29156694	The loss of SMAD4, an almost unique event in gastrointestinal malignancies (e.g.	('SMAD4', 'Gene', (12, 17))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (45, 74))	('SMAD4', 'Gene', '4089', (12, 17))	('gastrointestinal malignancies', 'Disease', (45, 74))	('loss', 'Var', (4, 8))
62475	29156694	Yet this underlying mechanism cannot alone explain all PDAC features associated with SMAD4 loss, as recently demonstrated by Whittle et al., who found that heterozygous SMAD4 mutation is associated with increased cellular proliferation but attenuates the metastatic potential of PDAC, while the complete loss of SMAD4 restores metastatic competency by regulating the expression of the transcription factor Runx3.	('transcription', 'biological_process', 'GO:0006351', ('385', '398'))	('Runx3', 'Gene', '864', (406, 411))	('cellular proliferation', 'CPA', (213, 235))	('SMAD4', 'Gene', '4089', (169, 174))	('metastatic potential of PDAC', 'CPA', (255, 283))	('increased', 'PosReg', (203, 212))	('expression', 'MPA', (367, 377))	('SMAD4', 'Gene', (85, 90))	('loss', 'NegReg', (304, 308))	('transcription factor', 'molecular_function', 'GO:0000981', ('385', '405'))	('loss', 'NegReg', (91, 95))	('restores', 'PosReg', (318, 326))	('SMAD4', 'Gene', (312, 317))	('mutation', 'Var', (175, 183))	('PDAC', 'Chemical', '-', (279, 283))	('attenuates', 'NegReg', (240, 250))	('regulating', 'Reg', (352, 362))	('SMAD4', 'Gene', '4089', (85, 90))	('SMAD4', 'Gene', (169, 174))	('Runx3', 'Gene', (406, 411))	('metastatic competency', 'CPA', (327, 348))	('PDAC', 'Chemical', '-', (55, 59))	('SMAD4', 'Gene', '4089', (312, 317))
62481	29156694	Overall, PDAC-associated immune cell alterations concur in masking tumor cells from immune detection, thus favoring tumor progression.	('favoring', 'PosReg', (107, 115))	('masking', 'NegReg', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('PDAC', 'Chemical', '-', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('alterations', 'Var', (37, 48))	('PDAC-associated', 'Gene', (9, 24))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (116, 121))
62488	29156694	It remains to be elucidated whether and, if so, how variations in the mutational landscape of PDAC, with a special focus on SMAD4 deletion, accelerates immunosuppression; this would lead to a greater understanding leading to new therapeutic targeting.	('mutational', 'Var', (70, 80))	('accelerates', 'PosReg', (140, 151))	('lead to', 'Reg', (182, 189))	('variations', 'Var', (52, 62))	('PDAC', 'Chemical', '-', (94, 98))	('deletion', 'Var', (130, 138))	('PDAC', 'Gene', (94, 98))	('SMAD4', 'Gene', '4089', (124, 129))	('SMAD4', 'Gene', (124, 129))	('immunosuppression', 'MPA', (152, 169))
62497	29156694	Complete and Exo free CM obtained from both BxPC3 and BxPC3-SMAD4+ cells induced a significant increase of CD11b+ immature myeloid cells (Repeated measures ANOVA: F = 11.190, p = 0.007 and F = 15.540, p = 0.001 respectively), while Exo enriched fraction did not (F = 0.102, p = 0.793) (Figure 1, bottom panels).	('SMAD4', 'Gene', '4089', (60, 65))	('CD11b', 'Gene', '3684', (107, 112))	('BxPC3', 'Var', (44, 49))	('SMAD4', 'Gene', (60, 65))	('increase', 'PosReg', (95, 103))	('CD11b', 'Gene', (107, 112))	('BxPC3', 'CellLine', 'CVCL:0186', (54, 59))	('BxPC3', 'CellLine', 'CVCL:0186', (44, 49))
62499	29156694	Complete CM obtained from both BxPC3-SMAD4+ and BxPC3 cells caused a significant increase in the percentage of mMDSCs (Repeated measures ANOVA: F = 12.50, p = 0.006) while reducing both DCs (F = 12.82, p = 0.009) and gMDSCs (F = 10.590, p = 0.013).	('BxPC3', 'CellLine', 'CVCL:0186', (48, 53))	('SMAD4', 'Gene', (37, 42))	('BxPC3', 'CellLine', 'CVCL:0186', (31, 36))	('gMDSCs', 'MPA', (217, 223))	('reducing', 'NegReg', (172, 180))	('mMDSCs', 'Disease', (111, 117))	('SMAD4', 'Gene', '4089', (37, 42))	('BxPC3', 'Var', (48, 53))	('DCs', 'MPA', (186, 189))	('increase', 'PosReg', (81, 89))
62505	29156694	Exo from BxPC3 appear to mediate the expansion of any immunosuppressive cell subtype.	('Exo', 'Var', (0, 3))	('BxPC3', 'CellLine', 'CVCL:0186', (9, 14))	('BxPC3', 'Gene', (9, 14))
62512	29156694	With respect to NC media, the release of TNF by PBMCs was reduced by BxPC3-SMAD4+ CM, but mainly by BxPC3 CM.	('TNF', 'Gene', (41, 44))	('TNF', 'Gene', '7124', (41, 44))	('BxPC3 CM', 'Var', (100, 108))	('BxPC3', 'CellLine', 'CVCL:0186', (100, 105))	('BxPC3', 'CellLine', 'CVCL:0186', (69, 74))	('SMAD4', 'Gene', (75, 80))	('reduced', 'NegReg', (58, 65))	('SMAD4', 'Gene', '4089', (75, 80))
62540	29156694	Focusing on glycolysis, we found that BxPC3 cells had a higher degree of glucose consumption and of lactate production than BxPC3-SMAD4+ cells (Figure 7, upper left panel).	('BxPC3', 'CellLine', 'CVCL:0186', (38, 43))	('lactate production', 'MPA', (100, 118))	('SMAD4', 'Gene', (130, 135))	('glucose consumption', 'Disease', 'MESH:D014397', (73, 92))	('BxPC3', 'CellLine', 'CVCL:0186', (124, 129))	('BxPC3', 'Var', (38, 43))	('glycolysis', 'biological_process', 'GO:0006096', ('12', '22'))	('glucose consumption', 'Disease', (73, 92))	('higher', 'PosReg', (56, 62))	('SMAD4', 'Gene', '4089', (130, 135))	('lactate', 'Chemical', 'MESH:D019344', (100, 107))
62542	29156694	BxPC3, not BxPC3-SMAD4+, Exo enriched media induced significantly greater glucose consumption and lactate production with respect to Exo enriched NC media.	('glucose consumption', 'Disease', (74, 93))	('BxPC3', 'CellLine', 'CVCL:0186', (11, 16))	('SMAD4', 'Gene', '4089', (17, 22))	('greater', 'PosReg', (66, 73))	('BxPC3', 'Var', (0, 5))	('lactate', 'Chemical', 'MESH:D019344', (98, 105))	('SMAD4', 'Gene', (17, 22))	('lactate production', 'MPA', (98, 116))	('glucose consumption', 'Disease', 'MESH:D014397', (74, 93))	('BxPC3', 'CellLine', 'CVCL:0186', (0, 5))
62546	29156694	Alterations in genetic and epigenetic, transcription and signaling programs converge and concur in determining PDAC, a tumor expected to become the second most common cause of cancer-related mortality in 2030 in the absence of advances in therapy.	('tumor', 'Disease', (119, 124))	('transcription', 'biological_process', 'GO:0006351', ('39', '52'))	('Alterations', 'Var', (0, 11))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('PDAC', 'Chemical', '-', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('PDAC', 'Disease', (111, 115))
62549	29156694	We first observed that, in the presence of PDAC CM, T cells subsets were unbalanced towards immunosuppression: CD8+ T immunoeffector cells were reduced while CD4+CD25+ cells underwent expansion.	('CD4', 'Gene', '920', (158, 161))	('reduced', 'NegReg', (144, 151))	('CD25', 'Gene', '3559', (162, 166))	('PDAC CM', 'Var', (43, 50))	('CD25', 'Gene', (162, 166))	('CD8', 'Gene', '925', (111, 114))	('PDAC', 'Chemical', '-', (43, 47))	('CD8', 'Gene', (111, 114))	('CD4', 'Gene', (158, 161))
62585	29156694	A number of glycolytic enzymes were overexpressed in BxPC3 than in BxPC3-SMAD4+ Exo, and glycolysis was one of the core biological processes significantly altered in an SMAD4 associated manner and this allows us to add SMAD4 to the repertoire of cancer-associated genetic alterations, which include KRAS activating mutations, TP53 loss of function and MYC overexpression, which regulate the metabolic reprogramming of cancer cells, also known as the Warburg effect.	('SMAD4', 'Gene', (73, 78))	('KRAS', 'Gene', (299, 303))	('glycolysis', 'biological_process', 'GO:0006096', ('89', '99'))	('cancer', 'Disease', 'MESH:D009369', (418, 424))	('MYC', 'Gene', (352, 355))	('SMAD4', 'Gene', '4089', (169, 174))	('TP53', 'Gene', '7157', (326, 330))	('overexpressed', 'PosReg', (36, 49))	('cancer', 'Disease', (246, 252))	('BxPC3', 'CellLine', 'CVCL:0186', (53, 58))	('SMAD4', 'Gene', '4089', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('SMAD4', 'Gene', (219, 224))	('cancer', 'Disease', (418, 424))	('mutations', 'Var', (315, 324))	('BxPC3', 'CellLine', 'CVCL:0186', (67, 72))	('TP53', 'Gene', (326, 330))	('cancer', 'Phenotype', 'HP:0002664', (418, 424))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('SMAD4', 'Gene', (169, 174))	('SMAD4', 'Gene', '4089', (219, 224))	('KRAS', 'Gene', '3845', (299, 303))	('overexpression', 'PosReg', (356, 370))	('core', 'cellular_component', 'GO:0019013', ('115', '119'))	('loss of function', 'NegReg', (331, 347))	('glycolytic', 'Enzyme', (12, 22))	('activating', 'PosReg', (304, 314))
62587	29156694	We demonstrated that PDAC derived Exo transfer to myeloid cells the glycolytic enzyme activity of LDH, this finding being correlated with a direct and SMAD4-associated impact of Exo on myeloid cell glycolysis, since BxPC3 derived Exo caused a greater glucose consumption and lactate production than BxPC3-SMAD4+ Exo.	('PDAC', 'Chemical', '-', (21, 25))	('LDH', 'Gene', (98, 101))	('glycolysis', 'biological_process', 'GO:0006096', ('198', '208'))	('glucose consumption', 'Disease', (251, 270))	('BxPC3', 'CellLine', 'CVCL:0186', (299, 304))	('BxPC3', 'Var', (216, 221))	('lactate production', 'MPA', (275, 293))	('SMAD4', 'Gene', (305, 310))	('SMAD4', 'Gene', '4089', (151, 156))	('glycolytic enzyme activity', 'MPA', (68, 94))	('lactate', 'Chemical', 'MESH:D019344', (275, 282))	('SMAD4', 'Gene', '4089', (305, 310))	('BxPC3', 'CellLine', 'CVCL:0186', (216, 221))	('enzyme activity', 'molecular_function', 'GO:0003824', ('79', '94'))	('SMAD4', 'Gene', (151, 156))	('glucose consumption', 'Disease', 'MESH:D014397', (251, 270))	('greater', 'PosReg', (243, 250))
62588	29156694	However Exo might impact on cellular glucose metabolism not only through the transfer of glycolytic enzymes, but also because they might interfere with gene transcription and translation.	('translation', 'biological_process', 'GO:0006412', ('175', '186'))	('transcription', 'biological_process', 'GO:0006351', ('157', '170'))	('interfere', 'NegReg', (137, 146))	('cellular glucose metabolism', 'MPA', (28, 55))	('transfer', 'MPA', (77, 85))	('glucose metabolism', 'biological_process', 'GO:0006006', ('37', '55'))	('translation', 'MPA', (175, 186))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('glycolytic enzymes', 'MPA', (89, 107))	('gene transcription', 'MPA', (152, 170))	('impact', 'Reg', (18, 24))	('Exo', 'Var', (8, 11))
62593	29156694	In conclusion, SMAD4 deletion might underlie a more aggressive PDAC phenotype through Exo transfer to immune cells of proteins and miRNAs that, by altering intracellular calcium and glycolysis, may cause the expansion of immunosuppressive myeloid cells.	('glycolysis', 'biological_process', 'GO:0006096', ('182', '192'))	('altering', 'Reg', (147, 155))	('cause', 'Reg', (198, 203))	('SMAD4', 'Gene', (15, 20))	('PDAC', 'Chemical', '-', (63, 67))	('calcium', 'Chemical', 'MESH:D002118', (170, 177))	('underlie', 'Reg', (36, 44))	('immunosuppressive myeloid cells', 'CPA', (221, 252))	('expansion', 'CPA', (208, 217))	('deletion', 'Var', (21, 29))	('intracellular calcium', 'MPA', (156, 177))	('SMAD4', 'Gene', '4089', (15, 20))	('glycolysis', 'MPA', (182, 192))	('intracellular', 'cellular_component', 'GO:0005622', ('156', '169'))
62594	29156694	The pancreatic cancer cell lines BxPC3, known to carry a homozygous deletion of the SMAD4/DPC4 gene, and BxPC3-SMAD4+, obtained from the BxPC3 cells stably transfected with the pBK-cytomegalovirus (CMV)-SMAD4/DPC4 expression vector, were used.	('SMAD4', 'Gene', (111, 116))	('DPC4', 'Gene', (209, 213))	('pBK', 'Gene', (177, 180))	('DPC4', 'Gene', (90, 94))	('pBK', 'Gene', '55872', (177, 180))	('DPC4', 'Gene', '4089', (209, 213))	('SMAD4', 'Gene', (84, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (4, 21))	('SMAD4', 'Gene', '4089', (111, 116))	('DPC4', 'Gene', '4089', (90, 94))	('SMAD4', 'Gene', (203, 208))	('pancreatic cancer', 'Disease', (4, 21))	('deletion', 'Var', (68, 76))	('SMAD4', 'Gene', '4089', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('SMAD4', 'Gene', '4089', (203, 208))	('BxPC3', 'CellLine', 'CVCL:0186', (33, 38))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (4, 21))	('BxPC3', 'CellLine', 'CVCL:0186', (105, 110))	('BxPC3', 'CellLine', 'CVCL:0186', (137, 142))
62612	29156694	BxPC3 and BxPC3-SMAD4+ cell lines were cultured in RPMI 1640 MEDIA FOR SILAC with 10% dialyzed fetal bovine serum (FBS), with the addition of either with the non-labelled aminoacids Lysin and Arginine (light medium) or with the labelled 13C6-Lysine and 13C615N4-arginine (heavy medium) (Chemical Research 2000 srl, Rome, Italy).	('BxPC3', 'CellLine', 'CVCL:0186', (10, 15))	('13C6-Lysine', 'Chemical', '-', (237, 248))	('Arginine', 'Chemical', 'MESH:D001120', (192, 200))	('SMAD4', 'Gene', (16, 21))	('13C615N4-arginine', 'Var', (253, 270))	('13C6-Lysine', 'Var', (237, 248))	('SMAD4', 'Gene', '4089', (16, 21))	('bovine', 'Species', '9913', (101, 107))	('RPMI 1640 MEDIA', 'Chemical', '-', (51, 66))	('BxPC3', 'CellLine', 'CVCL:0186', (0, 5))	('13C615N4-arginine', 'Chemical', '-', (253, 270))
62618	28356610	The aim of our study was to assess whether routinely used biomarkers such as CA19-9, Ca125, Ca15-3, and CEA, when combined, can potentially yield an accurate test predicting pancreatic lesion etiology.	('CA19-9', 'Var', (77, 83))	('CEA', 'Gene', '1084', (104, 107))	('yield', 'Reg', (140, 145))	('pancreatic lesion', 'Disease', (174, 191))	('Ca125', 'Var', (85, 90))	('CEA', 'Gene', (104, 107))	('Ca15-3', 'Var', (92, 98))
62633	28356610	Ca125 (also known as MUC16) is a protein that has a well-established role in the PDAC development, especially in the later stages; for instance, it promotes cancer cells motility and drug-resistance and reprograms PDAC metabolism.	('Ca125', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('PDAC', 'Phenotype', 'HP:0006725', (214, 218))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('MUC16', 'Gene', '94025', (21, 26))	('drug-resistance', 'biological_process', 'GO:0042493', ('183', '198'))	('drug-resistance', 'CPA', (183, 198))	('PDAC', 'Phenotype', 'HP:0006725', (81, 85))	('drug-resistance', 'biological_process', 'GO:0009315', ('183', '198'))	('MUC1', 'Gene', (21, 25))	('MUC1', 'Gene', '4582', (21, 25))	('promotes', 'PosReg', (148, 156))	('reprograms PDAC metabolism', 'CPA', (203, 229))	('cancer cells motility', 'CPA', (157, 178))	('MUC16', 'Gene', (21, 26))	('metabolism', 'biological_process', 'GO:0008152', ('219', '229'))
62648	25895870	NPs can bring cisplatin into cells via caveolin- or clathrin-mediated pathway, bypassing the defective transporter.	('NPs', 'Var', (0, 3))	('clathrin-mediated pathway', 'Pathway', (52, 77))	('caveolin-', 'Pathway', (39, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (14, 23))
62660	25895870	The modulation of these stromal cellular components by either small molecules or nanodrugs can facilitate the remodeling of tumor blood vessels or ECM.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('modulation', 'Var', (4, 14))	('tumor', 'Disease', (124, 129))	('ECM', 'CPA', (147, 150))	('facilitate', 'PosReg', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
62700	25895870	Ablation of pericytes by anti-PDGF antibody or VEGF has been reported to increase vascular tortuosity and tumor growth in low PDGF-BB tumor models.	('VEGF', 'Gene', '22339', (47, 51))	('antibody', 'cellular_component', 'GO:0019815', ('35', '43'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('PDGF-B', 'Gene', (126, 132))	('tumor', 'Disease', (106, 111))	('PDGF-B', 'Gene', '18591', (126, 132))	('antibody', 'cellular_component', 'GO:0019814', ('35', '43'))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('vascular tortuosity', 'CPA', (82, 101))	('vascular tortuosity', 'Phenotype', 'HP:0004948', (82, 101))	('Ablation', 'Var', (0, 8))	('PDGF', 'molecular_function', 'GO:0005161', ('30', '34'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('antibody', 'molecular_function', 'GO:0003823', ('35', '43'))	('tumor', 'Disease', (134, 139))	('antibody', 'cellular_component', 'GO:0042571', ('35', '43'))	('increase', 'PosReg', (73, 81))	('PDGF', 'molecular_function', 'GO:0005161', ('126', '130'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('VEGF', 'Gene', (47, 51))	('anti-PDGF', 'Protein', (25, 34))
62706	25895870	Disparate intratumoral NP transport in response to cytokine-mediated modification of pericyte coverage has been observed in these two types of tumors in a series of work by Kano et al.. Murine colon cancer CT26 is an example of low-pericyte coverage tumor, while the BxPC3 pancreatic model has been characterized by hypovasculature with more than 70 % pericyte (Fig.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('CT26', 'Var', (206, 210))	('pancreatic', 'Disease', 'MESH:D010195', (273, 283))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('Murine', 'Species', '10090', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('colon cancer', 'Disease', 'MESH:D015179', (193, 205))	('hypovasculature', 'Disease', (316, 331))	('tumors', 'Disease', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('BxPC3', 'CellLine', 'CVCL:0186', (267, 272))	('pancreatic', 'Disease', (273, 283))	('response to cytokine', 'biological_process', 'GO:0034097', ('39', '59'))	('transport', 'biological_process', 'GO:0006810', ('26', '35'))	('CT26', 'CellLine', 'CVCL:7254', (206, 210))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('colon cancer', 'Disease', (193, 205))	('tumor', 'Disease', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('hypovasculature', 'Disease', 'None', (316, 331))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('colon cancer', 'Phenotype', 'HP:0003003', (193, 205))
62708	25895870	By using the BxPC3 model, they are able to show that the TGF-beta inhibitor can improve 2 MDa dextran and Doxil penetration, leading to enhanced tumor inhibition (Fig.	('BxPC3', 'CellLine', 'CVCL:0186', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('enhanced', 'PosReg', (136, 144))	('TGF-beta', 'Gene', '21803', (57, 65))	('Doxil', 'Chemical', 'MESH:C506643', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('inhibitor', 'Var', (66, 75))	('tumor', 'Disease', (145, 150))	('TGF-beta', 'Gene', (57, 65))	('improve', 'PosReg', (80, 87))	('dextran', 'Chemical', 'MESH:D003911', (94, 101))
62711	25895870	These inhibitors increase vessel leakiness and improve the intratumoral penetration of sub-100 nm NP, including PEI-PEG-coated MSNP, liposome, and polymeric micelle in other high pericyte coverage tumors, such as diffuse-type gastric cancer and 4T1 breast cancer models.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('mice', 'Species', '10090', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('increase vessel leakiness', 'Phenotype', 'HP:0030005', (17, 42))	('vessel leakiness', 'Disease', (26, 42))	('vessel leakiness', 'Disease', 'MESH:C535298', (26, 42))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('polymer', 'Chemical', 'MESH:D011108', (147, 154))	('improve', 'PosReg', (47, 54))	('gastric cancer', 'Disease', (226, 240))	('sub-100', 'Var', (87, 94))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (249, 262))	('gastric cancer', 'Disease', 'MESH:D013274', (226, 240))	('increase', 'PosReg', (17, 25))	('MSNP', 'Chemical', '-', (127, 131))	('breast cancer', 'Disease', 'MESH:D001943', (249, 262))	('breast cancer', 'Disease', (249, 262))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('PEI-PEG', 'Chemical', '-', (112, 119))	('tumor', 'Disease', (197, 202))	('gastric cancer', 'Phenotype', 'HP:0012126', (226, 240))
62712	25895870	Two recent studies have indicated that TGF-beta knockdown can improve MRI contrast.	('TGF-beta', 'Gene', '21803', (39, 47))	('improve', 'PosReg', (62, 69))	('MRI contrast', 'Disease', (70, 82))	('TGF-beta', 'Gene', (39, 47))	('knockdown', 'Var', (48, 57))
62713	25895870	In contrast to the finding in the BxPC3 model, TGF-beta inhibitors cannot increase particle penetration and improve therapeutic outcome in CT26, since the pericyte coverage was too low to achieve any additional effect.	('TGF-beta', 'Gene', (47, 55))	('TGF-beta', 'Gene', '21803', (47, 55))	('increase', 'PosReg', (74, 82))	('inhibitors', 'Var', (56, 66))	('CT26', 'Disease', (139, 143))	('particle penetration', 'CPA', (83, 103))	('CT26', 'CellLine', 'CVCL:7254', (139, 143))	('BxPC3', 'CellLine', 'CVCL:0186', (34, 39))
62715	25895870	Inhibition of VEGF-A can efficiently diminish nonfunctional microvessels with low-pericyte coverage while increase pericyte coverage in the functional microvessels.	('pericyte', 'MPA', (115, 123))	('nonfunctional microvessels', 'CPA', (46, 72))	('diminish', 'NegReg', (37, 45))	('VEGF-A', 'Gene', (14, 20))	('VEGF-A', 'Gene', '22339', (14, 20))	('Inhibition', 'Var', (0, 10))	('increase', 'PosReg', (106, 114))
62718	25895870	Recent research by Jain's group indicated that normalization of tumor blood vessels not only improves small molecule-based chemotherapy, but also facilitates the delivery of nanomedicine with smaller sizes.	('tumor', 'Disease', (64, 69))	('delivery of nanomedicine', 'MPA', (162, 186))	('small molecule-based chemotherapy', 'MPA', (102, 135))	('facilitates', 'PosReg', (146, 157))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('normalization', 'Var', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('improves', 'PosReg', (93, 101))
62760	25895870	The EPR effect improves NP accumulation in tumor microvessels, whereas the tortuous vessel structure, compressed diameter, deficient function, high interstitial pressure, abnormal pericytes, and BM coverage limit NP extravasation from blood vessels into the interstitial space.	('tortuous vessel', 'Phenotype', 'HP:0004948', (75, 90))	('function', 'MPA', (133, 141))	('improves', 'PosReg', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('deficient', 'Var', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('NP accumulation', 'MPA', (24, 39))	('limit', 'NegReg', (207, 212))
62765	25895870	TGF-beta inhibitors were also found to lower interstitial hypertension.	('hypertension', 'Disease', 'MESH:D006973', (58, 70))	('TGF-beta', 'Gene', '21803', (0, 8))	('hypertension', 'Phenotype', 'HP:0000822', (58, 70))	('interstitial', 'Disease', (45, 57))	('hypertension', 'Disease', (58, 70))	('inhibitors', 'Var', (9, 19))	('lower', 'NegReg', (39, 44))	('TGF-beta', 'Gene', (0, 8))
62826	25895870	indicated that a combination of gemcitabine LCP NP and cisplatin LPC NP can target TAFs and block alpha-SMA positive fibroblast recruitment by more than 87 % after multiple injections in a stroma-rich bladder cancer model (Fig.	('bladder cancer', 'Phenotype', 'HP:0009725', (201, 215))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('TAFs', 'Protein', (83, 87))	('alpha-SMA', 'Gene', (98, 107))	('alpha-SMA', 'Gene', '11475', (98, 107))	('block', 'NegReg', (92, 97))	('stroma-rich bladder cancer', 'Disease', (189, 215))	('gemcitabine', 'Chemical', 'MESH:C056507', (32, 43))	('stroma-rich bladder cancer', 'Disease', 'MESH:D001749', (189, 215))	('LPC NP', 'Var', (65, 71))	('LPC', 'Chemical', '-', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
62828	25895870	Transient depletion of TAFs increased tumor permeability, suppressed IFP, increased NP accumulation, and inhibited tumor metastasis.	('increased', 'PosReg', (28, 37))	('IFP', 'MPA', (69, 72))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('inhibited', 'NegReg', (105, 114))	('tumor', 'Disease', (115, 120))	('depletion', 'Var', (10, 19))	('suppressed', 'NegReg', (58, 68))	('increased', 'PosReg', (74, 83))	('NP accumulation', 'MPA', (84, 99))	('TAFs', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor metastasis', 'Disease', 'MESH:D009362', (115, 131))	('tumor metastasis', 'Disease', (115, 131))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
62838	25895870	For example, fibroblast-secreted heparin growth factor (HGF) regulates MAPK and AKT signaling pathway, resulting in resistant to vemurafenib, a mutant Braf inhibitor, in the treatment of BrafV600E mutated melanoma.	('mutated', 'Var', (197, 204))	('Braf', 'Gene', (151, 155))	('vemurafenib', 'Chemical', 'MESH:D000077484', (129, 140))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanoma', 'Disease', (205, 213))	('HGF', 'Gene', '15234', (56, 59))	('MAPK', 'Pathway', (71, 75))	('heparin growth factor', 'Gene', '15234', (33, 54))	('heparin growth factor', 'Gene', (33, 54))	('AKT signaling pathway', 'Pathway', (80, 101))	('Braf', 'Gene', (187, 191))	('BrafV600E', 'Mutation', 'rs113488022', (187, 196))	('Braf', 'Gene', '109880', (151, 155))	('HGF', 'Gene', (56, 59))	('signaling pathway', 'biological_process', 'GO:0007165', ('84', '101'))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('AKT signaling', 'biological_process', 'GO:0043491', ('80', '93'))	('MAPK', 'molecular_function', 'GO:0004707', ('71', '75'))	('resistant', 'MPA', (116, 125))	('Braf', 'Gene', '109880', (187, 191))
62841	25895870	demonstrate that stroma targeted depletion results in undifferentiated and aggressive pancreatic cancer, uncovering a protective role of stroma in this cancer.	('undifferentiated', 'Disease', (54, 70))	('cancer', 'Disease', (152, 158))	('depletion', 'Var', (33, 42))	('results in', 'Reg', (43, 53))	('cancer', 'Disease', (97, 103))	('aggressive pancreatic cancer', 'Disease', 'MESH:D010190', (75, 103))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('aggressive pancreatic cancer', 'Disease', (75, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
62864	27446075	For example, colon cancers with many gene mutations such as those with microsatellite instability (MSI) tend to be immunogenic with a higher number of tumor-infiltrating lymphocytes (TILs), and many respond to immunotherapy with immune checkpoint inhibitors, although many patients with colon cancer do not achieve the same degree of effect with any given immunotherapy due to non-immunogenicity of the tumor.	('colon cancers', 'Disease', 'MESH:D015179', (13, 26))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (403, 408))	('respond', 'Reg', (199, 206))	('higher', 'PosReg', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('colon cancers', 'Disease', (13, 26))	('MSI', 'Disease', 'None', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('colon cancer', 'Phenotype', 'HP:0003003', (287, 299))	('MSI', 'Disease', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (403, 408))	('patients', 'Species', '9606', (273, 281))	('colon cancer', 'Phenotype', 'HP:0003003', (13, 25))	('colon cancer', 'Disease', 'MESH:D015179', (287, 299))	('microsatellite', 'Gene', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('colon cancers', 'Phenotype', 'HP:0003003', (13, 26))	('colon cancer', 'Disease', 'MESH:D015179', (13, 25))	('tumor', 'Disease', (151, 156))	('colon cancer', 'Disease', (287, 299))	('tumor', 'Disease', (403, 408))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
62865	27446075	The presence of high numbers of TILs has been found to be a major predictor of favorable clinical outcome in many types of solid cancer, such as colorectal, lung, ovarian, and pancreatic cancers.	('pancreatic cancers', 'Disease', 'MESH:D010190', (176, 194))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('colorectal', 'Disease', (145, 155))	('ovarian', 'Disease', (163, 170))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (176, 194))	('solid cancer', 'Disease', 'MESH:D009369', (123, 135))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('colorectal', 'Disease', 'MESH:D015179', (145, 155))	('presence', 'Var', (4, 12))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (176, 193))	('pancreatic cancers', 'Disease', (176, 194))	('solid cancer', 'Disease', (123, 135))	('lung', 'Disease', (157, 161))
62899	27446075	The presence of TLOs in cancer tissues has been reported to be a favorable prognostic indicator (Table 1), although some studies have concluded that this is not always the case, or may only apply to exceptional cancers such as renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (227, 247))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancers', 'Disease', 'MESH:D009369', (211, 218))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (227, 247))	('cancers', 'Disease', (211, 218))	('cancer', 'Disease', (211, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('cancer', 'Disease', (24, 30))	('TLOs', 'Gene', (16, 20))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('presence', 'Var', (4, 12))	('TLOs', 'Chemical', '-', (16, 20))	('renal cell carcinoma', 'Disease', (227, 247))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))
62928	27446075	The microsatellite instability (MSI) subset of colorectal cancer has been shown to have an immunogenic character with massive TIL, although the relationship between TLOs and MSI is controversial; in colorectal cancers, two studies found no significant association and one study demonstrated a significant association whereby a more marked Crohn's-like lymphoid reaction (extra-tumoral TLOs) was significantly associated with deficient expression of the mismatch repair enzyme.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('TLOs', 'Chemical', '-', (385, 389))	('colorectal cancer', 'Disease', 'MESH:D015179', (199, 216))	('tumor', 'Disease', (377, 382))	('colorectal cancers', 'Disease', 'MESH:D015179', (199, 217))	('deficient', 'Var', (425, 434))	('lymphoid reaction', 'Disease', (352, 369))	('mismatch repair enzyme', 'Enzyme', (453, 475))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('tumor', 'Disease', 'MESH:D009369', (377, 382))	('mismatch repair', 'biological_process', 'GO:0006298', ('453', '468'))	('colorectal cancer', 'Disease', (47, 64))	('MSI', 'Disease', 'None', (32, 35))	('MSI', 'Disease', 'None', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (377, 382))	('expression', 'MPA', (435, 445))	('MSI', 'Disease', (32, 35))	("Crohn's-", 'Phenotype', 'HP:0100280', (339, 347))	('TLOs', 'Chemical', '-', (165, 169))	('MSI', 'Disease', (174, 177))	('colorectal cancer', 'Phenotype', 'HP:0003003', (199, 216))	('colorectal cancers', 'Disease', (199, 217))	('lymphoid reaction', 'Disease', 'MESH:D004342', (352, 369))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))
62984	27446075	Murine vascular studies have shown that vascular normalization in tumors enhances the influx of immune effector cells into the tumor parenchyma and markedly prolongs the survival of tumor-bearing mice.	('mice', 'Species', '10090', (196, 200))	('prolongs', 'NegReg', (157, 165))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumor parenchyma', 'Disease', 'MESH:D010195', (127, 143))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('enhances', 'PosReg', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (66, 71))	('vascular normalization', 'Var', (40, 62))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('influx of immune effector cells into the', 'MPA', (86, 126))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor parenchyma', 'Disease', (127, 143))	('survival', 'CPA', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (127, 132))	('tumors', 'Disease', (66, 72))	('Murine', 'Species', '10090', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
62991	27446075	Meanwhile, TLOs with an active immune reaction were reportedly induced in high-grade cervical intraepithelial neoplasias (CIN2/3) after intramuscular vaccination with HPV16 E6/E7 antigens.	('CIN', 'Disease', (122, 125))	('HPV16', 'Gene', (167, 172))	('HPV16', 'Species', '333760', (167, 172))	('intraepithelial neoplasias', 'Phenotype', 'HP:0032187', (94, 120))	('cervical intraepithelial neoplasias', 'Disease', (85, 120))	('TLOs', 'Chemical', '-', (11, 15))	('neoplasias', 'Phenotype', 'HP:0002664', (110, 120))	('E6/E7', 'Var', (173, 178))	('CIN', 'Disease', 'MESH:D007674', (122, 125))	('induced', 'Reg', (63, 70))	('cervical intraepithelial neoplasias', 'Phenotype', 'HP:0032242', (85, 120))	('cervical intraepithelial neoplasias', 'Disease', 'MESH:D018290', (85, 120))
63008	27446075	Indeed, the presence of TLOs is significantly correlated with a favorable patient outcome and with a tumor immune microenvironment showing responses involving cellular and humoral immunity.	('patient', 'Species', '9606', (74, 81))	('TLOs', 'Chemical', '-', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('presence', 'Var', (12, 20))	('tumor', 'Disease', (101, 106))	('TLOs', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
63019	26735172	Kaplan-Meier analysis indicated that high EDIL3 expression was significantly associated with shorter overall survival times in PDAC patients.	('overall survival', 'MPA', (101, 117))	('high', 'Var', (37, 41))	('PDAC', 'Chemical', '-', (127, 131))	('PDAC', 'Phenotype', 'HP:0006725', (127, 131))	('expression', 'MPA', (48, 58))	('shorter', 'NegReg', (93, 100))	('EDIL3', 'Gene', (42, 47))	('patients', 'Species', '9606', (132, 140))
63041	26735172	EDIL3 is a well known ligand for alphavbeta3 integrin and activation of alphavbeta3 integrin can induce the expression of Bcl-2 in endothelial cell.	('activation', 'Var', (58, 68))	('alphavbeta3 integrin', 'Protein', (72, 92))	('Bcl-2', 'molecular_function', 'GO:0015283', ('122', '127'))	('induce', 'PosReg', (97, 103))	('expression', 'MPA', (108, 118))	('ligand', 'molecular_function', 'GO:0005488', ('22', '28'))	('Bcl-2', 'Gene', (122, 127))	('Bcl-2', 'Gene', '596', (122, 127))
63044	26735172	The results showed that EDIL3 expression was significantly up-regulated in PDAC tissues comparing with paired normal pancreatic tissues using GSE15471 (Figure 1A, n = 39, p = 1.33E-11) and GSE28735 (Figure 1B, n = 45, p = 3.73E-8).	('up-regulated', 'PosReg', (59, 71))	('expression', 'MPA', (30, 40))	('PDAC', 'Disease', (75, 79))	('PDAC', 'Phenotype', 'HP:0006725', (75, 79))	('PDAC', 'Chemical', '-', (75, 79))	('GSE15471', 'Var', (142, 150))	('pancreatic', 'Disease', 'MESH:D010195', (117, 127))	('EDIL3', 'Gene', (24, 29))	('pancreatic', 'Disease', (117, 127))	('GSE28735', 'Var', (189, 197))
63055	26735172	As shown in Figure 2A, patients with higher EDIL3 level (expression value > 8) had significantly shorter survival time than those with a lower EDIL3 level (expression value <= 8).	('patients', 'Species', '9606', (23, 31))	('survival time', 'CPA', (105, 118))	('EDIL3 level', 'Var', (44, 55))	('shorter', 'NegReg', (97, 104))
63056	26735172	At protein level, as demonstrated in TMA1, patients with higher EDIL3 expression had markedly decreased survival time than those with lower EDIL3 expression (Figure 2B, p = 0.0119).	('higher', 'Var', (57, 63))	('patients', 'Species', '9606', (43, 51))	('decreased', 'NegReg', (94, 103))	('TMA', 'Disease', 'MESH:D000783', (37, 40))	('EDIL3', 'Gene', (64, 69))	('survival time', 'CPA', (104, 117))	('protein', 'cellular_component', 'GO:0003675', ('3', '10'))	('TMA', 'Disease', (37, 40))
63067	26735172	Stable expression of two short hairpin RNA (sh-1, sh-2) targeting EDIL3 resulted in > 75% decrease in EDIL3 expression of SW1990 and BxPC-3 cells (Figure 3D).	('SW1990', 'CellLine', 'CVCL:1723', (122, 128))	('EDIL3', 'Gene', (102, 107))	('BxPC-3', 'CellLine', 'CVCL:0186', (133, 139))	('RNA', 'cellular_component', 'GO:0005562', ('39', '42'))	('decrease', 'NegReg', (90, 98))	('SW1990', 'Var', (122, 128))	('EDIL3', 'Gene', (66, 71))
63069	26735172	The result showed that knockdown of EDIL3 also failed to affect cell migration (Supplementary Figure 1C) or invasion (Supplementary Figure 1D) in SW1990 and BxPC-3 cells.	('EDIL3', 'Gene', (36, 41))	('knockdown', 'Var', (23, 32))	('affect', 'Reg', (57, 63))	('cell migration', 'biological_process', 'GO:0016477', ('64', '78'))	('BxPC-3', 'CellLine', 'CVCL:0186', (157, 163))	('invasion', 'CPA', (108, 116))	('cell migration', 'CPA', (64, 78))	('SW1990', 'CellLine', 'CVCL:1723', (146, 152))
63070	26735172	Indeed, cell apoptosis induced by serum deprivation for 48 h was not affected upon silencing of EDIL3 (Supplementary Figure 1E), which significantly inhibited anoikis resistance of SW1990 and BxPC-3 cells (Figure 3E).	('apoptosis', 'biological_process', 'GO:0097194', ('13', '22'))	('apoptosis', 'biological_process', 'GO:0006915', ('13', '22'))	('SW1990', 'CellLine', 'CVCL:1723', (181, 187))	('anoikis', 'biological_process', 'GO:0043276', ('159', '166'))	('anoikis resistance', 'CPA', (159, 177))	('inhibited', 'NegReg', (149, 158))	('EDIL3', 'Gene', (96, 101))	('BxPC-3', 'CellLine', 'CVCL:0186', (192, 198))	('silencing', 'Var', (83, 92))
63071	26735172	Consistent with this, we found caspase-3/7 activity in PDAC cells suspended in poly-Hema coated dishes for 48 h was markedly promoted by silencing of EDIL3 (Figure 3F).	('Hema coated', 'Disease', (84, 95))	('PDAC', 'Chemical', '-', (55, 59))	('caspase-3', 'Gene', '836', (31, 40))	('EDIL3', 'Gene', (150, 155))	('silencing', 'Var', (137, 146))	('activity', 'MPA', (43, 51))	('PDAC', 'Phenotype', 'HP:0006725', (55, 59))	('promoted', 'PosReg', (125, 133))	('caspase-3', 'Gene', (31, 40))	('Hema coated', 'Disease', 'MESH:D058456', (84, 95))
63072	26735172	As shown in Figure 3G, silencing of EDIL3 significantly reduced the anchorage-independent growth of SW1990 and BxPC-3 cells.	('BxPC-3', 'CellLine', 'CVCL:0186', (111, 117))	('anchorage-independent growth', 'CPA', (68, 96))	('reduced', 'NegReg', (56, 63))	('EDIL3', 'Gene', (36, 41))	('silencing', 'Var', (23, 32))	('SW1990', 'CellLine', 'CVCL:1723', (100, 106))
63077	26735172	Indeed, the tumor burden of PDAC in sh-EDIL3 group (sh-1 and sh-2) was significantly reduced compared with the sh-Ctrl group as revealed by tumor volume (Figure 5B) and tumor weight (Figure 5C).	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('PDAC', 'Chemical', '-', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('PDAC', 'Phenotype', 'HP:0006725', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (169, 174))	('sh-EDIL3', 'Var', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (12, 17))	('reduced', 'NegReg', (85, 92))	('tumor', 'Disease', (140, 145))
63078	26735172	Furthermore, the decreased expression of PCNA, a marker of cell proliferation, and increased cleaved caspase 3-positive cells were observed in sh-EDIL3 mice compared with those from sh-Ctrl mice (Figure 5E, 5F).	('increased', 'PosReg', (83, 92))	('decreased', 'NegReg', (17, 26))	('PCNA', 'Protein', (41, 45))	('cleaved caspase', 'CPA', (93, 108))	('expression', 'MPA', (27, 37))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('mice', 'Species', '10090', (152, 156))	('mice', 'Species', '10090', (190, 194))	('PCNA', 'molecular_function', 'GO:0003892', ('41', '45'))	('sh-EDIL3', 'Var', (143, 151))
63081	26735172	As shown in Figure 6A, knockdown of EDIL3 reduced the protein level of Bcl-2 and Bcl-xL.	('reduced', 'NegReg', (42, 49))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('Bcl-xL', 'Gene', (81, 87))	('knockdown', 'Var', (23, 32))	('EDIL3', 'Gene', (36, 41))	('Bcl-2', 'Gene', '596', (71, 76))	('Bcl-2', 'Gene', (71, 76))	('Bcl-xL', 'Gene', '598', (81, 87))	('Bcl-2', 'molecular_function', 'GO:0015283', ('71', '76'))
63083	26735172	The pro-apoptotic protein, Bax, was faintly influenced by knockdown or introduction of EDIL3.	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('Bax', 'Gene', '581', (27, 30))	('knockdown', 'Var', (58, 67))	('Bax', 'Gene', (27, 30))
63090	26735172	By silencing of EDIL3 expression and treatment with recombinant EDIL3 protein, we demonstrated that EDIL3 conferred PDAC cells with advantages of anoikis resistance and anchorage-independent growth through altering expression of Bcl-2 proteins.	('advantages', 'PosReg', (132, 142))	('silencing', 'Var', (3, 12))	('Bcl-2', 'molecular_function', 'GO:0015283', ('229', '234'))	('altering', 'Reg', (206, 214))	('PDAC', 'Phenotype', 'HP:0006725', (116, 120))	('EDIL3', 'Gene', (16, 21))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('Bcl-2', 'Gene', (229, 234))	('Bcl-2', 'Gene', '596', (229, 234))	('EDIL3', 'Gene', (100, 105))	('anoikis', 'biological_process', 'GO:0043276', ('146', '153'))	('PDAC', 'Chemical', '-', (116, 120))	('anchorage-independent growth', 'CPA', (169, 197))	('anoikis resistance', 'CPA', (146, 164))	('expression', 'MPA', (215, 225))
63097	26735172	Despite the critical roles of VEGF and the frequently mutation of p53 in pancreatic cancer, whether this type of modulation contributes to elevated EDIL3 expression remains further investigation.	('mutation', 'Var', (54, 62))	('pancreatic cancer', 'Disease', (73, 90))	('p53', 'Gene', '7157', (66, 69))	('elevated', 'PosReg', (139, 147))	('VEGF', 'Gene', '7422', (30, 34))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('EDIL3 expression', 'MPA', (148, 164))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('VEGF', 'Gene', (30, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))	('p53', 'Gene', (66, 69))
63112	26735172	Consistent with this, treatment with recombinant EDIL3 protein markedly promoted the level of anti-apoptotic protein Bcl-2 and Bcl-xL, and inhibitor of Bcl-2 can completely abolish EDIL3-mediated oncogenic functions.	('Bcl-2', 'Gene', '596', (117, 122))	('Bcl-2', 'molecular_function', 'GO:0015283', ('152', '157'))	('Bcl-2', 'Gene', '596', (152, 157))	('Bcl-2', 'molecular_function', 'GO:0015283', ('117', '122'))	('Bcl-xL', 'Gene', '598', (127, 133))	('abolish', 'NegReg', (173, 180))	('Bcl-2', 'Gene', (152, 157))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('Bcl-xL', 'Gene', (127, 133))	('EDIL3-mediated oncogenic functions', 'CPA', (181, 215))	('inhibitor', 'Var', (139, 148))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('promoted', 'PosReg', (72, 80))	('Bcl-2', 'Gene', (117, 122))
63113	26735172	Therefore, the mechanism by which EDIL3 promotes anoikis resistance and anchorage-independent growth may be due, in part, to the alternation of Bcl-2 family protein, which would protect the detached PDAC cells from anoikis.	('Bcl-2', 'Gene', '596', (144, 149))	('PDAC', 'Chemical', '-', (199, 203))	('anoikis', 'biological_process', 'GO:0043276', ('49', '56'))	('alternation', 'Var', (129, 140))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('EDIL3', 'Gene', (34, 39))	('PDAC', 'Phenotype', 'HP:0006725', (199, 203))	('anchorage-independent growth', 'CPA', (72, 100))	('Bcl-2', 'molecular_function', 'GO:0015283', ('144', '149'))	('anoikis resistance', 'CPA', (49, 67))	('anoikis', 'biological_process', 'GO:0043276', ('215', '222'))	('protect', 'PosReg', (178, 185))	('Bcl-2', 'Gene', (144, 149))	('promotes', 'PosReg', (40, 48))
63180	26405195	Thus, pharmacologic inhibition of the Shh pathway was thought to have a positive impact on gemcitabine delivery, by reducing the desmoplastic stroma.	('gemcitabine', 'Chemical', 'MESH:C056507', (91, 102))	('reducing', 'NegReg', (116, 124))	('Shh', 'Gene', '6469', (38, 41))	('desmoplastic stroma', 'Disease', 'MESH:D018220', (129, 148))	('pharmacologic', 'Var', (6, 19))	('desmoplastic stroma', 'Disease', (129, 148))	('Shh', 'Gene', (38, 41))	('gemcitabine', 'MPA', (91, 102))
63337	26405195	However, recent studies from Rhim et al have shown that stroma may have a restraining effect on the tumor In this study chronic depletion of stroma by embryonic deletion of Shh in pancreatic epithelial cells or by chronic administration of smoothened inhibitor to KPC mice led to aggressive tumors with increased vascularity, heightened proliferation and increased metastases.	('tumor', 'Disease', (100, 105))	('increased', 'PosReg', (355, 364))	('mice', 'Species', '10090', (268, 272))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('smoothened', 'Gene', (240, 250))	('pancreatic epithelial cells', 'Disease', 'MESH:D010195', (180, 207))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (291, 297))	('Shh', 'Gene', (173, 176))	('pancreatic epithelial cells', 'Disease', (180, 207))	('aggressive tumors', 'Disease', (280, 297))	('metastases', 'Disease', 'MESH:D009362', (365, 375))	('smoothened', 'Gene', '319757', (240, 250))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('depletion', 'NegReg', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('metastases', 'Disease', (365, 375))	('aggressive tumors', 'Disease', 'MESH:D001523', (280, 297))	('increased', 'PosReg', (303, 312))	('Shh', 'Gene', '20423', (173, 176))	('vascularity', 'CPA', (313, 324))	('deletion', 'Var', (161, 169))	('heightened', 'PosReg', (326, 336))	('tumor', 'Disease', (291, 296))
63369	26015068	Inactivation of LKB1 results in the activation of the mammalian target of rapamaycin (mTOR) pathway, which is crucial in controlling cellular energy metabolism, cell survival and growth under metabolic stress such as nutrient deficiency.	('mTOR', 'Gene', '2475', (86, 90))	('metabolism', 'biological_process', 'GO:0008152', ('149', '159'))	('mTOR', 'Gene', (86, 90))	('mammalian target of rapamaycin', 'Gene', (54, 84))	('activation', 'PosReg', (36, 46))	('mammalian target of rapamaycin', 'Gene', '2475', (54, 84))	('LKB1', 'Gene', (16, 20))	('Inactivation', 'Var', (0, 12))
63370	26015068	The PDAC tumor microenvironment is typically characterized by a diminished vascular network in the setting of striking desmoplastic response, and, under these conditions, LKB1 inactivation may be predicted to have a pro-tumorigenic response.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('LKB1', 'Gene', (171, 175))	('PDAC', 'Chemical', '-', (4, 8))	('diminished', 'NegReg', (64, 74))	('vascular network', 'CPA', (75, 91))	('tumor', 'Disease', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('PDAC', 'Disease', (4, 8))	('inactivation', 'Var', (176, 188))	('PDAC', 'Phenotype', 'HP:0006725', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
63371	26015068	Previous studies of LKB1 in pancreatic acinar cell carcinoma, intraductal papillary-mucinous neoplasms (IPMN) and PDAC have focused on germline or somatic mutations and inactivation.	('pancreatic acinar cell carcinoma', 'Disease', (28, 60))	('LKB1', 'Gene', (20, 24))	('PDAC', 'Phenotype', 'HP:0006725', (114, 118))	('pancreatic acinar cell carcinoma', 'Disease', 'MESH:D010190', (28, 60))	('intraductal papillary-mucinous neoplasms', 'Disease', 'MESH:D000077779', (62, 102))	('mucinous neoplasms', 'Phenotype', 'HP:0031495', (84, 102))	('intraductal papillary-mucinous neoplasms', 'Disease', (62, 102))	('PDAC', 'Chemical', '-', (114, 118))	('inactivation', 'Var', (169, 181))	('neoplasms', 'Phenotype', 'HP:0002664', (93, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
63372	26015068	In addition to mutations, allelic loss and promoter hypermethylation also have been reported as mechanisms that account for LKB1 loss in a variety of tumors.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('allelic loss', 'Var', (26, 38))	('LKB1', 'Gene', (124, 128))	('loss', 'NegReg', (129, 133))	('promoter hypermethylation', 'Var', (43, 68))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))
63373	26015068	However, the effect of these genetic and epigenetic alterations on LKB1 expression in large numbers of sporadic PDAC remain unclear.	('PDAC', 'Disease', (112, 116))	('PDAC', 'Phenotype', 'HP:0006725', (112, 116))	('epigenetic alterations', 'Var', (41, 63))	('LKB1', 'Gene', (67, 71))	('PDAC', 'Chemical', '-', (112, 116))
63374	26015068	We found that the expression of LKB1 was associated with poor prognosis of PDAC.	('associated', 'Reg', (41, 51))	('PDAC', 'Disease', (75, 79))	('PDAC', 'Phenotype', 'HP:0006725', (75, 79))	('LKB1', 'Gene', (32, 36))	('PDAC', 'Chemical', '-', (75, 79))	('expression', 'Var', (18, 28))
63406	26015068	Importantly, patients with a low level of LKB1 expression had significantly shorter survival times compared to those with a high level of LKB1 expression.	('LKB1', 'Gene', (42, 46))	('patients', 'Species', '9606', (13, 21))	('expression', 'Var', (47, 57))	('survival times', 'CPA', (84, 98))	('shorter', 'NegReg', (76, 83))
63430	25576918	Stable knock-down of APLP2 expression (with inducible shRNA) in pancreatic cancer cells reduced the ability of these cells to migrate and invade.	('knock-down', 'Var', (7, 17))	('rat', 'Species', '10116', (129, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('APLP2', 'Gene', (21, 26))	('pancreatic cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('reduced', 'NegReg', (88, 95))	('pancreatic cancer', 'Disease', 'MESH:D010190', (64, 81))
63431	25576918	Loss of APLP2 decreased cortical actin and increased intracellular actin filaments in pancreatic cancer cells.	('intracellular', 'cellular_component', 'GO:0005622', ('53', '66'))	('decreased', 'NegReg', (14, 23))	('pancreatic cancer', 'Disease', (86, 103))	('increased intracellular actin', 'Phenotype', 'HP:0003575', (43, 72))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('increased', 'PosReg', (43, 52))	('Loss', 'Var', (0, 4))	('intracellular actin filaments', 'MPA', (53, 82))	('APLP2', 'Gene', (8, 13))	('cortical actin', 'MPA', (24, 38))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
63439	25576918	APLP2 expression was also demonstrated to be elevated in colorectal cancer, and APLP2 knockdown increased the susceptibility of HCT116 colon cancer cells to an apoptotic stimulus.	('increased', 'PosReg', (96, 105))	('knockdown', 'Var', (86, 95))	('APLP2', 'Gene', (0, 5))	('colorectal cancer', 'Disease', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('colon cancer', 'Disease', (135, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('expression', 'MPA', (6, 16))	('susceptibility', 'MPA', (110, 124))	('rat', 'Species', '10116', (33, 36))	('colorectal cancer', 'Disease', 'MESH:D015179', (57, 74))	('elevated', 'PosReg', (45, 53))	('APLP2', 'Gene', (80, 85))	('HCT116', 'CellLine', 'CVCL:0291', (128, 134))	('colorectal cancer', 'Phenotype', 'HP:0003003', (57, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (135, 147))	('colon cancer', 'Disease', 'MESH:D015179', (135, 147))
63441	25576918	We have found that APLP2 increases MHC class I internalization in HeLa cells, which suggests it may contribute to cancer immune evasion.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('MHC class I', 'Protein', (35, 46))	('immune evasion', 'biological_process', 'GO:0051842', ('121', '135'))	('internalization', 'MPA', (47, 62))	('increases MHC', 'Phenotype', 'HP:0025548', (25, 38))	('increases', 'PosReg', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('contribute', 'Reg', (100, 110))	('immune evasion', 'biological_process', 'GO:0042783', ('121', '135'))	('HeLa', 'CellLine', 'CVCL:0030', (66, 70))	('APLP2', 'Var', (19, 24))	('cancer', 'Disease', (114, 120))
63471	25576918	By counting migrating cells in a chamber invasion assay, we determined that the average number of invading Dox-cultured cells expressing APLP2-shRNA (56+-3.6 cells) was significantly lower than the average number of invading control cells (148+-5.2 cells) (Figure 3B).	('lower', 'NegReg', (183, 188))	('APLP2-shRNA', 'Var', (137, 148))	('Dox', 'Chemical', 'MESH:D004318', (107, 110))	('rat', 'Species', '10116', (15, 18))
63478	25576918	We observed that Dox-treated S2-013-APLP2-shRNA cells have altered cytoskeletal morphology with substantial rearrangement of the actin cytoskeleton, as shown by staining with rhodamine phalloidin for visualization of actin filaments (Figure 4).	('S2-013-APLP2-shRNA', 'Var', (29, 47))	('altered', 'Reg', (59, 66))	('actin cytoskeleton', 'MPA', (129, 147))	('rearrangement', 'MPA', (108, 121))	('rhodamine phalloidin', 'Chemical', 'MESH:C504731', (175, 195))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('129', '147'))	('cytoskeletal morphology', 'CPA', (67, 90))	('Dox', 'Chemical', 'MESH:D004318', (17, 20))
63479	25576918	To investigate the extent to which APLP2 influences the growth and spread of tumors in vivo, we implanted S2-013-APLP2-shRNA-luciferase cells in the pancreas of athymic nude mice, using previously described procedures.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('pancreas of athymic', 'Disease', (149, 168))	('nude mice', 'Species', '10090', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('pancreas of athymic', 'Disease', 'MESH:D010190', (149, 168))	('S2-013-APLP2-shRNA-luciferase', 'Var', (106, 135))
63483	25576918	Upon imaging, it was apparent that the knockdown of APLP2 expression significantly inhibited tumor development.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('knockdown', 'Var', (39, 48))	('tumor', 'Disease', (93, 98))	('APLP2', 'Gene', (52, 57))	('inhibited', 'NegReg', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
63489	25576918	For mice that had received Dox to induce APLP2 shRNA expression, the resected primary tumors tended to be smaller (Figure 5C,D).	('Dox', 'Chemical', 'MESH:D004318', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('APLP2 shRNA', 'Var', (41, 52))	('smaller', 'NegReg', (106, 113))	('primary tumors', 'Disease', 'MESH:D009369', (78, 92))	('mice', 'Species', '10090', (4, 8))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('primary tumors', 'Disease', (78, 92))
63490	25576918	In fact, the average weight of the Dox group tumors was approximately half of the weight for the control group (No Dox) (Figure 5D).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Dox', 'Var', (35, 38))	('Dox', 'Chemical', 'MESH:D004318', (35, 38))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('Dox', 'Chemical', 'MESH:D004318', (115, 118))
63491	25576918	Sections of Dox mice-derived primary tumors that were stained with APLP2 antibody showed only weak APLP2 staining, confirming in vivo Dox-induced knockdown of APLP2 (Supplementary Figure 3).	('knockdown', 'Var', (146, 155))	('antibody', 'cellular_component', 'GO:0019814', ('73', '81'))	('antibody', 'molecular_function', 'GO:0003823', ('73', '81'))	('primary tumors', 'Disease', 'MESH:D009369', (29, 43))	('antibody', 'cellular_component', 'GO:0042571', ('73', '81'))	('APLP2', 'Gene', (159, 164))	('Dox', 'Chemical', 'MESH:D004318', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('primary tumors', 'Disease', (29, 43))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('APLP2', 'MPA', (99, 104))	('mice', 'Species', '10090', (16, 20))	('Dox', 'Chemical', 'MESH:D004318', (134, 137))	('antibody', 'cellular_component', 'GO:0019815', ('73', '81'))
63496	25576918	Surprisingly, immunoblotting for actin on the same tumors revealed that the APLP2 knockdown in vivo resulted in a decreased level of monomeric actin and the generation of high molecular weight, covalently linked complexes containing actin.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('knockdown', 'Var', (82, 91))	('tumors', 'Disease', (51, 57))	('decreased', 'NegReg', (114, 123))	('APLP2', 'Gene', (76, 81))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('rat', 'Species', '10116', (161, 164))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('level of monomeric actin', 'MPA', (124, 148))	('actin', 'Protein', (233, 238))	('high molecular weight', 'MPA', (171, 192))
63499	25576918	The exact nature of the large actin-containing protein complexes in the tumors that had APLP2 expression knocked down is presently unknown.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('knocked', 'Var', (105, 112))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('expression', 'MPA', (94, 104))	('APLP2', 'Gene', (88, 93))
63503	25576918	We also assessed the presence or absence of metastases in various anatomic sites within both groups of mice, and found that knockdown of APLP2 in the xenografted cancer cells caused major changes in the spread of the tumors.	('knockdown', 'Var', (124, 133))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('cancer', 'Disease', (162, 168))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('mice', 'Species', '10090', (103, 107))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('APLP2', 'Gene', (137, 142))	('metastases', 'Disease', (44, 54))	('changes', 'Reg', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('metastases', 'Disease', 'MESH:D009362', (44, 54))
63505	25576918	In addition, the group of mice that received Dox to induce the APLP2 shRNA had a trend toward having significantly lower percentages with metastases involving the spleen, mesenteric lymph nodes, peritoneum, liver, and ovary, though the differences from No Dox controls at these additional sites were not significant at P<0.05 (Figure 7).	('Dox', 'Chemical', 'MESH:D004318', (45, 48))	('metastases', 'Disease', (138, 148))	('APLP2', 'Var', (63, 68))	('shRNA', 'Gene', (69, 74))	('metastases', 'Disease', 'MESH:D009362', (138, 148))	('lower', 'NegReg', (115, 120))	('Dox', 'Chemical', 'MESH:D004318', (256, 259))	('mice', 'Species', '10090', (26, 30))
63506	25576918	The findings in our current research demonstrating high APLP2 expression in pancreatic cancer metastatic lesions from patients (Figure 1 and Table 1) suggest that APLP2 may facilitate the ability of these cancer cells to metastasize.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (205, 211))	('pancreatic cancer', 'Disease', (76, 93))	('patients', 'Species', '9606', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rat', 'Species', '10116', (44, 47))	('pancreatic cancer', 'Disease', 'MESH:D010190', (76, 93))	('facilitate', 'PosReg', (173, 183))	('APLP2', 'Gene', (56, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('APLP2', 'Var', (163, 168))
63512	25576918	Accordingly, we found that the high APLP2 expression in a pancreatic cancer cell line clearly increases its mobility and invasion capabilities (Figures 3B,C, Supplementary Figures 1, 2A, and 2B).	('pancreatic cancer', 'Disease', (58, 75))	('APLP2', 'Gene', (36, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (58, 75))	('mobility', 'CPA', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('expression', 'MPA', (42, 52))	('increases', 'PosReg', (94, 103))	('invasion capabilities', 'CPA', (121, 142))	('high', 'Var', (31, 35))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (58, 75))
63515	25576918	Our pancreatic tumor xenograft experiments also indicated that APLP2 has a profound impact on tumor spread, significantly increasing metastasis to sites in the intestine, kidney, and diaphragm (Figure 7).	('impact', 'Reg', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('pancreatic tumor', 'Disease', 'MESH:D010190', (4, 20))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('APLP2', 'Var', (63, 68))	('increasing', 'PosReg', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (94, 99))	('pancreatic tumor', 'Disease', (4, 20))	('tumor', 'Disease', (15, 20))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (4, 20))	('metastasis to sites', 'CPA', (133, 152))
63524	25576918	Our finding that APLP2 knockdown has a very disruptive influence on actin structure within pancreatic tumors in vivo (as shown in Figure 6) is particularly significant, since it has two implications for the development of novel therapies for pancreatic cancer.	('actin structure', 'MPA', (68, 83))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (91, 108))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (242, 259))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (91, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (242, 259))	('APLP2', 'Gene', (17, 22))	('knockdown', 'Var', (23, 32))	('pancreatic cancer', 'Disease', (242, 259))	('pancreatic tumors', 'Disease', 'MESH:D010190', (91, 108))	('pancreatic tumors', 'Disease', (91, 108))	('disruptive', 'NegReg', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
63526	25576918	The second implication is that APLP2 is involved in a pathway regulating actin morphology (and, thereby, pancreatic tumor migration and growth) that has not previously been delineated in detail, and which therefore may include multiple novel targets (in addition to APLP2) that could have utility in the treatment of pancreatic cancer.	('pancreatic tumor migration', 'Disease', 'MESH:D010190', (105, 131))	('pancreatic tumor migration', 'Disease', (105, 131))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (105, 121))	('pancreatic cancer', 'Disease', (317, 334))	('pancreatic cancer', 'Disease', 'MESH:D010190', (317, 334))	('APLP2', 'Var', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('actin morphology', 'MPA', (73, 89))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (317, 334))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('involved', 'Reg', (40, 48))
63527	25576918	We have previously shown that the growth of pancreatic cancer cells, but not non-transformed pancreatic cells, is diminished by chemical inhibitors of beta-secretase, an enzyme that generates APLP2 C-terminal fragments.	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('rat', 'Species', '10116', (186, 189))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('beta-secretase', 'Protein', (151, 165))	('growth', 'MPA', (34, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('inhibitors', 'Var', (137, 147))	('diminished', 'NegReg', (114, 124))	('pancreatic cancer', 'Disease', (44, 61))
63542	25576918	For immunohistochemical analysis of the tumors generated in mice from the S2-013-APLP2-shRNA cells (with or without Dox given to the mice), the standardized protocol was again used.	('Dox', 'Chemical', 'MESH:D004318', (116, 119))	('mice', 'Species', '10090', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('S2-013-APLP2-shRNA', 'Var', (74, 92))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('mice', 'Species', '10090', (60, 64))	('tumors', 'Disease', (40, 46))	('rat', 'Species', '10116', (51, 54))
63573	25576918	Beginning at that day, the expression of the APLP2 shRNA was induced in one of the randomized groups of tumor-bearing mice by giving the mice Dox.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Dox', 'Chemical', 'MESH:D004318', (142, 145))	('shRNA', 'Gene', (51, 56))	('tumor', 'Disease', (104, 109))	('induced', 'Reg', (61, 68))	('expression', 'MPA', (27, 37))	('APLP2', 'Var', (45, 50))	('mice', 'Species', '10090', (118, 122))	('mice', 'Species', '10090', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
63585	24518511	In an orthotopic model of a sensitive tumor, primary and metastatic tumor burden was significantly reduced and median survival significantly extended by Apo2L/TRAIL therapy.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (38, 43))	('extended', 'PosReg', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('median survival', 'CPA', (111, 126))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('Apo2L/TRAIL therapy', 'Var', (153, 172))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('reduced', 'NegReg', (99, 106))
63594	24518511	Apo2L/TRAIL directly induces apoptosis through the cell surface death receptors DR4 and DR5 and we have previously shown that some patient tumors grown subcutaneously in SCID mice are sensitive to treatment with Apo2L/TRAIL while others are quite resistant.	('apoptosis', 'CPA', (29, 38))	('mice', 'Species', '10090', (175, 179))	('DR4', 'Gene', '8797', (80, 83))	('Apo2L/TRAIL', 'Var', (0, 11))	('DR4', 'Gene', (80, 83))	('induces', 'Reg', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('DR5', 'Gene', (88, 91))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('patient', 'Species', '9606', (131, 138))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('cell surface', 'cellular_component', 'GO:0009986', ('51', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))	('SCID', 'Disease', 'MESH:D053632', (170, 174))	('SCID', 'Disease', (170, 174))
63625	24518511	1, p< 0.05), tumors were designated sensitive (#11424, #14244, #16096) and, if not, they were designated resistant (#12298, #12424, #12459).	('#14244', 'Var', (55, 61))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('#12298', 'Var', (116, 122))	('#12459', 'Var', (132, 138))	('#11424', 'Var', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('#16096', 'Var', (63, 69))
63632	24518511	Histologically identifiable tumors were seen in sections of pancreas in the three sensitive tumors between 2-5 weeks post-implantation (11424- 26 days, 14244- 39 days and 16096- 20 days).	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumors', 'Disease', (28, 34))	('14244- 39 days', 'Var', (152, 166))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('11424- 26 days', 'Var', (136, 150))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('16096- 20 days', 'Var', (171, 185))
63634	24518511	Liver metastases from 11424 and 14244 were found at 9 and 21 weeks respectively.	('metastases', 'Disease', 'MESH:D009362', (6, 16))	('14244', 'Var', (32, 37))	('11424', 'Var', (22, 27))	('metastases', 'Disease', (6, 16))
63641	24518511	Experiments were terminated when the majority of control mice developed large, externally palpable tumors (11424= 5/7, 14244= 7/7 and 16096= 4/5); upon necropsy tumors (too small to be palpated) were found in all control mice.	('mice', 'Species', '10090', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('11424=', 'Var', (107, 113))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('14244=', 'Var', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('mice', 'Species', '10090', (221, 225))	('necropsy tumors', 'Disease', (152, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('necropsy tumors', 'Disease', 'MESH:D009369', (152, 167))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))
63642	24518511	In contrast, very few mice in the treated groups had large, palpable tumors (11424= 0/7; 14244= 0/7 and 16096= 2/5), although histological evidence of small tumor foci was found in all mice.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor foci', 'Disease', (157, 167))	('mice', 'Species', '10090', (22, 26))	('mice', 'Species', '10090', (185, 189))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('11424=', 'Var', (77, 83))	('tumor foci', 'Disease', 'MESH:C565785', (157, 167))
63655	24518511	A significant increase (p<0.05) in primary tumor volume was observed in saline-treated controls on day 109 (1511+- 318 mm3), day 115 (1722 +- 18 mm3) and day 122 (1902 +- 70 mm3).	('1722 +-', 'Var', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('saline', 'Chemical', 'MESH:D012965', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('increase', 'PosReg', (14, 22))
63657	24518511	Differences in tumor volume between saline and TRAIL treatment groups were statistically significant on day 109, d115 and d122.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('d122', 'Var', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('d115', 'Var', (113, 117))	('saline', 'Chemical', 'MESH:D012965', (36, 42))
63667	24518511	MRI imaging revealed minimal tumor burden in pancreas and no evidence of metastases supporting the conclusion that inhibition of growth of both primary and metastatic tumors by Apo2L/TRAIL significantly improved the survival of these mice.	('inhibition', 'NegReg', (115, 125))	('metastases', 'Disease', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('improved', 'PosReg', (203, 211))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('mice', 'Species', '10090', (234, 238))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('survival', 'CPA', (216, 224))	('growth', 'MPA', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('metastases', 'Disease', 'MESH:D009362', (73, 83))	('inhibition of growth', 'biological_process', 'GO:0045926', ('115', '135'))	('tumor', 'Disease', (29, 34))	('Apo2L/TRAIL', 'Var', (177, 188))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('tumor', 'Disease', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
63679	24518511	However, instances in which the response of the metastases differed from that of the primary have also been observed, for example, inhibition of hedgehog signaling by cyclopamine did not significantly inhibit primary orthotopic pancreatic tumor growth, while it did significantly decrease the instance of metastases..	('metastases', 'Disease', 'MESH:D009362', (48, 58))	('inhibit', 'NegReg', (201, 208))	('pancreatic tumor', 'Disease', (228, 244))	('cyclopamine', 'Chemical', 'MESH:C000541', (167, 178))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (228, 244))	('metastases', 'Disease', (305, 315))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('pancreatic tumor', 'Disease', 'MESH:D010190', (228, 244))	('metastases', 'Disease', 'MESH:D009362', (305, 315))	('inhibition', 'Var', (131, 141))	('metastases', 'Disease', (48, 58))
63688	24518511	While there are many reports of selective apoptosis in tumor cells induced by Apo2L/TRAIL, there have also been cautionary reports of increased metastasis by cells that are resistant to apoptosis.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('metastasis', 'CPA', (144, 154))	('increased', 'PosReg', (134, 143))	('apoptosis', 'biological_process', 'GO:0097194', ('186', '195'))	('Apo2L/TRAIL', 'Var', (78, 89))	('apoptosis', 'biological_process', 'GO:0006915', ('186', '195'))
63701	24518511	Furthermore, the histological features of these tumor models are architecturally representative of human tumors and when tumors develop in the appropriate cells with genetic alterations found in patient tumors, they could be expected to act like patient tumors in response to therapies.	('tumors', 'Disease', (105, 111))	('tumor', 'Disease', (203, 208))	('tumors', 'Disease', (254, 260))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('patient', 'Species', '9606', (246, 253))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (254, 259))	('genetic alterations', 'Var', (166, 185))	('tumors', 'Disease', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('patient', 'Species', '9606', (195, 202))	('tumors', 'Disease', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('human', 'Species', '9606', (99, 104))
63703	24518511	In a second example, Olive and colleagues used a GEM model of pancreatic cancer which developed extensive desmoplasia to show that inhibition of stromal elements could facilitate delivery of chemotherapy and significantly improve anti-tumor efficacy.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('Olive', 'Species', '4146', (21, 26))	('improve', 'PosReg', (222, 229))	('desmoplasia', 'Disease', 'None', (106, 117))	('pancreatic cancer', 'Disease', 'MESH:D010190', (62, 79))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('pancreatic cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('stroma', 'Disease', (145, 151))	('stroma', 'Disease', 'None', (145, 151))	('tumor', 'Disease', (235, 240))	('delivery', 'MPA', (179, 187))	('desmoplasia', 'Disease', (106, 117))	('inhibition', 'Var', (131, 141))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (62, 79))	('facilitate', 'PosReg', (168, 178))
63704	24518511	GEM models are based on a limited number of relevant genetic mutations, however, and will be unlikely to reproduce all the genetic changes occurring in diverse patient derived tumor models.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('mutations', 'Var', (61, 70))	('patient', 'Species', '9606', (160, 167))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
63720	25234467	In conclusion, miR-217 suppresses tumour development in lung cancer by targeting KRAS and enhances cell sensitivity to cisplatin.	('targeting', 'Reg', (71, 80))	('KRAS', 'Gene', '3845', (81, 85))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('cell sensitivity to cisplatin', 'MPA', (99, 128))	('suppresses', 'NegReg', (23, 33))	('tumour', 'Disease', (34, 40))	('miR-217', 'Var', (15, 22))	('KRAS', 'Gene', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))	('enhances', 'PosReg', (90, 98))
63726	25234467	Gene alterations participate in cancer genesis.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('Gene alterations', 'Var', (0, 16))	('participate', 'Reg', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
63727	25234467	Alterations in many oncogenes and tumour suppressor genes have been reported in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('Alterations', 'Var', (0, 11))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', (34, 40))	('lung cancer', 'Disease', (80, 91))	('oncogenes', 'Gene', (20, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('reported', 'Reg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
63731	25234467	Conversely, miRNAs such as miR-451, miR-15/16, let-7, miR-125a/125b and miR-145 function as tumour suppressor genes.	('miR-145', 'Gene', '406937', (72, 79))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Disease', (92, 98))	('miR-125a', 'Gene', (54, 62))	('let-7', 'Gene', (47, 52))	('miR-451', 'Gene', '574411', (27, 34))	('miR-125a', 'Gene', '406910', (54, 62))	('miR-145', 'Gene', (72, 79))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('miR-15/16', 'Var', (36, 45))	('miR-451', 'Gene', (27, 34))
63732	25234467	Meanwhile, some miRNAs can function as oncogenes or tumour suppressor genes depending on cell type.	('function', 'Reg', (27, 35))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('miRNAs', 'Var', (16, 22))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('tumour', 'Disease', (52, 58))
63738	25234467	In NSCLC, miRNA-451 can up-regulate cisplatin sensitivity.	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('up-regulate', 'PosReg', (24, 35))	('miRNA-451', 'Var', (10, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('cisplatin sensitivity', 'MPA', (36, 57))
63748	25234467	MiR-217-precursor-F and miR-217-precursor-R extension was digested by BamHI and BglII.	('MiR-217', 'Gene', (0, 7))	('miR-217-precursor-R', 'Var', (24, 43))	('MiR-217', 'Gene', '406999', (0, 7))
63764	25234467	The membranes were incubated with 5% non-fat dried milk overnight at 4 C and with anti-KRAS antibody (CST, USA) at 1:1000 dilution for 2h at room temperature, anti-Bad/p/Bad antibody (Bio-world, USA) at 1:500 dilution, anti-AKT/p-AKT antibody (CST, USA) at 1:1000 dilution and anti-GAPDH antibody (Proteintech, USA) at 1:30,000 dilution.	('AKT', 'Gene', (230, 233))	('antibody', 'cellular_component', 'GO:0019814', ('92', '100'))	('anti-Bad/p/Bad', 'Var', (159, 173))	('GAPDH', 'Gene', (282, 287))	('antibody', 'molecular_function', 'GO:0003823', ('288', '296'))	('antibody', 'cellular_component', 'GO:0019814', ('174', '182'))	('antibody', 'cellular_component', 'GO:0019815', ('234', '242'))	('AKT', 'Gene', '207', (224, 227))	('antibody', 'cellular_component', 'GO:0042571', ('288', '296'))	('antibody', 'molecular_function', 'GO:0003823', ('174', '182'))	('antibody', 'molecular_function', 'GO:0003823', ('92', '100'))	('antibody', 'cellular_component', 'GO:0019814', ('234', '242'))	('AKT', 'Gene', '207', (230, 233))	('antibody', 'cellular_component', 'GO:0042571', ('174', '182'))	('antibody', 'cellular_component', 'GO:0042571', ('92', '100'))	('antibody', 'cellular_component', 'GO:0019815', ('288', '296'))	('KRAS', 'Gene', '3845', (87, 91))	('antibody', 'molecular_function', 'GO:0003823', ('234', '242'))	('KRAS', 'Gene', (87, 91))	('GAPDH', 'Gene', '2597', (282, 287))	('antibody', 'cellular_component', 'GO:0019815', ('92', '100'))	('antibody', 'cellular_component', 'GO:0042571', ('234', '242'))	('antibody', 'cellular_component', 'GO:0019814', ('288', '296'))	('AKT', 'Gene', (224, 227))	('antibody', 'cellular_component', 'GO:0019815', ('174', '182'))
63771	25234467	Compared with scramble transfection, miR-217 transfection significantly reduced the proliferation of A549 and A549 and SPC-A-1 cells.	('SPC-A-1', 'Gene', '27032', (119, 126))	('reduced', 'NegReg', (72, 79))	('SPC', 'molecular_function', 'GO:0009004', ('119', '122'))	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('A549', 'CellLine', 'CVCL:0023', (101, 105))	('transfection', 'Var', (45, 57))	('miR-217 transfection', 'Var', (37, 57))	('proliferation', 'CPA', (84, 97))	('SPC-A-1', 'Gene', (119, 126))
63772	25234467	We investigated the effect of miR-217 on the apoptosis of A549 and SPC-A-1 cells after miR-217 transfection.	('miR-217', 'Var', (87, 94))	('A549', 'CellLine', 'CVCL:0023', (58, 62))	('SPC', 'molecular_function', 'GO:0009004', ('67', '70'))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('SPC-A-1', 'Gene', (67, 74))	('SPC-A-1', 'Gene', '27032', (67, 74))
63773	25234467	Scramble transfection induced the early apoptosis of 22.9% SPC-A-1 cells and 20.8% A549 cells; meanwhile, miR-217 transfection induced the early apoptosis of 27.7% SPC-A-1 cells and 28.4% A549 cells (Figs.	('miR-217 transfection', 'Var', (106, 126))	('SPC-A-1', 'Gene', '27032', (164, 171))	('SPC', 'molecular_function', 'GO:0009004', ('59', '62'))	('SPC-A-1', 'Gene', (164, 171))	('SPC-A-1', 'Gene', '27032', (59, 66))	('A549', 'CellLine', 'CVCL:0023', (83, 87))	('SPC-A-1', 'Gene', (59, 66))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('induced', 'Reg', (127, 134))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('SPC', 'molecular_function', 'GO:0009004', ('164', '167'))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('A549', 'CellLine', 'CVCL:0023', (188, 192))
63774	25234467	These results indicate that miR-217 can suppress lung cancer cell survival by inducing early apoptosis.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('miR-217', 'Var', (28, 35))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('suppress', 'NegReg', (40, 48))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('early apoptosis', 'CPA', (87, 102))	('inducing', 'Reg', (78, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))
63777	25234467	In agreement with the tumour growth curve, the weights of tumours induced by scramble transfection were significantly higher than those induced by miR-217 overexpression (Fig.	('higher', 'PosReg', (118, 124))	('weights', 'CPA', (47, 54))	('scramble transfection', 'Var', (77, 98))	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('tumour', 'Disease', (22, 28))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('tumour', 'Disease', (58, 64))	('tumours', 'Disease', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))
63781	25234467	Results showed that both SPC-A-1 and A549 cell lines with miR-217 overexpression showed less migration ability than the scramble and untreated groups at 24 and 36 h after wound creation (Fig.	('overexpression', 'Var', (66, 80))	('SPC-A-1', 'Gene', '27032', (25, 32))	('less', 'NegReg', (88, 92))	('SPC-A-1', 'Gene', (25, 32))	('migration ability', 'CPA', (93, 110))	('SPC', 'molecular_function', 'GO:0009004', ('25', '28'))	('A549', 'CellLine', 'CVCL:0023', (37, 41))	('miR-217', 'Gene', (58, 65))
63785	25234467	As predicted by Targetscan, complementarity can be found between has-miR-217 and KRAS 3'-UTR (Fig.	('KRAS', 'Gene', '3845', (81, 85))	('KRAS', 'Gene', (81, 85))	('has-miR-217', 'Var', (65, 76))
63789	25234467	The same assay was performed for another reporter plasmid containing mutated KRAS 3'-UTR in miR-217 binding sites.	('mutated', 'Var', (69, 76))	('binding', 'Interaction', (100, 107))	('KRAS', 'Gene', (77, 81))	('binding', 'molecular_function', 'GO:0005488', ('100', '107'))	('KRAS', 'Gene', '3845', (77, 81))
63790	25234467	As expected, the miR-217-induced inhibition of luciferase activity was partly removed with binding site 1 orbinding site 2 mutant and almost abolished in the KRAS_MUT double mutant (Fig.	('activity', 'MPA', (58, 66))	('KRAS', 'Gene', '3845', (158, 162))	('luciferase activity', 'molecular_function', 'GO:0047077', ('47', '66'))	('luciferase', 'Enzyme', (47, 57))	('orbinding', 'Interaction', (106, 115))	('inhibition', 'NegReg', (33, 43))	('abolished', 'NegReg', (141, 150))	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))	('removed', 'NegReg', (78, 85))	('luciferase activity', 'molecular_function', 'GO:0047712', ('47', '66'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('47', '66'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('47', '66'))	('binding', 'Interaction', (91, 98))	('KRAS', 'Gene', (158, 162))	('luciferase activity', 'molecular_function', 'GO:0050248', ('47', '66'))	('mutant', 'Var', (123, 129))
63793	25234467	The protein expression of KRAS was down-regulated in the miR-217-treated SPC-A-1 and A549 cells but not in the scramble or untreated cells (Fig.	('protein expression', 'MPA', (4, 22))	('A549', 'CellLine', 'CVCL:0023', (85, 89))	('SPC-A-1', 'Gene', '27032', (73, 80))	('SPC-A-1', 'Gene', (73, 80))	('down-regulated', 'NegReg', (35, 49))	('KRAS', 'Gene', (26, 30))	('SPC', 'molecular_function', 'GO:0009004', ('73', '76'))	('miR-217-treated', 'Var', (57, 72))	('KRAS', 'Gene', '3845', (26, 30))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
63795	25234467	No significant difference was observed between miR-217-treated and scramble-treated or untreated SPC-A-1 and A549 cells (Fig.	('SPC', 'molecular_function', 'GO:0009004', ('97', '100'))	('miR-217-treated', 'Var', (47, 62))	('SPC-A-1', 'Gene', '27032', (97, 104))	('SPC-A-1', 'Gene', (97, 104))	('A549', 'CellLine', 'CVCL:0023', (109, 113))
63796	25234467	These results suggest-that miR-217 directly recognises the 3'-UTR of KRAS mRNA and inhibits KRAS translation.	('KRAS', 'Gene', (69, 73))	('miR-217', 'Var', (27, 34))	('KRAS', 'Gene', '3845', (69, 73))	('inhibits', 'NegReg', (83, 91))	('KRAS', 'Gene', (92, 96))	('translation', 'biological_process', 'GO:0006412', ('97', '108'))	('KRAS', 'Gene', '3845', (92, 96))
63807	25234467	Compared with miR-217 mimic, antagomiR-217 caused cisplatin torrent in both SPC-A-1 and A549 cells (Figs.	('antagomiR-217', 'Var', (29, 42))	('cisplatin torrent', 'MPA', (50, 67))	('SPC', 'molecular_function', 'GO:0009004', ('76', '79'))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('A549', 'CellLine', 'CVCL:0023', (88, 92))	('SPC-A-1', 'Gene', '27032', (76, 83))	('SPC-A-1', 'Gene', (76, 83))
63808	25234467	This result demonstrates that miR-217 can enhance the sensitivity of SPC-A-1 and A549 cells to cisplatin.	('SPC', 'molecular_function', 'GO:0009004', ('69', '72'))	('enhance', 'PosReg', (42, 49))	('SPC-A-1', 'Gene', (69, 76))	('SPC-A-1', 'Gene', '27032', (69, 76))	('miR-217', 'Var', (30, 37))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('sensitivity', 'MPA', (54, 65))	('A549', 'CellLine', 'CVCL:0023', (81, 85))
63822	25234467	In vitro and in vivo studies proved that miR-217 can also serve as a tumour suppressor gene in human lung cancer progression.	('tumour', 'Disease', (69, 75))	('human', 'Species', '9606', (95, 100))	('miR-217', 'Var', (41, 48))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
63826	25234467	This result indicates that KRAS also serves as a target of miR-217 in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('KRAS', 'Gene', '3845', (27, 31))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('KRAS', 'Gene', (27, 31))	('miR-217', 'Var', (59, 66))
63831	25234467	Previous research showed that two other proteins SIRT1 and E2F3 may also be targets of miR-217.	('SIRT1', 'Gene', (49, 54))	('E2F3', 'Gene', '1871', (59, 63))	('miR-217', 'Var', (87, 94))	('targets', 'Reg', (76, 83))	('SIRT1', 'Gene', '23411', (49, 54))	('E2F3', 'Gene', (59, 63))
63834	25234467	Therefore, combining cisplatin with miR-217 regulation may serve as a potential approach for lung cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('miR-217 regulation', 'Var', (36, 54))	('regulation', 'biological_process', 'GO:0065007', ('44', '54'))
63847	23373509	The expression levels of microRNAs and mRNAs were determined using microarray analysis to examine and compare five pancreatic cancer cell lines, two that can metastasize in vivo (S2VP10 and S2CP9) and three that do not metastasize (MiaPaCa2, Panc-1 and ASPC-1).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('S2VP10', 'Var', (179, 185))	('pancreatic cancer', 'Disease', (115, 132))	('Panc-1', 'CellLine', 'CVCL:0480', (242, 248))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('MiaPaCa2', 'CellLine', 'CVCL:0428', (232, 240))	('metastasize', 'CPA', (158, 169))	('S2CP9', 'Var', (190, 195))	('S2VP10', 'CellLine', 'CVCL:F972', (179, 185))
63858	23373509	Recently, scientists have focused on a new approach to target specific genes that decrease the progression and metastasis of pancreatic cancer.	('progression', 'CPA', (95, 106))	('metastasis of pancreatic cancer', 'Disease', (111, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('decrease', 'NegReg', (82, 90))	('genes', 'Var', (71, 76))	('metastasis of pancreatic cancer', 'Disease', 'MESH:D009362', (111, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))
63862	23373509	Specifically, miRNA-100 has been shown to have an anti-angiogenic function and to act as a tumor suppressor in human bladder carcinoma.	('bladder carcinoma', 'Phenotype', 'HP:0002862', (117, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('91', '107'))	('miRNA-100', 'Chemical', '-', (14, 23))	('bladder carcinoma', 'Disease', 'MESH:D001749', (117, 134))	('anti-angiogenic function', 'CPA', (50, 74))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('human', 'Species', '9606', (111, 116))	('miRNA-100', 'Var', (14, 23))	('bladder carcinoma', 'Disease', (117, 134))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor suppressor', 'biological_process', 'GO:0051726', ('91', '107'))
63864	23373509	The therapeutic effects of miRNA-100 and -138 on pancreatic adenocarcinoma remain unclear.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (49, 74))	('pancreatic adenocarcinoma', 'Disease', (49, 74))	('miRNA-100', 'Chemical', '-', (27, 36))	('miRNA-100', 'Var', (27, 36))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (49, 74))
63868	23373509	We examined the expression levels of miRNA-100 and miRNA-138 and their involvement with IGF1-R in pancreatic cancer cell lines that can metastasize in vivo.	('miRNA-138', 'Var', (51, 60))	('miRNA-100', 'Var', (37, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (98, 115))	('miRNA-100', 'Chemical', '-', (37, 46))	('miRNA-138', 'Chemical', '-', (51, 60))	('IGF1-R', 'Gene', (88, 94))	('pancreatic cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('pancreatic cancer', 'Disease', 'MESH:D010190', (98, 115))	('IGF1-R', 'Gene', '3480', (88, 94))
63872	23373509	These findings indicate that miRNA-100, and not miRNA-138, is associated with regulating IGF1-R in pancreatic cell lines.	('miRNA-138', 'Chemical', '-', (48, 57))	('pancreatic', 'Disease', 'MESH:D010195', (99, 109))	('IGF1-R', 'Gene', '3480', (89, 95))	('pancreatic', 'Disease', (99, 109))	('miRNA-100', 'Chemical', '-', (29, 38))	('IGF1-R', 'Gene', (89, 95))	('miRNA-100', 'Var', (29, 38))
63874	23373509	RNA was extracted from S2VP10, S2CP9, Miap-PaCa-2, Panc-1, and Aspc-1 cells using an Ambion RNAqueous isolation kit according to the manufacturer's instructions (LifeTechnologies, Grand Island, NY).	('S2VP10', 'Var', (23, 29))	('Panc-1', 'CellLine', 'CVCL:0480', (51, 57))	('Miap-PaCa-2', 'CellLine', 'CVCL:0428', (38, 49))	('S2CP9', 'Var', (31, 36))	('S2VP10', 'CellLine', 'CVCL:F972', (23, 29))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
63893	23373509	MiRNA-100, -23b, -31, and -18b showed greater expression in metastatic pancreatic cancer cell lines than in non-metastatic cell lines (p = 0.0001, 0.001, 0.001, 0.003, respectively).	('MiRNA-100', 'Chemical', '-', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('greater', 'PosReg', (38, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('pancreatic cancer', 'Disease', (71, 88))	('MiRNA-100', 'Var', (0, 9))	('expression', 'MPA', (46, 56))	('pancreatic cancer', 'Disease', 'MESH:D010190', (71, 88))
63922	23373509	By contrast, inhibition of miRNA-138 has been reported to cause apoptosis and cell cycle arrest in cell lines of head and neck squamous cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('miRNA-138', 'Chemical', '-', (27, 36))	('apoptosis', 'CPA', (64, 73))	('inhibition', 'Var', (13, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('miRNA-138', 'Gene', (27, 36))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (122, 151))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (127, 151))	('neck', 'cellular_component', 'GO:0044326', ('122', '126'))	('apoptosis', 'biological_process', 'GO:0097194', ('64', '73'))	('apoptosis', 'biological_process', 'GO:0006915', ('64', '73'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('78', '95'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('cell cycle arrest', 'CPA', (78, 95))	('neck squamous cell carcinomas', 'Disease', (122, 151))
63947	24326364	Examples include the recognition of microRNA-21 and RAD51 expression as associated with 5-fluorouracil and gemcitabine resistance.	('RAD', 'biological_process', 'GO:1990116', ('52', '55'))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (88, 102))	('RAD51', 'Gene', (52, 57))	('RAD51', 'Gene', '5888', (52, 57))	('associated', 'Reg', (72, 82))	('expression', 'Var', (58, 68))	('gemcitabine', 'Chemical', 'MESH:C056507', (107, 118))	('microRNA-21', 'Gene', (36, 47))	('microRNA-21', 'Gene', '406991', (36, 47))
64012	24326364	Surprisingly, loss of amylase, as a representative of the loss of pancreatic enzymes in the ductal fluids, is also associated with the worsening of the PDAC prognosis.	('amylase', 'Protein', (22, 29))	('pancreatic', 'Disease', (66, 76))	('PDAC', 'Disease', (152, 156))	('loss', 'Var', (14, 18))	('loss', 'NegReg', (58, 62))	('associated', 'Reg', (115, 125))	('PDAC', 'Chemical', '-', (152, 156))	('pancreatic', 'Disease', 'MESH:D010195', (66, 76))	('loss of pancreatic enzymes', 'Phenotype', 'HP:0001738', (58, 84))
64024	24326364	In one report, infusion of 100 mM phenylalanine into the duodenum stimulated the secretion of trypsin, amylase and lipase.	('secretion', 'biological_process', 'GO:0046903', ('81', '90'))	('lipase', 'MPA', (115, 121))	('amylase', 'MPA', (103, 110))	('secretion of trypsin', 'MPA', (81, 101))	('phenylalanine', 'Var', (34, 47))	('stimulated', 'PosReg', (66, 76))	('phenylalanine', 'Chemical', 'MESH:D010649', (34, 47))
64061	24281203	The risk factors for pancreatic cancer include smoking, long-standing diabetes and alcoholism, however, hypermethylation of p14 and p16 is now considered a risk factor in K-ras mutated subjects.	('hypermethylation', 'Var', (104, 120))	('pancreatic cancer', 'Disease', (21, 38))	('p16', 'Gene', '1029', (132, 135))	('pancreatic cancer', 'Disease', 'MESH:D010190', (21, 38))	('p14', 'Gene', (124, 127))	('diabetes', 'Disease', (70, 78))	('alcoholism', 'Disease', (83, 93))	('long-standing', 'Phenotype', 'HP:0003698', (56, 69))	('K-ras', 'Gene', (171, 176))	('diabetes', 'Disease', 'MESH:D003920', (70, 78))	('K-ras', 'Gene', '3845', (171, 176))	('alcoholism', 'Disease', 'MESH:D000437', (83, 93))	('p14', 'Gene', '1029', (124, 127))	('alcoholism', 'Phenotype', 'HP:0030955', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('p16', 'Gene', (132, 135))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (21, 38))	('risk', 'Reg', (156, 160))
64070	24281203	Oncogenic gain of function mutation in K-ras is a risk factor in pancreatic cancer and used for early detection of the cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('pancreatic cancer', 'Disease', (65, 82))	('K-ras', 'Gene', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutation', 'Var', (27, 35))	('gain of function', 'PosReg', (10, 26))	('cancer', 'Disease', (119, 125))	('K-ras', 'Gene', '3845', (39, 44))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
64071	24281203	K-ras mutations are also present in lung and colon cancers.	('colon cancers', 'Phenotype', 'HP:0003003', (45, 58))	('present', 'Reg', (25, 32))	('colon cancers', 'Disease', 'MESH:D015179', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung', 'Disease', (36, 40))	('K-ras', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('K-ras', 'Gene', '3845', (0, 5))	('colon cancers', 'Disease', (45, 58))	('mutations', 'Var', (6, 15))
64072	24281203	Studies were conducted to identify single nucleotide polymorphisms associated with pancreatic cancer but attempts were unsuccessful.	('pancreatic cancer', 'Disease', (83, 100))	('single nucleotide polymorphisms', 'Var', (35, 66))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('associated', 'Reg', (67, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))
64078	24281203	miR-21 and miR-196a are among those miRNAs which exhibit differential expression in pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (84, 101))	('miR-21', 'Gene', (0, 6))	('pancreatic cancer', 'Disease', (84, 101))	('pancreatic cancer', 'Disease', 'MESH:D010190', (84, 101))	('miR-196a', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('miR-21', 'Gene', '406991', (0, 6))
64252	22761868	These dismal statistics are due, in part, to the advanced stage of the cancer at presentation, a low rate of resectability, multiple molecular alterations that promote pancreatic cancer cell growth and survival, marked chemoresistance, and intense desmoplasia which attenuates drug penetration.	('promote', 'PosReg', (160, 167))	('pancreatic cancer', 'Disease', 'MESH:D010190', (168, 185))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cell growth', 'biological_process', 'GO:0016049', ('186', '197'))	('pancreatic cancer', 'Disease', (168, 185))	('desmoplasia', 'Disease', (248, 259))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (71, 77))	('survival', 'CPA', (202, 210))	('desmoplasia', 'Disease', 'None', (248, 259))	('chemoresistance', 'CPA', (219, 234))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (168, 185))	('cancer', 'Disease', (179, 185))	('alterations', 'Var', (143, 154))
64253	22761868	PDAC is associated with a high frequency of mutations in the K-ras oncogene (95%), and the p16 (85%), p53 (75%) and SMAD4 (55%) tumor suppressor genes.	('SMAD4', 'Gene', '4089', (116, 121))	('p16', 'Gene', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('PDAC', 'Chemical', '-', (0, 4))	('K-ras oncogene', 'Protein', (61, 75))	('p53', 'Gene', '7157', (102, 105))	('SMAD4', 'Gene', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('PDAC', 'Disease', (0, 4))	('p16', 'Gene', '1029', (91, 94))	('mutations', 'Var', (44, 53))	('tumor suppressor', 'biological_process', 'GO:0051726', ('128', '144'))	('p53', 'Gene', (102, 105))	('tumor', 'Disease', (128, 133))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('128', '144'))
64260	22761868	Moreover, pharmacological inhibition of TbetaRI with SB431542 or EGFR with erlotinib enhanced the efficacy of gemcitabine and cisplatin in human pancreatic cancer cells and in primary cell cultures established from pancreata of genetically-engineered mouse models of PDAC, underscoring the usefulness of this 3-D culture system for testing the efficacy of therapeutic agents.	('erlotinib', 'Chemical', 'MESH:D000069347', (75, 84))	('PDAC', 'Chemical', '-', (267, 271))	('erlotinib', 'Gene', (75, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (145, 162))	('EGFR', 'Gene', (65, 69))	('inhibition', 'Var', (26, 36))	('efficacy', 'MPA', (98, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('TbetaRI', 'Gene', '7046', (40, 47))	('mouse', 'Species', '10090', (251, 256))	('gemcitabine', 'Chemical', 'MESH:C056507', (110, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (145, 162))	('SB431542', 'Chemical', 'MESH:C459179', (53, 61))	('enhanced', 'PosReg', (85, 93))	('pancreatic cancer', 'Disease', (145, 162))	('TbetaRI', 'Gene', (40, 47))	('SB431542', 'Gene', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('human', 'Species', '9606', (139, 144))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))
64263	22761868	We now report that simultaneous suppression of both pathways attenuated colony formation of ASPC-1 human pancreatic cancer cells grown in 3-D culture and tumor growth in vivo, but targeting TGF-beta reversed the growth-inhibitory effects exerted by EGFR silencing in T3M4 human pancreatic cancer cells, and this reversal occurred in conjunction with src activation as reflected by increased src phosphorylation on tyrosine 419.	('pancreatic cancer', 'Disease', (278, 295))	('colony formation', 'CPA', (72, 88))	('increased', 'PosReg', (381, 390))	('human', 'Species', '9606', (272, 277))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('src', 'Gene', (391, 394))	('growth-inhibitory effects', 'MPA', (212, 237))	('ASPC-1', 'CellLine', 'CVCL:0152', (92, 98))	('tumor', 'Disease', (154, 159))	('EGFR', 'molecular_function', 'GO:0005006', ('249', '253'))	('src', 'Gene', (350, 353))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('pancreatic cancer', 'Disease', 'MESH:D010190', (105, 122))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (278, 295))	('phosphorylation', 'biological_process', 'GO:0016310', ('395', '410'))	('pancreatic cancer', 'Disease', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('attenuated', 'NegReg', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('src', 'Gene', '6714', (391, 394))	('pancreatic cancer', 'Disease', 'MESH:D010190', (278, 295))	('M4', 'CellLine', 'CVCL:U812', (269, 271))	('tyrosine', 'Chemical', 'MESH:D014443', (414, 422))	('formation', 'biological_process', 'GO:0009058', ('79', '88'))	('TGF-beta', 'Gene', (190, 198))	('silencing', 'Var', (254, 263))	('src', 'Gene', '6714', (350, 353))	('human', 'Species', '9606', (99, 104))
64265	22761868	To determine whether abrogating EGFR and TGF-beta signaling modulated the growth of such cell lines, ASPC-1 and T3M4 cells were co-infected at an m.o.i.	('ASPC-1', 'CellLine', 'CVCL:0152', (101, 107))	('abrogating', 'Var', (21, 31))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('M4', 'CellLine', 'CVCL:U812', (114, 116))	('modulated', 'Reg', (60, 69))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))
64270	22761868	Colony formation with ASPC-1 cells infected with pWPT-sTbetaRII or shEGFR-LV was decreased by 21% (p<0.05) and 33% (p<0.01), respectively, whereas infection with both shEGFR-LV and pWPT-sTbetaRII resulted in a 56% (p<0.01) decrease in colony number by comparison with shLuc-expressing ASPC-1 cells (Fig.	('decreased', 'NegReg', (81, 90))	('ASPC-1', 'CellLine', 'CVCL:0152', (22, 28))	('pWPT-sTbetaRII', 'Chemical', '-', (181, 195))	('decrease', 'NegReg', (223, 231))	('ASPC-1', 'CellLine', 'CVCL:0152', (285, 291))	('colony number', 'CPA', (235, 248))	('formation', 'biological_process', 'GO:0009058', ('7', '16'))	('pWPT-sTbetaRII', 'Var', (49, 63))	('Colony formation', 'CPA', (0, 16))	('pWPT-sTbetaRII', 'Chemical', '-', (49, 63))
64275	22761868	COLO-357 cells were only growth inhibited in response to concomitant EGFR knockdown and sTbetaRII expression.	('EGFR', 'Gene', (69, 73))	('knockdown', 'Var', (74, 83))	('sTbetaRII', 'Chemical', '-', (88, 97))	('COLO', 'Species', '307630', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('69', '73'))
64276	22761868	By contrast PANC-1 cells were growth inhibited by EGFR knockdown, but exhibited a reversal of this growth inhibitory effect in the presence of sTbetaRII (Fig.	('knockdown', 'Var', (55, 64))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('PANC-1', 'CellLine', 'CVCL:0480', (12, 18))	('EGFR', 'Gene', (50, 54))	('sTbetaRII', 'Chemical', '-', (143, 152))
64278	22761868	Compared with tumors generated by ASPC-1 cells infected with shLuc-LV, tumor volumes on day 24 were decreased by 36% (p<0.05) with shEGFR-LV, 38% (p<0.05) with pWPT-sTbetaRII, and 85% (p<0.01) with both vectors (Fig.	('tumor', 'Disease', (14, 19))	('pWPT-sTbetaRII', 'Var', (160, 174))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('ASPC-1', 'CellLine', 'CVCL:0152', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('pWPT-sTbetaRII', 'Chemical', '-', (160, 174))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('decreased', 'NegReg', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Disease', (71, 76))	('shEGFR-LV', 'Var', (131, 140))
64280	22761868	Dramatically, 4 of 8 mice injected with ASPC-1 cells expressing both pWPT-sTbetaRII and shEGFR-LV were tumor-free on day 24, and the remaining 4 tumors only became visible 21 days following injection of the cancer cells.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('pWPT-sTbetaRII', 'Chemical', '-', (69, 83))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mice', 'Species', '10090', (21, 25))	('cancer', 'Disease', (207, 213))	('ASPC-1', 'CellLine', 'CVCL:0152', (40, 46))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('pWPT-sTbetaRII', 'Var', (69, 83))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
64282	22761868	At this time point, tumor volume was decreased by 37% (p<0.05) for cells infected with pWPT-sTbetaRII and by 97% (p<0.01) for shEGFR-LV-infected cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('pWPT-sTbetaRII', 'Var', (87, 101))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('pWPT-sTbetaRII', 'Chemical', '-', (87, 101))	('decreased', 'NegReg', (37, 46))	('tumor', 'Disease', (20, 25))
64283	22761868	By contrast, T3M4 cells infected with both pWPT-sTbetaRII and shEGFR-LV formed large tumors, each of which exhibited areas of necrosis (Fig.	('necrosis', 'biological_process', 'GO:0019835', ('126', '134'))	('necrosis', 'biological_process', 'GO:0001906', ('126', '134'))	('necrosis', 'Disease', (126, 134))	('necrosis', 'biological_process', 'GO:0008220', ('126', '134'))	('pWPT-sTbetaRII', 'Var', (43, 57))	('necrosis', 'Disease', 'MESH:D009336', (126, 134))	('pWPT-sTbetaRII', 'Chemical', '-', (43, 57))	('necrosis', 'biological_process', 'GO:0070265', ('126', '134'))	('necrosis', 'biological_process', 'GO:0008219', ('126', '134'))	('M4', 'CellLine', 'CVCL:U812', (15, 17))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
64284	22761868	Tumors arising from either ASPC-1 or T3M4 cells exhibited abundant Ki-67 immunoreactivity and foci of CD-31-positive endothelial cells (Fig.	('T3M4', 'Var', (37, 41))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('immunoreactivity', 'MPA', (73, 89))	('M4', 'CellLine', 'CVCL:U812', (39, 41))	('ASPC-1', 'CellLine', 'CVCL:0152', (27, 33))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Ki-67', 'Protein', (67, 72))
64286	22761868	In T3M4 cells, expression of pWPT-sTbetaRII was associated with decreased proliferation (40%, p<0.01) and angiogenesis (77%, p<0.01), expression of shEGFR-LV did not significantly alter proliferation but markedly decreased CD31 immunoreactivity (71%, p<0.01), whereas expression of both vectors markedly increased cancer cell proliferation (196%, p<0.01) in spite of a persistent decrease (85%, p<0.01) in CD31 immunoreactivity (Fig.	('CD31', 'Gene', (406, 410))	('cancer', 'Disease', 'MESH:D009369', (314, 320))	('cancer', 'Disease', (314, 320))	('angiogenesis', 'biological_process', 'GO:0001525', ('106', '118'))	('decrease', 'NegReg', (380, 388))	('decreased', 'NegReg', (213, 222))	('pWPT-sTbetaRII', 'Chemical', '-', (29, 43))	('CD31', 'Gene', '5175', (406, 410))	('angiogenesis', 'CPA', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('cell proliferation', 'biological_process', 'GO:0008283', ('321', '339'))	('increased', 'PosReg', (304, 313))	('proliferation', 'CPA', (74, 87))	('CD31', 'Gene', (223, 227))	('M4', 'CellLine', 'CVCL:U812', (5, 7))	('pWPT-sTbetaRII', 'Var', (29, 43))	('CD31', 'Gene', '5175', (223, 227))	('decreased', 'NegReg', (64, 73))
64287	22761868	In view of the presence of regions of necrosis in T3M4 tumors expressing both pWPT-sTbetaRII and shEGFR-LV, it was important to avoid spurious results that may occur in areas about to undergo necrosis.	('necrosis', 'biological_process', 'GO:0008219', ('192', '200'))	('M4', 'CellLine', 'CVCL:U812', (52, 54))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('necrosis', 'biological_process', 'GO:0008220', ('38', '46'))	('T3M4', 'Gene', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('necrosis', 'biological_process', 'GO:0008220', ('192', '200'))	('necrosis', 'Disease', 'MESH:D009336', (38, 46))	('pWPT-sTbetaRII', 'Chemical', '-', (78, 92))	('necrosis', 'biological_process', 'GO:0070265', ('38', '46'))	('tumors', 'Disease', (55, 61))	('necrosis', 'biological_process', 'GO:0019835', ('38', '46'))	('necrosis', 'biological_process', 'GO:0070265', ('192', '200'))	('necrosis', 'biological_process', 'GO:0001906', ('38', '46'))	('necrosis', 'Disease', (38, 46))	('necrosis', 'biological_process', 'GO:0019835', ('192', '200'))	('necrosis', 'biological_process', 'GO:0001906', ('192', '200'))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('necrosis', 'Disease', 'MESH:D009336', (192, 200))	('pWPT-sTbetaRII', 'Var', (78, 92))	('necrosis', 'biological_process', 'GO:0008219', ('38', '46'))	('necrosis', 'Disease', (192, 200))
64289	22761868	Thus, pWPT-sTbetaRII did not significantly alter the percentage of cells undergoing apoptosis in either ASPC-1 or T3M4-drived tumors, whereas shEGFR-LV expression was associated with a marked increase in apoptosis in ASPC-1 cells (p<0.01), but not in T3M4 cells.	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('ASPC-1', 'CellLine', 'CVCL:0152', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('shEGFR-LV expression', 'Var', (142, 162))	('apoptosis', 'biological_process', 'GO:0097194', ('204', '213'))	('apoptosis', 'biological_process', 'GO:0006915', ('204', '213'))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('ASPC-1', 'CellLine', 'CVCL:0152', (104, 110))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('increase', 'PosReg', (192, 200))	('pWPT-sTbetaRII', 'Chemical', '-', (6, 20))	('M4', 'CellLine', 'CVCL:U812', (116, 118))	('M4', 'CellLine', 'CVCL:U812', (253, 255))	('apoptosis', 'CPA', (204, 213))
64290	22761868	Moreover, in ASPC-1-derived tumors, pWPT-sTbetaRII did not alter shEGFR-LV-associated apoptosis, but in T3M4-derived tumors it was associated with enhanced apoptosis (Fig.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('M4', 'CellLine', 'CVCL:U812', (106, 108))	('enhanced', 'PosReg', (147, 155))	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (28, 34))	('ASPC-1', 'CellLine', 'CVCL:0152', (13, 19))	('pWPT-sTbetaRII', 'Chemical', '-', (36, 50))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('apoptosis', 'biological_process', 'GO:0097194', ('156', '165'))	('T3M4-derived', 'Var', (104, 116))	('apoptosis', 'biological_process', 'GO:0006915', ('156', '165'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('apoptosis', 'CPA', (156, 165))
64292	22761868	Since EGFR forms heterodimers with HER2 and HER3, it was important to determine whether its silencing could modulate signaling by these EGFR family members.	('modulate', 'Reg', (108, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('6', '10'))	('heterodimers', 'Interaction', (17, 29))	('HER2', 'Gene', (35, 39))	('EGFR', 'Gene', (6, 10))	('HER2', 'Gene', '2064', (35, 39))	('silencing', 'Var', (92, 101))	('signaling', 'MPA', (117, 126))	('HER3', 'Gene', (44, 48))	('HER3', 'Gene', '2065', (44, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('136', '140'))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))
64294	22761868	Densitometric analysis of data from three experiments showed that pWPT-sTbetaRII expression in ASPC-1 cells induced a 17% and 20% decrease in phospho-HER2 and phospho-HER3 levels, respectively (p<0.05), whereas EGFR knockdown induced a 61% decrease in phospho-HER2 levels (p<0.01) and a 30% decrease in phospho-HER3 (p<0.01) levels.	('pWPT-sTbetaRII expression', 'Var', (66, 91))	('ASPC-1', 'CellLine', 'CVCL:0152', (95, 101))	('decrease', 'NegReg', (291, 299))	('decrease', 'NegReg', (130, 138))	('decrease', 'NegReg', (240, 248))	('HER2', 'Gene', (260, 264))	('EGFR', 'molecular_function', 'GO:0005006', ('211', '215'))	('HER2', 'Gene', (150, 154))	('knockdown', 'Var', (216, 225))	('HER2', 'Gene', '2064', (260, 264))	('HER3', 'Gene', (311, 315))	('HER2', 'Gene', '2064', (150, 154))	('HER3', 'Gene', (167, 171))	('EGFR', 'Gene', (211, 215))	('HER3', 'Gene', '2065', (311, 315))	('pWPT-sTbetaRII', 'Chemical', '-', (66, 80))	('HER3', 'Gene', '2065', (167, 171))
64295	22761868	ASPC-1 cells expressing both shEGFR-LV and pWPT-sTbetaRII exhibited a similar decrease in phospho-HER2 levels (52%, p<0.01), but a more pronounced decrease in phospho-HER3 levels (56%, p<0.01).	('pWPT-sTbetaRII', 'Var', (43, 57))	('decrease', 'NegReg', (78, 86))	('decrease', 'NegReg', (147, 155))	('HER2', 'Gene', (98, 102))	('pWPT-sTbetaRII', 'Chemical', '-', (43, 57))	('ASPC-1', 'CellLine', 'CVCL:0152', (0, 6))	('HER2', 'Gene', '2064', (98, 102))	('HER3', 'Gene', '2065', (167, 171))	('HER3', 'Gene', (167, 171))	('shEGFR-LV', 'Var', (29, 38))
64296	22761868	By contrast, in T3M4 cells, pWPT-sTbetaRII did not alter phospho-HER2 or phospho-HER3 levels, whereas EGFR knockdown was associated with increased levels of both phospho-receptors (Fig.	('knockdown', 'Var', (107, 116))	('HER2', 'Gene', '2064', (65, 69))	('M4', 'CellLine', 'CVCL:U812', (18, 20))	('increased', 'PosReg', (137, 146))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('pWPT-sTbetaRII', 'Chemical', '-', (28, 42))	('HER3', 'Gene', (81, 85))	('EGFR', 'Gene', (102, 106))	('HER2', 'Gene', (65, 69))	('levels', 'MPA', (147, 153))	('HER3', 'Gene', '2065', (81, 85))
64297	22761868	In three experiments, there was a 60% increase in phospho-HER2 and phospho-HER3 levels in T3M4 cells following EGFR knockdown, and 100% and 80% increases in phospho-HER2 and phospho-HER3 levels, respectively, in cells expressing both vectors.	('HER3', 'Gene', (182, 186))	('increases', 'PosReg', (144, 153))	('increase', 'PosReg', (38, 46))	('HER3', 'Gene', (75, 79))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('HER3', 'Gene', '2065', (182, 186))	('knockdown', 'Var', (116, 125))	('EGFR', 'Gene', (111, 115))	('HER2', 'Gene', (165, 169))	('HER2', 'Gene', (58, 62))	('HER2', 'Gene', '2064', (58, 62))	('HER2', 'Gene', '2064', (165, 169))	('M4', 'CellLine', 'CVCL:U812', (92, 94))	('HER3', 'Gene', '2065', (75, 79))
64303	22761868	Therefore, ASPC-1 and T3M4 cell lysates were subjected to immunoblotting to assess the effects of EGFR knockdown and sTbetaRII expression on these pathways (Fig.	('EGFR', 'Gene', (98, 102))	('M4', 'CellLine', 'CVCL:U812', (24, 26))	('sTbetaRII', 'Chemical', '-', (117, 126))	('ASPC-1', 'CellLine', 'CVCL:0152', (11, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('knockdown', 'Var', (103, 112))
64304	22761868	In ASPC-1 cells, shEGFR-LV, pWPT-sTbetaRII, and their combination was associated with attenuated phospho-ERK levels, but only the combination decreased phospho-AKT levels whereas none of these transfection conditions induced the de-phosphorylation of Src(Tyr527), which would be reflective of src activation (Fig.	('src', 'Gene', (293, 296))	('ERK', 'molecular_function', 'GO:0004707', ('105', '108'))	('Tyr527', 'Chemical', '-', (255, 261))	('AKT', 'Gene', '207', (160, 163))	('Src', 'Gene', (251, 254))	('ERK', 'Gene', '5594', (105, 108))	('attenuated', 'NegReg', (86, 96))	('decreased', 'NegReg', (142, 151))	('ASPC-1', 'CellLine', 'CVCL:0152', (3, 9))	('pWPT-sTbetaRII', 'Var', (28, 42))	('shEGFR-LV', 'Var', (17, 26))	('Src', 'Gene', '6714', (251, 254))	('ERK', 'Gene', (105, 108))	('src', 'Gene', '6714', (293, 296))	('de-phosphorylation', 'MPA', (229, 247))	('phosphorylation', 'biological_process', 'GO:0016310', ('232', '247'))	('AKT', 'Gene', (160, 163))	('pWPT-sTbetaRII', 'Chemical', '-', (28, 42))
64305	22761868	By contrast, in T3M4 cells, shEGFR-LV alone or in combination with pWPT-sTbetaRII resulted in increased phospho-ERK and decreased phospho-src(Tyr527) levels, without any alterations in phospho-AKT levels (Fig.	('decreased', 'NegReg', (120, 129))	('AKT', 'Gene', '207', (193, 196))	('ERK', 'molecular_function', 'GO:0004707', ('112', '115'))	('src', 'Gene', '6714', (138, 141))	('increased', 'PosReg', (94, 103))	('ERK', 'Gene', '5594', (112, 115))	('M4', 'CellLine', 'CVCL:U812', (18, 20))	('pWPT-sTbetaRII', 'Chemical', '-', (67, 81))	('AKT', 'Gene', (193, 196))	('shEGFR-LV', 'Var', (28, 37))	('Tyr527', 'Chemical', '-', (142, 148))	('ERK', 'Gene', (112, 115))	('src', 'Gene', (138, 141))
64306	22761868	To confirm that the combination of shEGFR-LV and pWPT-sTbetaRII activated src in T3M4 cells, lysates were also subjected to a phospho-kinase antibody array.	('antibody', 'molecular_function', 'GO:0003823', ('141', '149'))	('M4', 'CellLine', 'CVCL:U812', (83, 85))	('src', 'Gene', (74, 77))	('antibody', 'cellular_component', 'GO:0042571', ('141', '149'))	('antibody', 'cellular_component', 'GO:0019815', ('141', '149'))	('activated', 'PosReg', (64, 73))	('src', 'Gene', '6714', (74, 77))	('antibody', 'cellular_component', 'GO:0019814', ('141', '149'))	('pWPT-sTbetaRII', 'Var', (49, 63))	('pWPT-sTbetaRII', 'Chemical', '-', (49, 63))
64307	22761868	EGFR silencing led to inhibition of the phosphorylation of src(Tyr419), Fyn, Hck, Lyn, Yes and Fgr, which was especially pronounced with respect to src (Fig.	('Yes', 'Gene', (87, 90))	('Hck', 'Gene', '3055', (77, 80))	('Lyn', 'Gene', '4067', (82, 85))	('Fyn', 'Gene', '2534', (72, 75))	('phosphorylation', 'MPA', (40, 55))	('inhibition', 'NegReg', (22, 32))	('silencing', 'Var', (5, 14))	('src', 'Gene', '6714', (148, 151))	('Tyr419', 'Chemical', '-', (63, 69))	('Hck', 'Gene', (77, 80))	('EGFR', 'Gene', (0, 4))	('Fgr', 'Gene', (95, 98))	('src', 'Gene', '6714', (59, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('Fgr', 'Gene', '2268', (95, 98))	('Fyn', 'Gene', (72, 75))	('src', 'Gene', (148, 151))	('Lyn', 'Gene', (82, 85))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('src', 'Gene', (59, 62))
64308	22761868	By contrast, expression of sTbetaRII inhibited the phosphorylation of Lyn Yes, and Fgr, without altering src, Fyn or Hck phosphorylation (Fig.	('sTbetaRII', 'Gene', (27, 36))	('Hck', 'Gene', '3055', (117, 120))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('Lyn', 'Gene', '4067', (70, 73))	('inhibited', 'NegReg', (37, 46))	('sTbetaRII', 'Chemical', '-', (27, 36))	('src', 'Gene', (105, 108))	('Fyn', 'Gene', '2534', (110, 113))	('Hck', 'Gene', (117, 120))	('phosphorylation', 'MPA', (51, 66))	('Fyn', 'Gene', (110, 113))	('expression', 'Var', (13, 23))	('Fgr', 'Gene', (83, 86))	('Lyn', 'Gene', (70, 73))	('src', 'Gene', '6714', (105, 108))	('Fgr', 'Gene', '2268', (83, 86))	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))
64310	22761868	5), indicating that expression of sTbetaRII reactivated src family kinases.	('src', 'Gene', (56, 59))	('src', 'Gene', '6714', (56, 59))	('sTbetaRII', 'Var', (34, 43))	('reactivated', 'Reg', (44, 55))	('sTbetaRII', 'Chemical', '-', (34, 43))
64313	22761868	Moreover, T3M4 cells expressing either shEGFR-LV or shHER2-LV exhibited a significant decrease in colony numbers in the 3-D assay (Fig.	('shEGFR-LV', 'Var', (39, 48))	('HER2', 'Gene', (54, 58))	('HER2', 'Gene', '2064', (54, 58))	('M4', 'CellLine', 'CVCL:U812', (12, 14))	('decrease', 'NegReg', (86, 94))	('colony numbers in the 3-D assay', 'CPA', (98, 129))
64314	22761868	In the case of shEGFR-LV, but not shHER2-LV or shEGFR-LV together with shHER2-LV, this effect was reversed by pWPT-sTbetaRII (Fig.	('HER2', 'Gene', '2064', (73, 77))	('pWPT-sTbetaRII', 'Chemical', '-', (110, 124))	('HER2', 'Gene', (36, 40))	('HER2', 'Gene', '2064', (36, 40))	('HER2', 'Gene', (73, 77))	('shEGFR-LV', 'Var', (15, 24))
64324	22761868	EGFR heterodimerization with other members of the EGFR family leads to the activation of other signaling pathways that include Src, Raf1, B-Raf, Crk, and Nck, which further promote tumor progression and biological aggressiveness.	('Crk', 'Gene', (145, 148))	('Src', 'Gene', (127, 130))	('activation', 'PosReg', (75, 85))	('signaling', 'biological_process', 'GO:0023052', ('95', '104'))	('Raf1', 'Gene', '5894', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('signaling pathways', 'Pathway', (95, 113))	('Raf1', 'Gene', (132, 136))	('Src', 'Gene', '6714', (127, 130))	('Nck', 'Gene', (154, 157))	('B-Raf', 'Gene', '673', (138, 143))	('heterodimerization', 'Var', (5, 23))	('promote', 'PosReg', (173, 180))	('aggressiveness', 'Disease', (214, 228))	('EGFR', 'Gene', (0, 4))	('aggressiveness', 'Phenotype', 'HP:0000718', (214, 228))	('aggressiveness', 'Disease', 'MESH:D001523', (214, 228))	('Crk', 'Gene', '1398', (145, 148))	('tumor', 'Disease', (181, 186))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('Nck', 'Gene', '4690', (154, 157))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('B-Raf', 'Gene', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (181, 186))
64325	22761868	EGFR cross talk with multiple pathways is enhanced by the high frequency of Kras and Smad4 mutations, and by the abundance of TGF-beta which alters the extracellular matrix in a manner that promotes cancer cell growth, induces aberrant epithelial-mesenchymal interactions, enhances angiogenesis, and promotes metastasis.	('TGF-beta', 'Gene', (126, 134))	('enhances', 'PosReg', (273, 281))	('enhanced', 'PosReg', (42, 50))	('promotes', 'PosReg', (300, 308))	('cancer', 'Disease', (199, 205))	('Smad4', 'Gene', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('induces', 'Reg', (219, 226))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('152', '172'))	('promotes', 'PosReg', (190, 198))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('Smad4', 'Gene', '4089', (85, 90))	('epithelial-mesenchymal interactions', 'CPA', (236, 271))	('cell growth', 'biological_process', 'GO:0016049', ('206', '217'))	('alters', 'Reg', (141, 147))	('mutations', 'Var', (91, 100))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('angiogenesis', 'biological_process', 'GO:0001525', ('282', '294'))	('metastasis', 'CPA', (309, 319))	('Kras', 'Gene', (76, 80))	('angiogenesis', 'CPA', (282, 294))
64326	22761868	Together, these observations suggest that aberrant EGFR and TGF-beta-dependent signaling pathways are pivotal in promoting pancreatic cancer progression and may represent crucial therapeutic targets in PDAC.	('PDAC', 'Chemical', '-', (202, 206))	('pancreatic cancer', 'Disease', (123, 140))	('pancreatic cancer', 'Disease', 'MESH:D010190', (123, 140))	('EGFR', 'Pathway', (51, 55))	('aberrant', 'Var', (42, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('TGF-beta-dependent signaling pathways', 'Pathway', (60, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('promoting', 'PosReg', (113, 122))
64327	22761868	In the present study we demonstrated that lentiviral-based silencing of EGFR efficiently attenuated its pro-mitogenic actions in 3 of 4 pancreatic cancer cell lines, and that lentiviral-based sequestration of TGF-beta also attenuated proliferation in 3-D culture in the same three cell lines.	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('attenuated', 'NegReg', (223, 233))	('proliferation in 3-D culture', 'CPA', (234, 262))	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('pro-mitogenic actions', 'MPA', (104, 125))	('EGFR', 'Gene', (72, 76))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('silencing', 'Var', (59, 68))	('pancreatic cancer', 'Disease', (136, 153))	('attenuated', 'NegReg', (89, 99))
64332	22761868	In agreement with this conclusion, the growth-inhibitory effects induced by silencing HER2 or both EGFR and HER2 were not reversed by sTbetaRII.	('HER2', 'Gene', (86, 90))	('HER2', 'Gene', (108, 112))	('EGFR', 'Gene', (99, 103))	('growth-inhibitory', 'MPA', (39, 56))	('HER2', 'Gene', '2064', (86, 90))	('HER2', 'Gene', '2064', (108, 112))	('silencing', 'Var', (76, 85))	('sTbetaRII', 'Chemical', '-', (134, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('99', '103'))
64336	22761868	First, src inhibition by EGFR silencing was completely reversed by TGF-beta sequestration.	('src', 'Gene', '6714', (7, 10))	('EGFR', 'Gene', (25, 29))	('src', 'Gene', (7, 10))	('silencing', 'Var', (30, 39))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
64350	22761868	Thus, with respect to ASPC-1 cells, either EGFR down-regulation or TGF-beta sequestration resulted in significant (36 to 38%) decreases in tumor volume, with a further decrease to 85% when both approaches were combined.	('down-regulation', 'NegReg', (48, 63))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('ASPC-1', 'CellLine', 'CVCL:0152', (22, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('sequestration', 'Var', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('TGF-beta', 'Gene', (67, 75))	('regulation', 'biological_process', 'GO:0065007', ('53', '63'))	('EGFR', 'Gene', (43, 47))	('decreases', 'NegReg', (126, 135))
64351	22761868	Impressively, tumors failed to form in 2 of 8 mice injected with ASPC-1 cells expressing pWPT-sTbetaRII, and in 4 of 8 mice expressing both pWPT-sTbetaRII and shEGFR-LV.	('mice', 'Species', '10090', (119, 123))	('pWPT-sTbetaRII', 'Var', (89, 103))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('pWPT-sTbetaRII', 'Chemical', '-', (89, 103))	('mice', 'Species', '10090', (46, 50))	('pWPT-sTbetaRII', 'Chemical', '-', (140, 154))	('ASPC-1', 'CellLine', 'CVCL:0152', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
64352	22761868	Moreover, there was a marked delay in the appearance of the 4 tumors that arose from cells expressing both pWPT-sTbetaRII and shEGFR-LV, all of which exhibited greatly decreased proliferation and angiogenesis, and increased apoptosis.	('pWPT-sTbetaRII', 'Chemical', '-', (107, 121))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('decreased', 'NegReg', (168, 177))	('shEGFR-LV', 'Gene', (126, 135))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('apoptosis', 'biological_process', 'GO:0097194', ('224', '233'))	('apoptosis', 'biological_process', 'GO:0006915', ('224', '233'))	('angiogenesis', 'CPA', (196, 208))	('increased', 'PosReg', (214, 223))	('apoptosis', 'CPA', (224, 233))	('angiogenesis', 'biological_process', 'GO:0001525', ('196', '208'))	('delay', 'NegReg', (29, 34))	('pWPT-sTbetaRII', 'Var', (107, 121))
64355	22761868	In T3M4-derived tumors, TGF-beta sequestration resulted in a 37% decrease in tumor volume and decreased proliferation and angiogenesis, whereas EGFR down-regulation resulted either in the failure to form tumors or in the formation of exceedingly small tumors and markedly attenuated angiogenesis.	('formation', 'biological_process', 'GO:0009058', ('221', '230'))	('attenuated', 'NegReg', (272, 282))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('proliferation', 'CPA', (104, 117))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('angiogenesis', 'CPA', (122, 134))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('tumors', 'Disease', (16, 22))	('M4', 'CellLine', 'CVCL:U812', (5, 7))	('regulation', 'biological_process', 'GO:0065007', ('154', '164'))	('down-regulation', 'NegReg', (149, 164))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('sequestration', 'Var', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('angiogenesis', 'biological_process', 'GO:0001525', ('122', '134'))	('tumors', 'Disease', (204, 210))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (252, 258))	('EGFR', 'Gene', (144, 148))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('decreased', 'NegReg', (94, 103))	('decrease', 'NegReg', (65, 73))	('tumor', 'Disease', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('TGF-beta', 'Gene', (24, 32))	('EGFR', 'molecular_function', 'GO:0005006', ('144', '148'))	('angiogenesis', 'CPA', (283, 295))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', (252, 257))	('tumor', 'Disease', (77, 82))	('angiogenesis', 'biological_process', 'GO:0001525', ('283', '295'))
64359	22761868	Moreover, it has been recently demonstrated that angiogenesis is important in a Kras-driven genetically engineered mouse model of PDAC and that variant 161R form of interlukin-17F (IL-17F), which is a natural antagonist of the anti-angiogenic effects of wild-type 161H IL-17F, is associated with a worse prognosis in PDAC, providing indirect evidence that angiogenesis may play an important role in its metastatic spread.	('IL-17F', 'Gene', (269, 275))	('interlukin-17F', 'Gene', (165, 179))	('IL-17', 'molecular_function', 'GO:0030367', ('269', '274'))	('IL-17F', 'Gene', '257630', (181, 187))	('mouse', 'Species', '10090', (115, 120))	('PDAC', 'Chemical', '-', (317, 321))	('interlukin-17F', 'Gene', '257630', (165, 179))	('IL-17F', 'Gene', '257630', (269, 275))	('angiogenesis', 'biological_process', 'GO:0001525', ('49', '61'))	('IL-17', 'molecular_function', 'GO:0030367', ('181', '186'))	('IL-17F', 'Gene', (181, 187))	('angiogenesis', 'biological_process', 'GO:0001525', ('356', '368'))	('PDAC', 'Chemical', '-', (130, 134))	('PDAC', 'Disease', (317, 321))	('variant 161R', 'Var', (144, 156))
64361	22761868	ASPC-1 and T3M4 cells harbor mutated KRAS and p53 genes, and express high EGFR levels.	('M4', 'CellLine', 'CVCL:U812', (13, 15))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('p53', 'Gene', (46, 49))	('KRAS', 'Gene', (37, 41))	('p53', 'Gene', '7157', (46, 49))	('ASPC-1', 'CellLine', 'CVCL:0152', (0, 6))	('mutated', 'Var', (29, 36))	('EGFR levels', 'MPA', (74, 85))	('KRAS', 'Gene', '3845', (37, 41))
64363	22761868	Moreover, ASPC-1 cells harbor a mutated SMAD4 gene, whereas T3M4 cells are wild type for Smad4.	('M4', 'CellLine', 'CVCL:U812', (62, 64))	('SMAD4', 'Gene', (40, 45))	('mutated', 'Var', (32, 39))	('ASPC-1', 'CellLine', 'CVCL:0152', (10, 16))	('Smad4', 'Gene', (89, 94))	('Smad4', 'Gene', '4089', (89, 94))	('SMAD4', 'Gene', '4089', (40, 45))
64365	22761868	In spite of the presence of oncogenic Kras in ASPC-1 cells, the concomitant targeting of EGFR and TGF-beta provided an effective therapeutic strategy in these cells, suggesting that targeting two key upstream events in PDAC may overcome therapeutic resistance engendered by oncogenic Kras in some pancreatic cancer cells.	('ASPC-1', 'CellLine', 'CVCL:0152', (46, 52))	('PDAC', 'Chemical', '-', (219, 223))	('PDAC', 'Gene', (219, 223))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (297, 314))	('targeting', 'Var', (182, 191))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (297, 314))	('pancreatic cancer', 'Disease', (297, 314))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))
64366	22761868	However, as evidenced in T3M4 cells, targeting both EGFR and TGF-beta can also lead to deleterious effects as a consequence of HER2/3 and src activation.	('targeting', 'Var', (37, 46))	('activation', 'PosReg', (142, 152))	('M4', 'CellLine', 'CVCL:U812', (27, 29))	('EGFR', 'Gene', (52, 56))	('src', 'Gene', '6714', (138, 141))	('HER2', 'Gene', (127, 131))	('HER2', 'Gene', '2064', (127, 131))	('TGF-beta', 'Gene', (61, 69))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))	('src', 'Gene', (138, 141))
64369	22761868	Moreover, targeting TGF-beta in an orthotopic murine model of PDAC markedly suppresses metastasis.	('TGF-beta', 'Gene', (20, 28))	('metastasis', 'CPA', (87, 97))	('murine', 'Species', '10090', (46, 52))	('PDAC', 'Chemical', '-', (62, 66))	('targeting', 'Var', (10, 19))	('suppresses', 'NegReg', (76, 86))
64392	22761868	Membranes were incubated overnight with the following primary antibodies: anti-EGFR (15F8) (#4405), anti-phospho-EGFR (Tyr845) (#2231), anti-phospho-HER2 (Tyr1221/1222) (#2243), anti-phospho-HER3 (Tyr1289) (#4791), anti-HA-Tag (#2367), and anti-phospho-src(Tyr527) all form Cell Signaling Technology (Danvers, MA; 1:500 to 1:1000 dilution); and anti-HER2 (#06-562) and anti-HER3 (#05-390) from Upstate Biotechnology, Lake Placid, NY).	('HER3', 'Gene', '2065', (374, 378))	('Signaling', 'biological_process', 'GO:0023052', ('279', '288'))	('HER2', 'Gene', (149, 153))	('#06-562', 'Var', (356, 363))	('Tyr527', 'Chemical', '-', (257, 263))	('HER3', 'Gene', (191, 195))	('src', 'Gene', (253, 256))	('HER2', 'Gene', '2064', (149, 153))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('HER3', 'Gene', '2065', (191, 195))	('HER2', 'Gene', (350, 354))	('Tyr1289) (#4791', 'Var', (197, 212))	('EGFR', 'molecular_function', 'GO:0005006', ('113', '117'))	('HER2', 'Gene', '2064', (350, 354))	('src', 'Gene', '6714', (253, 256))	('HER3', 'Gene', (374, 378))	('#2367', 'Var', (228, 233))
64464	21676539	Similar results were observed with Panc-1 cells (results not shown), suggesting that myricetin induces cell death via caspase activation.	('caspase', 'CPA', (118, 125))	('myricetin', 'Chemical', 'MESH:C040015', (85, 94))	('caspase activation', 'biological_process', 'GO:0006919', ('118', '136'))	('activation', 'PosReg', (126, 136))	('Panc-1', 'CellLine', 'CVCL:0480', (35, 41))	('cell death', 'CPA', (103, 113))	('cell death', 'biological_process', 'GO:0008219', ('103', '113'))	('myricetin', 'Var', (85, 94))
64470	21676539	Previous data from our laboratory demonstrated that the flavonoid quercetin inhibits HSP70 expression which results in pancreatic cancer cell death, and that siRNA-mediated knockdown of HSP70 causes cell death in pancreatic cancer in vitro.	('results in', 'Reg', (108, 118))	('expression', 'MPA', (91, 101))	('pancreatic cancer cell death', 'Disease', 'MESH:D010190', (119, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (213, 230))	('knockdown', 'Var', (173, 182))	('HSP70', 'Gene', (186, 191))	('quercetin', 'Chemical', 'MESH:D011794', (66, 75))	('pancreatic cancer', 'Disease', (213, 230))	('pancreatic cancer cell death', 'Disease', (119, 147))	('cell death', 'CPA', (199, 209))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cell death', 'biological_process', 'GO:0008219', ('137', '147'))	('HSP70', 'Gene', '3308', (85, 90))	('cell death', 'biological_process', 'GO:0008219', ('199', '209'))	('HSP70', 'Gene', '3308', (186, 191))	('inhibits', 'NegReg', (76, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (213, 230))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (119, 136))	('flavonoid', 'Chemical', 'MESH:D005419', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('HSP70', 'Gene', (85, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (119, 136))
64473	21676539	Similar results were obtained for Panc-1 cells (data not shown), suggesting that myricetin induces apoptosis by a mechanism other than those regulated by HSP70.	('Panc-1', 'CellLine', 'CVCL:0480', (34, 40))	('myricetin', 'Var', (81, 90))	('myricetin', 'Chemical', 'MESH:C040015', (81, 90))	('HSP70', 'Gene', '3308', (154, 159))	('apoptosis', 'CPA', (99, 108))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('HSP70', 'Gene', (154, 159))
64498	21676539	Importantly, though myricetin was a potent inducer of pancreatic cancer cell death, it did not affect the viability of normal pancreatic ductal cells (Fig.	('myricetin', 'Var', (20, 29))	('pancreatic ductal', 'Disease', 'MESH:D021441', (126, 143))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('myricetin', 'Chemical', 'MESH:C040015', (20, 29))	('cell death', 'biological_process', 'GO:0008219', ('72', '82'))	('pancreatic cancer cell death', 'Disease', 'MESH:D010190', (54, 82))	('pancreatic ductal', 'Disease', (126, 143))	('pancreatic cancer cell death', 'Disease', (54, 82))
64519	21676539	Additionally, in vivo analysis of tumors obtained from both control and myricetin treated animals show a myricetin-induced decrease in pAkt levels.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('myricetin', 'Chemical', 'MESH:C040015', (105, 114))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('decrease', 'NegReg', (123, 131))	('Akt', 'Gene', '207', (136, 139))	('myricetin', 'Chemical', 'MESH:C040015', (72, 81))	('myricetin-induced', 'Var', (105, 122))	('Akt', 'Gene', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
64521	21676539	found that inhibition of PI3K/Akt with LY294002 enhanced the anti-tumour activity of cisplatin in pancreatic cancer cells in vitro and in vivo.	('pancreatic cancer', 'Disease', 'MESH:D010190', (98, 115))	('Akt', 'Gene', '207', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('PI3K', 'molecular_function', 'GO:0016303', ('25', '29'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (98, 115))	('LY294002', 'Chemical', 'MESH:C085911', (39, 47))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('PI3', 'Gene', '5266', (25, 28))	('enhanced', 'PosReg', (48, 56))	('Akt', 'Gene', (30, 33))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('pancreatic cancer', 'Disease', (98, 115))	('tumour', 'Disease', (66, 72))	('LY294002', 'Var', (39, 47))	('PI3', 'Gene', (25, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
64522	21676539	In conclusion, myricetin causes pancreatic cancer cell death in vitro and in vivo by induction of apoptosis and its mechanism of action is via the inhibition of the PI-3 kinase pathway.	('apoptosis', 'CPA', (98, 107))	('cell death', 'biological_process', 'GO:0008219', ('50', '60'))	('PI-3 kinase pathway', 'Pathway', (165, 184))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (32, 49))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('85', '107'))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('myricetin', 'Var', (15, 24))	('inhibition', 'NegReg', (147, 157))	('pancreatic cancer cell death', 'Disease', (32, 60))	('pancreatic cancer cell death', 'Disease', 'MESH:D010190', (32, 60))	('myricetin', 'Chemical', 'MESH:C040015', (15, 24))
64527	19922913	Forty-three patients underwent EUS of the esophagus, stomach, pancreas, and surrounding intra-abdominal and mediastinal lymph nodes (19 from previous pilot study and 24 additional patients).	('patients', 'Species', '9606', (12, 20))	('intra-abdominal', 'Disease', (88, 103))	('intra-abdominal', 'Disease', 'MESH:D059325', (88, 103))	('EUS', 'Var', (31, 34))	('patients', 'Species', '9606', (180, 188))
64627	18157915	Acid treatment of the conditioned media (CM) activates latent TGF-beta, probably by denaturing the LAP either by conformational change or by disturbing the interaction between LAP and TGF-beta.	('activates', 'PosReg', (45, 54))	('LAP', 'Gene', (176, 179))	('disturbing', 'NegReg', (141, 151))	('denaturing', 'Var', (84, 94))	('TGF-beta', 'Gene', (62, 70))	('TGF-beta', 'Gene', '7040', (184, 192))	('LAP', 'Gene', (99, 102))	('LAP', 'Gene', '7040', (176, 179))	('TGF-beta', 'Gene', (184, 192))	('interaction', 'Interaction', (156, 167))	('LAP', 'Gene', '7040', (99, 102))	('TGF-beta', 'Gene', '7040', (62, 70))	('conformational change', 'MPA', (113, 134))
64681	18157915	All isoforms of retinoic acid (9-cis, 13-cis and all trans) were equipotent in inducing growth inhibition in these cell lines.	('growth inhibition', 'CPA', (88, 105))	('9-cis', 'Var', (31, 36))	('retinoic acid', 'Chemical', 'MESH:D014212', (16, 29))
64703	18157915	The induction of latent and active TGF-beta2 is independent of the DPC-4 status of the cells, since, activation was seen in cells with wild-type SMAD-4 (Capan-2) as well as in Hs766T cells, which have a homozygous deletion of this gene.	('SMAD-4', 'Gene', (145, 151))	('deletion', 'Var', (214, 222))	('activation', 'PosReg', (101, 111))	('Hs766T', 'CellLine', 'CVCL:0334', (176, 182))	('SMAD-4', 'Gene', '4089', (145, 151))	('Capan-2', 'CellLine', 'CVCL:0026', (153, 160))	('DPC-4', 'Gene', '4089', (67, 72))	('DPC-4', 'Gene', (67, 72))
64710	18157915	Since both cell lines have inactivating mutations in the p53WAF-1 gene, the inhibitory effects of TGF-beta in these cell lines are also clearly independent of p53WAF-1 signaling.	('p53', 'Gene', (159, 162))	('inactivating mutations', 'Var', (27, 49))	('p53', 'Gene', '7157', (159, 162))	('TGF-beta', 'Gene', '7040', (98, 106))	('p53', 'Gene', (57, 60))	('TGF-beta', 'Gene', (98, 106))	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('p53', 'Gene', '7157', (57, 60))
64759	33392191	Moreover, central and sympathetic nervous system dysfunctions and psychological stress-induced hormone network disorders may influence the malignant progression of cancer through multiple mechanisms.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('disorders', 'Var', (111, 120))	('sympathetic nervous system dysfunctions', 'Disease', 'MESH:D001342', (22, 61))	('sympathetic nervous system dysfunctions', 'Disease', (22, 61))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('influence', 'Reg', (125, 134))	('malignant progression of', 'CPA', (139, 163))
64799	33392191	It is postulated that alterations in neurotrophic factor signaling before tumorigenesis can impact the progression from precancerous lesions to cancer by influencing tumor precursor cells and/or tissue innervation.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancer', 'Disease', (144, 150))	('tumor', 'Disease', (74, 79))	('tissue innervation', 'CPA', (195, 213))	('influencing', 'Reg', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('precancerous lesions', 'Disease', (120, 140))	('progression', 'CPA', (103, 114))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('innervation', 'biological_process', 'GO:0060384', ('202', '213'))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('impact', 'Reg', (92, 98))	('precancerous lesions', 'Disease', 'MESH:D011230', (120, 140))	('alterations', 'Var', (22, 33))	('cancer', 'Disease', (123, 129))
64818	33392191	Similarly, evidence from other cancers including lung, breast, kidney, and cervical cancer has also implicated aberrant SLIT/ROBO signaling in carcinogenesis.	('SLIT', 'Disease', 'None', (120, 124))	('cervical cancer', 'Disease', 'MESH:D002583', (75, 90))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('lung', 'Disease', (49, 53))	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('cervical cancer', 'Disease', (75, 90))	('SLIT', 'Disease', (120, 124))	('breast', 'Disease', (55, 61))	('kidney', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('aberrant', 'Var', (111, 119))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('carcinogenesis', 'Disease', (143, 157))	('cancers', 'Disease', (31, 38))	('cancers', 'Disease', 'MESH:D009369', (31, 38))	('signaling', 'biological_process', 'GO:0023052', ('130', '139'))
64842	33392191	On the contrary, a recent study demonstrated that the ablation of SNS contributes to the immature myeloid-derived suppressor cells (MDSCs) accumulation, which facilitates the expansion of Tregs and suppresses tumor immunity.	('tumor', 'Disease', (209, 214))	('Tregs', 'CPA', (188, 193))	('ablation', 'Var', (54, 62))	('suppresses', 'NegReg', (198, 208))	('Tregs', 'Chemical', '-', (188, 193))	('SNS', 'Gene', (66, 69))	('facilitates', 'PosReg', (159, 170))	('expansion', 'CPA', (175, 184))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('accumulation', 'PosReg', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
64862	33392191	In addition, monoamine oxidase A (MAOA), a catecholamine neurotransmitter degrading enzyme, was found to be remarkably decreased by epigenetic alterations in clinical HCC samples.	('decreased', 'NegReg', (119, 128))	('MAOA', 'Gene', '4128', (34, 38))	('epigenetic alterations', 'Var', (132, 154))	('MAOA', 'Gene', (34, 38))	('monoamine oxidase A', 'Gene', (13, 32))	('catecholamine', 'Chemical', 'MESH:D002395', (43, 56))	('monoamine oxidase A', 'Gene', '4128', (13, 32))
64943	33392191	PNI causes prominent cancer pain, such as severe back pain in PDAC patients.	('back pain', 'Disease', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('patients', 'Species', '9606', (67, 75))	('PNI', 'Var', (0, 3))	('PDAC', 'Chemical', '-', (62, 66))	('pain', 'Phenotype', 'HP:0012531', (54, 58))	('back pain', 'Phenotype', 'HP:0003418', (49, 58))	('causes', 'Reg', (4, 10))	('pain', 'Phenotype', 'HP:0012531', (28, 32))	('cancer pain', 'Disease', 'MESH:D000072716', (21, 32))	('back pain', 'Disease', 'MESH:D001416', (49, 58))	('cancer pain', 'Disease', (21, 32))
64946	33392191	PNI of the head and neck cancer can result in cranial neuropathy, such as trigeminal neuropathy, which is characterized as facial or paresthesias pain.	('pain', 'Phenotype', 'HP:0012531', (146, 150))	('trigeminal neuropathy', 'Disease', 'MESH:D020433', (74, 95))	('trigeminal neuropathy', 'Disease', (74, 95))	('cancer', 'Disease', (25, 31))	('head and neck cancer', 'Phenotype', 'HP:0012288', (11, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('result in', 'Reg', (36, 45))	('cranial neuropathy', 'Phenotype', 'HP:0006824', (46, 64))	('neuropathy', 'Phenotype', 'HP:0009830', (54, 64))	('neuropathy', 'Phenotype', 'HP:0009830', (85, 95))	('PNI', 'Var', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cranial neuropathy', 'Disease', 'MESH:D003389', (46, 64))	('paresthesias pain', 'Disease', (133, 150))	('neck', 'cellular_component', 'GO:0044326', ('20', '24'))	('paresthesias', 'Phenotype', 'HP:0003401', (133, 145))	('cranial neuropathy', 'Disease', (46, 64))	('trigeminal neuropathy', 'Phenotype', 'HP:0100661', (74, 95))	('paresthesias pain', 'Disease', 'MESH:D010292', (133, 150))
64949	33392191	L1-CAM might also be involved in the occurrence of neuropathic pain by activating intracellular signaling cascades, such as p38 MAPK in nociceptive pathways.	('MAPK', 'molecular_function', 'GO:0004707', ('128', '132'))	('intracellular', 'MPA', (82, 95))	('signaling', 'biological_process', 'GO:0023052', ('96', '105'))	('intracellular', 'cellular_component', 'GO:0005622', ('82', '95'))	('neuropathic pain', 'Disease', (51, 67))	('involved', 'Reg', (21, 29))	('L1-CAM', 'Gene', '3897', (0, 6))	('neuropathic pain', 'Disease', 'MESH:D009437', (51, 67))	('p38', 'Var', (124, 127))	('activating', 'PosReg', (71, 81))	('pain', 'Phenotype', 'HP:0012531', (63, 67))	('nociceptive pathways', 'Pathway', (136, 156))	('L1-CAM', 'Gene', (0, 6))
64995	33392191	For instance, denervation has been shown to promote the development of cancer-related lesions in the gastric remnant.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('promote', 'PosReg', (44, 51))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('denervation', 'Var', (14, 25))
65000	33392191	Various clinical trials are assessing the efficacy of beta-blockers (e.g., propranolol, propranolol hydrochloride) for the treatment of prostate (NCT02944201 and NCT03152786), colorectal (NCT03919461), breast (NCT02596867), gastrointestinal (NCT03245554), pancreatic (NCT03838029) cancers, and melanoma (NCT01988831) as well as locally recurrent or metastatic solid tumors (NCT02013492).	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('prostate', 'Disease', (136, 144))	('melanoma', 'Disease', (294, 302))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('NCT02944201', 'Var', (146, 157))	('cancers', 'Disease', (281, 288))	('NCT01988831', 'Var', (304, 315))	('NCT03838029', 'Var', (268, 279))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('propranolol', 'Chemical', 'MESH:D011433', (88, 99))	('gastrointestinal', 'Disease', (224, 240))	('colorectal', 'Disease', 'MESH:D015179', (176, 186))	('NCT03245554', 'Var', (242, 253))	('locally recurrent', 'Disease', (328, 345))	('breast', 'Disease', (202, 208))	('solid tumors', 'Disease', (360, 372))	('melanoma', 'Disease', 'MESH:D008545', (294, 302))	('pancreatic', 'Disease', (256, 266))	('NCT03152786', 'Var', (162, 173))	('cancers', 'Disease', 'MESH:D009369', (281, 288))	('NCT02596867', 'Var', (210, 221))	('tumors', 'Phenotype', 'HP:0002664', (366, 372))	('NCT03919461', 'Var', (188, 199))	('propranolol', 'Chemical', 'MESH:D011433', (75, 86))	('solid tumors', 'Disease', 'MESH:D009369', (360, 372))	('colorectal', 'Disease', (176, 186))
65001	33392191	Propranolol has been tested in combination with neoadjuvant chemotherapy in breast (NCT01847001) and gastric (NCT04005365) cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('gastric', 'Disease', (101, 108))	('breast', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('patients', 'Species', '9606', (130, 138))	('cancer', 'Disease', (123, 129))	('NCT04005365', 'Var', (110, 121))	('NCT01847001', 'Var', (84, 95))	('Propranolol', 'Chemical', 'MESH:D011433', (0, 11))
65005	33392191	Given the impact of NGF in cancer pain, NGF blockade inhibits the sprouting of sensory nerve fibers and alleviates cancer-associated pain, especially bone cancer pain, through anti-hyperalgesia (i.e., normalizing a downregulated nociceptive threshold).	('pain', 'Disease', (34, 38))	('blockade', 'Var', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('NGF', 'Gene', (40, 43))	('NGF', 'Gene', '4803', (20, 23))	('cancer pain', 'Disease', 'MESH:D000072716', (27, 38))	('pain', 'Phenotype', 'HP:0012531', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('bone cancer pain', 'Phenotype', 'HP:0002653', (150, 166))	('pain', 'Disease', 'MESH:D010146', (162, 166))	('bone cancer pain', 'Disease', (150, 166))	('hyperalgesia', 'Disease', 'MESH:D006930', (181, 193))	('pain', 'Disease', (133, 137))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('inhibits', 'NegReg', (53, 61))	('pain', 'Disease', 'MESH:D010146', (34, 38))	('bone cancer pain', 'Disease', 'MESH:D001859', (150, 166))	('NGF', 'Gene', '4803', (40, 43))	('pain', 'Phenotype', 'HP:0012531', (133, 137))	('hyperalgesia', 'Disease', (181, 193))	('NGF', 'Gene', (20, 23))	('hyperalgesia', 'Phenotype', 'HP:0031005', (181, 193))	('sprouting of sensory nerve fibers', 'CPA', (66, 99))	('cancer', 'Disease', (155, 161))	('alleviates', 'NegReg', (104, 114))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('pain', 'Disease', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('pain', 'Disease', 'MESH:D010146', (133, 137))	('cancer', 'Disease', (27, 33))	('cancer pain', 'Disease', 'MESH:D000072716', (155, 166))	('pain', 'Phenotype', 'HP:0012531', (162, 166))	('cancer pain', 'Disease', (27, 38))
65007	33392191	NGF blockade at early bone sarcoma stages has been shown to relieve tumor-induced bone destruction as well as reduce pain by 40-70%.	('tumor', 'Disease', (68, 73))	('bone sarcoma', 'Disease', (22, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('pain', 'Phenotype', 'HP:0012531', (117, 121))	('pain', 'Disease', 'MESH:D010146', (117, 121))	('pain', 'Disease', (117, 121))	('blockade', 'Var', (4, 12))	('bone sarcoma', 'Disease', 'MESH:D012509', (22, 34))	('bone sarcoma', 'Phenotype', 'HP:0002669', (22, 34))	('NGF', 'Gene', '4803', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('bone destruction', 'Phenotype', 'HP:0002797', (82, 98))	('NGF', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('relieve', 'PosReg', (60, 67))	('reduce pain', 'Phenotype', 'HP:0007328', (110, 121))	('reduce', 'NegReg', (110, 116))
65008	33392191	Therefore, inhibiting NGF could play a dual effect against both cancer growth and cancer-associated pain.	('pain', 'Phenotype', 'HP:0012531', (100, 104))	('NGF', 'Gene', (22, 25))	('pain', 'Disease', 'MESH:D010146', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('pain', 'Disease', (100, 104))	('inhibiting', 'Var', (11, 21))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('NGF', 'Gene', '4803', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
65011	33392191	The TRK antagonist, K252a, was reported to inhibit the growth and invasion of gastric cancer as well as choriocarcinoma in vivo and in vitro.	('choriocarcinoma', 'Disease', 'MESH:D002822', (104, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('growth', 'CPA', (55, 61))	('inhibit', 'NegReg', (43, 50))	('choriocarcinoma', 'Disease', (104, 119))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (104, 119))	('gastric cancer', 'Disease', (78, 92))	('K252a', 'Var', (20, 25))	('TRK', 'Gene', (4, 7))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('TRK', 'Gene', '4914', (4, 7))	('invasion', 'CPA', (66, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))
65012	33392191	Several clinical trials are investigating the therapeutic potential of entrectinib, which is an orally bioavailable TRKA/B/C, ROS1, and ALK inhibitor in multiple tumors (NCT02097810, NCT02568267, and NCT02650401).	('TRKA', 'Gene', (116, 120))	('entrectinib', 'Chemical', 'MESH:C000607349', (71, 82))	('TRKA', 'Gene', '4914', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('ROS1', 'Gene', (126, 130))	('ROS1', 'Gene', '6098', (126, 130))	('NCT02097810', 'Var', (170, 181))	('ALK', 'Gene', (136, 139))	('NCT02568267', 'Var', (183, 194))	('tumors', 'Disease', (162, 168))	('NCT02650401', 'Var', (200, 211))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('ALK', 'Gene', '238', (136, 139))
65013	33392191	In addition, several TRK inhibitors, including NOV1601 (NCT04014257), VMD-928 (NCT03556228), TSR-011 (NCT02048488), and DS-6051b (NCT02279433), are being evaluated in the on-going clinical trials.	('NCT02048488', 'Var', (102, 113))	('NCT02279433', 'Var', (130, 141))	('TSR', 'molecular_function', 'GO:0047362', ('93', '96'))	('TRK', 'Gene', (21, 24))	('TRK', 'Gene', '4914', (21, 24))	('NCT03556228', 'Var', (79, 90))	('NCT04014257', 'Var', (56, 67))
65042	33187209	Even prior to cancer cell dissemination, alteration of the ECM in distant organs is responsible for shaping an immune microenvironment conducive for metastasis.	('cancer', 'Disease', (14, 20))	('alteration', 'Var', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
65064	33187209	This structural arrangement effectively partitions tumours into cancer cells nests and stromal regions, whilst the alterations in BM physics associated with these structural changes promotes the malignant behaviour of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('behaviour', 'biological_process', 'GO:0007610', ('205', '214'))	('BM physics', 'Gene', (130, 140))	('cancer', 'Disease', (218, 224))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('alterations', 'Var', (115, 126))	('partitions tumours', 'Disease', 'MESH:D009369', (40, 58))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('promotes', 'PosReg', (182, 190))	('partitions tumours', 'Disease', (40, 58))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
65073	33187209	These physical features are sensed by cancer and stromal cells through mechanotransduction pathways and inhibition of mechanotransduction pathways including FAK, Rock/Rho and YAP/TAZ have demonstrated efficacy in pre-clinical models.	('YAP', 'Gene', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Rock', 'Gene', (162, 166))	('mechanotransduction pathways', 'Pathway', (118, 146))	('TAZ', 'Gene', '6901', (179, 182))	('FAK', 'molecular_function', 'GO:0004717', ('157', '160'))	('FAK', 'Gene', (157, 160))	('FAK', 'Gene', '5747', (157, 160))	('TAZ', 'Gene', (179, 182))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('YAP', 'Gene', '55249', (175, 178))	('pre', 'molecular_function', 'GO:0003904', ('213', '216'))	('inhibition', 'Var', (104, 114))	('cancer', 'Disease', (38, 44))	('Rock', 'Gene', '6093', (162, 166))
65089	33187209	Through a series of experiments in was shown that blockade of DDR1 by a recombinant soluble protein DDR1:Fc leads to a reduction of T cell migration in 3D collagen in a dose-dependent manner.	('DDR1', 'Gene', (62, 66))	('blockade', 'Var', (50, 58))	('soluble', 'cellular_component', 'GO:0005625', ('84', '91'))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('T cell migration', 'biological_process', 'GO:0072678', ('132', '148'))	('collagen', 'molecular_function', 'GO:0005202', ('155', '163'))	('reduction of T cell', 'Phenotype', 'HP:0005403', (119, 138))	('reduction', 'NegReg', (119, 128))	('DDR1', 'Gene', '780', (100, 104))	('DDR1', 'Gene', '780', (62, 66))	('T cell migration in 3D collagen', 'CPA', (132, 163))	('DDR1', 'Gene', (100, 104))
65092	33187209	In KRAS mutant mice that develop spontaneous pancreatic cancer, the liver pre-metastatic niche displays enhanced deposition of type I collagen and fibronectin in association with F4/80+ macrophage and neutrophil infiltration.	('pre', 'molecular_function', 'GO:0003904', ('74', '77'))	('KRAS', 'Gene', '16653', (3, 7))	('pancreatic cancer', 'Disease', (45, 62))	('pancreatic cancer', 'Disease', 'MESH:D010190', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('enhanced', 'PosReg', (104, 112))	('mutant', 'Var', (8, 14))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (45, 62))	('mice', 'Species', '10090', (15, 19))	('collagen', 'molecular_function', 'GO:0005202', ('134', '142'))	('F4/80', 'Gene', (179, 184))	('KRAS', 'Gene', (3, 7))	('F4/80', 'Gene', '13733', (179, 184))
65094	33187209	STAT3 inhibition prevented the hepatic immune infiltrate and limited metastatic dissemination, indicating that liver fibrosis plays a key role in metastatic dissemination through alteration of local hepatic immunity.	('limited', 'NegReg', (61, 68))	('hepatic immune infiltrate', 'MPA', (31, 56))	('liver fibrosis', 'Disease', 'MESH:D008103', (111, 125))	('STAT3', 'Gene', (0, 5))	('metastatic dissemination', 'CPA', (69, 93))	('prevented', 'NegReg', (17, 26))	('liver fibrosis', 'Phenotype', 'HP:0001395', (111, 125))	('STAT3', 'Gene', '6774', (0, 5))	('inhibition', 'Var', (6, 16))	('liver fibrosis', 'Disease', (111, 125))	('alteration', 'Reg', (179, 189))
65104	33187209	In support of this theory, modulation of MMP and TIMP activity is associated with altered tumour immunity, whilst proteolytic fragments of type I collagen were responsible for M2 macrophage recruitment to the involuting breast; a high-risk microenvironment for breast cancer development.	('TIMP', 'Gene', (49, 53))	('modulation', 'Var', (27, 37))	('MMP', 'molecular_function', 'GO:0004235', ('41', '44'))	('collagen', 'molecular_function', 'GO:0005202', ('146', '154'))	('responsible', 'Reg', (160, 171))	('altered tumour', 'Disease', (82, 96))	('MMP', 'Gene', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', (261, 274))	('breast cancer', 'Disease', 'MESH:D001943', (261, 274))	('breast cancer', 'Phenotype', 'HP:0003002', (261, 274))	('TIMP', 'Gene', '7076', (49, 53))	('altered tumour', 'Disease', 'MESH:D009369', (82, 96))	('MMP', 'Gene', '4318', (41, 44))
65105	33187209	Treatment of nude mice bearing subcutaneously injected breast cancer cells, with an adenovirus carrying the MMP-9 gene resulted in a significant reduction in tumour growth and an increase in intra-tumoural endostatin; a proteolytic fragment of collagen type XVIII.	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('endostatin', 'Gene', (206, 216))	('tumour growth', 'Disease', (158, 171))	('MMP-9', 'Gene', '4318', (108, 113))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('MMP-9', 'Gene', (108, 113))	('breast cancer', 'Disease', (55, 68))	('intra-tumoural', 'Disease', (191, 205))	('gene', 'Var', (114, 118))	('increase', 'PosReg', (179, 187))	('intra-tumoural', 'Disease', 'MESH:D009369', (191, 205))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('reduction', 'NegReg', (145, 154))	('adenovirus', 'Species', '10508', (84, 94))	('nude mice', 'Species', '10090', (13, 22))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour growth', 'Disease', 'MESH:D006130', (158, 171))	('endostatin', 'Gene', '80781', (206, 216))	('MMP-9', 'molecular_function', 'GO:0004229', ('108', '113'))	('collagen', 'molecular_function', 'GO:0005202', ('244', '252'))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))
65106	33187209	Adenoviral-treated tumours displayed a florid innate immune response consisting of neutrophils and macrophages and the anti-cancer effect of MMP-9 delivery was abolished by therapeutic ablation of neutrophils, indicating that the immune influx dependent upon MMP-9 activity is responsible for delaying tumour progression.	('innate immune response', 'biological_process', 'GO:0045087', ('46', '68'))	('MMP-9', 'molecular_function', 'GO:0004229', ('141', '146'))	('MMP-9', 'Gene', '4318', (141, 146))	('tumours', 'Disease', (19, 26))	('MMP-9', 'Gene', (141, 146))	('MMP-9', 'Gene', (259, 264))	('MMP-9', 'Gene', '4318', (259, 264))	('abolished', 'NegReg', (160, 169))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('tumour', 'Disease', (19, 25))	('tumour', 'Phenotype', 'HP:0002664', (302, 308))	('tumour', 'Disease', 'MESH:D009369', (302, 308))	('tumour', 'Disease', (302, 308))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Adenoviral-treated', 'Var', (0, 18))	('MMP-9', 'molecular_function', 'GO:0004229', ('259', '264'))
65113	33187209	Aged fibroblasts lacking HAPLN1 expression generate a highly-aligned, stiffer matrix than that produced by fibroblasts from young patients that express HAPLN1, whilst in-vivo, addition of HAPLN1 to old mice reverses ECM fiber alignment in skin specimens.	('highly-aligned', 'MPA', (54, 68))	('mice', 'Species', '10090', (202, 206))	('HAPLN1', 'Var', (152, 158))	('HAPLN1', 'Var', (188, 194))	('patients', 'Species', '9606', (130, 138))	('stiffer matrix', 'CPA', (70, 84))	('ECM fiber alignment', 'CPA', (216, 235))
65114	33187209	Treatment of melanomas with recombinant HAPLN1 inhibits tumour growth as a result of increased cytotoxic T-cell infiltration, leading to the conclusion that loss of HAPLN1 inhibits T-cell based rejection of melanoma through effects on ECM structure.	('effects', 'Reg', (224, 231))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanoma', 'Disease', (207, 215))	('melanomas', 'Disease', (13, 22))	('tumour growth', 'Disease', (56, 69))	('increased', 'PosReg', (85, 94))	('HAPLN1', 'Var', (165, 171))	('inhibits', 'NegReg', (47, 55))	('loss', 'Var', (157, 161))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Disease', (13, 21))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('melanoma', 'Disease', 'MESH:D008545', (207, 215))	('inhibits', 'NegReg', (172, 180))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour growth', 'Disease', 'MESH:D006130', (56, 69))	('HAPLN1', 'Var', (40, 46))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('melanomas', 'Disease', 'MESH:D008545', (13, 22))
65117	33187209	Short hairpin RNA knockdown of TNC in glioma cells enabled T-cells to move freely across their ECM indicating that TNC production by tumour cells is a means of paralysing infiltrating T-lymphocytes.	('knockdown', 'Var', (18, 27))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('TNC', 'Gene', (31, 34))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('tumour', 'Disease', (133, 139))	('glioma', 'Disease', (38, 44))
65131	33187209	For example, colorectal cancers displaying proteolysis of versican demonstrate enhanced T-lymphocyte infiltration, whilst fragments derived from versican proteolysis (matriknes) promote dendritic cell accumulation, indicating a role for matrikines in the modulation of cancer immunity.	('proteolysis', 'Var', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('dendritic cell accumulation', 'CPA', (186, 213))	('proteolysis', 'biological_process', 'GO:0006508', ('43', '54'))	('colorectal cancers', 'Disease', 'MESH:D015179', (13, 31))	('enhanced T-lymphocyte', 'Phenotype', 'HP:0100828', (79, 100))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('T-lymphocyte infiltration', 'CPA', (88, 113))	('promote', 'PosReg', (178, 185))	('colorectal cancers', 'Disease', (13, 31))	('proteolysis', 'biological_process', 'GO:0006508', ('154', '165'))	('enhanced', 'PosReg', (79, 87))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))
65132	33187209	These findings, however, are contrasted by those in B16F1 murine melanomas, where inhibition of the proteolytic enzyme a disintegrin and metalloprotease with thrombospondin motif 1 (ADAMTS1), which is responsible for versican proteolysis, led to a reduction in tumour growth in association with increased intratumoural lymphoid and myeloid populations.	('melanomas', 'Disease', 'MESH:D008545', (65, 74))	('inhibition', 'Var', (82, 92))	('tumour growth', 'Disease', (261, 274))	('melanomas', 'Disease', (65, 74))	('proteolysis', 'biological_process', 'GO:0006508', ('226', '237'))	('reduction', 'NegReg', (248, 257))	('ADAMTS1', 'Gene', '11504', (182, 189))	('murine', 'Species', '10090', (58, 64))	('ADAMTS1', 'Gene', (182, 189))	('tumour', 'Phenotype', 'HP:0002664', (310, 316))	('tumour', 'Disease', 'MESH:D009369', (310, 316))	('increased', 'PosReg', (295, 304))	('melanomas', 'Phenotype', 'HP:0002861', (65, 74))	('tumour', 'Disease', (261, 267))	('tumour', 'Disease', (310, 316))	('tumour', 'Phenotype', 'HP:0002664', (261, 267))	('tumour growth', 'Disease', 'MESH:D006130', (261, 274))	('tumour', 'Disease', 'MESH:D009369', (261, 267))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))
65169	33187209	Spontaneous breast cancers developed in MMTV-PyVT mice crossed with mice expressing a mutant version of type I collagen that is insensitive to collagenase-based cleavage, demonstrate excessive ECM deposition and accelerated tumour growth compared to those in wild-type mice.	('mice', 'Species', '10090', (68, 72))	('collagen', 'molecular_function', 'GO:0005202', ('111', '119'))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('tumour growth', 'Disease', (224, 237))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('mutant', 'Var', (86, 92))	('Spontaneous breast cancers', 'Disease', (0, 26))	('MMTV', 'Species', '11757', (40, 44))	('ECM', 'MPA', (193, 196))	('tumour growth', 'Disease', 'MESH:D006130', (224, 237))	('accelerated', 'PosReg', (212, 223))	('mice', 'Species', '10090', (269, 273))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mice', 'Species', '10090', (50, 54))	('Spontaneous breast cancers', 'Disease', 'MESH:D001943', (0, 26))	('breast cancers', 'Phenotype', 'HP:0003002', (12, 26))
65170	33187209	Comparison of the immune composite from collagen mutant and wild-type mice failed to demonstrate a difference in absolute cell number, but a significant increase was detected in the proportion of neutrophil-specific cytokines in the collagen mutant murine tumours.	('tumours', 'Phenotype', 'HP:0002664', (256, 263))	('mutant', 'Var', (49, 55))	('tumours', 'Disease', 'MESH:D009369', (256, 263))	('collagen', 'Gene', (233, 241))	('collagen', 'molecular_function', 'GO:0005202', ('40', '48'))	('tumours', 'Disease', (256, 263))	('murine', 'Species', '10090', (249, 255))	('increase', 'PosReg', (153, 161))	('mice', 'Species', '10090', (70, 74))	('mutant', 'Var', (242, 248))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('proportion', 'MPA', (182, 192))	('collagen', 'molecular_function', 'GO:0005202', ('233', '241'))
65171	33187209	Depletion of neutrophils in this model abrogated the tumour-promoting effects of the collagen mutation indicating that collagen in the ECM modulates a pro-tumourigenic phenotype in neutrophils.	('tumour', 'Disease', (53, 59))	('collagen', 'molecular_function', 'GO:0005202', ('119', '127'))	('collagen', 'Gene', (85, 93))	('abrogated', 'NegReg', (39, 48))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('collagen', 'molecular_function', 'GO:0005202', ('85', '93'))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('modulates', 'Reg', (139, 148))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('mutation', 'Var', (94, 102))	('tumour', 'Disease', (155, 161))
65178	33187209	Contrasting these findings, SPARC expression was down-regulated in malignant melanoma that failed to respond to the chemotherapeutic agent dacarbazine with the authors concluding that expression of SPARC promoted effective tumour immunity.	('expression', 'Var', (184, 194))	('malignant melanoma', 'Disease', 'MESH:D008545', (67, 85))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('dacarbazine', 'Chemical', 'MESH:D003606', (139, 150))	('down-regulated', 'NegReg', (49, 63))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('SPARC', 'Gene', (28, 33))	('tumour', 'Disease', (223, 229))	('malignant melanoma', 'Phenotype', 'HP:0002861', (67, 85))	('promoted', 'PosReg', (204, 212))	('malignant melanoma', 'Disease', (67, 85))	('SPARC', 'Gene', (198, 203))
65193	33187209	Under physiological conditions, the transcription factor IRF8 represses myeloid-derived SPP1 expression; however, in the murine colorectal cancer microenvironment, forced loss of IRF8 led to enhanced production of SPP1 by PMN-MDSCs and tumour cells.	('colorectal cancer', 'Disease', 'MESH:D015179', (128, 145))	('tumour', 'Disease', 'MESH:D009369', (236, 242))	('tumour', 'Disease', (236, 242))	('IRF8', 'Gene', (57, 61))	('IRF8', 'Gene', '15900', (57, 61))	('colorectal cancer', 'Disease', (128, 145))	('enhanced', 'PosReg', (191, 199))	('SPP', 'molecular_function', 'GO:0042499', ('88', '91'))	('PMN', 'biological_process', 'GO:0034727', ('222', '225'))	('SPP', 'molecular_function', 'GO:0042499', ('214', '217'))	('loss', 'Var', (171, 175))	('transcription', 'biological_process', 'GO:0006351', ('36', '49'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (128, 145))	('murine', 'Species', '10090', (121, 127))	('IRF8', 'Gene', (179, 183))	('IRF8', 'Gene', '15900', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumour', 'Phenotype', 'HP:0002664', (236, 242))	('production', 'MPA', (200, 210))	('transcription factor', 'molecular_function', 'GO:0000981', ('36', '56'))
65201	33187209	In support of this, in murine colorectal cancers, high galectin-9 expression is associated with better prognosis and higher levels of NK cell infiltration.	('colorectal cancers', 'Disease', 'MESH:D015179', (30, 48))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('colorectal cancers', 'Disease', (30, 48))	('galectin-9', 'Gene', '16859', (55, 65))	('galectin', 'molecular_function', 'GO:0001577', ('55', '63'))	('better', 'PosReg', (96, 102))	('expression', 'MPA', (66, 76))	('murine', 'Species', '10090', (23, 29))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('galectin-9', 'Gene', (55, 65))	('higher', 'PosReg', (117, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (30, 47))	('high', 'Var', (50, 54))
65214	33187209	In a melanoma model, mice lacking tumour lymphatics through loss of VEGFR3, which is responsible for modulating lymphangiogenesis, displayed reduced leukocyte infiltration into the tumour, whilst adoptive transfer of cytotoxic T-cells to these mice inhibited tumour growth.	('tumour', 'Disease', (259, 265))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('mice', 'Species', '10090', (21, 25))	('mice', 'Species', '10090', (244, 248))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('112', '129'))	('tumour', 'Disease', (181, 187))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('leukocyte infiltration into', 'CPA', (149, 176))	('inhibited', 'NegReg', (249, 258))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('reduced leukocyte', 'Phenotype', 'HP:0001882', (141, 158))	('tumour', 'Disease', (34, 40))	('loss', 'Var', (60, 64))	('tumour growth', 'Disease', (259, 272))	('reduced', 'NegReg', (141, 148))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('VEGFR3', 'Gene', (68, 74))	('melanoma', 'Disease', (5, 13))	('VEGFR3', 'Gene', '14257', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (259, 265))	('tumour growth', 'Disease', 'MESH:D006130', (259, 272))	('tumour', 'Disease', 'MESH:D009369', (259, 265))
65218	33187209	The cancer ECM can be therapeutically targeted in a number of ways including targeting ECM molecules or ECM-remodelling enzymes, altering the structural or physical properties of the matrix, or modulation of fibroblast function as an indirect method to alter ECM deposition.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('modulation', 'Var', (194, 204))	('structural', 'MPA', (142, 152))	('ECM', 'Gene', (87, 90))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('altering', 'Reg', (129, 137))
65224	33187209	As indicated by the wealth of data presented in the review thus far, it is likely that these changes will improve tumour immunity through promotion of T-cell migration and inhibition of a myelosuppressive phenotype.	('tumour', 'Disease', (114, 120))	('myelosuppressive', 'Disease', (188, 204))	('promotion', 'PosReg', (138, 147))	('improve', 'PosReg', (106, 113))	('myelosuppressive', 'Disease', 'MESH:D001855', (188, 204))	('T-cell migration', 'biological_process', 'GO:0072678', ('151', '167'))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('T-cell migration', 'CPA', (151, 167))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('inhibition', 'NegReg', (172, 182))	('changes', 'Var', (93, 100))
65232	33187209	However, pancreatic cancer is notoriously resistant to chemotherapy as a result of both stromal and cancer cell-specific resistance mechanisms and so it is reasonable to consider that because hyaluronin depletion improves chemotherapy delivery, it may also improve the success of immunotherapy.	('hyaluronin', 'Chemical', '-', (192, 202))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (9, 26))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('chemotherapy delivery', 'MPA', (222, 243))	('depletion', 'Var', (203, 212))	('improves', 'PosReg', (213, 221))	('improve', 'PosReg', (257, 264))	('pancreatic cancer', 'Disease', (9, 26))	('hyaluronin depletion', 'Var', (192, 212))	('cancer', 'Disease', (20, 26))	('pancreatic cancer', 'Disease', 'MESH:D010190', (9, 26))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('success of immunotherapy', 'CPA', (269, 293))
65235	33187209	Fibroblast depletion has primarily focused on the targeting of FAP-positive fibroblast populations and depletion of these fibroblasts reduces tumour ECM in lung and pancreatic cancer models.	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('tumour ECM', 'Disease', 'MESH:D009369', (142, 152))	('tumour ECM', 'Disease', (142, 152))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('lung', 'Disease', (156, 160))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('reduces', 'NegReg', (134, 141))	('depletion', 'Var', (103, 112))	('pancreatic cancer', 'Disease', (165, 182))
65236	33187209	In the treatment of murine melanoma, ablation of FAP-expressing stromal cells induced a reduction in immuno-suppressive myeloid cells, although it is likely that this was related to paracrine effects rather than alteration in the tumour ECM.	('FAP-expressing', 'Gene', (49, 63))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('immuno-suppressive myeloid cells', 'MPA', (101, 133))	('reduction', 'NegReg', (88, 97))	('ablation', 'Var', (37, 45))	('murine', 'Species', '10090', (20, 26))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('tumour ECM', 'Disease', 'MESH:D009369', (230, 240))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('tumour ECM', 'Disease', (230, 240))
65253	32850429	For IIb-stage patients in the VE group, the overall survival time (18.3 vs. 9.3 months, p < 0.001) and disease-free survival time (12.2 vs. 5.1 months, p = 0.045) were longer in those with LN14cd (-) than those with LN14cd (+).	('disease-free survival time', 'CPA', (103, 129))	('longer', 'PosReg', (168, 174))	('LN14cd', 'Chemical', '-', (216, 222))	('LN14cd', 'Chemical', '-', (189, 195))	('LN14cd (-', 'Var', (189, 198))	('patients', 'Species', '9606', (14, 22))
65260	32850429	It has been shown that high-grade LN stage according to the American Joint Commission on Cancer (AJCC), 8th edition, predicts poor survival outcomes.	('Cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Cancer', 'Disease', (89, 95))	('LN stage', 'Disease', (34, 42))	('Cancer', 'Disease', 'MESH:D009369', (89, 95))	('poor', 'NegReg', (126, 130))	('high-grade', 'Var', (23, 33))
65291	32850429	Patients in the VE group were more likely to be involved with LN14 metastasis than patients in the DE group (22.9 vs. 5.9%, p = 0.005, in which LN14ab: 15.9 vs. 5.9%, p = 0.064, LN14cd: 10 vs. 0.0%, p = 0.022).	('LN14ab', 'Var', (144, 150))	('LN14cd', 'Chemical', '-', (178, 184))	('LN14', 'Disease', (62, 66))	('cd: 10', 'molecular_function', 'GO:0004245', ('182', '188'))	('involved', 'Reg', (48, 56))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (83, 91))
65308	32850429	Except for the extent of LN dissection, the univariate survival analysis results show that preoperative albumin level, total bilirubin level, tumor marker, dilation of main pancreatic duct or common bile duct, preoperative biliary drainage, intraoperative vein reconstruction, N stage, and LN14 (+-) did not make a difference on OS and DFS time (Tables 6, 7) although the MDFST of patients with a T4 stage tumor was shorter than those with not-T4 stage (8.3 months vs. 12.7 months, p = 0.020).	('tumor', 'Disease', 'MESH:D009369', (406, 411))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('shorter', 'NegReg', (416, 423))	('tumor', 'Disease', (142, 147))	('albumin', 'Gene', '213', (104, 111))	('T4 stage', 'Var', (397, 405))	('tumor', 'Phenotype', 'HP:0002664', (406, 411))	('tumor', 'Disease', (406, 411))	('albumin', 'Gene', (104, 111))	('patients', 'Species', '9606', (381, 389))	('OS', 'Gene', '17451', (329, 331))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
65309	32850429	In the subgroup of patients in the VE group with IIb stage, the OS time of patients with LN14cd (+) and the DFS time were both shorter than those with LN14cd (-) (OS: 9.3 months vs. 18.3 months, p = 0.000, DFS: 5.1 months vs. 12.2 months, p = 0.045; Figure 5).	('shorter', 'NegReg', (127, 134))	('patients', 'Species', '9606', (19, 27))	('OS', 'Gene', '17451', (163, 165))	('LN14cd', 'Chemical', '-', (89, 95))	('patients', 'Species', '9606', (75, 83))	('LN14cd', 'Chemical', '-', (151, 157))	('LN14cd (+', 'Var', (89, 98))	('OS', 'Gene', '17451', (64, 66))
65318	32850429	The results show that the number of positive LNs detected in the VE group was significantly higher than that in the DE group, and the difference was mainly contributed by the higher positive rate of LN14ab and LN14cd.	('higher', 'PosReg', (92, 98))	('LN14ab', 'Var', (199, 205))	('higher', 'PosReg', (175, 181))	('LN14cd', 'Var', (210, 216))	('LN14cd', 'Chemical', '-', (210, 216))
65321	32850429	As a conclusion, this study suggests that there would be a high risk of both LN14ab and LN14cd metastasis in patients with PDAC located in the ventral head of the pancreas.	('LN14ab', 'Var', (77, 83))	('patients', 'Species', '9606', (109, 117))	('PDAC', 'Phenotype', 'HP:0006725', (123, 127))	('LN14cd', 'Var', (88, 94))	('LN14cd', 'Chemical', '-', (88, 94))	('PDAC', 'Chemical', '-', (123, 127))
65322	32850429	Thus, positive LN14cd may be missed under standard lymphadenectomy with dissection of LN14ab, leading to the inaccurate tumor stage and the overestimation of prognosis.	('LN14cd', 'Chemical', '-', (15, 21))	('overestimation', 'PosReg', (140, 154))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('LN14ab', 'Gene', (86, 92))	('tumor', 'Disease', (120, 125))	('LN14cd', 'Var', (15, 21))
65451	31857726	This pathway is persistently activated either through aberrant ligand overexpression by pancreatic cancer cells or aberrant activation in the surrounding stromal compartment.	('activated', 'PosReg', (29, 38))	('activation', 'PosReg', (124, 134))	('ligand', 'molecular_function', 'GO:0005488', ('63', '69'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (88, 105))	('pancreatic cancer', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('aberrant', 'Var', (115, 123))	('pancreatic cancer', 'Disease', 'MESH:D010190', (88, 105))	('overexpression', 'PosReg', (70, 84))	('ligand', 'Protein', (63, 69))
65501	31857726	qRT-PCR was carried out using TaqMan probes (Applied Biosystems) against human ACTB (Hs99999903_m1), GLI-1 (Hs01110766_m1) and PTCH-1 (Hs00181117_m1).	('GLI-1', 'Gene', '2735', (101, 106))	('ACTB', 'Gene', (79, 83))	('GLI-1', 'Gene', (101, 106))	('PTCH-1', 'Gene', '5727', (127, 133))	('Hs99999903_m1', 'Var', (85, 98))	('human', 'Species', '9606', (73, 78))	('Hs00181117_m1', 'Var', (135, 148))	('Hs01110766_m1', 'Var', (108, 121))	('ACTB', 'Gene', '60', (79, 83))	('PTCH-1', 'Gene', (127, 133))
65529	31857726	Although simply having an elevated (defined as >= 37) CA 19-9 at baseline was not associated with either progression or OS, individuals with a baseline CA 19-9 >= 5000 had a significantly shorter time to progression (HR = 2.8, 95% CI: 1.56-5.03, p = 0.0005) and death (HR = 3.15, 95% CI: 1.74, 5.70, p = 0.0001) than those with a baseline CA 19-9 < 5000.	('>= 5000', 'Var', (160, 167))	('death', 'Disease', 'MESH:D003643', (262, 267))	('death', 'Disease', (262, 267))	('progression', 'MPA', (204, 215))	('shorter', 'NegReg', (188, 195))
65612	31908530	Mounting evidence has demonstrated that the aberrant expression of miRNAs triggers tumorigenesis and tumor progression of a wide range of human malignancies.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('malignancies', 'Disease', 'MESH:D009369', (144, 156))	('tumor', 'Disease', (83, 88))	('triggers', 'Reg', (74, 82))	('human', 'Species', '9606', (138, 143))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('malignancies', 'Disease', (144, 156))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('miRNAs', 'Protein', (67, 73))	('aberrant expression', 'Var', (44, 63))
65656	31908530	Then the membranes were incubated with primary antibodies against RAP1A, MMP9, vimentin, and GAPDH overnight at 4 C. Anti-RAP1A (ab115776), anti-MMP9 (ab58803), anti-vimentin (ab137321), and anti-GAPDH (ab181603) were purchased from Abcam (Cambridge, MA, USA) and used at the following dilutions: anti-RAP1A (1:500), anti-MMP9 (1:500), anti-vimentin (1:500), and anti-GAPDH (1:1,000).	('MMP9', 'molecular_function', 'GO:0004229', ('322', '326'))	('GAPDH', 'Gene', (368, 373))	('MMP9', 'molecular_function', 'GO:0004229', ('145', '149'))	('GAPDH', 'Gene', (196, 201))	('vimentin', 'cellular_component', 'GO:0045099', ('79', '87'))	('1:500', 'Var', (351, 356))	('MMP9', 'Gene', (322, 326))	('MMP9', 'Gene', '4318', (322, 326))	('vimentin', 'cellular_component', 'GO:0045098', ('166', '174'))	('vimentin', 'cellular_component', 'GO:0045098', ('341', '349'))	('vimentin', 'Gene', '7431', (79, 87))	('vimentin', 'Gene', (79, 87))	('vimentin', 'Gene', '7431', (341, 349))	('vimentin', 'Gene', '7431', (166, 174))	('GAPDH', 'Gene', '2597', (93, 98))	('vimentin', 'Gene', (166, 174))	('vimentin', 'Gene', (341, 349))	('MMP9', 'molecular_function', 'GO:0004229', ('73', '77'))	('GAPDH', 'Gene', '2597', (368, 373))	('GAPDH', 'Gene', '2597', (196, 201))	('GAPDH', 'Gene', (93, 98))	('MMP9', 'Gene', '4318', (73, 77))	('MMP9', 'Gene', (73, 77))	('vimentin', 'cellular_component', 'GO:0045099', ('341', '349'))	('vimentin', 'cellular_component', 'GO:0045098', ('79', '87'))	('MMP9', 'Gene', (145, 149))	('vimentin', 'cellular_component', 'GO:0045099', ('166', '174'))	('MMP9', 'Gene', '4318', (145, 149))
65695	31908530	As exhibited in Figure 4B, transfection of miR-410-3p mimics significantly reduced the luciferase activity of the reporter vectors carrying wild-type RAP1A 3'UTR fragments, whereas transfection of miR-410-3p did not elicit significant alterations in the luciferase activity of the reporter vectors carrying mutant RAP1A mRNA 3'UTR fragments.	('luciferase activity', 'molecular_function', 'GO:0050248', ('87', '106'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('87', '106'))	('miR-410', 'Gene', '574434', (43, 50))	('luciferase', 'Enzyme', (87, 97))	('miR-410', 'Gene', (197, 204))	('luciferase activity', 'molecular_function', 'GO:0047077', ('254', '273'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('254', '273'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('254', '273'))	('miR-410', 'Gene', '574434', (197, 204))	('luciferase activity', 'molecular_function', 'GO:0047077', ('87', '106'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('254', '273'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('254', '273'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('87', '106'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('87', '106'))	('reduced', 'NegReg', (75, 82))	('mutant', 'Var', (307, 313))	('miR-410', 'Gene', (43, 50))	('activity', 'MPA', (98, 106))	('RAP1A', 'Gene', (314, 319))
65696	31908530	Furthermore, miR-410-3p over-expression was observed to decrease the mRNA and protein expression levels of RAP1A compared with negative control group, whereas miR-410-3p depletion increased the mRNA and protein expression levels of RAP1A (Figures 4C and D).	('miR-410', 'Gene', (159, 166))	('increased', 'PosReg', (180, 189))	('miR-410', 'Gene', '574434', (13, 20))	('miR-410', 'Gene', '574434', (159, 166))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('over-expression', 'Var', (24, 39))	('decrease', 'NegReg', (56, 64))	('RAP1A', 'Protein', (107, 112))	('miR-410', 'Gene', (13, 20))
65701	31908530	As displayed in Figures 5B-D, rescue of RAP1A expression accelerated proliferation, migration, and invasion of miR-410-3p mimics-treated U251MG cells, suggesting that miR-410-3p-dependent inhibition of proliferation, migration, and invasion was mediated by RAP1A.	('proliferation', 'CPA', (202, 215))	('RAP1A', 'Gene', (40, 45))	('proliferation', 'CPA', (69, 82))	('accelerated', 'PosReg', (57, 68))	('miR-410', 'Gene', (111, 118))	('invasion', 'CPA', (232, 240))	('U251MG', 'CellLine', 'CVCL:0021', (137, 143))	('migration', 'CPA', (84, 93))	('miR-410', 'Gene', '574434', (111, 118))	('invasion', 'CPA', (99, 107))	('miR-410', 'Gene', (167, 174))	('rescue', 'Var', (30, 36))	('miR-410', 'Gene', '574434', (167, 174))	('migration', 'CPA', (217, 226))
65702	31908530	Additionally, Western blotting analysis demonstrated that rescue of RAP1A alleviated the suppressing effects of miR-410-3p over-expression on MMP9 and vimentin protein expression (Figure 5E).	('over-expression', 'PosReg', (123, 138))	('vimentin', 'cellular_component', 'GO:0045099', ('151', '159'))	('MMP9', 'Gene', (142, 146))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('vimentin', 'cellular_component', 'GO:0045098', ('151', '159'))	('RAP1A', 'Gene', (68, 73))	('MMP9', 'Gene', '4318', (142, 146))	('MMP9', 'molecular_function', 'GO:0004229', ('142', '146'))	('alleviated', 'NegReg', (74, 84))	('vimentin', 'Gene', '7431', (151, 159))	('miR-410', 'Gene', (112, 119))	('miR-410', 'Gene', '574434', (112, 119))	('vimentin', 'Gene', (151, 159))	('rescue', 'Var', (58, 64))
65706	31908530	Furthermore, tumors collected from the over-expression group weighed significantly lighter than those harvested from the negative control group.	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('over-expression', 'Var', (39, 54))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('lighter', 'NegReg', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('weighed', 'MPA', (61, 68))
65708	31908530	In addition, TUNEL analysis revealed that more apoptotic cells were observed in the tumors collected from the over-expression group compared with those from the negative control group (Figure 6C).	('apoptotic cells', 'CPA', (47, 62))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('more', 'PosReg', (42, 46))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('over-expression', 'Var', (110, 125))
65749	31410216	Although more traditional efforts based on modulating tumorigenic processes at the genetic level have made, recent advances have yielded a wealth of epigenetic insights suggesting that many mechanisms including DNA methylation and long non-coding RNAs (lncRNAs) may be key regulators of oncogenesis and may thus represent novel and untapped therapeutic strategies for treating PC patients and improving clinical outcomes.	('methylation', 'Var', (215, 226))	('long non-coding RNAs', 'Var', (231, 251))	('DNA', 'cellular_component', 'GO:0005574', ('211', '214'))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('DNA methylation', 'Var', (211, 226))	('oncogenesis', 'biological_process', 'GO:0007048', ('287', '298'))	('clinical', 'Species', '191496', (403, 411))	('patients', 'Species', '9606', (380, 388))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('PC', 'Phenotype', 'HP:0002894', (377, 379))	('DNA methylation', 'biological_process', 'GO:0006306', ('211', '226'))	('tumor', 'Disease', (54, 59))
65754	31410216	LncRNA-LOC389641 promotes PC progression and metastasis via regulating E-cadherin with the involvement of TNFRSF10A.	('metastasis', 'CPA', (45, 55))	('regulating', 'Reg', (60, 70))	('TNFRSF10A', 'Gene', '8797', (106, 115))	('PC', 'Phenotype', 'HP:0002894', (26, 28))	('cadherin', 'molecular_function', 'GO:0008014', ('73', '81'))	('promotes', 'PosReg', (17, 25))	('E-cadherin', 'Gene', (71, 81))	('E-cadherin', 'Gene', '999', (71, 81))	('LncRNA-LOC389641', 'Var', (0, 16))	('TNFRSF10A', 'Gene', (106, 115))
65815	31410216	MTA2TR knockdown significantly disrupted BxPC-3/SW1990 cells cell proliferation and colony formation as determined via MTT and colony formation assay (Figure 2B, C).	('MTT', 'Chemical', 'MESH:C070243', (119, 122))	('MTA2', 'Gene', '9219', (0, 4))	('PC', 'Phenotype', 'HP:0002894', (43, 45))	('formation', 'biological_process', 'GO:0009058', ('134', '143'))	('colony formation', 'CPA', (84, 100))	('MTA2', 'Gene', (0, 4))	('formation', 'biological_process', 'GO:0009058', ('91', '100'))	('colony formation', 'CPA', (127, 143))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('disrupted', 'NegReg', (31, 40))	('knockdown', 'Var', (7, 16))	('BxPC-3/SW1990', 'CellLine', 'CVCL:0186', (41, 54))
65816	31410216	Similarly, invasion and migration of these cells were disrupted upon MTA2TR knockdown as determined based on Transwell and wound healing analyses (Figure 2D, E).	('disrupted', 'NegReg', (54, 63))	('knockdown', 'Var', (76, 85))	('MTA2', 'Gene', '9219', (69, 73))	('MTA2', 'Gene', (69, 73))	('invasion', 'CPA', (11, 19))	('wound healing', 'biological_process', 'GO:0042060', ('123', '136'))
65831	31410216	Meanwhile, MTA2 pre-mRNA was also decreased by MTA2TR knockdown but increased after MTA2TR overexpression (Figure 4D, E).	('MTA2', 'Gene', (84, 88))	('pre', 'molecular_function', 'GO:0003904', ('16', '19'))	('knockdown', 'Var', (54, 63))	('MTA2', 'Gene', (47, 51))	('decreased', 'NegReg', (34, 43))	('MTA2', 'Gene', '9219', (11, 15))	('MTA2', 'Gene', '9219', (84, 88))	('MTA2', 'Gene', (11, 15))	('increased', 'PosReg', (68, 77))	('MTA2', 'Gene', '9219', (47, 51))
65832	31410216	Meanwhile, stability of MTA2 mRNA had no significant changes in MTA2TR knockdown and overexpression BxPC-3 cells, which indicated MTA2 is regulated by MTA2TR but not in post-transcriptional level (Figure 4F, G).	('MTA2', 'Gene', '9219', (151, 155))	('BxPC-3', 'CellLine', 'CVCL:0186', (100, 106))	('MTA2', 'Gene', '9219', (24, 28))	('MTA2', 'Gene', (64, 68))	('MTA2', 'Gene', (130, 134))	('stability', 'MPA', (11, 20))	('knockdown', 'Var', (71, 80))	('MTA2', 'Gene', (151, 155))	('PC', 'Phenotype', 'HP:0002894', (102, 104))	('MTA2', 'Gene', (24, 28))	('MTA2', 'Gene', '9219', (64, 68))	('MTA2', 'Gene', '9219', (130, 134))
65841	31410216	Moreover, MTA2 knockdown significantly reversed the proliferation and invasive ability in those MTA2TR overexpression PC cells (Figure S4B, C).	('PC', 'Phenotype', 'HP:0002894', (118, 120))	('proliferation', 'CPA', (52, 65))	('MTA2', 'Gene', '9219', (96, 100))	('knockdown', 'Var', (15, 24))	('MTA2', 'Gene', '9219', (10, 14))	('invasive ability', 'CPA', (70, 86))	('PC cells', 'CellLine', 'CVCL:0152', (118, 126))	('MTA2', 'Gene', (96, 100))	('MTA2', 'Gene', (10, 14))	('overexpression', 'PosReg', (103, 117))
65849	31410216	In addition, RNA immunoprecipitation (RIP) assay showed significant accumulation of MTA2TR transcript by anti-ATF3 antibody but not IgG and SNRNP70 (Figure 5E).	('MTA2', 'Gene', (84, 88))	('accumulation', 'PosReg', (68, 80))	('antibody', 'cellular_component', 'GO:0042571', ('115', '123'))	('anti-ATF3', 'Var', (105, 114))	('SNRNP', 'molecular_function', 'GO:0003734', ('140', '145'))	('SNRNP70', 'Gene', (140, 147))	('antibody', 'cellular_component', 'GO:0019815', ('115', '123'))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('SNRNP', 'cellular_component', 'GO:0030532', ('140', '145'))	('antibody', 'cellular_component', 'GO:0019814', ('115', '123'))	('SNRNP70', 'Gene', '6625', (140, 147))	('antibody', 'molecular_function', 'GO:0003823', ('115', '123'))	('MTA2', 'Gene', '9219', (84, 88))
65854	31410216	ATF3 knockdown significantly decreased, while ATF3 overexpression increased MTA2 expression both in mRNA and protein levels (Figure 6A, B).	('knockdown', 'Var', (5, 14))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('MTA2', 'Gene', '9219', (76, 80))	('decreased', 'NegReg', (29, 38))	('ATF3', 'Gene', (0, 4))	('MTA2', 'Gene', (76, 80))	('expression', 'MPA', (81, 91))
65855	31410216	ChIP assay showed that the MTA2 promoter segments containing both P1 and P2 were markedly accumulated by anti-ATF3 antibody but not IgG (Figure 6C).	('accumulated', 'PosReg', (90, 101))	('MTA2', 'Gene', '9219', (27, 31))	('antibody', 'cellular_component', 'GO:0042571', ('115', '123'))	('anti-ATF3', 'Var', (105, 114))	('MTA2', 'Gene', (27, 31))	('antibody', 'cellular_component', 'GO:0019815', ('115', '123'))	('antibody', 'cellular_component', 'GO:0019814', ('115', '123'))	('antibody', 'molecular_function', 'GO:0003823', ('115', '123'))
65857	31410216	Results showed the luciferase density of WT, MUT1, MUT2, but not MUT3 was markedly enhanced by ATF3 overexpression, which indicates both P1 and P2 are required for the binding between ATF3 and MTA2 promoter (Figure 6D, E).	('density', 'MPA', (30, 37))	('enhanced', 'PosReg', (83, 91))	('binding', 'Interaction', (168, 175))	('luciferase', 'Enzyme', (19, 29))	('overexpression', 'Var', (100, 114))	('MTA2', 'Gene', '9219', (193, 197))	('ATF3', 'Gene', (95, 99))	('MTA2', 'Gene', (193, 197))	('binding', 'molecular_function', 'GO:0005488', ('168', '175'))
65858	31410216	Meanwhile, the MTA2TR-induced MTA2 overexpression was dramatically inhibited by ATF3 knockdown (Figure 6F).	('MTA2', 'Gene', '9219', (30, 34))	('MTA2', 'Gene', (15, 19))	('inhibited', 'NegReg', (67, 76))	('ATF3', 'Gene', (80, 84))	('MTA2', 'Gene', (30, 34))	('knockdown', 'Var', (85, 94))	('MTA2', 'Gene', '9219', (15, 19))	('overexpression', 'PosReg', (35, 49))
65860	31410216	Similarly, knockdown of ATF3 decreased the luciferase density in MTA2TR-overexpression cells (Figure 6H).	('density', 'MPA', (54, 61))	('luciferase', 'Enzyme', (43, 53))	('MTA2', 'Gene', '9219', (65, 69))	('decreased', 'NegReg', (29, 38))	('MTA2', 'Gene', (65, 69))	('knockdown', 'Var', (11, 20))	('ATF3', 'Gene', (24, 28))
65863	31410216	Moreover, ATF3 knockdown significantly reversed the proliferation and invasive ability in those MTA2TR overexpression PC cells (Figure S7A, B).	('PC', 'Phenotype', 'HP:0002894', (118, 120))	('proliferation', 'CPA', (52, 65))	('MTA2', 'Gene', '9219', (96, 100))	('knockdown', 'Var', (15, 24))	('invasive ability', 'CPA', (70, 86))	('PC cells', 'CellLine', 'CVCL:0152', (118, 126))	('MTA2', 'Gene', (96, 100))	('overexpression', 'PosReg', (103, 117))
65868	31410216	In addition, the RT-PCR results showed that HIF-1alpha knockdown dramatically inhibited the hypoxia-induced MTA2TR overexpression (Figure 7B), which was further validated by RNA-FISH assay (Figure 7C).	('knockdown', 'Var', (55, 64))	('inhibited', 'NegReg', (78, 87))	('hypoxia', 'Disease', (92, 99))	('hypoxia', 'Disease', 'MESH:D000860', (92, 99))	('HIF-1alpha', 'Gene', '3091', (44, 54))	('RNA', 'cellular_component', 'GO:0005562', ('174', '177'))	('MTA2', 'Gene', '9219', (108, 112))	('PC', 'Phenotype', 'HP:0002894', (20, 22))	('HIF-1alpha', 'Gene', (44, 54))	('MTA2', 'Gene', (108, 112))
65872	31410216	To confirm functional binding of HIF-1alpha to the MTA2TR promoter, BxPC-3 cells were transfected with luciferase reporter vectors bearing wild-type (WT) or mutated HRE (MUT).	('HIF-1alpha', 'Gene', '3091', (33, 43))	('binding', 'molecular_function', 'GO:0005488', ('22', '29'))	('MTA2', 'Gene', '9219', (51, 55))	('MTA2', 'Gene', (51, 55))	('HIF-1alpha', 'Gene', (33, 43))	('mutated', 'Var', (157, 164))	('BxPC-3', 'CellLine', 'CVCL:0186', (68, 74))	('PC', 'Phenotype', 'HP:0002894', (70, 72))	('HRE', 'Protein', (165, 168))
65873	31410216	The results showed that MTA2TR promoter activity was enhanced by hypoxia, but impaired by HIF-1alpha knockdown (Figure 7G).	('MTA2', 'Gene', '9219', (24, 28))	('HIF-1alpha', 'Gene', (90, 100))	('MTA2', 'Gene', (24, 28))	('impaired', 'NegReg', (78, 86))	('activity', 'MPA', (40, 48))	('hypoxia', 'Disease', (65, 72))	('hypoxia', 'Disease', 'MESH:D000860', (65, 72))	('HIF-1alpha', 'Gene', '3091', (90, 100))	('enhanced', 'PosReg', (53, 61))	('knockdown', 'Var', (101, 110))
65875	31410216	In addition, ChIP assay verified that the combination of ATF3 on the MTA2 promoter region was also increased (Figure S8C).	('MTA2', 'Gene', '9219', (69, 73))	('combination', 'Var', (42, 53))	('ATF3', 'Gene', (57, 61))	('MTA2', 'Gene', (69, 73))	('increased', 'PosReg', (99, 108))
65881	31410216	Hypoxia-induced HIF-1alpha protein in PC cells was destabilized with MTA2TR knockdown, but stabilized by MTA2TR overexpression (Figure 8B, Figure S9B).	('MTA2', 'Gene', (105, 109))	('knockdown', 'Var', (76, 85))	('PC cells', 'CellLine', 'CVCL:0152', (38, 46))	('Hypoxia-induced HIF-1alpha', 'Disease', (0, 26))	('MTA2', 'Gene', '9219', (69, 73))	('PC', 'Phenotype', 'HP:0002894', (38, 40))	('MTA2', 'Gene', (69, 73))	('MTA2', 'Gene', '9219', (105, 109))	('Hypoxia-induced HIF-1alpha', 'Disease', 'MESH:D000860', (0, 26))	('destabilized', 'NegReg', (51, 63))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))
65882	31410216	Nevertheless, both MTA2TR knockdown or overexpression-induced HIF-1alpha modulation were abolished by the proteasome inhibitor MG132 (Figure 8C, Figure S9C).	('HIF-1alpha', 'Gene', (62, 72))	('MG132', 'Chemical', 'MESH:C072553', (127, 132))	('HIF-1alpha', 'Gene', '3091', (62, 72))	('knockdown', 'Var', (26, 35))	('proteasome', 'molecular_function', 'GO:0004299', ('106', '116'))	('proteasome', 'cellular_component', 'GO:0000502', ('106', '116'))	('MTA2', 'Gene', '9219', (19, 23))	('abolished', 'NegReg', (89, 98))	('MTA2', 'Gene', (19, 23))
65883	31410216	Moreover, we found that MTA2TR knockdown markedly increased acetylation of HIF-1alpha, accompanied with reduction of the binding of MTA2 and HIF-1alpha under hypoxic conditions (Figure 8D, E).	('HIF-1alpha', 'Gene', '3091', (75, 85))	('reduction', 'NegReg', (104, 113))	('MTA2', 'Gene', '9219', (24, 28))	('HIF-1alpha', 'Gene', (141, 151))	('acetylation', 'MPA', (60, 71))	('increased', 'PosReg', (50, 59))	('MTA2', 'Gene', (24, 28))	('HIF-1alpha', 'Gene', (75, 85))	('MTA2', 'Gene', '9219', (132, 136))	('binding', 'Interaction', (121, 128))	('MTA2', 'Gene', (132, 136))	('HIF-1alpha', 'Gene', '3091', (141, 151))	('knockdown', 'Var', (31, 40))
65886	31410216	On the contrary, MTA2 knockdown decreased the HIF-1alpha expression and association of HIF-1alpha and MTA2, as well as increased acetylation of HIF-1alpha, which were induced by MTA2TR overexpression (Figure S9F).	('expression', 'MPA', (57, 67))	('MTA2', 'Gene', '9219', (17, 21))	('increased', 'PosReg', (119, 128))	('HIF-1alpha', 'Gene', '3091', (87, 97))	('MTA2', 'Gene', (17, 21))	('HIF-1alpha', 'Gene', (87, 97))	('MTA2', 'Gene', '9219', (178, 182))	('association', 'Interaction', (72, 83))	('MTA2', 'Gene', (102, 106))	('HIF-1alpha', 'Gene', '3091', (144, 154))	('HIF-1alpha', 'Gene', (46, 56))	('knockdown', 'Var', (22, 31))	('acetylation', 'MPA', (129, 140))	('MTA2', 'Gene', (178, 182))	('MTA2', 'Gene', '9219', (102, 106))	('decreased', 'NegReg', (32, 41))	('HIF-1alpha', 'Gene', (144, 154))	('HIF-1alpha', 'Gene', '3091', (46, 56))
65887	31410216	Meanwhile, MTA2TR knockdown significantly decreased the mRNA level of HIF-1alpha targets including VEGFa, VEGFb, LOX, LOXL2 and PLOD2 (Figure 8G).	('VEGFb', 'Gene', (106, 111))	('decreased', 'NegReg', (42, 51))	('HIF-1alpha', 'Gene', (70, 80))	('PLOD2', 'Gene', (128, 133))	('VEGFa', 'Gene', '7422', (99, 104))	('MTA2', 'Gene', (11, 15))	('LOX', 'Gene', (113, 116))	('LOXL2', 'Gene', '4017', (118, 123))	('LOX', 'Gene', '4015', (118, 121))	('MTA2', 'Gene', '9219', (11, 15))	('PLOD2', 'Gene', '5352', (128, 133))	('knockdown', 'Var', (18, 27))	('LOX', 'Gene', (118, 121))	('HIF-1alpha', 'Gene', '3091', (70, 80))	('LOXL2', 'Gene', (118, 123))	('mRNA level', 'MPA', (56, 66))	('VEGFb', 'Gene', '7423', (106, 111))	('LOX', 'Gene', '4015', (113, 116))	('VEGFa', 'Gene', (99, 104))
65890	31410216	Moreover, the immunofluorescence results confirmed that the hypoxia-induced HIF-1alpha was decreased by knockdown of both MTA2TR and MTA2 in PC cells (Figure 9A).	('MTA2', 'Gene', '9219', (133, 137))	('MTA2', 'Gene', '9219', (122, 126))	('MTA2', 'Gene', (133, 137))	('PC', 'Phenotype', 'HP:0002894', (141, 143))	('MTA2', 'Gene', (122, 126))	('hypoxia-induced HIF-1alpha', 'Disease', 'MESH:D000860', (60, 86))	('hypoxia-induced HIF-1alpha', 'Disease', (60, 86))	('PC cells', 'CellLine', 'CVCL:0152', (141, 149))	('decreased', 'NegReg', (91, 100))	('knockdown', 'Var', (104, 113))
65891	31410216	In addition, overexpression of MTA2TR or MTA2 could rescue the HIF-1alpha that was inhibited by HIF-1alpha knockdown during hypoxia (Figure 9B).	('rescue', 'PosReg', (52, 58))	('knockdown', 'Var', (107, 116))	('HIF-1alpha', 'Gene', (96, 106))	('HIF-1alpha', 'Gene', (63, 73))	('hypoxia', 'Disease', 'MESH:D000860', (124, 131))	('MTA2', 'Gene', '9219', (41, 45))	('MTA2', 'Gene', '9219', (31, 35))	('MTA2', 'Gene', (41, 45))	('HIF-1alpha', 'Gene', '3091', (96, 106))	('HIF-1alpha', 'Gene', '3091', (63, 73))	('hypoxia', 'Disease', (124, 131))	('MTA2', 'Gene', (31, 35))
65894	31410216	However, knockdown MTA2TR under hypoxia, the proliferation of cells is weakened (Figure S10A).	('knockdown', 'Var', (9, 18))	('weakened', 'NegReg', (71, 79))	('S10A', 'SUBSTITUTION', 'None', (88, 92))	('hypoxia', 'Disease', 'MESH:D000860', (32, 39))	('S10A', 'Var', (88, 92))	('MTA2', 'Gene', '9219', (19, 23))	('hypoxia', 'Disease', (32, 39))	('MTA2', 'Gene', (19, 23))
65895	31410216	We also found that hypoxia significantly increased the invasive ability of these cells (Figure S10B).	('increased', 'PosReg', (41, 50))	('hypoxia', 'Disease', 'MESH:D000860', (19, 26))	('hypoxia', 'Disease', (19, 26))	('S10B', 'Var', (95, 99))	('invasive ability of', 'CPA', (55, 74))	('S10B', 'SUBSTITUTION', 'None', (95, 99))
65896	31410216	Upon knockdown MTA2TR, there was a substantial decrease in the invasive potential of these PC cells (Figure S10B).	('MTA2', 'Gene', (15, 19))	('knockdown', 'Var', (5, 14))	('S10B', 'SUBSTITUTION', 'None', (108, 112))	('PC', 'Phenotype', 'HP:0002894', (91, 93))	('decrease', 'NegReg', (47, 55))	('invasive potential', 'CPA', (63, 81))	('PC cells', 'CellLine', 'CVCL:0152', (91, 99))	('MTA2', 'Gene', '9219', (15, 19))	('S10B', 'Var', (108, 112))
65902	31410216	Coincidently, survival data of TCGA from OncoLnc showed that PC patients with high MTA2 expression had a shorter survival time (Figure 10C).	('high', 'Var', (78, 82))	('survival time', 'CPA', (113, 126))	('patients', 'Species', '9606', (64, 72))	('PC', 'Phenotype', 'HP:0002894', (61, 63))	('MTA2', 'Gene', '9219', (83, 87))	('MTA2', 'Gene', (83, 87))	('shorter', 'NegReg', (105, 112))	('expression', 'MPA', (88, 98))
65928	31410216	Research demonstrated the loss of ATF3 promotes prostate cancer progression of in PTEN knockout mice through activating AKT pathway.	('AKT', 'Gene', (120, 123))	('promotes', 'PosReg', (39, 47))	('prostate cancer', 'Disease', 'MESH:D011471', (48, 63))	('mice', 'Species', '10090', (96, 100))	('AKT', 'Gene', '11651', (120, 123))	('PTEN', 'Gene', '19211', (82, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('PTEN', 'Gene', (82, 86))	('loss', 'Var', (26, 30))	('prostate cancer', 'Disease', (48, 63))	('ATF3', 'Gene', (34, 38))	('activating', 'PosReg', (109, 119))
65930	31410216	Moreover, NSAIDs increased ATF3 expression and consequently repressed invasive ability of human colorectal cancer cells.	('increased', 'PosReg', (17, 26))	('NSAIDs', 'Var', (10, 16))	('ATF3', 'Protein', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('human', 'Species', '9606', (90, 95))	('repressed', 'NegReg', (60, 69))	('colorectal cancer', 'Disease', (96, 113))	('invasive ability of human', 'CPA', (70, 95))	('expression', 'MPA', (32, 42))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
65936	31410216	LncRNA-AK123072 was induced under hypoxia and promoted migration and invasion of gastric cancer cells by upregulating EGFR.	('promoted', 'PosReg', (46, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))	('migration', 'CPA', (55, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('gastric cancer', 'Disease', (81, 95))	('EGFR', 'Gene', '1956', (118, 122))	('invasion', 'CPA', (69, 77))	('hypoxia', 'Disease', (34, 41))	('EGFR', 'Gene', (118, 122))	('hypoxia', 'Disease', 'MESH:D000860', (34, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('118', '122'))	('LncRNA-AK123072', 'Var', (0, 15))	('upregulating', 'PosReg', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
65962	29526803	For example, DCLK1-expressing cells in intestinal tumors have been thought to be tumor progenitor cells, as diphtheria toxin-mediated ablation of DCLK1+ cells led to tumor regression.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('intestinal tumors', 'Disease', (39, 56))	('intestinal tumors', 'Disease', 'MESH:D007414', (39, 56))	('DCLK1+', 'Gene', (146, 152))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ablation', 'Var', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', (81, 86))
65969	29526803	We have reported that mutant Kras in the context of inactivated activin signaling promotes the development of IPMN/PDA in our recently established Acvr1bflox/flox;LSL-KrasG12D;Pdx1-Cre GEMM.	('Kras', 'Gene', '16653', (29, 33))	('Acvr1b', 'Gene', '11479', (147, 153))	('Pdx1', 'Gene', '18609', (176, 180))	('IPMN', 'Chemical', '-', (110, 114))	('development', 'CPA', (95, 106))	('activin', 'molecular_function', 'GO:0005160', ('64', '71'))	('Pdx1', 'Gene', (176, 180))	('Kras', 'Gene', (167, 171))	('Acvr1b', 'Gene', (147, 153))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('promotes', 'PosReg', (82, 90))	('activin', 'molecular_function', 'GO:0016915', ('64', '71'))	('PDA', 'Chemical', '-', (115, 118))	('Kras', 'Gene', '16653', (167, 171))	('mutant', 'Var', (22, 28))	('PDA', 'Phenotype', 'HP:0006725', (115, 118))	('Cre', 'Gene', (181, 184))	('Kras', 'Gene', (29, 33))	('Cre', 'Gene', '39441', (181, 184))	('IPMN/PDA', 'Disease', (110, 118))
65971	29526803	Using these established GEMMs with specific IPMN or PanIN genesis, we observed that DCLK1+ cells were predominately detected in the pancreatic tissues with activated mutant Kras and not in the Cre-negative normal control mice.	('pancreatic', 'Disease', 'MESH:D010195', (132, 142))	('Kras', 'Gene', (173, 177))	('Kras', 'Gene', '16653', (173, 177))	('Cre', 'Gene', (193, 196))	('IPMN', 'Chemical', '-', (44, 48))	('pancreatic', 'Disease', (132, 142))	('Cre', 'Gene', '39441', (193, 196))	('mice', 'Species', '10090', (221, 225))	('mutant', 'Var', (166, 172))
65989	29526803	We have previously reported a GEMM for IPMNs (Acvr1bflox/flox;LSL-KrasG12D;Pdx1-Cre or the AKP GEMM) which was generated by tissue-specific and conditional inactivation of the Acvr1b gene (Acvr1bflox/flox) in the pancreas in the context of oncogenic Kras activation (LSL-KrasG12D;Pdx1-Cre or the KP GEMM).	('Pdx1', 'Gene', (280, 284))	('Kras', 'Gene', (250, 254))	('Acvr1b', 'Gene', (46, 52))	('Acvr1b', 'Gene', '11479', (176, 182))	('Kras', 'Gene', (271, 275))	('Kras', 'Gene', (66, 70))	('Pdx1', 'Gene', (75, 79))	('inactivation', 'Var', (156, 168))	('Acvr1b', 'Gene', (189, 195))	('Kras', 'Gene', '16653', (250, 254))	('IPMN', 'Chemical', '-', (39, 43))	('Kras', 'Gene', '16653', (271, 275))	('IPMNs', 'Disease', (39, 44))	('Kras', 'Gene', '16653', (66, 70))	('Cre', 'Gene', (285, 288))	('Acvr1b', 'Gene', (176, 182))	('Cre', 'Gene', (80, 83))	('Cre', 'Gene', '39441', (285, 288))	('Cre', 'Gene', '39441', (80, 83))	('Acvr1b', 'Gene', '11479', (46, 52))	('Acvr1b', 'Gene', '11479', (189, 195))	('Pdx1', 'Gene', '18609', (280, 284))	('Pdx1', 'Gene', '18609', (75, 79))
65996	29526803	The DCLK1+ cells were particularly prevalent in KRAS-induced hyperplastic lesions, such as in the metaplastic ducts of ADM in the KP GEMM and IPMN lesions in the AKP GEMM (Fig.	('KRAS', 'Gene', (48, 52))	('prevalent', 'Reg', (35, 44))	('hyperplastic lesions', 'Disease', (61, 81))	('IPMN lesions', 'Disease', (142, 154))	('metaplastic ducts', 'CPA', (98, 115))	('DCLK1+', 'Var', (4, 10))	('hyperplastic lesions', 'Disease', 'MESH:D051437', (61, 81))	('KRAS', 'Gene', '16653', (48, 52))	('IPMN', 'Chemical', '-', (142, 146))
66000	29526803	The paucity of mucinous granules in the DCLK1+ cells was also easily discernible from the mucin-abundant IPMN tumor cells by Alcian blue and PAS staining (Fig.	('IPMN tumor', 'Disease', 'MESH:D000077779', (105, 115))	('PAS', 'cellular_component', 'GO:0000407', ('141', '144'))	('DCLK1+', 'Var', (40, 46))	('PAS', 'Chemical', 'MESH:D011478', (141, 144))	('Alcian blue', 'Chemical', 'MESH:D000423', (125, 136))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('IPMN tumor', 'Disease', (105, 115))
66004	29526803	In our AKP GEMM, the mIPMN lesions are mostly devoid of ACVR1B expression due to the engineered Pdx1-Cre-induced Acvr1b deletion in the pancreas.	('Acvr1b', 'Gene', '11479', (113, 119))	('Cre', 'Gene', (101, 104))	('Pdx1', 'Gene', '18609', (96, 100))	('devoid', 'NegReg', (46, 52))	('ACVR1B', 'Gene', (56, 62))	('IPMN', 'Chemical', '-', (22, 26))	('ACVR1B', 'Gene', '11479', (56, 62))	('expression', 'MPA', (63, 73))	('mIPMN', 'Disease', (21, 26))	('Cre', 'Gene', '39441', (101, 104))	('Acvr1b', 'Gene', (113, 119))	('deletion', 'Var', (120, 128))	('Pdx1', 'Gene', (96, 100))
66006	29526803	Those ACVR1B+cells with DCLK1 expression are not only in a scattered-distribution pattern as in the intestine but also morphologically resemble tuft cells in the intestine (Fig.	('ACVR1B', 'Gene', (6, 12))	('expression', 'Var', (30, 40))	('ACVR1B', 'Gene', '11479', (6, 12))	('DCLK1', 'Gene', (24, 29))
66028	29526803	The upregulation of those embryonic molecular signaling pathways in acinar cells by DCLK1+ cells may be one of the mechanisms for the initiation of ADM and promoting the development of IPMN tumors in our GEMM.	('DCLK1+ cells', 'Var', (84, 96))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('promoting', 'PosReg', (156, 165))	('IPMN tumors', 'Disease', (185, 196))	('ADM', 'Disease', (148, 151))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('upregulation', 'PosReg', (4, 16))	('IPMN tumors', 'Disease', 'MESH:D000077779', (185, 196))	('embryonic molecular signaling pathways', 'Pathway', (26, 64))
66062	29526803	Trans-differentiation of acinar to ductal cell induced by mutant Kras has been proposed to be the primary event in the PDA initiation.	('mutant', 'Var', (58, 64))	('PDA', 'Phenotype', 'HP:0006725', (119, 122))	('PDA', 'Disease', (119, 122))	('PDA', 'Chemical', '-', (119, 122))	('Trans-differentiation', 'CPA', (0, 21))	('Kras', 'Gene', (65, 69))	('Kras', 'Gene', '16653', (65, 69))
66091	29526803	Although DCLK1-positivity doesn't serve as a stem cell marker for IPMNs, DCLK1+ cells are important cellular components of "IPMN niches", and remain potential targets for future therapies.	('IPMN', 'Chemical', '-', (124, 128))	('IPMN', 'Chemical', '-', (66, 70))	('IPMNs', 'Disease', (66, 71))	('DCLK1+', 'Var', (73, 79))
66257	29467554	Beside age, we also found BMI >= 24 kg/m2, pancreaticoduodenectomy and length of operation >= 241 min (median) were independent risk factors for severe postoperative complications (grades IIIb-V).	('pancreatic', 'Disease', 'MESH:D010195', (43, 53))	('>= 241', 'Var', (91, 97))	('pancreatic', 'Disease', (43, 53))
66301	29215586	A combination therapy containing difluoromethylornithine (DFMO, an ODC inhibitor) and a polyamine transport inhibitor (PTI) were shown to significantly deplete intracellular polyamine pools.	('difluoromethylornithine', 'Var', (33, 56))	('polyamine', 'Chemical', 'MESH:D011073', (88, 97))	('ODC', 'Gene', (67, 70))	('polyamine', 'Chemical', 'MESH:D011073', (174, 183))	('ODC', 'Gene', '4953', (67, 70))	('deplete', 'NegReg', (152, 159))	('polyamine transport', 'biological_process', 'GO:0015846', ('88', '107'))	('PTI', 'biological_process', 'GO:0052033', ('119', '122'))	('difluoromethylornithine', 'Chemical', 'MESH:D000518', (33, 56))	('intracellular', 'cellular_component', 'GO:0005622', ('160', '173'))	('PTI', 'Gene', '5269', (119, 122))	('PTI', 'Gene', (119, 122))	('DFMO', 'Chemical', 'MESH:D000518', (58, 62))
66305	29215586	The most frequently mutated gene in human PDAC is KRAS (95%) and human PDAC cell lines often (50%) have a copy number gain in MYC (c-myc).	('MYC', 'Gene', (126, 129))	('human', 'Species', '9606', (65, 70))	('PDAC', 'Phenotype', 'HP:0006725', (71, 75))	('PDAC', 'Chemical', '-', (42, 46))	('PDAC', 'Phenotype', 'HP:0006725', (42, 46))	('KRAS', 'Gene', (50, 54))	('c-myc', 'Gene', '4609', (131, 136))	('c-myc', 'Gene', (131, 136))	('copy number', 'Var', (106, 117))	('KRAS', 'Gene', '3845', (50, 54))	('gain', 'PosReg', (118, 122))	('MYC', 'Gene', '4609', (126, 129))	('PDAC', 'Chemical', '-', (71, 75))	('human', 'Species', '9606', (36, 41))
66307	29215586	Both KRAS and MYC are upstream activators of polyamine metabolism, and their mutations are known to increase intracellular polyamine levels to presumably drive tumor growth.	('intracellular polyamine levels', 'MPA', (109, 139))	('drive', 'PosReg', (154, 159))	('MYC', 'Gene', (14, 17))	('polyamine', 'Chemical', 'MESH:D011073', (123, 132))	('KRAS', 'Gene', (5, 9))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('polyamine metabolism', 'biological_process', 'GO:0006595', ('45', '65'))	('KRAS', 'Gene', '3845', (5, 9))	('polyamine', 'Chemical', 'MESH:D011073', (45, 54))	('mutations', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('intracellular', 'cellular_component', 'GO:0005622', ('109', '122'))	('MYC', 'Gene', '4609', (14, 17))	('tumor', 'Disease', (160, 165))	('increase', 'PosReg', (100, 108))
66309	29215586	As a result, polyamines have pleiotropic effects in cells and play critical roles in chromatin remodeling, transcription, translation, eIF5A activation, potassium channel regulation, and in the immune response.	('polyamines', 'Chemical', 'MESH:D011073', (13, 23))	('eIF5A', 'Gene', (135, 140))	('polyamines', 'Var', (13, 23))	('chromatin', 'MPA', (85, 94))	('eIF5A', 'Gene', '1984', (135, 140))	('activation', 'PosReg', (141, 151))
66350	29215586	The L3.6pl 72 h IC50 value of PTI trimer44 was 69.6 +- 1.8 microM and typically the trimer44 alone could be dosed at 4 microM with no effect on cell growth.	('PTI', 'biological_process', 'GO:0052033', ('30', '33'))	('cell growth', 'biological_process', 'GO:0016049', ('144', '155'))	('trimer44', 'Var', (34, 42))	('PTI', 'Gene', '5269', (30, 33))	('PTI', 'Gene', (30, 33))
66355	29215586	As shown in Figure 4 Panel B, the presence of either MCHA, the trimer44 PTI, or the combination of MCHA + PTI with DFMO decreased cell growth.	('decreased', 'NegReg', (120, 129))	('PTI', 'Gene', (106, 109))	('PTI', 'biological_process', 'GO:0052033', ('72', '75'))	('MCHA', 'Gene', (53, 57))	('PTI', 'Gene', '5269', (72, 75))	('DFMO', 'Chemical', 'MESH:D000518', (115, 119))	('PTI', 'biological_process', 'GO:0052033', ('106', '109'))	('cell growth', 'CPA', (130, 141))	('PTI', 'Gene', (72, 75))	('MCHA', 'Chemical', 'MESH:C059116', (53, 57))	('trimer44', 'Var', (63, 71))	('MCHA', 'Chemical', 'MESH:C059116', (99, 103))	('PTI', 'Gene', '5269', (106, 109))	('cell growth', 'biological_process', 'GO:0016049', ('130', '141'))	('presence', 'Var', (34, 42))
66356	29215586	The combination of DFMO + MCHA + PTI + Spd resembled the DFMO + MCHA control, which is consistent with the trimer44 PTI inhibiting spermidine import.	('spermidine', 'Chemical', 'MESH:D013095', (131, 141))	('inhibiting', 'NegReg', (120, 130))	('PTI', 'Gene', '5269', (116, 119))	('Spd', 'Chemical', 'MESH:D013095', (39, 42))	('MCHA', 'Chemical', 'MESH:C059116', (64, 68))	('DFMO', 'Chemical', 'MESH:D000518', (19, 23))	('PTI', 'biological_process', 'GO:0052033', ('116', '119'))	('PTI', 'biological_process', 'GO:0052033', ('33', '36'))	('DFMO', 'Chemical', 'MESH:D000518', (57, 61))	('MCHA', 'Chemical', 'MESH:C059116', (26, 30))	('PTI', 'Gene', (33, 36))	('PTI', 'Gene', '5269', (33, 36))	('trimer44', 'Var', (107, 115))	('spermidine import', 'MPA', (131, 148))	('PTI', 'Gene', (116, 119))
66357	29215586	Indeed, the presence of the PTI prevented spermidine rescue because L3.6pl cells treated with DFMO + MCHA + Spd gave 87% relative cell growth, whereas cells treated with DFMO + MCHA + PTI + Spd gave 46% relative cell growth and gave nearly identical intracellular polyamine pools to the DFMO + MCHA entry.	('DFMO', 'Chemical', 'MESH:D000518', (170, 174))	('PTI', 'biological_process', 'GO:0052033', ('28', '31'))	('PTI', 'biological_process', 'GO:0052033', ('184', '187'))	('polyamine', 'Chemical', 'MESH:D011073', (264, 273))	('spermidine', 'Chemical', 'MESH:D013095', (42, 52))	('cell growth', 'biological_process', 'GO:0016049', ('130', '141'))	('PTI', 'Gene', '5269', (28, 31))	('Spd', 'Chemical', 'MESH:D013095', (190, 193))	('MCHA', 'Chemical', 'MESH:C059116', (101, 105))	('DFMO', 'Chemical', 'MESH:D000518', (287, 291))	('Spd', 'Chemical', 'MESH:D013095', (108, 111))	('intracellular', 'cellular_component', 'GO:0005622', ('250', '263'))	('cell growth', 'biological_process', 'GO:0016049', ('212', '223'))	('PTI', 'Gene', (28, 31))	('PTI', 'Gene', '5269', (184, 187))	('intracellular polyamine pools', 'MPA', (250, 279))	('DFMO', 'Chemical', 'MESH:D000518', (94, 98))	('cell growth', 'CPA', (130, 141))	('MCHA', 'Chemical', 'MESH:C059116', (177, 181))	('PTI', 'Gene', (184, 187))	('MCHA', 'Chemical', 'MESH:C059116', (294, 298))	('DFMO + MCHA + Spd', 'Var', (94, 111))
66366	29215586	The combination of CDAP (100 microM) and DFMO (4.2 mM) resulted in decreased cell growth and decreased intracellular spermidine pools.	('CDAP', 'Chemical', 'MESH:C081181', (19, 23))	('cell growth', 'CPA', (77, 88))	('intracellular', 'cellular_component', 'GO:0005622', ('103', '116'))	('decreased', 'NegReg', (93, 102))	('spermidine', 'Chemical', 'MESH:D013095', (117, 127))	('DFMO', 'Chemical', 'MESH:D000518', (41, 45))	('cell growth', 'biological_process', 'GO:0016049', ('77', '88'))	('intracellular spermidine pools', 'MPA', (103, 133))	('decreased', 'NegReg', (67, 76))	('DFMO', 'Var', (41, 45))
66371	29215586	Indeed, the commitment to maintain spermine pools in the presence of DFMO (4.2 mM), DFMO + Spd, and DFMO + CDAP (1 microM) becomes obvious in Panel B.	('DFMO', 'Var', (100, 104))	('spermine pools', 'MPA', (35, 49))	('spermine', 'Chemical', 'MESH:D013096', (35, 43))	('DFMO + Spd', 'Var', (84, 94))	('Spd', 'Chemical', 'MESH:D013095', (91, 94))	('DFMO', 'Chemical', 'MESH:D000518', (84, 88))	('DFMO', 'Chemical', 'MESH:D000518', (69, 73))	('CDAP', 'Chemical', 'MESH:C081181', (107, 111))	('DFMO', 'Chemical', 'MESH:D000518', (100, 104))
66372	29215586	Both DFMO and DFMO + CDAP (1 microM) caused a significant decrease in relative cell growth (46.7% and 35%, respectively), which could be rescued to >90% relative cell growth by the availability of exogenous spermidine (1 microM).	('cell growth', 'biological_process', 'GO:0016049', ('162', '173'))	('DFMO', 'Chemical', 'MESH:D000518', (5, 9))	('DFMO', 'Var', (5, 9))	('relative cell growth', 'CPA', (70, 90))	('spermidine', 'Chemical', 'MESH:D013095', (207, 217))	('cell growth', 'biological_process', 'GO:0016049', ('79', '90'))	('decrease', 'NegReg', (58, 66))	('CDAP', 'Chemical', 'MESH:C081181', (21, 25))	('DFMO', 'Chemical', 'MESH:D000518', (14, 18))
66378	29215586	The trimer44 PTI was shown to be a competitive inhibitor of polyamine transport via 3H-Spd uptake assays.	('PTI', 'biological_process', 'GO:0052033', ('13', '16'))	('PTI', 'Gene', '5269', (13, 16))	('polyamine', 'Chemical', 'MESH:D011073', (60, 69))	('polyamine transport', 'MPA', (60, 79))	('trimer44', 'Var', (4, 12))	('3H-Spd', 'Chemical', '-', (84, 90))	('PTI', 'Gene', (13, 16))	('uptake', 'biological_process', 'GO:0098739', ('91', '97'))	('uptake', 'biological_process', 'GO:0098657', ('91', '97'))	('polyamine transport', 'biological_process', 'GO:0015846', ('60', '79'))
66382	29215586	The presence of the trimer44 PTI (4 microM) with DFMO + CDAP (100 microM) significantly lowered the cell growth to 6.8%.	('cell growth', 'CPA', (100, 111))	('CDAP', 'Chemical', 'MESH:C081181', (56, 60))	('lowered', 'NegReg', (88, 95))	('PTI', 'biological_process', 'GO:0052033', ('29', '32'))	('trimer44', 'Var', (20, 28))	('PTI', 'Gene', '5269', (29, 32))	('cell growth', 'biological_process', 'GO:0016049', ('100', '111'))	('PTI', 'Gene', (29, 32))	('DFMO', 'Chemical', 'MESH:D000518', (49, 53))
66387	29215586	Indeed, this modest potentiation of DFMO was noted at as low as 100 nM CDAP, suggesting that even mild perturbation of spermine biosynthesis via SMS inhibition can augment the effectiveness of DFMO.	('SMS', 'Gene', '6611', (145, 148))	('spermine biosynthesis', 'MPA', (119, 140))	('DFMO', 'Chemical', 'MESH:D000518', (193, 197))	('CDAP', 'Chemical', 'MESH:C081181', (71, 75))	('DFMO', 'Chemical', 'MESH:D000518', (36, 40))	('spermine biosynthesis', 'biological_process', 'GO:0006597', ('119', '140'))	('effectiveness', 'MPA', (176, 189))	('SMS', 'Gene', (145, 148))	('inhibition', 'Var', (149, 159))	('spermine', 'Chemical', 'MESH:D013096', (119, 127))	('perturbation', 'NegReg', (103, 115))	('augment', 'PosReg', (164, 171))
66389	29215586	Of all three native polyamines, spermine has been shown to be the most effective immune suppressant, with inhibitory activity noted in T-cells, monocytes, and macrophages.	('polyamines', 'Chemical', 'MESH:D011073', (20, 30))	('spermine', 'Chemical', 'MESH:D013096', (32, 40))	('spermine', 'Var', (32, 40))	('immune suppressant', 'CPA', (81, 99))
66398	29215586	Prior in vivo studies in healthy rats using MCHA showed that delivery was more effective via MCHA (0.1%, pH 6) in the drinking water than by a single intraperitoneal (i.p.)	('MCHA', 'Chemical', 'MESH:C059116', (44, 48))	('delivery', 'MPA', (61, 69))	('MCHA', 'Var', (93, 97))	('rats', 'Species', '10116', (33, 37))	('drinking water', 'Chemical', 'MESH:D060766', (118, 132))	('MCHA', 'Chemical', 'MESH:C059116', (93, 97))
66429	29215586	For example, combination therapies like DFMO + CDAP + PTI, which reduce intratumoral spermine pools, even in the presence of exogenous polyamines, may provide a new approach to PDAC tumors by targeting their high reliance upon spermine.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('CDAP', 'Chemical', 'MESH:C081181', (47, 51))	('PTI', 'Gene', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('DFMO', 'Chemical', 'MESH:D000518', (40, 44))	('DFMO', 'Var', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('spermine', 'Chemical', 'MESH:D013096', (85, 93))	('PDAC tumors', 'Disease', 'MESH:C537768', (177, 188))	('rat', 'Species', '10116', (75, 78))	('spermine', 'Chemical', 'MESH:D013096', (227, 235))	('polyamines', 'Chemical', 'MESH:D011073', (135, 145))	('tumor', 'Disease', (182, 187))	('PDAC', 'Phenotype', 'HP:0006725', (177, 181))	('PTI', 'Gene', '5269', (54, 57))	('reduce', 'NegReg', (65, 71))	('PDAC tumors', 'Disease', (177, 188))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (77, 82))	('PTI', 'biological_process', 'GO:0052033', ('54', '57'))
66434	27732944	Germline mutations in Japanese familial pancreatic cancer patients Clinicopathologic and genetic features of familial pancreatic cancer (FPC) in Asian countries remain largely unknown.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('FPC', 'cellular_component', 'GO:1990900', ('137', '140'))	('familial pancreatic cancer', 'Disease', (109, 135))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (118, 135))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (109, 135))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('Germline', 'Var', (0, 8))	('familial pancreatic cancer', 'Disease', (31, 57))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (31, 57))
66438	27732944	In the FPC patients, we then investigated the prevalence of germline mutations in 21 genes associated with hereditary predispositions for pancreatic, breast and ovarian cancers by means of the next-generation sequencing using a custom multiple-gene panel.	('patients', 'Species', '9606', (11, 19))	('ovarian cancer', 'Phenotype', 'HP:0100615', (161, 175))	('ovarian cancers', 'Phenotype', 'HP:0100615', (161, 176))	('germline mutations', 'Var', (60, 78))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('pancreatic, breast and ovarian cancers', 'Disease', 'MESH:D001943', (138, 176))	('investigated', 'Reg', (29, 41))	('FPC', 'cellular_component', 'GO:1990900', ('7', '10'))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
66439	27732944	We found that eight (14.5%) of the 54 FPC patients with available germline DNA carried deleterious mutations in BRCA2, PALB2, ATM, or MLH1.	('ATM', 'Gene', '472', (126, 129))	('FPC', 'cellular_component', 'GO:1990900', ('38', '41'))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('MLH1', 'Gene', '4292', (134, 138))	('PALB2', 'Gene', (119, 124))	('BRCA2', 'Gene', (112, 117))	('MLH1', 'Gene', (134, 138))	('mutations', 'Var', (99, 108))	('ATM', 'Gene', (126, 129))	('PALB2', 'Gene', '79728', (119, 124))	('patients', 'Species', '9606', (42, 50))	('BRCA2', 'Gene', '675', (112, 117))
66440	27732944	These results indicate that a significant fraction of patients with PDAC in Japan have a family history of pancreatic cancer, and some of them harbor deleterious causative mutations in known FPC predisposition genes.	('mutations', 'Var', (172, 181))	('pancreatic cancer', 'Disease', (107, 124))	('PDAC', 'Phenotype', 'HP:0006725', (68, 72))	('patients', 'Species', '9606', (54, 62))	('pancreatic cancer', 'Disease', 'MESH:D010190', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('FPC', 'cellular_component', 'GO:1990900', ('191', '194'))	('PDAC', 'Chemical', '-', (68, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))
66446	27732944	The prevalence of deleterious mutations in these genes varies significantly in different populations (e.g., Ashkenazi Jews have high rates of germline BRCA2 mutations).	('BRCA2', 'Gene', '675', (151, 156))	('mutations', 'Var', (157, 166))	('BRCA2', 'Gene', (151, 156))
66448	27732944	In the present study, we retrospectively reviewed 1,197 PDAC patients diagnosed at one of two hospitals to evaluate incidence of FPC and we performed targeted-sequencing of germline variants for previously reported FPC susceptibility genes in the Western countries in 54 patients with available DNA, who had a family history of PDAC, and 13 patients who had a personal history of breast or ovarian cancer.	('PDAC', 'Phenotype', 'HP:0006725', (56, 60))	('patients', 'Species', '9606', (341, 349))	('cancer', 'Phenotype', 'HP:0002664', (398, 404))	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (380, 404))	('FPC', 'cellular_component', 'GO:1990900', ('215', '218'))	('PDAC', 'Disease', (328, 332))	('PDAC', 'Chemical', '-', (328, 332))	('PDAC', 'Phenotype', 'HP:0006725', (328, 332))	('variants', 'Var', (182, 190))	('patients', 'Species', '9606', (61, 69))	('DNA', 'cellular_component', 'GO:0005574', ('295', '298'))	('PDAC', 'Chemical', '-', (56, 60))	('patients', 'Species', '9606', (271, 279))	('FPC', 'cellular_component', 'GO:1990900', ('129', '132'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (390, 404))	('breast or ovarian cancer', 'Disease', (380, 404))
66457	27732944	Eight (14.5%) of the 54 FPC patients carried deleterious variants, three in BRCA2, two in PALB2, two in ATM, and the remaining one in MLH1, as summarized in Table 2.	('PALB2', 'Gene', (90, 95))	('BRCA2', 'Gene', (76, 81))	('ATM', 'Gene', '472', (104, 107))	('MLH1', 'Gene', '4292', (134, 138))	('BRCA2', 'Gene', '675', (76, 81))	('FPC', 'Disease', (24, 27))	('MLH1', 'Gene', (134, 138))	('FPC', 'cellular_component', 'GO:1990900', ('24', '27'))	('variants', 'Var', (57, 65))	('ATM', 'Gene', (104, 107))	('PALB2', 'Gene', '79728', (90, 95))	('patients', 'Species', '9606', (28, 36))
66458	27732944	One of the mutations found in BRCA2 gene, c.9076C>T/p.Gln3026Ter, has previously been identified in Japanese families with a history of breast or ovarian cancer.	('Ter', 'cellular_component', 'GO:0097047', ('61', '64'))	('breast or ovarian cancer', 'Disease', (136, 160))	('identified', 'Reg', (86, 96))	('c.9076C>T', 'Mutation', 'rs80359159', (42, 51))	('BRCA2', 'Gene', '675', (30, 35))	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (136, 160))	('BRCA2', 'Gene', (30, 35))	('ovarian cancer', 'Phenotype', 'HP:0100615', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('c.9076C>T/p.Gln3026Ter', 'Var', (42, 64))	('p.Gln3026Ter', 'Mutation', 'rs80359159', (52, 64))
66459	27732944	Details for clinicopathologic features in FPC patients with the deleterious mutations are shown in Table 3.	('mutations', 'Var', (76, 85))	('FPC', 'cellular_component', 'GO:1990900', ('42', '45'))	('patients', 'Species', '9606', (46, 54))	('FPC', 'Disease', (42, 45))
66460	27732944	All of tumors having developed in patients with these deleterious mutations were histopathologically conventional ductal adenocarcinomas.	('mutations', 'Var', (66, 75))	('adenocarcinomas', 'Disease', 'MESH:D000230', (121, 136))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Disease', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('adenocarcinomas', 'Disease', (121, 136))	('patients', 'Species', '9606', (34, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
66462	27732944	The patient (ID, NCCH-16) who carried a nonsense mutation in ATM had a personal history of breast cancer and ureter cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('nonsense mutation', 'Var', (40, 57))	('ureter cancer', 'Disease', (109, 122))	('patient', 'Species', '9606', (4, 11))	('ureter cancer', 'Disease', 'MESH:D014516', (109, 122))	('ATM', 'Gene', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ATM', 'Gene', '472', (61, 64))	('ureter cancer', 'Phenotype', 'HP:0100516', (109, 122))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
66469	27732944	Three (23%) of the 13 PDAC patients with a personal history of breast or ovarian cancer had deleterious mutations, two BRCA2 mutations and one ATM mutation, the latter of which was described in the previous section (NCCH-16) (Table 4).	('mutations', 'Var', (125, 134))	('breast or ovarian cancer', 'Disease', (63, 87))	('PDAC', 'Phenotype', 'HP:0006725', (22, 26))	('patients', 'Species', '9606', (27, 35))	('BRCA2', 'Gene', (119, 124))	('ATM', 'Gene', (143, 146))	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (63, 87))	('ovarian cancer', 'Phenotype', 'HP:0100615', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ATM', 'Gene', '472', (143, 146))	('PDAC', 'Chemical', '-', (22, 26))	('BRCA2', 'Gene', '675', (119, 124))
66470	27732944	One of mutations found in BRCA2 gene, c.6952C>T/p.Arg2318Ter, has previously been identified in Japanese having a strong family history of breast cancer.	('Ter', 'cellular_component', 'GO:0097047', ('57', '60'))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('BRCA2', 'Gene', (26, 31))	('c.6952C>T/p.Arg2318Ter', 'Var', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', (139, 152))	('c.6952C>T', 'Mutation', 'rs80358920', (38, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('p.Arg2318Ter', 'Mutation', 'rs80358920', (48, 60))	('BRCA2', 'Gene', '675', (26, 31))
66473	27732944	Our present study provides compelling evidence that a subset of PDAC in the Japanese population is familial and attributable to germline mutations in known familial pancreatic cancer genes.	('germline mutations', 'Var', (128, 146))	('PDAC', 'Phenotype', 'HP:0006725', (64, 68))	('familial pancreatic cancer', 'Disease', (156, 182))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (156, 182))	('PDAC', 'Disease', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('PDAC', 'Chemical', '-', (64, 68))
66479	27732944	Interestingly, these mutations were found to be heterogeneous but to primarily affect genes involved in DNA repair pathway, namely, BRCA2, PALB2, ATM, and MLH1.	('DNA repair pathway', 'Pathway', (104, 122))	('affect', 'Reg', (79, 85))	('ATM', 'Gene', (146, 149))	('PALB2', 'Gene', (139, 144))	('BRCA2', 'Gene', (132, 137))	('ATM', 'Gene', '472', (146, 149))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('BRCA2', 'Gene', '675', (132, 137))	('MLH1', 'Gene', '4292', (155, 159))	('MLH1', 'Gene', (155, 159))	('DNA repair', 'biological_process', 'GO:0006281', ('104', '114'))	('PALB2', 'Gene', '79728', (139, 144))	('mutations', 'Var', (21, 30))
66480	27732944	BRCA2 germline mutations are the most common in most Western cohorts of FPC.	('BRCA2', 'Gene', '675', (0, 5))	('germline', 'Var', (6, 14))	('FPC', 'cellular_component', 'GO:1990900', ('72', '75'))	('BRCA2', 'Gene', (0, 5))	('FPC', 'Disease', (72, 75))	('common', 'Reg', (38, 44))
66482	27732944	identified PALB2 mutations in 3 out of 96 American FPC families, which suggests that 3-4% of familial pancreatic cancer kindreds in Japan as well as USA likely to be attributable to germline PALB2 mutations.	('PALB2', 'Gene', '79728', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('PALB2', 'Gene', (191, 196))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('mutations', 'Var', (197, 206))	('FPC', 'cellular_component', 'GO:1990900', ('51', '54'))	('familial pancreatic cancer', 'Disease', (93, 119))	('familial pancreatic cancer', 'Disease', 'MESH:D010190', (93, 119))	('PALB2', 'Gene', (11, 16))	('PALB2', 'Gene', '79728', (11, 16))	('mutations', 'Var', (17, 26))
66488	27732944	In addition, our Japanese PDAC patients with a personal history of breast/ovarian cancer, although number is small, frequently carried deleterious mutations in these genes.	('mutations', 'Var', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (74, 88))	('breast/ovarian cancer', 'Disease', (67, 88))	('PDAC', 'Phenotype', 'HP:0006725', (26, 30))	('patients', 'Species', '9606', (31, 39))	('breast/ovarian cancer', 'Disease', 'MESH:D010051', (67, 88))	('carried', 'Reg', (127, 134))	('PDAC', 'Chemical', '-', (26, 30))
66496	27732944	We identified deleterious heterozygous germline mutations in well-established familial cancer-associated genes, BRCA2, PALB2, ATM and MLH1, in 14.5% (8/54) of our FPC patients.	('ATM', 'Gene', '472', (126, 129))	('FPC', 'cellular_component', 'GO:1990900', ('163', '166'))	('germline mutations', 'Var', (39, 57))	('familial cancer', 'Disease', (78, 93))	('familial cancer', 'Disease', 'MESH:D009369', (78, 93))	('patients', 'Species', '9606', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('MLH1', 'Gene', '4292', (134, 138))	('PALB2', 'Gene', (119, 124))	('BRCA2', 'Gene', (112, 117))	('MLH1', 'Gene', (134, 138))	('PALB2', 'Gene', '79728', (119, 124))	('ATM', 'Gene', (126, 129))	('BRCA2', 'Gene', '675', (112, 117))
66497	27732944	Our findings indicate that a subset of Japanese FPC patients may be associated with deleterious mutations of classical FPC genes as evidenced in Western populations.	('associated', 'Reg', (68, 78))	('FPC', 'Disease', (48, 51))	('FPC', 'cellular_component', 'GO:1990900', ('119', '122'))	('FPC', 'cellular_component', 'GO:1990900', ('48', '51'))	('mutations', 'Var', (96, 105))	('patients', 'Species', '9606', (52, 60))
66505	27732944	Variants in 21 genes were considered for analysis if they were (1) called nonreference by GATK; (2) predicted to affect the protein sequence or the splice site (i.e., +-5 base pairs); and (3) had an allele frequency of less than 1% in the 1000 Genome project, dbSNP, ExAC Browser (available at Exome Aggregation Consortium, http://exac.broadinstitute.org), or the Japanese genetic variation (available at the Human Genetic Variation Browser, http://www.genome.med.kyoto-u.ac.jp/SnpDB/).	('Variants', 'Var', (0, 8))	('Human', 'Species', '9606', (409, 414))	('splice site', 'MPA', (148, 159))	('protein sequence', 'MPA', (124, 140))	('affect', 'Reg', (113, 119))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))
66507	27732944	For BRCA1 and BRCA2, variants were classified using the database generated by Vallee et al., accessed through the LOVD Website (available at: http://brca.iarc.fr/LOVD).	('variants', 'Var', (21, 29))	('BRCA1', 'Gene', (4, 9))	('BRCA2', 'Gene', '675', (14, 19))	('BRCA2', 'Gene', (14, 19))	('brca', 'Gene', (149, 153))	('brca', 'Gene', '672', (149, 153))	('BRCA1', 'Gene', '672', (4, 9))
66508	27732944	These groups have classified large numbers of variants in BRCA1, BRCA2, MLH1, MSH2, MSH6, and PMS2, according to the International Agency for Research on Cancer system based on available information from the literature.	('MSH6', 'Gene', '2956', (84, 88))	('MSH2', 'Gene', (78, 82))	('BRCA2', 'Gene', '675', (65, 70))	('Cancer', 'Disease', (154, 160))	('MSH2', 'Gene', '4436', (78, 82))	('BRCA1', 'Gene', (58, 63))	('Cancer', 'Disease', 'MESH:D009369', (154, 160))	('Cancer', 'Phenotype', 'HP:0002664', (154, 160))	('PMS2', 'Gene', (94, 98))	('MSH6', 'Gene', (84, 88))	('variants', 'Var', (46, 54))	('BRCA2', 'Gene', (65, 70))	('MLH1', 'Gene', '4292', (72, 76))	('PMS2', 'Gene', '5395', (94, 98))	('MLH1', 'Gene', (72, 76))	('BRCA1', 'Gene', '672', (58, 63))
66509	27732944	PROVEN (available at: http://provean.jcvi.org/index.php), SIFT (available at: http://sift.jcvi.org) and PolyPhen-2 (available at: http://genetics.bwh.harvard.edu/pph2/) were used for identification of functional missense mutations along with a literature review.	('SIFT', 'Disease', (58, 62))	('missense mutations', 'Var', (212, 230))	('SIFT', 'Disease', 'None', (58, 62))	('pph', 'molecular_function', 'GO:0033978', ('162', '165'))	('pph', 'molecular_function', 'GO:0004238', ('162', '165'))
66513	26725115	The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('deregulation', 'Var', (18, 30))	('tumor epithelia', 'Disease', 'MESH:D009369', (88, 103))	('lead to', 'Reg', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('disruption', 'Var', (4, 14))	('invasion', 'CPA', (118, 126))	('tumor epithelia', 'Disease', (88, 103))
66516	26725115	We assess E-cadherin stability in native pancreatic tissue upon genetic manipulation involving Kras and p53 or in response to anti-invasive drug treatment and gain insights into the dynamic remodeling of E-cadherin during in situ cancer progression.	('E-cadherin', 'Protein', (10, 20))	('p53', 'Gene', (104, 107))	('genetic manipulation', 'Var', (64, 84))	('situ cancer', 'Disease', (225, 236))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('Kras', 'Gene', (95, 99))	('Kras', 'Gene', '16653', (95, 99))	('cadherin', 'molecular_function', 'GO:0008014', ('206', '214'))	('cadherin', 'molecular_function', 'GO:0008014', ('12', '20'))	('situ cancer', 'Disease', 'MESH:D002278', (225, 236))	('pancreatic', 'Disease', 'MESH:D010195', (41, 51))	('pancreatic', 'Disease', (41, 51))
66518	26725115	The E-cadherin-GFP mouse allows in situ quantification of E-cadherin mobility We monitored E-cadherin mobility during tissue homeostasis and disease development Invasive pancreatic cancer driven by mutant Kras/p53 increases E-cadherin mobility Dasatinib treatment reverts E-cadherin mobility and reinforces tumor cell junctions  Erami et al.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (170, 187))	('E-cadherin mobility', 'MPA', (272, 291))	('tumor', 'Disease', (307, 312))	('Dasatinib', 'Chemical', 'MESH:D000069439', (244, 253))	('reverts', 'NegReg', (264, 271))	('cadherin', 'molecular_function', 'GO:0008014', ('6', '14'))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('mutant', 'Var', (198, 204))	('E-cadherin mobility', 'MPA', (224, 243))	('cadherin', 'molecular_function', 'GO:0008014', ('93', '101'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (170, 187))	('Kras', 'Gene', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('pancreatic cancer', 'Disease', (170, 187))	('mouse', 'Species', '10090', (19, 24))	('Kras', 'Gene', '16653', (205, 209))	('reinforces', 'PosReg', (296, 306))	('cadherin', 'molecular_function', 'GO:0008014', ('60', '68'))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cadherin', 'molecular_function', 'GO:0008014', ('226', '234'))	('tissue homeostasis', 'biological_process', 'GO:0001894', ('118', '136'))	('cadherin', 'molecular_function', 'GO:0008014', ('274', '282'))
66526	26725115	Here we mimic the disease etiology of pancreatic cancer in situ, from acquisition of an initiating Kras mutation that occurs in 95% of pancreatic cancers to subsequent loss- or gain-of-function mutations in the tumor suppressor p53, which occur in 50%-75% of pancreatic cancers.	('pancreatic cancers', 'Disease', (135, 153))	('pancreatic cancer', 'Disease', 'MESH:D010190', (38, 55))	('Kras', 'Gene', (99, 103))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (259, 277))	('pancreatic cancer', 'Disease', 'MESH:D010190', (259, 276))	('tumor', 'Disease', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('pancreatic cancers', 'Disease', (259, 277))	('pancreatic cancer', 'Disease', (38, 55))	('pancreatic cancers', 'Disease', 'MESH:D010190', (135, 153))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cancers', 'Phenotype', 'HP:0002664', (270, 277))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Kras', 'Gene', '16653', (99, 103))	('mutation', 'Var', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('pancreatic cancers', 'Disease', 'MESH:D010190', (259, 277))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (135, 152))	('p53', 'Gene', (228, 231))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('211', '227'))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (38, 55))	('loss-', 'NegReg', (168, 173))	('gain-of-function', 'PosReg', (177, 193))	('tumor suppressor', 'biological_process', 'GO:0051726', ('211', '227'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (259, 276))	('mutations', 'Var', (194, 203))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (135, 153))	('pancreatic cancer', 'Disease', 'MESH:D010190', (135, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
66528	26725115	However, in mice with KrasG12D and gain-of-function mutations in p53 (p53R172H), E-cadherin is mobilized, facilitating the weakening of cell-cell contacts, correlating with the enhanced metastasis seen in this model.	('mutations', 'Var', (52, 61))	('p53', 'Gene', (65, 68))	('metastasis', 'CPA', (186, 196))	('Kras', 'Gene', (22, 26))	('Kras', 'Gene', '16653', (22, 26))	('gain-of-function', 'PosReg', (35, 51))	('E-cadherin', 'Protein', (81, 91))	('cell-cell contacts', 'CPA', (136, 154))	('mice', 'Species', '10090', (12, 16))	('weakening', 'NegReg', (123, 132))	('enhanced', 'PosReg', (177, 185))	('cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))
66535	26725115	In the liver, E-cadherin-GFP OFF mice were crossed to Cyp1a1-Cre mice, and deletion of the stop cassette was achieved after three doses of 2 mg beta-naphthoflavone over 8 hr (Movie S1, second panel).	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('Cyp1a1', 'Gene', '13076', (54, 60))	('deletion', 'Var', (75, 83))	('mice', 'Species', '10090', (65, 69))	('beta-naphthoflavone', 'Chemical', 'MESH:D019324', (144, 163))	('Cyp1a1', 'Gene', (54, 60))	('mice', 'Species', '10090', (33, 37))
66542	26725115	Using these cells, we generated stable pancreatic ductal adenocarcinoma (PDAC) p53-/- cells expressing empty vector alone (p53-/- vector) or the human equivalent of murine p53R172H (p53-/- R175H) with E-cadherin-GFP.	('cadherin', 'molecular_function', 'GO:0008014', ('203', '211'))	('pancreatic ductal adenocarcinoma', 'Disease', (39, 71))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (39, 71))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (39, 71))	('p53R172H', 'Var', (172, 180))	('human', 'Species', '9606', (145, 150))	('PDAC', 'Phenotype', 'HP:0006725', (73, 77))	('murine', 'Species', '10090', (165, 171))	('R175H', 'Mutation', 'rs28934578', (189, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
66544	26725115	FRAP recovery curves from time-lapse movies of p53-/- vector or p53-/- R175H primary PDAC cells were then analyzed (; Supplemental Experimental Procedures; Figure S2).	('R175H', 'Mutation', 'rs28934578', (71, 76))	('p53-/- R175H', 'Var', (64, 76))	('p53-/- vector', 'Var', (47, 60))	('PDAC', 'Phenotype', 'HP:0006725', (85, 89))
66546	26725115	Critically, assessment in a 3D environment using cells grown on cell-derived matrices (CDMs) to mimic in vivo conditions revealed enhanced mobilization of E-cadherin in invasive cells, where mutant p53-/- R175H cells had a significantly higher mobile fraction of E-cadherin compared with p53-/- vector cells (Figures 2B, orange recovery curve versus purple, and 2C, average mobile fraction 39.9% +- 2.8% versus 65.6% +- 4.4%; Figure S3A).	('enhanced', 'PosReg', (130, 138))	('mobilization', 'MPA', (139, 151))	('mutant p53-/- R175H', 'Var', (191, 210))	('cadherin', 'molecular_function', 'GO:0008014', ('157', '165'))	('higher', 'PosReg', (237, 243))	('mobile fraction of E-cadherin', 'MPA', (244, 273))	('R175H', 'Mutation', 'rs28934578', (205, 210))	('cadherin', 'molecular_function', 'GO:0008014', ('265', '273'))
66547	26725115	To further assess E-cadherin mobility and corroborate our findings in this 3D setting, complementary fluorescence loss in photobleaching (FLIP) analysis was performed on p53-/- vector versus mutant p53-/- R175H cells grown on CDMs (Figures 2D-2G).	('cadherin', 'molecular_function', 'GO:0008014', ('20', '28'))	('p53-/- vector', 'Var', (170, 183))	('R175H', 'Mutation', 'rs28934578', (205, 210))	('mutant p53-/- R175H', 'Var', (191, 210))
66548	26725115	In contrast, mutant p53-/- R175H cells exhibited a significant loss of fluorescence intensity in junctions adjacent to the bleach region over time (Figures 2F and 2G, dark blue line and bar graph), commensurate with the transfer of bleached E-cadherin molecules into this area and an enhanced mobilization of E-cadherin junctions in mutant p53 cells compared with p53-/- vector cells.	('mutant', 'Var', (333, 339))	('mobilization', 'MPA', (293, 305))	('cadherin', 'molecular_function', 'GO:0008014', ('311', '319'))	('cadherin', 'molecular_function', 'GO:0008014', ('243', '251'))	('fluorescence intensity in junctions', 'MPA', (71, 106))	('mutant p53-/- R175H', 'Var', (13, 32))	('enhanced', 'PosReg', (284, 292))	('p53', 'Gene', (340, 343))	('loss', 'NegReg', (63, 67))	('E-cadherin', 'Protein', (309, 319))	('R175H', 'Mutation', 'rs28934578', (27, 32))
66549	26725115	To assess whether E-cadherin is distributed equally at distinct points of the membrane in PDAC cells, we created kymographs of unbleached junctions from p53-/- vector and p53-/- R175H cells (Figures S3B-S3D).	('PDAC', 'Phenotype', 'HP:0006725', (90, 94))	('S3B', 'Gene', '11778', (199, 202))	('membrane', 'cellular_component', 'GO:0016020', ('78', '86'))	('p53-/- vector', 'Var', (153, 166))	('cadherin', 'molecular_function', 'GO:0008014', ('20', '28'))	('S3B', 'Gene', (199, 202))	('R175H', 'Mutation', 'rs28934578', (178, 183))	('p53-/- R175H', 'Var', (171, 183))
66550	26725115	We observed an elevated distribution of high-intensity zones of E-cadherin-GFP in p53-/- vector cells compared with p53-/- R175H cells (Figures S3C and S3D, blue arrows).	('cadherin', 'molecular_function', 'GO:0008014', ('66', '74'))	('elevated', 'PosReg', (15, 23))	('distribution', 'MPA', (24, 36))	('E-cadherin-GFP', 'Protein', (64, 78))	('p53-/- vector', 'Var', (82, 95))	('R175H', 'Mutation', 'rs28934578', (123, 128))
66554	26725115	In line with previous work, p53-/- R175H tumor-bearing mice demonstrated collective local invasion compared with encapsulated non-invasive p53-/- vector tumors (Figure 3A).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('R175H', 'Mutation', 'rs28934578', (35, 40))	('p53-/- R175H', 'Var', (28, 40))	('tumor', 'Disease', (41, 46))	('mice', 'Species', '10090', (55, 59))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('local invasion', 'CPA', (84, 98))
66555	26725115	FRAP recovery curves from time-lapse movies of xenograft tumors obtained using intravital FRAP imaging (Figure 3B) revealed an enhanced mobile fraction in p53-/- R175H versus p53-/- vector cells in this setting (Figures 3C and 3D, 32.1% +- 2.9% versus 18.8% +- 1.7%; Figure S3F; Movie S5).	('R175H', 'Mutation', 'rs28934578', (162, 167))	('enhanced', 'PosReg', (127, 135))	('p53-/- R175H', 'Var', (155, 167))	('xenograft tumors', 'Disease', (47, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mobile fraction', 'MPA', (136, 151))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('xenograft tumors', 'Disease', 'MESH:D009369', (47, 63))
66556	26725115	Similarly, FLIP analysis of the xenograft tumors (Figures 3E-3H; Movie S6) shows a significantly higher loss of fluorescence in areas proximal to the bleach region in p53-/- R175H tumors compared with p53-/- vector tumors, corroborating our FRAP analysis (Figures 3G and 3H, compare light blue and dark blue FLIP traces and bar graphs).	('p53-/- R175H', 'Var', (167, 179))	('loss', 'NegReg', (104, 108))	('xenograft tumors', 'Disease', (32, 48))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('fluorescence in areas', 'MPA', (112, 133))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('xenograft tumors', 'Disease', 'MESH:D009369', (32, 48))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('R175H', 'Mutation', 'rs28934578', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (215, 221))
66557	26725115	Furthermore, OD-GLCM analysis of unbleached junctions again showed a higher contrast of high versus low E-cadherin-GFP intensity/texture in p53-/- vector tumors compared with p53-/- R175H tumors (Figures S3G-S3I), indicating an increased stabilization of E-cadherin in p53-/- vector control cells in vivo.	('cadherin', 'molecular_function', 'GO:0008014', ('106', '114'))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cadherin', 'molecular_function', 'GO:0008014', ('257', '265'))	('low', 'NegReg', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('p53-/- vector', 'Var', (140, 153))	('R175H', 'Mutation', 'rs28934578', (182, 187))
66559	26725115	Here we find that the width of the bleached region expands significantly faster in p53-/- R175H xenografts compared with p53-/- vector xenografts, indicating faster lateral motion of E-cadherin in the mutant xenografts (Figures 4C-4H; compare the slopes as a measure of the recovery speed between Figures 4E and 4H, with the effective diffusion coefficient Deff = 4.88 +- 0.3 x 10-3 mum2 s-1 versus 1.70 +- 0.1 x 10-3 mum2 s-1, respectively).	('R175H', 'Mutation', 'rs28934578', (90, 95))	('p53-/- R175H', 'Var', (83, 95))	('faster', 'PosReg', (73, 79))	('lateral motion', 'CPA', (165, 179))	('faster', 'PosReg', (158, 164))	('cadherin', 'molecular_function', 'GO:0008014', ('185', '193'))
66560	26725115	This indicates that the increase in E-cadherin mobility observed in locally invasive p53-/- R175H xenografts may be primarily attributed to increased mobility within the membrane.	('increase', 'PosReg', (24, 32))	('p53-/- R175H', 'Var', (85, 97))	('mobility', 'MPA', (47, 55))	('R175H', 'Mutation', 'rs28934578', (92, 97))	('E-cadherin', 'Protein', (36, 46))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('membrane', 'cellular_component', 'GO:0016020', ('170', '178'))	('increased', 'PosReg', (140, 149))
66564	26725115	The E-cadherin-GFP mouse was therefore crossed with either wild-type mice expressing Pdx1-Cre, mice bearing a Pdx1-Cre-driven initiating KrasG12D mutation alone, Pdx1-Cre; KrasG12D; p53-/- mice, or Pdx1-Cre; KrasG12D; mutant p53R172H mice and monitored for ~150 days to allow tumor formation to occur.	('mice', 'Species', '10090', (95, 99))	('Kras', 'Gene', (137, 141))	('Pdx1', 'Gene', (162, 166))	('mice', 'Species', '10090', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('mice', 'Species', '10090', (69, 73))	('Kras', 'Gene', '16653', (172, 176))	('mutation', 'Var', (146, 154))	('cadherin', 'molecular_function', 'GO:0008014', ('6', '14'))	('Kras', 'Gene', (208, 212))	('Kras', 'Gene', '16653', (137, 141))	('Pdx1', 'Gene', '18609', (110, 114))	('mice', 'Species', '10090', (234, 238))	('formation', 'biological_process', 'GO:0009058', ('282', '291'))	('Pdx1', 'Gene', '18609', (198, 202))	('p53R172H', 'Var', (225, 233))	('Pdx1', 'Gene', (110, 114))	('Kras', 'Gene', '16653', (208, 212))	('Pdx1', 'Gene', (198, 202))	('tumor', 'Disease', (276, 281))	('mouse', 'Species', '10090', (19, 24))	('Pdx1', 'Gene', '18609', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('Pdx1', 'Gene', '18609', (162, 166))	('Pdx1', 'Gene', (85, 89))	('Kras', 'Gene', (172, 176))
66568	26725115	This indicates that initiating KrasG12D mutations in the pancreas are not sufficient to drive E-cadherin mobilization in situ.	('Kras', 'Gene', '16653', (31, 35))	('mutations', 'Var', (40, 49))	('E-cadherin mobilization', 'MPA', (94, 117))	('Kras', 'Gene', (31, 35))	('cadherin', 'molecular_function', 'GO:0008014', ('96', '104'))
66569	26725115	Importantly, loss of p53 on a KrasG12D background from age-matched tumors also had no effect on E-cadherin mobility compared with normal pancreatic tissue or KrasG12D tumors alone (Figures 5D and 5E, purple line, 21.6% +- 1.7% mobile fraction).	('KrasG12D tumors', 'Disease', (158, 173))	('KrasG12D tumors', 'Disease', 'MESH:D009369', (158, 173))	('Kras', 'Gene', '16653', (30, 34))	('loss', 'Var', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('E-cadherin mobility', 'MPA', (96, 115))	('pancreatic', 'Disease', 'MESH:D010195', (137, 147))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Kras', 'Gene', (158, 162))	('cadherin', 'molecular_function', 'GO:0008014', ('98', '106'))	('pancreatic', 'Disease', (137, 147))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Disease', (67, 73))	('p53', 'Gene', (21, 24))	('Kras', 'Gene', (30, 34))	('Kras', 'Gene', '16653', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
66570	26725115	This demonstrates that, although loss of the tumor suppressor p53 in combination with initiating KrasG12D mutations enhances tumor progression, it does not act to mobilize E-cadherin, correlating with the lack of invasion or metastasis we observed previously in KrasG12D; p53-/- mice.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('loss of the tumor', 'Disease', 'MESH:D009369', (33, 50))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('Kras', 'Gene', (97, 101))	('loss of the tumor', 'Disease', (33, 50))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('45', '61'))	('Kras', 'Gene', (262, 266))	('p53', 'Gene', (62, 65))	('Kras', 'Gene', '16653', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor suppressor', 'biological_process', 'GO:0051726', ('45', '61'))	('mice', 'Species', '10090', (279, 283))	('Kras', 'Gene', '16653', (262, 266))	('enhances', 'PosReg', (116, 124))	('tumor', 'Disease', (125, 130))	('mutations', 'Var', (106, 115))	('cadherin', 'molecular_function', 'GO:0008014', ('174', '182'))
66571	26725115	Critically, FRAP analysis of tumors from ~150-day-old, KrasG12D; p53R172H; E-cadherin-GFP mice revealed that gain-of-function mutations in p53 on a KrasG12D background significantly mobilizes E-cadherin junctions in the pancreas (Figures 5D and 5E, orange line, 31.8% +- 1.8% mobile fraction compared with the average of 22.4% +- 1.1% found in normal pancreas, KrasG12D, or KrasG12D; p53-/- tumors).	('gain-of-function', 'PosReg', (109, 125))	('tumors', 'Disease', (391, 397))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('p53', 'Gene', (139, 142))	('E-cadherin', 'Protein', (192, 202))	('cadherin', 'molecular_function', 'GO:0008014', ('77', '85'))	('Kras', 'Gene', '16653', (361, 365))	('tumors', 'Disease', 'MESH:D009369', (391, 397))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Kras', 'Gene', (374, 378))	('mutations', 'Var', (126, 135))	('Kras', 'Gene', (55, 59))	('tumors', 'Disease', (29, 35))	('mobilizes', 'PosReg', (182, 191))	('Kras', 'Gene', '16653', (374, 378))	('mobile fraction', 'MPA', (276, 291))	('mice', 'Species', '10090', (90, 94))	('Kras', 'Gene', '16653', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('Kras', 'Gene', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('tumors', 'Phenotype', 'HP:0002664', (391, 397))	('Kras', 'Gene', '16653', (148, 152))	('Kras', 'Gene', (361, 365))	('cadherin', 'molecular_function', 'GO:0008014', ('194', '202'))
66572	26725115	This indicates that acquisition of mutant p53R172H, which we have shown previously to drive an invasive and metastatic program over and above the loss of p53 in pancreatic cancer, could partially achieve this by allowing early tumor dissolution via mobilization of E-cadherin-based cell-cell contacts (Figure 5F).	('pancreatic cancer', 'Disease', 'MESH:D010190', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cadherin', 'molecular_function', 'GO:0008014', ('267', '275'))	('tumor', 'Disease', (227, 232))	('mobilization', 'MPA', (249, 261))	('mutant p53R172H', 'Var', (35, 50))	('E-cadherin-based', 'Protein', (265, 281))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (161, 178))	('p53R172H', 'Var', (42, 50))	('drive', 'PosReg', (86, 91))	('allowing', 'Reg', (212, 220))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('pancreatic cancer', 'Disease', (161, 178))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
66576	26725115	As before, Pdx1-Cre; KrasG12D; p53R172H; E-cadherin-GFP mice were allowed to form tumors for ~150 days and, upon signs of tumor burden, were placed on daily dasatinib treatment (10 mg/kg) for 3 consecutive days (Figure 6A), followed by FRAP analysis (Figure 6B; Movie S7).	('dasatinib', 'Chemical', 'MESH:D000069439', (157, 166))	('Pdx1', 'Gene', (11, 15))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('p53R172H', 'Var', (31, 39))	('Pdx1', 'Gene', '18609', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Kras', 'Gene', (21, 25))	('Kras', 'Gene', '16653', (21, 25))	('mice', 'Species', '10090', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cadherin', 'molecular_function', 'GO:0008014', ('43', '51'))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (122, 127))
66579	26725115	Similar results were obtained in E-cadherin-GFP-transfected p53-/- R175H and p53-/- vector cells (Figure 6E, columns 3 and 4), confirming that mutant p53 reduces junction integrity in PDAC cells.	('mutant', 'Var', (143, 149))	('R175H', 'Mutation', 'rs28934578', (67, 72))	('p53', 'Gene', (150, 153))	('junction integrity', 'MPA', (162, 180))	('cadherin', 'molecular_function', 'GO:0008014', ('35', '43'))	('reduces', 'NegReg', (154, 161))	('PDAC', 'Phenotype', 'HP:0006725', (184, 188))
66580	26725115	In line with our results demonstrating that dasatinib impairs invasion via potentially enhancing cell-cell adhesions, TEER analysis of dasatinib-treated mutant p53-expressing PDAC cells (E-cadherin-GFP-transfected p53R172H or p53-/- R175H cells) revealed that Src inhibition (Figures S4D and S4E) stabilized and strengthened junctions to a similar level as that found in a non-invasive p53-/- setting (Figure 6E, columns 5-8).	('Src', 'Gene', '20779', (260, 263))	('impairs', 'NegReg', (54, 61))	('cadherin', 'molecular_function', 'GO:0008014', ('189', '197'))	('Src', 'Gene', (260, 263))	('dasatinib', 'Chemical', 'MESH:D000069439', (44, 53))	('cell-cell adhesions', 'CPA', (97, 116))	('enhancing', 'PosReg', (87, 96))	('mutant', 'Var', (153, 159))	('PDAC', 'Phenotype', 'HP:0006725', (175, 179))	('dasatinib', 'Chemical', 'MESH:D000069439', (135, 144))	('invasion', 'CPA', (62, 70))	('junctions', 'MPA', (325, 334))	('strengthened', 'PosReg', (312, 324))	('R175H', 'Mutation', 'rs28934578', (233, 238))
66581	26725115	This was confirmed using the Dispase II assay, where mutant p53 cells (E-cadherin-GFP-transfected p53R172H or p53-/- R175H cells) show an increased number of single cells upon mechanical disruption compared with p53-/- E-cadherin-GFP-transfected counterparts (Figure 6F, columns 1-4).	('R175H', 'Mutation', 'rs28934578', (117, 122))	('increased', 'PosReg', (138, 147))	('cadherin', 'molecular_function', 'GO:0008014', ('221', '229'))	('cadherin', 'molecular_function', 'GO:0008014', ('73', '81'))	('p53', 'Gene', (60, 63))	('mutant', 'Var', (53, 59))
66582	26725115	Importantly, cell dissociation was reverted to similar levels as those found in non-invasive p53-/- or vector-alone counterparts when mutant p53 cells were treated with dasatinib (Figure 6F, compare columns 1-4 with columns 5-8).	('p53', 'Gene', (141, 144))	('mutant', 'Var', (134, 140))	('cell dissociation', 'CPA', (13, 30))	('dasatinib', 'Chemical', 'MESH:D000069439', (169, 178))
66583	26725115	These results illustrate that mutant p53 on an initiating KrasG12D background weakens cell-cell junction strength, which could lead to tumor dissociation, and that Src inhibition can partially impair this breakdown.	('tumor dissociation', 'Disease', (135, 153))	('Src', 'Gene', '20779', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cell-cell junction strength', 'CPA', (86, 113))	('Src', 'Gene', (164, 167))	('lead to', 'Reg', (127, 134))	('p53', 'Gene', (37, 40))	('Kras', 'Gene', '16653', (58, 62))	('Kras', 'Gene', (58, 62))	('weakens', 'NegReg', (78, 85))	('mutant', 'Var', (30, 36))	('cell-cell junction', 'cellular_component', 'GO:0005911', ('86', '104'))	('breakdown', 'biological_process', 'GO:0009056', ('205', '214'))	('tumor dissociation', 'Disease', 'MESH:D004213', (135, 153))
66586	26725115	In line with the concept of stabilizing E-cadherin junctions via Src inhibition, we isolated metastatic tumor cells that had colonized the liver of invasive Pdx1-Cre; KrasG12D; p53R172H; E-cadherin-GFP mice using whole-body fluorescence imaging (Figures 7A and 7B, whole-body imaging and inset, respectively, showing primary tumor and liver micro-metastases isolated from the same mouse).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cadherin', 'molecular_function', 'GO:0008014', ('42', '50'))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('mice', 'Species', '10090', (202, 206))	('mouse', 'Species', '10090', (381, 386))	('Kras', 'Gene', (167, 171))	('Src', 'Gene', '20779', (65, 68))	('primary tumor', 'Disease', 'MESH:D009369', (317, 330))	('Pdx1', 'Gene', '18609', (157, 161))	('metastases', 'Disease', 'MESH:D009362', (347, 357))	('primary tumor', 'Disease', (317, 330))	('Kras', 'Gene', '16653', (167, 171))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (325, 330))	('Pdx1', 'Gene', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('metastases', 'Disease', (347, 357))	('cadherin', 'molecular_function', 'GO:0008014', ('189', '197'))	('p53R172H', 'Var', (177, 185))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('Src', 'Gene', (65, 68))
66588	26725115	Importantly, upon treatment of these invasive cells with dasatinib, invasion was reduced significantly compared with control cells (Figures 7F, 7G, and S5C, right, for three independent metastatic lines from three independent mice [101912 met, 101025 met, and 111375 met, respectively]).	('[101912 met', 'Var', (231, 242))	('mice', 'Species', '10090', (226, 230))	('invasion', 'CPA', (68, 76))	('101025 met', 'Var', (244, 254))	('111375 met', 'Var', (260, 270))	('reduced', 'NegReg', (81, 88))	('dasatinib', 'Chemical', 'MESH:D000069439', (57, 66))
66592	26725115	Collectively, these data indicate that Src inhibition may partially stabilize E-cadherin-based cell-cell junctions and could retard early pancreatic tumor cell dissociation and, subsequently, decrease invasive efficiency by inducing tumor cell clustering.	('inhibition', 'Var', (43, 53))	('inducing', 'Reg', (224, 232))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('stabilize', 'Reg', (68, 77))	('invasive efficiency', 'Disease', 'MESH:D009362', (201, 220))	('Src', 'Gene', (39, 42))	('retard', 'Disease', 'MESH:D008607', (125, 131))	('tumor', 'Disease', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('retard', 'Disease', (125, 131))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (138, 154))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('invasive efficiency', 'Disease', (201, 220))	('decrease', 'NegReg', (192, 200))	('pancreatic tumor', 'Disease', (138, 154))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))	('Src', 'Gene', '20779', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('pancreatic tumor', 'Disease', 'MESH:D010190', (138, 154))	('tumor', 'Disease', (149, 154))	('E-cadherin-based', 'Protein', (78, 94))
66593	26725115	This led us to examine whether the enhanced mobilization of E-cadherin and weakening of junction strength observed in invasive mutant p53 pancreatic tumors (Figures 3 and 5) could also be partly reverted in these more aggressive metastatic lines from the E-cadherin-GFP mouse.	('mutant', 'Var', (127, 133))	('pancreatic tumors', 'Disease', 'MESH:D010190', (138, 155))	('pancreatic tumors', 'Disease', (138, 155))	('cadherin', 'molecular_function', 'GO:0008014', ('62', '70'))	('mobilization', 'MPA', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (138, 155))	('junction strength', 'MPA', (88, 105))	('enhanced', 'PosReg', (35, 43))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('E-cadherin', 'Protein', (60, 70))	('cadherin', 'molecular_function', 'GO:0008014', ('257', '265'))	('weakening', 'NegReg', (75, 84))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (138, 154))	('p53', 'Gene', (134, 137))	('mouse', 'Species', '10090', (270, 275))
66597	26725115	Lastly, in line with our CDM and xenograft data (Figures 2 and 3), OD-GLCM analysis of mutant metastatic lines also revealed a reduction in contrast and a more uniform, malleable organization of E-cadherin-GFP distribution compared with primary tumor cells isolated from Pdx1-Cre; KrasG12D; p53-/-; E-cadherin-GFP mice (Figures S6J and S6K), suggesting that E-cadherin destabilization is maintained in mutant p53 metastatic cells derived from the E-cadherin-GFP mouse.	('Pdx1', 'Gene', '18609', (271, 275))	('cadherin', 'molecular_function', 'GO:0008014', ('301', '309'))	('mutant', 'Var', (402, 408))	('primary tumor', 'Disease', (237, 250))	('Kras', 'Gene', (281, 285))	('Kras', 'Gene', '16653', (281, 285))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('primary tumor', 'Disease', 'MESH:D009369', (237, 250))	('mutant', 'Var', (87, 93))	('mouse', 'Species', '10090', (462, 467))	('cadherin', 'molecular_function', 'GO:0008014', ('197', '205'))	('mice', 'Species', '10090', (314, 318))	('cadherin', 'molecular_function', 'GO:0008014', ('360', '368'))	('contrast', 'MPA', (140, 148))	('reduction', 'NegReg', (127, 136))	('cadherin', 'molecular_function', 'GO:0008014', ('449', '457'))	('Pdx1', 'Gene', (271, 275))	('p53', 'Gene', (409, 412))
66601	26725115	This indicates that, in many cases, deregulation of E-cadherin mobility rather than expression level may play an additional role in promoting invasion and suggests that monitoring E-cadherin behavior in this context could lead to a greater understanding of cancer invasion and response to new therapeutics.	('E-cadherin', 'Protein', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('lead to', 'Reg', (222, 229))	('promoting', 'PosReg', (132, 141))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cadherin', 'molecular_function', 'GO:0008014', ('54', '62'))	('cadherin', 'molecular_function', 'GO:0008014', ('182', '190'))	('deregulation', 'Var', (36, 48))	('cancer', 'Disease', (257, 263))	('invasion', 'CPA', (142, 150))
66607	26725115	Crossing the E-cadherin-GFP mouse with distinct genetic models of pancreatic cancer has demonstrated its utility for examining the effects of specific mutations on E-cadherin in a time- and tissue-specific and subcellular manner.	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('mouse', 'Species', '10090', (28, 33))	('pancreatic cancer', 'Disease', (66, 83))	('pancreatic cancer', 'Disease', 'MESH:D010190', (66, 83))	('cadherin', 'molecular_function', 'GO:0008014', ('166', '174'))	('E-cadherin', 'Gene', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (151, 160))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (66, 83))
66608	26725115	In pancreatic cancer, initiating mutations in the KRAS gene occur in approximately 95% of patients and are often followed by sequential accumulation of genetic alterations, such as loss of expression, function, or mutations in tumor suppressors and regulators, such as TP53, CDKN2A, INK4A/ARF, and/or PTEN.	('tumor', 'Disease', (227, 232))	('INK4A/ARF', 'Gene', (283, 292))	('mutations', 'Var', (33, 42))	('KRAS', 'Gene', '3845', (50, 54))	('TP53', 'Gene', (269, 273))	('PTEN', 'Gene', '5728', (301, 305))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('CDKN2A', 'Gene', '1029', (275, 281))	('mutations', 'Var', (214, 223))	('KRAS', 'Gene', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('loss of', 'NegReg', (181, 188))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('TP53', 'Gene', '7157', (269, 273))	('INK4A/ARF', 'Gene', '1029', (283, 292))	('patients', 'Species', '9606', (90, 98))	('pancreatic cancer', 'Disease', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('expression', 'MPA', (189, 199))	('PTEN', 'Gene', (301, 305))	('function', 'Disease', (201, 209))	('CDKN2A', 'Gene', (275, 281))
66609	26725115	Although we know the frequency of such mutations in PDAC, their specific function during development of invasive pancreatic cancer remains unclear.	('invasive pancreatic cancer', 'Disease', 'MESH:D010190', (104, 130))	('invasive pancreatic cancer', 'Disease', (104, 130))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('PDAC', 'Gene', (52, 56))	('mutations', 'Var', (39, 48))	('PDAC', 'Phenotype', 'HP:0006725', (52, 56))
66610	26725115	Here, we show that acquiring KrasG12D mutations or subsequent loss of p53 on a KrasG12D background in the pancreas is not sufficient to drive alterations to E-cadherin mobility, whereas acquisition of a gain-of-function mutation in p53 on the same initiating KrasG12D background mobilizes E-cadherin, consistent with the tumor dissolution and metastasis found in these mice.	('loss', 'NegReg', (62, 66))	('Kras', 'Gene', '16653', (29, 33))	('alterations', 'Reg', (142, 153))	('p53', 'Gene', (232, 235))	('tumor', 'Disease', (321, 326))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('gain-of-function', 'PosReg', (203, 219))	('Kras', 'Gene', (79, 83))	('mice', 'Species', '10090', (369, 373))	('cadherin', 'molecular_function', 'GO:0008014', ('291', '299'))	('mobilizes E-cadherin', 'MPA', (279, 299))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('Kras', 'Gene', '16653', (79, 83))	('Kras', 'Gene', (259, 263))	('Kras', 'Gene', (29, 33))	('p53', 'Gene', (70, 73))	('E-cadherin mobility', 'MPA', (157, 176))	('mutation', 'Var', (220, 228))	('cadherin', 'molecular_function', 'GO:0008014', ('159', '167'))	('Kras', 'Gene', '16653', (259, 263))
66611	26725115	Importantly, reduction or reversion of cell-cell junction strength was achieved by molecular manipulation in the form of overexpressing the human equivalent of murine p53R172H (R175H) or inhibiting E-cadherin mobilization via Src inactivation, respectively.	('E-cadherin mobilization', 'MPA', (198, 221))	('murine', 'Species', '10090', (160, 166))	('overexpressing', 'PosReg', (121, 135))	('human', 'Species', '9606', (140, 145))	('cadherin', 'molecular_function', 'GO:0008014', ('200', '208'))	('Src', 'Gene', (226, 229))	('p53R172H', 'Var', (167, 175))	('Src', 'Gene', '20779', (226, 229))	('R175H', 'Mutation', 'rs28934578', (177, 182))	('cell-cell junction strength', 'CPA', (39, 66))	('inhibiting', 'NegReg', (187, 197))	('reduction', 'NegReg', (13, 22))	('cell-cell junction', 'cellular_component', 'GO:0005911', ('39', '57'))
66612	26725115	This demonstrates that mutant p53 can partially drive the breakdown of tumors by disrupting E-cadherin cell-cell engagement via Src.	('disrupting', 'NegReg', (81, 91))	('breakdown', 'biological_process', 'GO:0009056', ('58', '67'))	('Src', 'Gene', '20779', (128, 131))	('E-cadherin', 'Protein', (92, 102))	('p53', 'Gene', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Src', 'Gene', (128, 131))	('breakdown', 'Disease', (58, 67))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('cadherin', 'molecular_function', 'GO:0008014', ('94', '102'))	('mutant', 'Var', (23, 29))
66613	26725115	It should be noted that both dasatinib and saracatenib, while inhibiting Src kinase, also target Abl and other kinases and were used here in a proof-of-principle context to demonstrate the utility of the mouse in pre-clinical drug discovery applications.	('kinases', 'MPA', (111, 118))	('saracatenib', 'Var', (43, 54))	('Abl', 'Gene', '11350', (97, 100))	('dasatinib', 'Chemical', 'MESH:D000069439', (29, 38))	('saracatenib', 'Chemical', '-', (43, 54))	('pre', 'molecular_function', 'GO:0003904', ('213', '216'))	('inhibiting', 'NegReg', (62, 72))	('Src', 'Gene', '20779', (73, 76))	('mouse', 'Species', '10090', (204, 209))	('Src', 'Gene', (73, 76))	('target', 'Reg', (90, 96))	('Abl', 'Gene', (97, 100))
66614	26725115	To this end, the E-cadherin-GFP mouse could also be used to decipher other molecular pathways downstream of mutant p53 to be targeted in future studies or be used with other Kras or p53 mutations to determine whether E-cadherin mobilization is a general phenomenon for all mutant p53 variants in this disease.	('E-cadherin mobilization', 'MPA', (217, 240))	('cadherin', 'molecular_function', 'GO:0008014', ('219', '227'))	('Kras', 'Gene', (174, 178))	('p53', 'Gene', (115, 118))	('mutant', 'Var', (108, 114))	('p53', 'Gene', (280, 283))	('Kras', 'Gene', '16653', (174, 178))	('cadherin', 'molecular_function', 'GO:0008014', ('19', '27'))	('mouse', 'Species', '10090', (32, 37))	('variants', 'Var', (284, 292))	('mutant', 'Var', (273, 279))
66696	25674740	Evidence for the optimal management of this rare histological type of pancreatic cancer, estimated to represent 3% to 4% of primary pancreatic cancer cases, is scant, although it has been reported that squamous differentiation is associated with more biologically aggressive behavior and that chemoradiotherapy can be associated with improved overall survival.	('biologically aggressive behavior', 'CPA', (251, 283))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (70, 87))	('type of pancreatic cancer', 'Disease', 'MESH:D010190', (62, 87))	('improved', 'PosReg', (334, 342))	('more', 'PosReg', (246, 250))	('pancreatic cancer', 'Disease', (132, 149))	('type of pancreatic cancer', 'Disease', (62, 87))	('pancreatic cancer', 'Disease', 'MESH:D010190', (70, 87))	('pancreatic cancer', 'Disease', 'MESH:D010190', (132, 149))	('overall', 'MPA', (343, 350))	('aggressive behavior', 'biological_process', 'GO:0002118', ('264', '283'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('squamous', 'Var', (202, 210))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 149))	('aggressive behavior', 'Phenotype', 'HP:0000718', (264, 283))
66723	25604078	However, there are other reports showing that activation of PKCalpha inhibits the proliferation of pancreatic cancer cell lines and increases the expression of pro-apoptotic proteins.	('pancreatic cancer', 'Disease', (99, 116))	('inhibits', 'NegReg', (69, 77))	('PKCalpha', 'Gene', '5578', (60, 68))	('PKCalpha', 'Gene', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (99, 116))	('increases', 'PosReg', (132, 141))	('proliferation', 'CPA', (82, 95))	('activation', 'Var', (46, 56))	('expression of', 'MPA', (146, 159))	('PKCalpha', 'molecular_function', 'GO:0004697', ('60', '68'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (99, 116))
66732	25604078	For example, aprinocarsen (LY900003), an antisense oligonucleotide inhibitor that selectively-targets the mRNA encoding PKCalpha failed in phase III cancer trials.	('PKCalpha', 'molecular_function', 'GO:0004697', ('120', '128'))	('cancer', 'Disease', (149, 155))	('LY900003', 'Var', (27, 35))	('oligonucleotide', 'Chemical', 'MESH:D009841', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('aprinocarsen', 'Chemical', 'MESH:C488084', (13, 25))	('PKCalpha', 'Gene', '5578', (120, 128))	('PKCalpha', 'Gene', (120, 128))	('LY900003', 'Chemical', 'MESH:C108494', (27, 35))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
66733	25604078	Similarly, enzastaurin (LY317615), a potent inhibitor with a high selectivity for PKCbeta (IC50 of 6 nM), although it demonstrated anti-tumor activity on freshly-explanted primary pancreatic cancer specimen, was ineffective in clinical trials.	('PKCbeta', 'molecular_function', 'GO:0004697', ('82', '89'))	('PKCbeta', 'Gene', (82, 89))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (180, 197))	('pancreatic cancer', 'Disease', 'MESH:D010190', (180, 197))	('LY317615', 'Chemical', 'MESH:C504878', (24, 32))	('pancreatic cancer', 'Disease', (180, 197))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('PKCbeta', 'Gene', '5579', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('enzastaurin', 'Chemical', 'MESH:C504878', (11, 22))	('tumor', 'Disease', (136, 141))	('LY317615', 'Var', (24, 32))
66738	25604078	In pancreatic cancer cell lines expressing mutant Kras, PKCdelta and PKCepsilon regulate anchorage-independent growth.	('regulate', 'Reg', (80, 88))	('pancreatic cancer', 'Disease', (3, 20))	('anchorage-independent growth', 'CPA', (89, 117))	('PKCdelta', 'Gene', '5580', (56, 64))	('PKCepsilon', 'Gene', '5581', (69, 79))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('PKCdelta', 'Gene', (56, 64))	('PKCepsilon', 'Gene', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('PKCdelta', 'molecular_function', 'GO:0004697', ('56', '64'))	('mutant', 'Var', (43, 49))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('69', '79'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('Kras', 'Gene', (50, 54))
66749	25604078	KAM1 showed increased PKCdelta-specificity, potent activity against human cancer cells expressing mutant Kras, and also was effective in in vivo animal models.	('activity', 'MPA', (51, 59))	('Kras', 'Gene', (105, 109))	('human', 'Species', '9606', (68, 73))	('PKCdelta', 'molecular_function', 'GO:0004697', ('22', '30'))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('increased', 'PosReg', (12, 21))	('cancer', 'Disease', (74, 80))	('PKCdelta', 'Gene', '5580', (22, 30))	('PKCdelta', 'Gene', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('mutant', 'Var', (98, 104))
66751	25604078	BJE6-106 inhibits PKCdelta with an IC50 of 50 nM and is approximately 1000-fold selective versus PKCalpha.	('PKCdelta', 'Gene', '5580', (18, 26))	('PKCalpha', 'molecular_function', 'GO:0004697', ('97', '105'))	('PKCalpha', 'Gene', '5578', (97, 105))	('PKCalpha', 'Gene', (97, 105))	('PKCdelta', 'Gene', (18, 26))	('BJE6-106', 'Var', (0, 8))	('BJE6-106', 'Chemical', '-', (0, 8))	('PKCdelta', 'molecular_function', 'GO:0004697', ('18', '26'))	('inhibits', 'NegReg', (9, 17))
66766	25604078	Of the two isoforms PKCzeta seems to be the main activator of the canonical NF-kappaB pathway, and activation of NF-kappaB is impaired in PKCzeta knockout mice.	('PKCzeta', 'molecular_function', 'GO:0004697', ('20', '27'))	('PKCzeta', 'molecular_function', 'GO:0004697', ('138', '145'))	('activation', 'PosReg', (99, 109))	('impaired', 'NegReg', (126, 134))	('mice', 'Species', '10090', (155, 159))	('PKCzeta', 'Gene', '5590', (20, 27))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('99', '122'))	('PKCzeta', 'Gene', (20, 27))	('PKCzeta', 'Gene', (138, 145))	('PKCzeta', 'Gene', '5590', (138, 145))	('knockout', 'Var', (146, 154))
66782	25604078	This is mediated by the formation of gold-cystein adducts with Cys69 on PKCiota.	('PKC', 'Gene', (72, 75))	('PKC', 'Gene', '112476', (72, 75))	('Cys69', 'Var', (63, 68))	('gold-cystein adducts', 'MPA', (37, 57))	('Cys69', 'Chemical', '-', (63, 68))	('formation', 'biological_process', 'GO:0009058', ('24', '33'))	('gold-cystein', 'Chemical', '-', (37, 49))
66874	24476519	In several prior reports, we have shown that PAM4 identifies a biomarker expressed by 90% of PDAC, as well as the precursor lesions PanIN and intraductal papillary mucinous neoplasm, and shows high specificity for PDAC and precursor lesions versus benign, nonneoplastic pancreatic tissues.	('mucinous neoplasm', 'Phenotype', 'HP:0031495', (164, 181))	('PDAC', 'Disease', (214, 218))	('PDAC', 'Phenotype', 'HP:0006725', (214, 218))	('nonneoplastic pancreatic tissues', 'Disease', 'MESH:D010182', (256, 288))	('intraductal papillary mucinous neoplasm', 'Disease', 'MESH:D000077779', (142, 181))	('nonneoplastic pancreatic tissues', 'Disease', (256, 288))	('PDAC', 'Chemical', '-', (93, 97))	('PDAC', 'Chemical', '-', (214, 218))	('neoplasm', 'Phenotype', 'HP:0002664', (173, 181))	('intraductal papillary mucinous neoplasm', 'Disease', (142, 181))	('PDAC', 'Disease', (93, 97))	('PDAC', 'Phenotype', 'HP:0006725', (93, 97))	('PAM4', 'Var', (45, 49))
66878	24476519	We included several other potential biomarkers in our studies for comparative purposes: MUC1 (MAb-MA5), MUC4 (MAb-8G7), CEACAM5/6 (MAb-MN-15), and CA19-9.	('CA19-9', 'Chemical', 'MESH:C086528', (147, 153))	('MN-15', 'CellLine', 'CVCL:U508', (135, 140))	('MUC4', 'Var', (104, 108))	('CEACAM5/6', 'Gene', '1048;4680', (120, 129))	('CEACAM5/6', 'Gene', (120, 129))
66900	24476519	We are now conducting a paired specimen evaluation of presurgical serum and tissue specimens from the same individuals undergoing resection of the pancreas because of CP, in order to determine if a clear biological association exists between the presence of PAM4-positive neoplasia in the tissue and circulating antigen levels.	('neoplasia', 'Phenotype', 'HP:0002664', (272, 281))	('CP', 'Phenotype', 'HP:0006280', (167, 169))	('neoplasia', 'Disease', 'MESH:D009369', (272, 281))	('PAM4-positive', 'Var', (258, 271))	('neoplasia', 'Disease', (272, 281))	('circulating antigen levels', 'MPA', (300, 326))
66918	23864708	The resistance of pancreatic cancer to treatment and the high rate of recurrence have been attributed to a highly tumorigenic CSC subpopulation expressing cell surface CD44, CD24, CD133, and epithelial-specific antigen.)	('CD133', 'Gene', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('pancreatic cancer', 'Disease', (18, 35))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('CD24', 'Var', (174, 178))	('cell surface', 'cellular_component', 'GO:0009986', ('155', '167'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (18, 35))	('CD133', 'Gene', '8842', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (114, 119))	('CD44', 'Gene', '960', (168, 172))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (18, 35))	('CD44', 'Gene', (168, 172))
66921	23864708	Down-regulating uPA expression by silencing Ets-1 transcription factors sensitizes pancreatic cancer cells to gemcitabine-induced apoptosis.	('uPA', 'Gene', (16, 19))	('uPA', 'molecular_function', 'GO:0008243', ('16', '19'))	('pancreatic cancer', 'Disease', (83, 100))	('Down-regulating', 'NegReg', (0, 15))	('transcription', 'biological_process', 'GO:0006351', ('50', '63'))	('gemcitabine', 'Chemical', 'MESH:C056507', (110, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('Ets-1', 'Gene', '2113', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Ets-1', 'Gene', (44, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('silencing', 'Var', (34, 43))	('sensitizes', 'Reg', (72, 82))
66924	23864708	We previously demonstrated that silencing uPA and uPAR inhibits the growth of pancreatic tumors in animal models.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('uPA', 'molecular_function', 'GO:0008243', ('42', '45'))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (78, 95))	('uPAR', 'molecular_function', 'GO:0030377', ('50', '54'))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('inhibits', 'NegReg', (55, 63))	('uPAR', 'Gene', '5329', (50, 54))	('silencing', 'Var', (32, 41))	('pancreatic tumors', 'Disease', 'MESH:D010190', (78, 95))	('pancreatic tumors', 'Disease', (78, 95))	('uPA', 'Gene', (42, 45))	('uPAR', 'Gene', (50, 54))	('growth of', 'CPA', (68, 77))
66949	23864708	To further assess the role of uPA in establishing the cancer stem cell phenotype, we overexpressed uPA in both SP and DeltaSP MIA PaCa-2 cells (uPAOE-SP and uPAOE-DeltaSP, respectively) and compared their proliferation and growth patterns using the sphere formation assay.	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (126, 136))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('formation', 'biological_process', 'GO:0009058', ('256', '265'))	('uPA', 'Gene', (99, 102))	('SP', 'Chemical', '-', (111, 113))	('cancer', 'Disease', (54, 60))	('DeltaSP', 'Var', (118, 125))	('uPA', 'molecular_function', 'GO:0008243', ('99', '102'))	('SP', 'Chemical', '-', (150, 152))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('overexpressed', 'PosReg', (85, 98))	('SP', 'Chemical', '-', (123, 125))	('SP', 'Chemical', '-', (168, 170))	('uPA', 'molecular_function', 'GO:0008243', ('30', '33'))
66958	23864708	We observed that 1) SP cells are resistant to gemcitabine treatment and 2) silencing uPA expression sensitizes chemoresistant SP cells to gemcitabine, exemplified by a decrease in the proportion of cells in G0/G1 phase indicative of cell cycle arrest (Figure 2A).	('cell cycle', 'CPA', (233, 243))	('G1 phase', 'biological_process', 'GO:0051318', ('210', '218'))	('uPA', 'molecular_function', 'GO:0008243', ('85', '88'))	('uPA', 'Gene', (85, 88))	('gemcitabine', 'Chemical', 'MESH:C056507', (138, 149))	('silencing', 'Var', (75, 84))	('decrease', 'NegReg', (168, 176))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('233', '250'))	('SP', 'Chemical', '-', (126, 128))	('gemcitabine', 'Chemical', 'MESH:C056507', (46, 57))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (233, 250))	('SP', 'Chemical', '-', (20, 22))
66962	23864708	Mice implanted with DeltaSP cells treated with gemcitabine alone showed the greatest reduction in tumor burden, whereas mice implanted with SP tumors did not respond to gemcitabine.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('SP', 'Chemical', '-', (25, 27))	('gemcitabine', 'Chemical', 'MESH:C056507', (47, 58))	('mice', 'Species', '10090', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('DeltaSP', 'Var', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('gemcitabine', 'Chemical', 'MESH:C056507', (169, 180))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('reduction', 'NegReg', (85, 94))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (98, 103))	('SP tumors', 'Disease', (140, 149))	('SP tumors', 'Disease', 'MESH:D009369', (140, 149))	('SP', 'Chemical', '-', (140, 142))
66966	23864708	More recently, we reported that uPA binds to the transcription factor Lhx2 within the nuclei of pancreatic cancer cells and knockdown of uPA suppresses Lhx2 expression.	('knockdown', 'Var', (124, 133))	('Lhx2', 'Gene', (70, 74))	('transcription factor', 'molecular_function', 'GO:0000981', ('49', '69'))	('Lhx2', 'Gene', (152, 156))	('uPA', 'Var', (137, 140))	('pancreatic cancer', 'Disease', (96, 113))	('expression', 'MPA', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('uPA', 'molecular_function', 'GO:0008243', ('32', '35'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('uPA', 'molecular_function', 'GO:0008243', ('137', '140'))	('transcription', 'biological_process', 'GO:0006351', ('49', '62'))	('suppresses', 'NegReg', (141, 151))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))
66975	23864708	To address the role of uPAR in the regulation of Lhx2 expression by uPA specifically, we then studied the effect of these uPA deletion mutants on expression levels of Lhx2.	('uPAR', 'Gene', (23, 27))	('uPA', 'molecular_function', 'GO:0008243', ('68', '71'))	('regulation', 'biological_process', 'GO:0065007', ('35', '45'))	('uPA', 'Gene', (122, 125))	('uPAR', 'molecular_function', 'GO:0030377', ('23', '27'))	('deletion', 'Var', (126, 134))	('uPAR', 'Gene', '5329', (23, 27))	('Lhx2', 'Gene', (49, 53))	('uPA', 'molecular_function', 'GO:0008243', ('122', '125'))
66976	23864708	PANC-1(uPA-) cells overexpressed Lhx2 in response to exogenously added WT-uPA and DeltaGFD-uPA, whereas levels were unchanged after addition of identical concentrations of DeltaK-uPA (Supplemental Figure S4C).	('Lhx2', 'Gene', (33, 37))	('uPA', 'molecular_function', 'GO:0008243', ('91', '94'))	('DeltaGFD-uPA', 'Var', (82, 94))	('response', 'MPA', (41, 49))	('uPA', 'molecular_function', 'GO:0008243', ('179', '182'))	('uPA', 'molecular_function', 'GO:0008243', ('7', '10'))	('overexpressed', 'PosReg', (19, 32))	('uPA', 'molecular_function', 'GO:0008243', ('74', '77'))	('PANC-1', 'CellLine', 'CVCL:0480', (0, 6))
66978	23864708	Specifically, we identified an 8-mer (CGUGCCUU) motif in the 3' untranslated region (UTR) of Lhx2 that is highly conserved in multiple mammalian species as a potential binding site for miR-124 (Figure 4B).	('mammalian', 'Species', '9606', (135, 144))	('binding', 'Interaction', (168, 175))	('miR-124', 'Var', (185, 192))	('Lhx2', 'Gene', (93, 97))	('binding', 'molecular_function', 'GO:0005488', ('168', '175'))
66981	23864708	Overexpression of miR-124 repressed the Lhx2 3'-UTR reporter (Figure 4C), whereas anti-miR-124 prevented the miR-124-mediated repression of Lhx2 3'-UTR luciferase activity in both MIA PaCa-2 and PANC-1 cells, confirming the specificity of miR-124 toward the 3'-UTR region of Lhx2.	('prevented', 'NegReg', (95, 104))	('Lhx2', 'Gene', (40, 44))	('luciferase activity', 'molecular_function', 'GO:0047077', ('152', '171'))	('activity', 'MPA', (163, 171))	('PANC-1', 'CellLine', 'CVCL:0480', (195, 201))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (180, 190))	('luciferase activity', 'molecular_function', 'GO:0045289', ('152', '171'))	('anti-miR-124', 'Var', (82, 94))	('luciferase activity', 'molecular_function', 'GO:0047712', ('152', '171'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('152', '171'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('152', '171'))
66985	23864708	We observed that tumor tissues did not express miR-124 (Figure 5C), in contrast to its expression in normal pancreatic tissues (Figure 5D).	('tumor', 'Disease', (17, 22))	('miR-124', 'Var', (47, 54))	('pancreatic', 'Disease', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('pancreatic', 'Disease', 'MESH:D010195', (108, 118))
66993	23864708	Of interest, hsa-miR-124 also suppressed expression of both Lhx2 and uPA in MIA PaCa-2 and PANC-1 cells, whereas transfection of these cells with anti-miR-124 enhanced expression of Lhx2 and uPA (Figure 4D).	('uPA', 'molecular_function', 'GO:0008243', ('69', '72'))	('hsa-miR-124', 'Chemical', '-', (13, 24))	('expression', 'MPA', (168, 178))	('expression', 'MPA', (41, 51))	('suppressed', 'NegReg', (30, 40))	('anti-miR-124', 'Var', (146, 158))	('Lhx2', 'Gene', (60, 64))	('enhanced', 'PosReg', (159, 167))	('PANC-1', 'CellLine', 'CVCL:0480', (91, 97))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (76, 86))	('uPA', 'MPA', (191, 194))	('uPA', 'Gene', (69, 72))	('uPA', 'molecular_function', 'GO:0008243', ('191', '194'))
67012	23864708	Exogenously added WT-uPA down-regulated p53 mRNA in Capan-2 cells by 1.6 +- 0.2 times (p < 0.05), and silencing uPA expression in Capan-2 cells up-regulated p53 mRNA (Supplemental Figure S5B).	('up-regulated', 'PosReg', (144, 156))	('silencing uPA expression', 'Var', (102, 126))	('p53', 'Gene', '7157', (157, 160))	('Capan-2', 'CellLine', 'CVCL:0026', (130, 137))	('uPA', 'molecular_function', 'GO:0008243', ('21', '24'))	('p53', 'Gene', (40, 43))	('down-regulated', 'NegReg', (25, 39))	('p53', 'Gene', '7157', (40, 43))	('uPA', 'molecular_function', 'GO:0008243', ('112', '115'))	('p53', 'Gene', (157, 160))	('Capan-2', 'CellLine', 'CVCL:0026', (52, 59))
67013	23864708	Finally, WT-uPA and DeltaGFD-uPA but not DeltaK-uPA increased resistance of uPA-targeting, shRNA-treated Capan-2 cells to gemcitabine-induced apoptosis (Supplemental Figure S5C).	('gemcitabine', 'Chemical', 'MESH:C056507', (122, 133))	('Capan-2', 'CellLine', 'CVCL:0026', (105, 112))	('increased', 'PosReg', (52, 61))	('uPA', 'molecular_function', 'GO:0008243', ('48', '51'))	('uPA', 'molecular_function', 'GO:0008243', ('29', '32'))	('DeltaGFD-uPA', 'Var', (20, 32))	('uPA', 'molecular_function', 'GO:0008243', ('76', '79'))	('apoptosis', 'biological_process', 'GO:0097194', ('142', '151'))	('uPA', 'molecular_function', 'GO:0008243', ('12', '15'))	('apoptosis', 'biological_process', 'GO:0006915', ('142', '151'))	('resistance', 'MPA', (62, 72))
67020	23864708	Pancreatic cancer cell lines (MIA Pa Ca-2 and PANC-1) cultured under serum-free conditions expressed stem cell markers CD44 and CD24 (Figure 1 and Supplemental Figure S1), had an increased proportion of SP cancer stem cell-like cells, formed pancreatospheres (Figure 1E and Supplemental Figure S2), and showed gemcitabine resistance, in contrast to mixed or DeltaSP populations (Figure 2A).	('SP cancer', 'Disease', (203, 212))	('SP', 'Chemical', '-', (203, 205))	('Pancreatic cancer', 'Disease', (0, 17))	('CD44', 'Gene', '960', (119, 123))	('SP cancer', 'Disease', 'MESH:D009369', (203, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))	('gemcitabine', 'Chemical', 'MESH:C056507', (310, 321))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('CD44', 'Gene', (119, 123))	('PANC-1', 'CellLine', 'CVCL:0480', (46, 52))	('formed pancreatospheres', 'CPA', (235, 258))	('gemcitabine resistance', 'MPA', (310, 332))	('CD24', 'Var', (128, 132))	('MIA Pa Ca-2', 'CellLine', 'CVCL:0428', (30, 41))	('increased', 'PosReg', (179, 188))	('SP', 'Chemical', '-', (363, 365))
67044	23864708	Thus, to our knowledge, this is the first evidence that links nuclear uPA to the maintenance of pancreatic cancer cell stemness and chemoresistance in an uPAR-independent manner.	('uPA', 'molecular_function', 'GO:0008243', ('70', '73'))	('chemoresistance', 'CPA', (132, 147))	('pancreatic cancer cell stemness', 'Disease', 'MESH:D010190', (96, 127))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('uPAR', 'Gene', (154, 158))	('pancreatic cancer cell stemness', 'Disease', (96, 127))	('nuclear', 'Var', (62, 69))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))	('uPAR', 'Gene', '5329', (154, 158))	('uPAR', 'molecular_function', 'GO:0030377', ('154', '158'))
67050	23864708	In separate experiments, SP cells were labeled with anti-CD44 and anti-CD24 antibodies using a similar staining protocol.	('anti-CD24', 'Var', (66, 75))	('SP', 'Chemical', '-', (25, 27))	('CD44', 'Gene', (57, 61))	('CD44', 'Gene', '960', (57, 61))
67060	23864708	The following antibodies were obtained from Santa Cruz Biotechnology: anti-uPA (sc-14019), anti-Lhx2 (sc-81311), anti-HOXA5 (sc-13199), anti-P53 (sc-126), anti-p-P53 (Ser-15; sc-101762), and anti-GAPDH (sc-59541).	('anti-Lhx2', 'Var', (91, 100))	('Ser', 'Chemical', 'MESH:D012694', (167, 170))	('Ser', 'cellular_component', 'GO:0005790', ('167', '170'))	('P53', 'Gene', '7157', (162, 165))	('GAPDH', 'Gene', '2597', (196, 201))	('anti-uPA', 'Var', (70, 78))	('uPA', 'molecular_function', 'GO:0008243', ('75', '78'))	('GAPDH', 'Gene', (196, 201))	('HOXA5', 'Gene', '3202', (118, 123))	('HOXA5', 'Gene', (118, 123))	('P53', 'Gene', (141, 144))	('P53', 'Gene', (162, 165))	('P53', 'Gene', '7157', (141, 144))
67089	24212616	Additionally, defective apoptosis signaling is the underlying cause of failure to respond to current treatment approaches, since therapy-mediated antitumor activity requires the intactness of apoptosis signaling pathways in cancer cells.	('apoptosis signaling', 'biological_process', 'GO:0006915', ('24', '43'))	('defective', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('apoptosis', 'MPA', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('tumor', 'Disease', (150, 155))	('cancer', 'Disease', (224, 230))	('apoptosis signaling', 'biological_process', 'GO:0006915', ('192', '211'))
67094	24212616	Deregulated apoptosis programs are often also the underlying cause of primary or acquired resistance of pancreatic carcinoma to current therapies, including chemo-, radio- or immunotherapy, since these treatment strategies primarily act by triggering the intrinsic cell death program in target cancer cells.	('cause', 'Reg', (61, 66))	('cell death', 'biological_process', 'GO:0008219', ('265', '275'))	('Deregulated', 'Var', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (104, 124))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Disease', (294, 300))	('intrinsic', 'CPA', (255, 264))	('apoptosis', 'biological_process', 'GO:0097194', ('12', '21'))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('apoptosis', 'biological_process', 'GO:0006915', ('12', '21'))	('pancreatic carcinoma', 'Disease', (104, 124))	('apoptosis', 'CPA', (12, 21))
67106	24212616	Once activated caspase-8 either directly cleaves effector caspases such as caspase-3 or, alternatively, initiates the mitochondrial pathway by cleaving Bid.	('Bid', 'Gene', (152, 155))	('caspase-3', 'Gene', '836', (75, 84))	('initiates', 'Reg', (104, 113))	('caspases', 'Gene', '841;842', (58, 66))	('cleaves', 'Reg', (41, 48))	('caspase-3', 'Gene', (75, 84))	('caspases', 'Gene', (58, 66))	('mitochondrial pathway', 'Pathway', (118, 139))	('caspase-8', 'Gene', (15, 24))	('cleaving', 'Var', (143, 151))	('caspase-8', 'Gene', '841', (15, 24))	('Bid', 'Gene', '637', (152, 155))
67123	24212616	Also, pharmacologic or genetic inhibition of CDK4 enhanced the TRAIL sensitivity.	('CDK', 'molecular_function', 'GO:0004693', ('45', '48'))	('CDK4', 'Gene', (45, 49))	('enhanced', 'PosReg', (50, 58))	('CDK4', 'Gene', '1019', (45, 49))	('genetic inhibition', 'Var', (23, 41))	('TRAIL sensitivity', 'CPA', (63, 80))
67127	24212616	Expression levels of O-glycosyltransferases may serve as biomarkers to predict TRAIL sensitivity, as they are overexpressed in several cancers and regulate TRAIL-induced apoptosis via modulation of TRAIL-R1 or -R2.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('modulation', 'Var', (184, 194))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('apoptosis', 'biological_process', 'GO:0097194', ('170', '179'))	('overexpressed', 'PosReg', (110, 123))	('TRAIL-induced apoptosis', 'CPA', (156, 179))	('regulate', 'Reg', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('TRAIL sensitivity', 'Disease', (79, 96))	('apoptosis', 'biological_process', 'GO:0006915', ('170', '179'))	('TRAIL-R1', 'Gene', (198, 206))	('TRAIL-R1', 'Gene', '8797', (198, 206))
67135	24212616	Among the IAP family proteins, XIAP has shown the most potent anti-apoptotic effects by inhibiting active caspase-3 and -7 and by preventing caspase-9 activation.	('caspase-9', 'Gene', (141, 150))	('caspase-3 and -7', 'Gene', '836;840', (106, 122))	('activation', 'MPA', (151, 161))	('preventing', 'NegReg', (130, 140))	('caspase-9', 'Gene', '842', (141, 150))	('anti-apoptotic effects', 'MPA', (62, 84))	('inhibiting', 'NegReg', (88, 98))	('XIAP', 'Var', (31, 35))
67141	24212616	So far, most of these strategies are directed against XIAP, since XIAP possesses the most potent anti-apoptotic properties among the IAP proteins, for example, RNA interference (RNAi) or antisense oligonucleotides.	('RNA interference', 'biological_process', 'GO:0016246', ('160', '176'))	('RNA', 'cellular_component', 'GO:0005562', ('160', '163'))	('RNA interference', 'MPA', (160, 176))	('RNAi', 'biological_process', 'GO:0016246', ('178', '182'))	('anti-apoptotic properties', 'MPA', (97, 122))	('antisense oligonucleotides', 'Var', (187, 213))	('oligonucleotides', 'Chemical', 'MESH:D009841', (197, 213))
67145	24212616	Also, inhibition of XIAP cooperated with TRAIL to trigger regression of established pancreatic carcinoma in a tumor regression model in xenograft-bearing mice.	('XIAP', 'Gene', (20, 24))	('mice', 'Species', '10090', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('pancreatic carcinoma', 'Disease', (84, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('inhibition', 'Var', (6, 16))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (84, 104))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
67146	24212616	Similarly, loss of XIAP protein upon administration of XIAP antisense oligonucleotides increased TRAIL-mediated apoptosis in a pancreatic carcinoma cell line.	('increased', 'PosReg', (87, 96))	('oligonucleotides', 'Chemical', 'MESH:D009841', (70, 86))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (127, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('loss', 'NegReg', (11, 15))	('protein', 'Protein', (24, 31))	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('antisense', 'Var', (60, 69))	('XIAP', 'Gene', (19, 23))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('TRAIL-mediated apoptosis', 'CPA', (97, 121))	('pancreatic carcinoma', 'Disease', (127, 147))
67148	24212616	Loss of XIAP protein upon administration of XIAP antisense oligonucleotides correlated with increased sensitization to TRAIL-mediated apoptosis in a pancreatic carcinoma cell line.	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('antisense oligonucleotides', 'Var', (49, 75))	('apoptosis', 'biological_process', 'GO:0006915', ('134', '143'))	('pancreatic carcinoma', 'Disease', (149, 169))	('sensitization', 'biological_process', 'GO:0046960', ('102', '115'))	('Loss', 'NegReg', (0, 4))	('increased', 'PosReg', (92, 101))	('XIAP', 'Gene', (8, 12))	('XIAP', 'Gene', (44, 48))	('oligonucleotides', 'Chemical', 'MESH:D009841', (59, 75))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (149, 169))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('apoptosis', 'biological_process', 'GO:0097194', ('134', '143'))	('sensitization', 'Reg', (102, 115))	('protein', 'Protein', (13, 20))
67149	24212616	XIAP antisense oligonucleotides against XIAP are currently under evaluation in early clinical trials.	('antisense', 'Var', (5, 14))	('XIAP', 'Gene', (40, 44))	('oligonucleotides', 'Chemical', 'MESH:D009841', (15, 31))
67155	24212616	Also, XIAP inhibitors potentiated radiosensitivity of pancreatic carcinoma cells by enhancing caspase cleavage and subsequently apoptosis in response to gamma-irradiation.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('XIAP', 'Gene', (6, 10))	('radiosensitivity', 'MPA', (34, 50))	('potentiated', 'PosReg', (22, 33))	('pancreatic carcinoma', 'Disease', (54, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('128', '137'))	('inhibitors', 'Var', (11, 21))	('apoptosis', 'biological_process', 'GO:0006915', ('128', '137'))	('caspase cleavage', 'MPA', (94, 110))	('potentiated radiosensitivity', 'Phenotype', 'HP:0010997', (22, 50))	('enhancing', 'PosReg', (84, 93))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (54, 74))	('apoptosis', 'CPA', (128, 137))
67171	24212616	ABT-737 was shown to directly trigger apoptosis in susceptible cell lines, e.g.	('trigger', 'Reg', (30, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('38', '47'))	('apoptosis', 'CPA', (38, 47))	('apoptosis', 'biological_process', 'GO:0006915', ('38', '47'))	('ABT-737', 'Chemical', 'MESH:C501332', (0, 7))	('ABT-737', 'Var', (0, 7))
67177	24212616	TW-37 presents another small-molecule inhibitor of Bcl-2, which was shown to inhibit cell growth and invasion and increased apoptosis in pancreatic cancer.	('small-molecule', 'Var', (23, 37))	('TW-37', 'Chemical', '-', (0, 5))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('Bcl-2', 'Gene', (51, 56))	('inhibit', 'NegReg', (77, 84))	('Bcl-2', 'Gene', '596', (51, 56))	('increased', 'PosReg', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (137, 154))	('Bcl-2', 'molecular_function', 'GO:0015283', ('51', '56'))	('pancreatic cancer', 'Disease', (137, 154))	('apoptosis', 'CPA', (124, 133))	('cell growth', 'biological_process', 'GO:0016049', ('85', '96'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (137, 154))
67179	24212616	For example, Bcl-XL antisense oligonucleotides enhanced gemcitabine-or irradiation-induced cytotoxicity in pancreatic cancer cells.	('enhanced', 'PosReg', (47, 55))	('pancreatic cancer', 'Disease', (107, 124))	('pancreatic cancer', 'Disease', 'MESH:D010190', (107, 124))	('cytotoxicity', 'Disease', 'MESH:D064420', (91, 103))	('Bcl-XL', 'Gene', '598', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('oligonucleotides', 'Chemical', 'MESH:D009841', (30, 46))	('gemcitabine', 'Chemical', 'MESH:C056507', (56, 67))	('Bcl-XL', 'Gene', (13, 19))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))	('cytotoxicity', 'Disease', (91, 103))	('antisense oligonucleotides', 'Var', (20, 46))
67187	23696899	Knocking down HMGA2 attenuates the effect of collagen on histone H3K9 and H3K27 acetylation and on collagen-induced p300, PCAF and GCN5 expression.	('attenuates', 'NegReg', (20, 30))	('GCN5', 'Gene', (131, 135))	('collagen', 'molecular_function', 'GO:0005202', ('45', '53'))	('acetylation', 'MPA', (80, 91))	('PCAF', 'Gene', (122, 126))	('H3K27', 'Protein', (74, 79))	('p300', 'Gene', '2033', (116, 120))	('HMGA2', 'Gene', '8091', (14, 19))	('HMGA2', 'Gene', (14, 19))	('collagen', 'molecular_function', 'GO:0005202', ('99', '107'))	('histone H3K9', 'Protein', (57, 69))	('Knocking', 'Var', (0, 8))	('p300', 'Gene', (116, 120))
67199	23696899	PDAC patients whose tumors demonstrated a low expression of histone H3 lysine 27 tri-methylation (H3K27Me3) or histone H3 lysine 9 di-methylation (H3K9Me2), which are marks of closed chromatin ('heterochromatin') and gene repression, had significantly shorter overall survival than PDAC patients whose cancers displayed high histone H3K27Me3 or histone H3K9Me2 expression.	('histone H3 lysine', 'Var', (111, 128))	('histone H3K9Me', 'biological_process', 'GO:0051567', ('345', '359'))	('low', 'NegReg', (42, 45))	('cancers', 'Phenotype', 'HP:0002664', (302, 309))	('heterochromatin', 'cellular_component', 'GO:0000792', ('195', '210'))	('cancers', 'Disease', (302, 309))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('patients', 'Species', '9606', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('PDAC', 'Chemical', '-', (282, 286))	('lysine', 'Chemical', 'MESH:D008239', (122, 128))	('methylation', 'biological_process', 'GO:0032259', ('134', '145'))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('PDAC', 'Phenotype', 'HP:0006725', (282, 286))	('histone H3K27Me', 'biological_process', 'GO:0070734', ('325', '340'))	('histone H3 lysine', 'Var', (60, 77))	('tumors', 'Disease', (20, 26))	('methylation', 'biological_process', 'GO:0032259', ('85', '96'))	('overall', 'MPA', (260, 267))	('cancers', 'Disease', 'MESH:D009369', (302, 309))	('expression', 'MPA', (46, 56))	('chromatin', 'cellular_component', 'GO:0000785', ('183', '192'))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('PDAC', 'Chemical', '-', (0, 4))	('patients', 'Species', '9606', (287, 295))	('lysine', 'Chemical', 'MESH:D008239', (71, 77))	('PDAC', 'Phenotype', 'HP:0006725', (0, 4))	('shorter', 'NegReg', (252, 259))
67200	23696899	However, PDAC patients with low histone H3K4Me2, which is a mark of a more open chromatin ('euchromatin') state, also demonstrated shorter overall survival than PDAC patients whose cancers displayed high H3K4Me2 expression.	('PDAC', 'Phenotype', 'HP:0006725', (9, 13))	('PDAC', 'Chemical', '-', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('chromatin', 'cellular_component', 'GO:0000785', ('80', '89'))	('histone H3K4Me2', 'Var', (32, 47))	('PDAC', 'Chemical', '-', (9, 13))	('PDAC', 'Phenotype', 'HP:0006725', (161, 165))	('overall', 'MPA', (139, 146))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('shorter', 'NegReg', (131, 138))	('low', 'NegReg', (28, 31))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancers', 'Disease', (181, 188))	('patients', 'Species', '9606', (14, 22))	('histone H3K4Me', 'biological_process', 'GO:0051568', ('32', '46'))	('patients', 'Species', '9606', (166, 174))	('euchromatin', 'cellular_component', 'GO:0000791', ('92', '103'))
67216	23696899	Moreover, since p300 and GCN5 HATs are involved in chromatin relaxation by promoting acetylation at sites of DNA damage and facilitating repair, we examined changes in acetylation of histone H3 lysine residues mediated by these two HATs.	('p300', 'Gene', (16, 20))	('GCN5 HATs', 'Var', (25, 34))	('chromatin', 'cellular_component', 'GO:0000785', ('51', '60'))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('p300', 'Gene', '2033', (16, 20))	('lysine', 'Chemical', 'MESH:D008239', (194, 200))	('acetylation', 'MPA', (85, 96))	('promoting', 'PosReg', (75, 84))
67229	23696899	2E, human PDAC tumors with HMGA2 expression also demonstrated increased histone H3K9 and H3K27 acetylation.	('increased', 'PosReg', (62, 71))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('human', 'Species', '9606', (4, 9))	('expression', 'Var', (33, 43))	('PDAC', 'Chemical', '-', (10, 14))	('acetylation', 'MPA', (95, 106))	('histone H3K9', 'Protein', (72, 84))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('HMGA2', 'Gene', '8091', (27, 32))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('H3K27', 'Protein', (89, 94))	('HMGA2', 'Gene', (27, 32))	('PDAC', 'Phenotype', 'HP:0006725', (10, 14))	('tumors', 'Disease', (15, 21))
67230	23696899	The association between HMGA2 and H3K9 acetylation in our TMAs was statistically significant (p = 0.03), while the association between HMGA2 and H3K27 acetylation trended towards significance (p = 0.10).	('HMGA2', 'Gene', (135, 140))	('significant', 'Reg', (81, 92))	('HMGA2', 'Gene', '8091', (24, 29))	('H3K9', 'Protein', (34, 38))	('TMAs', 'Chemical', '-', (58, 62))	('acetylation', 'Var', (39, 50))	('HMGA2', 'Gene', (24, 29))	('HMGA2', 'Gene', '8091', (135, 140))
67254	23696899	5C, CD18 cells transfected with p300, PCAF and GCN5 HAT siRNAs also show reduced number of colonies compared to CD18 cells transfected with control siRNA.	('CD18', 'Gene', (112, 116))	('CD18', 'Gene', '3689', (4, 8))	('p300', 'Gene', '2033', (32, 36))	('CD18', 'Gene', (4, 8))	('reduced', 'NegReg', (73, 80))	('PCAF', 'Var', (38, 42))	('p300', 'Gene', (32, 36))	('CD18', 'Gene', '3689', (112, 116))	('GCN5 HAT', 'Var', (47, 55))
67279	23696899	Although we have not examined the effect of targeting HATs in vivo, our findings strongly suggest that targeting HATs will allow us to increase the efficacy of chemotherapy in mouse models of pancreatic cancer and in patients with pancreatic cancer.	('efficacy', 'MPA', (148, 156))	('increase', 'PosReg', (135, 143))	('chemotherapy', 'CPA', (160, 172))	('mouse', 'Species', '10090', (176, 181))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (192, 209))	('pancreatic cancer', 'Disease', (231, 248))	('pancreatic cancer', 'Disease', 'MESH:D010190', (231, 248))	('targeting', 'Var', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('patients', 'Species', '9606', (217, 225))	('pancreatic cancer', 'Disease', 'MESH:D010190', (192, 209))	('pancreatic cancer', 'Disease', (192, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (231, 248))
67285	23696899	Recently, compound C646 was designed by virtual ligand screening and was shown to be a potent, highly selective, cell permeable small molecule p300 HAT inhibitor.	('p300 HAT', 'Gene', '2033', (143, 151))	('C646', 'Chemical', '-', (19, 23))	('ligand', 'molecular_function', 'GO:0005488', ('48', '54'))	('C646', 'Var', (19, 23))	('p300 HAT', 'Gene', (143, 151))
67289	23696899	Given that very little progress has been made in the treatment of pancreatic cancer, targeting HATs could be a novel approach to sensitize pancreatic tumors to chemotherapy.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('pancreatic cancer', 'Disease', (66, 83))	('pancreatic tumors', 'Disease', 'MESH:D010190', (139, 156))	('pancreatic cancer', 'Disease', 'MESH:D010190', (66, 83))	('targeting', 'Var', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('pancreatic tumors', 'Disease', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (139, 156))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (66, 83))
67292	23696899	HMGA2 #1 (279254), HMGA2 #2 (279255), GCN5 (s5659), PCAF (s16894), and p300 (s4696) siRNAs were purchased from Life Technologies (Carlsbad, CA).	('s16894', 'Var', (58, 64))	('HMGA2', 'Gene', (19, 24))	('HMGA2', 'Gene', '8091', (0, 5))	('p300', 'Gene', '2033', (71, 75))	('HMGA2', 'Gene', (0, 5))	('279255', 'Var', (29, 35))	('HMGA2', 'Gene', '8091', (19, 24))	('p300', 'Gene', (71, 75))
67294	23696899	The slides were trichrome stained or stained for H3K9 acetylation, H3K27 acetylation, and HMGA2 according to standard IHC procedures.	('HMGA2', 'Gene', (90, 95))	('H3K27', 'Protein', (67, 72))	('H3K9', 'Protein', (49, 53))	('acetylation', 'Var', (54, 65))	('HMGA2', 'Gene', '8091', (90, 95))	('acetylation', 'MPA', (73, 84))
67303	22466166	Cellblocks containing carcinoma (n=26) or benign pancreatic lesions (n=11) from FNA biopsies were subjected to qRT-PCR for miR-21, miR-221, miR-181b, miR-196a and miR-217.	('miR-21', 'Gene', (123, 129))	('miR-217', 'Gene', '406999', (163, 170))	('miR-21', 'Gene', '406991', (163, 169))	('benign pancreatic lesions', 'Disease', 'MESH:D010182', (42, 67))	('miR-217', 'Gene', (163, 170))	('benign pancreatic lesions', 'Disease', (42, 67))	('miR-221', 'Gene', (131, 138))	('miR-196a', 'Var', (150, 158))	('miR-181b', 'Var', (140, 148))	('miR-21', 'Gene', (163, 169))	('carcinoma', 'Disease', 'MESH:D002277', (22, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('miR-21', 'Gene', '406991', (123, 129))	('miR-221', 'Gene', '407006', (131, 138))	('carcinoma', 'Disease', (22, 31))
67317	22466166	For example, miR-21, miR-221, miR-181b, miR-155, miR-100 and miR-196a show significantly higher expression in pancreatic carcinoma when compared to the non-neoplastic pancreas; whereas miR-217 is normally found in the pancreas, but shows consistently decreased or absent expression in adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('miR-155', 'Gene', (40, 47))	('miR-155', 'Gene', '406947', (40, 47))	('non-neoplastic pancreas', 'Disease', 'MESH:D010190', (152, 175))	('miR-217', 'Gene', '406999', (185, 192))	('miR-21', 'Gene', (13, 19))	('miR-196a', 'Var', (61, 69))	('miR-100', 'Gene', (49, 56))	('expression', 'MPA', (96, 106))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (110, 130))	('miR-221', 'Gene', (21, 28))	('miR-21', 'Gene', '406991', (185, 191))	('miR-217', 'Gene', (185, 192))	('pancreatic carcinoma', 'Disease', (110, 130))	('neoplastic pancreas', 'Phenotype', 'HP:0002894', (156, 175))	('miR-221', 'Gene', '407006', (21, 28))	('miR-100', 'Gene', '406892', (49, 56))	('miR-181b', 'Var', (30, 38))	('adenocarcinomas', 'Disease', 'MESH:D000230', (285, 300))	('miR-21', 'Gene', (185, 191))	('higher', 'PosReg', (89, 95))	('miR-21', 'Gene', '406991', (13, 19))	('adenocarcinomas', 'Disease', (285, 300))	('non-neoplastic pancreas', 'Disease', (152, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('carcinomas', 'Phenotype', 'HP:0030731', (290, 300))
67320	22466166	We first examined expression of 5 miRNAs (miR-21, miR-221, miR-181b, miR-100 and miR-155) in pancreatic resection specimens containing ductal adenocarcinoma (n=17), intraductal papillary mucinous neoplasms (IPMNs, n=11) and adjacent non-neoplastic pancreatic tissue (n=15) using qRT-PCR.	('IPMN', 'Chemical', '-', (207, 211))	('pancreatic', 'Disease', 'MESH:D010195', (93, 103))	('miR-221', 'Gene', '407006', (50, 57))	('neoplastic pancreatic tissue', 'Phenotype', 'HP:0002894', (237, 265))	('ductal adenocarcinoma', 'Disease', 'MESH:D044584', (135, 156))	('neoplasms', 'Phenotype', 'HP:0002664', (196, 205))	('miR-21', 'Gene', '406991', (42, 48))	('intraductal papillary mucinous neoplasms', 'Disease', (165, 205))	('miR-100', 'Gene', '406892', (69, 76))	('pancreatic', 'Disease', (93, 103))	('pancreatic', 'Disease', 'MESH:D010195', (248, 258))	('intraductal papillary mucinous neoplasms', 'Disease', 'MESH:D000077779', (165, 205))	('non-neoplastic pancreatic', 'Disease', 'MESH:D010190', (233, 258))	('miR-21', 'Gene', (42, 48))	('ductal adenocarcinoma', 'Disease', (135, 156))	('pancreatic', 'Disease', (248, 258))	('miR-155', 'Gene', (81, 88))	('miR-100', 'Gene', (69, 76))	('mucinous neoplasms', 'Phenotype', 'HP:0031495', (187, 205))	('miR-181b', 'Var', (59, 67))	('miR-221', 'Gene', (50, 57))	('miR-155', 'Gene', '406947', (81, 88))	('non-neoplastic pancreatic', 'Disease', (233, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
67322	22466166	Based on these results and those in the literature, we compiled a panel of 5 miRNA species (miR-21, miR-221, miR-181b, miR-196a and miR-217) for further evaluation in cytology aspirate specimens.	('miR-181b', 'Var', (109, 117))	('miR-21', 'Gene', '406991', (132, 138))	('miR-221', 'Gene', (100, 107))	('miR-196a', 'Var', (119, 127))	('miR-217', 'Gene', '406999', (132, 139))	('miR-217', 'Gene', (132, 139))	('miR-21', 'Gene', '406991', (92, 98))	('miR-21', 'Gene', (132, 138))	('miR-221', 'Gene', '407006', (100, 107))	('miR-21', 'Gene', (92, 98))
67354	22466166	Significantly higher expression of miR-21, miR-221, miR-155 and miR-181b was also observed in pancreatic ductal adenocarcinoma relative to IPMN (p<0.001, p<0.001, p<0.001 and p=0.019, respectively) and increased expression of miR-100 in the former was nearly significant (p=0.06) as depicted in Figure 1.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (94, 126))	('higher', 'PosReg', (14, 20))	('IPMN', 'Chemical', '-', (139, 143))	('miR-181b', 'Var', (64, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('miR-221', 'Gene', '407006', (43, 50))	('pancreatic ductal adenocarcinoma', 'Disease', (94, 126))	('miR-155', 'Gene', '406947', (52, 59))	('expression', 'MPA', (21, 31))	('miR-21', 'Gene', '406991', (35, 41))	('miR-21', 'Gene', (35, 41))	('miR-100', 'Gene', '406892', (226, 233))	('miR-221', 'Gene', (43, 50))	('miR-155', 'Gene', (52, 59))	('miR-100', 'Gene', (226, 233))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (94, 126))
67355	22466166	Flexmir  miRNA microarray analysis largely confirmed these results and demonstrated higher expression of miR-21, miR-221, and miR-181b in pancreatic ductal adenocarcinomas relative to IPMNs.	('expression', 'MPA', (91, 101))	('IPMN', 'Chemical', '-', (184, 188))	('higher', 'PosReg', (84, 90))	('miR-221', 'Gene', '407006', (113, 120))	('miR-21', 'Gene', '406991', (105, 111))	('miR-181b', 'Var', (126, 134))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (138, 171))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (138, 170))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))	('miR-221', 'Gene', (113, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('miR-21', 'Gene', (105, 111))	('pancreatic ductal adenocarcinomas', 'Disease', (138, 171))
67363	22466166	As previously noted, expression of three miRNAs (miR-21, miR-221 and miR-181b) was increased in pancreatic ductal adenocarcinoma compared to benign pancreatic lesions by both qRT-PCR and microarray.	('increased', 'PosReg', (83, 92))	('miR-221', 'Gene', '407006', (57, 64))	('expression', 'MPA', (21, 31))	('benign pancreatic lesions', 'Disease', (141, 166))	('miR-21', 'Gene', (49, 55))	('miR-181b', 'Var', (69, 77))	('benign pancreatic lesions', 'Disease', 'MESH:D010182', (141, 166))	('miR-221', 'Gene', (57, 64))	('pancreatic ductal adenocarcinoma', 'Disease', (96, 128))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (96, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (96, 128))	('miR-21', 'Gene', '406991', (49, 55))
67365	22466166	For this reason, we chose to evaluate cellblock material using a panel of 5 miRNAs (miR-21, miR-221, miR-181b, miR-196a, miR-217).	('miR-221', 'Gene', '407006', (92, 99))	('miR-21', 'Gene', (121, 127))	('miR-217', 'Gene', '406999', (121, 128))	('miR-21', 'Gene', '406991', (84, 90))	('miR-217', 'Gene', (121, 128))	('miR-221', 'Gene', (92, 99))	('miR-21', 'Gene', (84, 90))	('miR-196a', 'Var', (111, 119))	('miR-181b', 'Var', (101, 109))	('miR-21', 'Gene', '406991', (121, 127))
67367	22466166	Twenty-six cancers were definitively diagnosed by cytologic assessment and expression of miR-21, miR-221, and miR-196a in these cases was significantly higher than that of the 11 benign lesions (p<0.001, p=0.009, and p<0.001, respectively).	('higher', 'PosReg', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('miR-221', 'Gene', (97, 104))	('miR-196a', 'Var', (110, 118))	('miR-21', 'Gene', '406991', (89, 95))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Disease', (11, 18))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('expression', 'MPA', (75, 85))	('miR-221', 'Gene', '407006', (97, 104))	('miR-21', 'Gene', (89, 95))
67369	22466166	MicroRNA-21, miR-221 and miR-196a were overexpressed in pancreatic carcinomas compared to benign aspirates, but there was considerable overlap in the range of values between groups (Figure 2a) that precluded use of any single species as a reliable diagnostic tool.	('MicroRNA-21', 'Gene', (0, 11))	('miR-196a', 'Var', (25, 33))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (56, 77))	('miR-221', 'Gene', '407006', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('MicroRNA-21', 'Gene', '406991', (0, 11))	('pancreatic carcinomas', 'Disease', (56, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('overexpressed', 'PosReg', (39, 52))	('miR-221', 'Gene', (13, 20))
67371	22466166	Parsimonious logistic regression modeling was performed utilizing the three most promising markers: miR-21, miR-221 and miR-196a.	('miR-21', 'Gene', '406991', (100, 106))	('miR-221', 'Gene', (108, 115))	('miR-21', 'Gene', (100, 106))	('miR-196a', 'Var', (120, 128))	('miR-221', 'Gene', '407006', (108, 115))
67376	22466166	We first used qRT-PCR to assess expression of miR-21, miR-221, miR-181b, miR-155 and miR-100 in pancreatic resection specimens that contained pancreatic ductal adenocarcinoma or IPMN, as well as non-neoplastic pancreatic tissues.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (142, 174))	('miR-100', 'Gene', '406892', (85, 92))	('pancreatic', 'Disease', (142, 152))	('miR-155', 'Gene', '406947', (73, 80))	('neoplastic pancreatic tissue', 'Phenotype', 'HP:0002894', (199, 227))	('miR-21', 'Gene', (46, 52))	('pancreatic', 'Disease', 'MESH:D010195', (210, 220))	('non-neoplastic pancreatic tissues', 'Disease', 'MESH:D010190', (195, 228))	('miR-221', 'Gene', (54, 61))	('miR-181b', 'Var', (63, 71))	('pancreatic', 'Disease', 'MESH:D010195', (96, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('IPMN', 'Disease', (178, 182))	('pancreatic', 'Disease', (210, 220))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (142, 174))	('miR-221', 'Gene', '407006', (54, 61))	('miR-100', 'Gene', (85, 92))	('pancreatic ductal adenocarcinoma', 'Disease', (142, 174))	('pancreatic', 'Disease', 'MESH:D010195', (142, 152))	('pancreatic', 'Disease', (96, 106))	('non-neoplastic pancreatic tissues', 'Disease', (195, 228))	('miR-21', 'Gene', '406991', (46, 52))	('miR-155', 'Gene', (73, 80))	('IPMN', 'Chemical', '-', (178, 182))
67378	22466166	Sixteen of these cases, including 8 pancreatic ductal adenocarcinomas and 8 IPMNs were further evaluated using the Flexmir  miRNA microarray assay, which confirmed higher expression of miR-21, miR-221 and miR-181b in cancers and these species were subsequently tested in cellblock specimens.	('expression', 'MPA', (171, 181))	('miR-221', 'Gene', '407006', (193, 200))	('IPMN', 'Chemical', '-', (76, 80))	('miR-21', 'Gene', '406991', (185, 191))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (36, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('pancreatic ductal adenocarcinomas', 'Disease', (36, 69))	('miR-21', 'Gene', (185, 191))	('higher', 'PosReg', (164, 170))	('miR-221', 'Gene', (193, 200))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancers', 'Disease', 'MESH:D009369', (217, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('cancers', 'Disease', (217, 224))	('miR-181b', 'Var', (205, 213))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (36, 69))
67379	22466166	Cellblock materials were also evaluated for miR-196a and miR-217, both of which are reportedly dysregulated in pancreatic adenocarcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('miR-196a', 'Var', (44, 52))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (111, 137))	('pancreatic adenocarcinomas', 'Disease', (111, 137))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (111, 137))	('miR-217', 'Gene', '406999', (57, 64))	('miR-217', 'Gene', (57, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (111, 136))
67388	22466166	K-ras mutations are detected in patients with benign and malignant pancreatobiliary diseases.	('detected', 'Reg', (20, 28))	('patients', 'Species', '9606', (32, 40))	('malignant pancreatobiliary diseases', 'Disease', 'MESH:D009369', (57, 92))	('malignant pancreatobiliary diseases', 'Disease', (57, 92))	('benign', 'Disease', (46, 52))	('K-ras', 'Gene', (0, 5))	('K-ras', 'Gene', '3845', (0, 5))	('mutations', 'Var', (6, 15))
67389	22466166	found k-ras mutations in aspirates from 31/57 (54%) pancreatic ductal adenocarcinomas, 23/67 (34%) chronic pancreatitis cases, and 13/61 (21%) patients with biliary stones who did not have cancer.	('chronic', 'Disease', (99, 106))	('k-ras', 'Gene', '3845', (6, 11))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (99, 119))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('k-ras', 'Gene', (6, 11))	('pancreatitis', 'Phenotype', 'HP:0001733', (107, 119))	('biliary stones', 'Phenotype', 'HP:0000787', (157, 171))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (52, 85))	('cancer', 'Disease', (189, 195))	('pancreatitis', 'Disease', 'MESH:D010195', (107, 119))	('pancreatic ductal adenocarcinomas', 'Disease', (52, 85))	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('patients', 'Species', '9606', (143, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('pancreatitis', 'Disease', (107, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (52, 84))	('biliary stones', 'Disease', (157, 171))
67390	22466166	improved the sensitivity (94%) and specificity (89%) of k-ras testing by using DNA ligation and PCR amplification to compare ratios of mutated versus wild-type k-ras in surgically-collected pancreatic duct juice samples.	('pancreatic', 'Disease', 'MESH:D010195', (190, 200))	('k-ras', 'Gene', '3845', (56, 61))	('pancreatic', 'Disease', (190, 200))	('mutated', 'Var', (135, 142))	('k-ras', 'Gene', (56, 61))	('k-ras', 'Gene', '3845', (160, 165))	('DNA ligation', 'biological_process', 'GO:0006266', ('79', '91'))	('k-ras', 'Gene', (160, 165))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
67391	22466166	Routine assessment for p53 mutations is challenging because the gene is large and mutations occur in multiple exons.	('mutations', 'Var', (27, 36))	('mutations', 'Var', (82, 91))	('p53', 'Gene', '7157', (23, 26))	('p53', 'Gene', (23, 26))
67392	22466166	used a functional assay for p53 wherein PCR-amplified p53 DNA from pancreatic aspirates was transformed into yeast colonies yielding white colonies for wild-type p53 and red colonies for mutant p53.	('p53', 'Gene', (28, 31))	('pancreatic', 'Disease', 'MESH:D010195', (67, 77))	('p53', 'Gene', (162, 165))	('p53', 'Gene', '7157', (28, 31))	('pancreatic', 'Disease', (67, 77))	('yeast', 'Species', '4932', (109, 114))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('p53', 'Gene', '7157', (162, 165))	('p53', 'Gene', (54, 57))	('mutant', 'Var', (187, 193))	('p53', 'Gene', (194, 197))	('p53', 'Gene', '7157', (194, 197))	('p53', 'Gene', '7157', (54, 57))
67394	22466166	evaluated 45 patients with pancreatic adenocarcinoma and found that 67% had methylated ppENK in their pancreatic juice, but also found methylated ppENK in duodenal secretions from patients without cancer and in samples from histologically normal duodenum.	('pancreatic', 'Disease', 'MESH:D010195', (27, 37))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('ppENK', 'Gene', (87, 92))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (27, 52))	('patients', 'Species', '9606', (13, 21))	('cancer', 'Disease', (197, 203))	('pancreatic adenocarcinoma'